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Патент USA US3048600

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United States Patent U“
it
3,048,591
18-0-HETERO-RESERPATES
Robert Armistead Lucas, Mendham, N.J., assignor to
Ciha Qorporatioma corporation of Delaware
No Drawing. Filed Jan. 7, 1960, Ser. No. 931
15 Claims. (Cl. 260—287)
3,048,591
Patented Aug. 7,, 1962
2
butyl, isobutyl and the like, but represents above all
methyl.
The 2-cyclo-oxa-alkyl radical R3, attached to the oxygen
atom of the position 18 of the deserpidate portion is more
especially represented ‘by a 2-cyclo-oxa-alkyl radical con
taining from ?ve to seven atoms as ring members, such as
a tetrahydro-Z-furanyl (Z-cyclo-oxapentyl), a tetrahydroe2
The present invention concerns compounds derived
pyranyl (Z-cyclo-oxahexyl), a 2-cyclo~oxaheptyl radical
from deserpidic acids. More particularly, it relates to
and the like.
compounds of the formula:
The carbon atoms of the cyclo-oxa-alkyl, particularly a
10
2-cyclo-oxa-alkyl, nucleus may be unsubstituted or substi
tuted by lower aliphatic ‘hydrocarbon, particularly lower
alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso
butyl and the like, as well as, for example, lower cyclo
alkyl, e.g. cyclopentyl, cyclohexyl and the like, or carbo~
cyclic aryl, such as monocyclic or bicyclic carbocyclic aryl,
e.g. phenyl, naphthyl and the like, or carbocyclic aryl
lower aliphatic hydrocarbon, such as monocyclic or bi
cyclic carbocyclic aryl-lower alkyl, e.g. benzyl, l-phenyl
in which R1 represents lower alkyl, lower alkoxy-lower
alkyl or tertiary amino-lower alkyl, R2 stands for lower
alkyl, R3 represents cyclo-oxa-alkyl, particularly 2-cyclo
oXa-alkyl, which contains at least ?ve atoms as ring mem
bers, each of the radicals R4 and R5 stands for hydrogen,
lower aliphatic hydrocarbon, or a functional group, such
as, for example, etheri?ed hydroxyl, esteri?ed hydroxyl,
etheri?ed mercapto, nit-ro, amino, halogeno or halogen-o
lower alkyl, or, when attached to adjacent positions and
taken together, for lower :alkylene-dioxy, and R6, attached
to either one of the positions 5 or 6, stands for hydrogen
or lower alkyl, salts or N~oxides thereof, as well as process
for the preparation of such compounds.
A lower alkyl group R1, containing from one to seven,
preferably from one to four, carbon atoms, stands, for ex
ample, for methyl, ethyl, n-propyl, isopropyl, n~butyl, iso
butyl as Well as n-pentyl, isopentyl, n-hexyl and the like.
In a lower alkoxy-lower alkyl group R1, the lower
alkoxy portion contains from one to {our carbon atoms
and represents, for example, methoxy, ethoxy, n~pr-opyl
oxy, isopropyloxy, n-butyloxy and the like. The amino
group of a tertiary amino-lower alkyl radical R1 is pri
marily an I‘J,N-di-lower alkyl-amino group, in which lower
ethyl, 2-phenylethyl and the like. Two of the carbon
atoms of the cyclo-oxa-alkyl nucleus may also be part of
a second, especially of a carbocyclic, ring system fused
onto the cyclo-oxa-alkyl nucleus; carbocyclic rings, which
may be ‘fused onto the :cyclo-oxa-alkyl nucleus, may be
represented, for example, by cycloalkyl containing from
?ve to seven carbon atoms, e.g. cyclopentyl, cyclohexyl,
cycloheptyl and the like, or carbocyclic aryl, such as mono
cyclic or bicyclic carbocyclic aryl, e.g. phenyl, naphthyl
and the like.
Other substituents attached to any of the available car
bon atoms of the cyclo~oxa-alkyl, particularly the Z-cyclo
oxa-alkyl, radical are, for example, halogen atoms, e.g.
?uorine, chlorine, bromine and the like, as well as other
functional groups.
The group R3 may, therefore, be represented by tetra
hydrofuranyl (cyclo-oxapentyl) radicals, particularly tetra
hydro-Z-furanyl (Z-cyclo-oxapentyl) radicals, e.g. tetrahy
dro-Z-furanyl (Lcyclo-oxapentyl), 4-methyl-tetrahydro-2
furanyl (4-methyl-2-cyclo-oxapentyl), S-methyl-tetrahydro
Z-furanyl (S-methyl-Z-cyclo-oxapentyl), 3-chloro~tetrahy
dro-Z-furanyl (3-chloro~2-cyclo~oxapentyl) and the like,
tetrahydropyranyl (cyclo-oxahexyl) radicals, particularly
tetrahydro-Z-pyranyl (2-cyclo-oxahexyl) radicals, e. g. tetra
amino, N,N-di-n-propylamino, N,N-idi-isopropylamino and
hydro-Z-pyranyl (Z-cyclo-oxahexyl), 4-methyl~tetrahydro
2~pyranyl (4-methyl-2-cyclo-oxahexyl), 6-methyl-tetrahy—
dro-Z-pyranyl (6-methyl-2-cyclo-oxahexyl), l?-phenyl-tetra
hydro-Z-pyranyl (6-phenyl-2-cyclo-oxahexyl), hexahydro
the like, an N,N-lower alkylene-irnino group, in which
benz[e]tetrahydro - 2 - pyranyl (bicyclo[4,4,0]-2-oxa-3
lower alkylene contains from four to six carbon atoms, e. g.
decyl), benZ[e]dihydro-2-pyranyl (2-benz[e]cyclo-oxa
hexyl), 3-chloro-tetrahydro-2~pyranyl (3-chloro-2-cyclo
oxahexyl), 3~bromo-tetrahydro-2-pyranyl (3-bromo-2
alkyl contains from one to four carbon atoms, e.g. N,N
dimethylamino, N-ethyl~N-methyl-amino, N,N-diethyl_
l-pyrrolidino, l-piperidino, l-hexamethyleneimino and the
like, an N,N-lower oxa-alkylene~imino group, in which
lower oxa-alkylene contains preferably four carbon atoms,
cyclooxahexyl) and the like, or cyclo-oxaheptyl radicals,
e.g. l~morpholino and the like, or an N,N-lower aza
particularly 2-cyclo-oxaheptyl radicals, e.g. Z-cyclo-oxa
alkylene-irnino group, in which lower aza-alkylene con
tains preferably four carbon atoms, e.g. 4-methyl-1-piper 55
heptyl and the like.
The substituents R4 and R5 may represent hydrogen
azino and the like.
or any of the groups mentioned hereinabove.
The lower alkyl portion of a lower alkoxy-lower alkyl
or a tertiary amino-lower alkyl radical R1 is represented
groups are, for example, lower aliphatic hydrocarbon,
and separates the lower alkoxy and the amino group from
the carboxy group by the same number of carbon atoms.
Such radicals are primarily 1,2-ethylene, l-methyl-1,2
ethylene, 2-methyl~l,2-ethylene or 1,3-propylene; other
lower alkylene radicals may be, for example, 1,4-butylene
well as cycloalkyloxy, e.g. cyclohexyloxy andthe like,
carbocyclic aryloxy, such as monocyclic carbocyclic aryl~
oxy, e.g. phenyloxy and the like, carbocyclic aryl-lower
alkoxy, such as monocyclic carbocyclic aryl-lower alkoxy,
for example, phenyl-lower alkoxy, e.g. benzyloxy and the
carbon atoms, stands for ethyl, n~propyl, isopropyl, n
nyloxy and the like, etheri?ed mercapto, particularly low~
Such
primarily lower alkyl containing from one to four car
by a lower alkylene radical containing from two to seven
bon atoms, e.g., methyl, ethyl, n-propyl, isopropyl and the
carbon atoms, which separates the lower alkoxy group or 60 like, or functional groups, such as, for example, etheri?ed
hydroxy, particularly lower alkoxy containing ‘from one
the amino group from the carbon atom of the carboxy
to ‘four carbon atoms, e.g. methoxy, ethoxy, n-propyloxy,
group by at least two carbon atoms. Preferably, the lower
isopropyloxy, n-butyloxy, i-butyloxy, and the like, as
alkylene radical contains ‘from two to three carbon atoms
like, esteri?ed hydroxyl, particularly lower alkoxy-car
or 1-methyl-1,3-propylene and the like.
bonyloxy, e.g. methoxycarbonyloxy, ethoxycarbonyloxy
The lower alkyl group R2, containing from one to four 70 and the like, or lower alkanoyloxy, e.g. acetoxy, propio
3,048,591
3
4
er alkyl-mercapto containing from one to four carbon
carbon atoms, and lower alkyl, separating N,N~di-lower
atoms, e.g. methylmercapto, ethylmercapto and the like,
alkyl-amino from the carboxy group by two to three car
bon atoms, contains from two to three carbon ‘atoms, R2
nitro, amino, particularly N,N-disubstituted amino, such
as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino,
N,N-diethylamino and the like, halogeno, e.g. ?uoro,
represents lower alkyl containing from one to four car
chloro, bromo, iodo and the like, halogeno-lower alkyl,
from ?ve to seven atoms as ring members, lower alkyl
bon atoms, R3 stands for 2-cyclo-oxa-alkyl containing
substituted Z-cyclo-oxa-alkyl containing from ?ve to
e.g. tri?uoromethyl and the like, or any other suitable
‘functional group. Whenever attached to two adjacent
seven atoms as ring members, or halogeno-substituted 2
cyclo-oxa-alkyl containing from ?ve to seven atoms as
positions, the radicals R4 and R5, when taken together,
may also form a cyclic substituent; such substituent may 10 ring members, each of the radicals R4 and R5 stands for
hydrogen, lower alkyl containing from one to \four car—
be represented, for example, by lower alkylene-dioxy,
bon atoms, lower alkoxy containing from one to four
e.g. methylenedioxy, or any other analogous substituent.
carbon atoms, lower alkyl-mercapto containing from one
The radical R6 stands preferably for hydrogen; when
to four carbon atoms, or halogeno, R6, attached to one of
representing lower alkyl, such radical may stand for
15 the positions 5 and 6, stands for hydrogen of lower alkyl
'methyl, as well as ethyl and the like.
containing from one to four carbon atoms, the therapeu
Salts of the compounds of this invention are primarily
tically useful mineral acid addition salts or the N-oxides
therapeutically acceptable acid addition salts with inor
of these compounds, as well as their various isomeric
ganic or organic acids, particularly with mineral acids,
forms.
e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids
This group of compounds is represented, for example,
and the like.
by lower alkyl reserpate compounds of the formula:
Due to the presence of a tertiary amino group in the
molecule, the compounds may also be present in the
form of their N-oxides.
In view of the fact that several asymmetric carbon
atoms are present in the compounds of this invention, 25
the latter may :be obtained in the form of a mixture of
racemates, racemates or optically pure compounds.
The new compounds of this invention have antihyper
tensive properties, as well as sedative and tranquilizing
e?ects on the central nervous system.
They are char
acterized by a quick onset of the physiological action.
Furthermore, tests show that animals, treated with the
compounds of the present invention, recover ‘faster and
more completely from the pharmacological effects than
those treated with known, naturally occurring Rauwol?a
30
in which R1 stands for lower alkyl containing from one
to four carbon atoms, or the N-oxides thereof, whereby
these compounds may be in different isomeric forms.
. Speci?c members illustrating this group of ‘compounds are
lower alkyl 18-0-(tetrahydro-Z-furanyl)-reserpates, in
alkaloids, for example, with reserpine, deserpidine or
which lower alkyl contains ‘from one to four carbon atoms,
rescinnamine. In addition, certain quantitative di?eren
e.g. methyl 18-0-(tetrahydro-Z-furanyl) -reserpate, ethyl
tiations may be observed within the group of the new
compounds of this invention.
For example, when com
pared with the established ratio existing between antihy
pertensive and sedative e?ects in the above-mentioned
18-0-(tetrahydro-Z-furanyl)-reserpate, n-propyl l8-O-(tet
~10
alkyl contains from one to four carbon atoms, e.g. methyl
natural Rauwol?a alkaloids, some of the compounds of
this invention have more predominant sedative e?ects
with negligible antihypertensive activity, whereas in others,
rahydro-Z-fur-anyl)-rese1‘pate and the like, lower alkyl
18-0-(tetrahydro-Z-pyranyl)~reserpates, in which lower
l
the latter may be more pronounced than the sedative and as 5.)
tranquilizing component.
The compounds of the present invention may, there
fore, be used as antihypertensive agents to relieve hyper
tensive conditions, such as, for example, benign or malig
18-0-(tetrahydro-Z-pyranyl)-reserpate, ethyl l8-O-(tetra
hydro-2-pyranyl)- reserpate, n-propyl IS-O-(tetrahydro
Z-pyranyD-reserpate, isopropyl 18-O-(tetral1ydro-2-py—
ranyl)-reserpate, n-butyl 18-O-(tetrahydro-2~pyranyl)—
reserpate, isobu-tyl 18-O-(tetrahydro-Z-pyranyl)-reserpate,
n-pentyl l8-0-(tetrahydro-2-pyranyl)-reserpate and the
like, or the lower alkyl l8-O-(2-cyclo-oxaheptyl)- reserp
ates, in which lower alkyl contains from one to four carbon
nant hypertension, renal hypertension or hypertension as
atoms, e.g. methyl 18-O-(2-cyclo'oxaheptyl)-reserpate,
sociated with pregnancy, such as toxemia of pregnancy,
and/or as sedative agents to relieve states of hyperactiv
ethyl 18-0-(2—cyclo-oxaheptyl)-reserpate, n-propyl 18-O
(Z-cyclo-oxaheptyl)-reserpate and the like, and the N
oxides of such compounds, which compounds may be
present in di?erent isomeric forms.
The above group of compounds may also be represented
by those of the formula:
ity, tension and agitation, as, for example, associated with
‘_ mental disturbances and the like.
Very pronounced antihypertensive and/or sedative ef
: fects are exhibited by compounds of the formula:
“It
65
in which R1 represents lower alkyl containing from one
to four carbon atoms, lower alkoxy-lower alkyl, in which
lower alkoxy contains from one to four carbon atoms
in which R, stands for lower alkyl containing from one
to four carbon atoms, or their N-oxides, whereby these
compounds may be in different isomeric forms. Lower
and lower alkyl, containing from two to three carbon
alkyl l8-0-(tetrahydro-Z-furanyl)-deserpidates, in which
atoms, separates lower alkoxy from the carboxy group by
lower alkyl contains from one to \four carbon atoms, e.g.
from two to three carbon atoms, or N,N-di~lower alkyl
methyl 18-O~(tetrahydro-Z-furanyl)-deserpidate, ethyl l8
amino-lower alkyl, in which lower alkyl of the N,N-di
O-(tetrahydro-Z-furanyl)-deserpidate and the like, lower
lower alkyl-amino portion contains from one to four 75 alkyl 18-O-(2-cyclo-oxaheptyl)-deserpidates, in, which
3,048,591
5
6
lower alkyl contains from one to four carbon atoms, e.g.
Lower alkyl l0-chloro-l8-O-(tetrahydro-Z-furanyl)~reser
pates, lower alkyl 10‘-bromo—l8-O-(tetrahydro-Z-furanyl)
reserpates, lower alkyl 10-chloro-18-O-(tetrahydro-Z-py
ranyl)-deserpidates and lower alkyl 10-bromo-18-O-(tetra
methyl 18-0-(tetrahydro-Z-pyranyl)-deserpidate, ethyl 18
O-(tetrahydro-Z-p-yranyl)-deserpidate, n-propyl 18-0‘
(tetrahydro-Z-pyranyl)-deserpidate and the like, or lower
alkyl 18-0-(2-cyclo=oxaheptyl)-deserpidates, in which
hydro-2-pyranyl)-deserpidates, in which lower alkyl con
lower alkyl contains from one to four carbon atoms,
tains from one to four carbon atoms, illustrate this group;
methyl 1O - chloro-18-0‘(tetrahydro-Z-furanyl)~deserpi
e.g. methyl 18-0-(2-cyclo-2-oxaheptyl)-deserpidate, ethyl
l8-O-(2-cyclo-oxaheptyl)-descrpidate and the like, and
date, ethyl lO-chloro-l8-O-i(tetrahydro-Z-furanyl)-deser
the N-oxides of such compounds, which compounds may
pidate, n-propyl 10'chloro-l8-O-(tetrahydro-2-furanyl)
be present in different isomeric forms, represent this 10 deserpidate, methyl lO-bromo-lS-O-(tetrahydro-Z-furan
yD-deserpidate, ethyl 10-‘bromo-l8-O-(tetrahydro-2-fur—
anyl)-deserpidate, n-propyl 10-bromo-18-O-(tetrahydro-2
group.
The new compounds may also be represented by the 2
lower alkoxy-lower alkyl 18-O~R3-11-R4—deserpidates, in
furanyD-deserpidate and the like, methyl l?-chloro-lS-O
which lower alkoxy contains from one to four carbon
atoms, lower alkyl contains from two to three carbon
atoms and separates alkoxy from the carboxy group by
from two to three carbon atoms, R3 represents 2-cyclo-oxa
alkyl containing from ?ve to seven atoms as ring mem
bers, and R4 represents hydrogen or methoxy. This group
(tetrahydro-Z-pyranyl)-deserpidate, ethyl 10-chloro-18-O
(tetrahydro-Z-pyranyl)-deserpidate, n-propyl l0-chloro
18-O~(tetrahydro-2-pyranyl) -deserpidate, methyl 104bro
mo-lS-O-(tetrahydro-Z-pyranyl)-deserpidate, ethyl l0
is represented by 2-l-ower alkoxy-ethyl IB-O-(tetrahydro
the like, are speci?c members of such compounds.
hromo-l8-O-(tetrahydro-Z-pyranyl)-deserpidate, n-propyl
l0 - bromo-l8-O-(tetrahydro-Z-pyranyl)-d-eserpidate and
2-furanyl)~reserpates, in which alkoxy contains from one
An additional group of compounds are the lower alkyl
to four carbon atoms, such as Z-methoxy-ethyl 18-O
6-methyl~l8-O-R3-reserpates, in which R3 stands for 2
(tetrahydro-Z-furanyl)-reserpate and the like, and the 2
cyclo-oxa-alkyl containing from ?ve to seven atoms as
ring members, and lower alkyl contains from one to four
lower alkoxy-ethyl 18-O-(tetrahydro-Z-furanyl)-deserpi
dates, in which lower alkoxy contains from one to four 25 carbon atoms. The lower alkyl 6-methyl-18-O-(tetra
hydro-Z-furanyl)-reserpates and the lower alkyl 6-methyl
carbon atoms, such as Z-methoxyethyl IS-O-(tetrahydro
l8~O-(tetrahydro-Z-pyranyl)-reserpates, in which lower
Z-furanyD-deserpidate and the like, 2-lowe-r alkoXy-cthyl
18-0-(tetrahydro-Z-pyranyl)-reserpates, in which alkoxy
alkyl contains from one to four carbon atoms, are more
speci?c groups of these compounds, which may be illus
contains from one to four carbon atoms, such as 2
methoxy-ethyl l8-0-(-tetrahydro-Z-pyranyl)-reserpate and
30
trated, for example, ‘by methyl 6-metl1yl-lS-O-(tetrahydro
the like, and the 2-lower ialkoxy-ethyl 18-O-(tetrahydro-2
pyranyD-deserpidates, in which lower alkoxy contains
Z-furanyD-reserpate, ethyl 6-methyl~IS-O-(tetrahydro-Z
furanyU-reserpate, n-propyl 6-methyl-l 8-O-(tetrahydro-2
from one to four carbon atoms, such as 2~methoxyethyl
furanyl)-reserpate and the like, methyl 6-methyl-l8-O
1S-O-(tetrahydro-Z-pyranyl)-deserpidate and the like.
An additional group of the new compounds is repre
sented by the lower alkyl l0~methoXy~l8-O~R3-deserpi
dates, in which R3 stands for 2-cyclo-oxa-alkyl containing
from ?ve to seven atoms as ring members, and lower alkyl
contains from one to four carbon atoms; such compounds
are, for example, lower alkyl rlO-rnethoxy-lS-O-(tetrahy
dro-Z-furanyl)~deserpidate, in which lower alkyl contains
from one to four carbon atoms, e.g. methyl lO-methoxy
l8-0-(tetrahydro-Z-furanyl)-deserpidate, ethyl lO-meth
oxy-lS-O-(tetrahydro-Z-furanyl)-deserpidate, n-propyl 10
methoxy~l8-0-(tetrahydro-Z-furanyl)-deserpidate and the
like, lower alkyl IO-methoxy-l8-O-(tetrahydro-2-pyran
ly)-deserpidate, in which lower alkyl contains from one
to four carbon atoms, e.g. methyl 10-methoxy-18-O~
(tctrahydro-2-pyranyl)-deserpidate, ethyl lO-methoxy-IS
O-(tetrahydro-Z-pyranyl)-deserpidate, n-propyl IO-meth
oxy-18-0-(itetrahydrO-Z-pyranyl)-deserpidate and the like.
A further group of highly active compounds are the
lower alkyl 12-methoxy-18-O-R3-deserpidates, in which
R3 represents Z-cyclo-oxa-alkyl containing from ?ve to
seven atoms as ring members, and lower alkyl contains
from one to four carbon atoms as ring members.
This
group may be illustrated by lower alkyl l2-methoxy-l8-O~
(tetrahydro-2~furanyl)-deserpidates, in which lower alkyl
contains from one to four carbon atoms; methyl 12-meth
oxy-18-0-(tetrahydro-Z-furanyl)-deserpidate, ethyl 12
methoxy-l 8-0- (tetrahydro-Lfuranyl ) -deserpidate, n-pro
pyl 12-methoxy-18-O-(tctrahydro-Z-furanyl)-deserpidate
and the like, lower alkyl 12-methoXy-1S-O-(tetrahydro-Z
pyranyD-deserpidates, in which lower alkyl contains from
one to four carbon atoms; methyl l2-methoxy-l8-O-(tctra
hydro-Z-pyranyl)-deserpidate, ethyl 12~methoxy-18-O
tetrahydro-Z-pyranyl)-deserpidate, n~propyl IZ-methoxy
(tetrahydro-Z-pyranyl)-reserpate, ethyl 6<methyl-18-O
(tetrahydro~2-pyranyl)-reserpate, n-propyl ,6-methyl-l8
O-(tetrahydro-Z-pyranyl)-reserpate and the like.
Other lower alkyl 18-O-R3-deserpidate compounds, in
which R3 represents 2-cyclo-oxa-alkyl containing from
?ve to seven atoms as ring members, and lower alkyl
contains from one to four carbon atoms, are, for example,
lower alkyl S-methyl-l8-O-R3-deserpidates, lower alkyl 5
methyl-l8-O~R3-reserpates, lower alkyl 6-methyl-1S-O-R3
deserpidates, lower alkyl 9-methyl-l8-O-R3-deserpidates,
lower alkyl ll-methyl-l8-O-R3-deserpidates, lower alkyl
9-methoxy-l8-O-R3-deserpidates, lower alkyl lO-methoxy
18-O—R3-rese1jpates, lower alkyl ll-ethoxy-l8-O-R3-deser
pidates, lower alkyl 11-n-propyloxy-l8-O-R3-deserpidates,
lower alkyl 1l-isopropyloxy-l8-O-R3-deserpidates, lower
alkyl ll-n4butyloxy-l8-O-R3—deserpidates, lower alkyl 10,
1l-methylenedioxy-18-O—R3-dcscrpidates, lower alkyl 10
benzyloxy-l8-O-R3-deserpidates, lower alkyl ll-‘benzyl
0xy—l8-O-R3-deserpidates, lower alkyl ll-methylmercapto
l8~O-R3-deserpidates, lower alkyl ll-ethylmercapto-lS-O
Ra-deserpidates, lower alkyl l7-desmethoxy-l7-ethoxy-18
o-Rg-deserpidates, lower alkyl l7-desmethoxy-l7-ethoxy
l8-O-R3-reserpates, lower alkyl l7-desmethoxy-17-n-pro
pyloxy-l8#O-R3-reserpates, lower alkyl l7-desmethoxy
l7-isopropyloxy-l8-O-R3-reserpates and the like, in which
R3 represents cyclo-oxa-alkyl containing from ?ve to seven
atoms as ring members, represented primarily by tetra
60 hydro-Z-furanyl or tetrahydro-Z-pyranyl, and in which
lower alkyl contains from one to four carbon atoms.
The compounds of this invention may be 'used as me
dicaments in the form of pharmaceutical preparations,
which contain the new compounds in admixture with a
65 pahrmaceutical organic or inorganic, solid or liquid car~
rier suitable for enteral or parenteral administration. For
making up the preparations there can be employed sub
l8-0-(tetrahydro~2-pyranyl)-deserpidate and the like, are
stances which do not react with the new compounds,
speci?c examples of such compounds.
such as ‘water, gelatine, lactose, starches, magnesium stear
Lower alkyl 10~halogeno~l8-O-R3-deserpidates, in 70 ate,
stearyl alcohol, talc, vegetable oils, benzyl alcohols,
which R3 stands for 2-cyclo-oxa-alkyl containing from
gums, waxes, propylene glycol, polyalkylene glycols or
?ve to seven atoms as ring members, halogeno represents
any other ‘known carrier for medicaments. Thte pharma
ceutical preparations maybe in solid form, for example, as
tablets, dragees, capsules and the like, or in liquid form,
additional series of new compounds of this invention. 75
for example, as solutions, suspensions, emulsions and
primarily chloro or bromo, as well as iodo, and lower
alkyl contains from one to four carbon atoms, are an
3,015.8,591
7
the like.
by alcoholysis of deserpidic acid (l6—>18)-lactones with
If desired, they may contain auxiliary sub
stances such as preserving, stabilizing, wetting or emulsi~
alkali metal compounds of lower alkanols, lower alkoxy
fying agents and the like, salts for varying the osmotic
lower alkanols or tertiary amino-lower alkanols.
pressure, bulfers and the like. They may also contain, in
combination, other therapeutically useful substances. The
compounds of this invention may also be used in composi
tions for veterinary use by adding them to standard feed
formulae.
For example, to ‘a solution of the diazo reagent in an
inert solvent, such as an ether, particularly diethylether,
may be added the deserpidic acid compound or a salt
thereof, which is preferably kept in a suspension or a
solution, for example, of a lower alkanol, e.g. methanol,
ethanol and the like, a halogenated lower aliphatic hy
drocarbon, e.g. chloroform, methylene chloride and the
like, or any other suitable, inert solvent. Or, the diazo
Compounds of the present invention may be prepared
by reacting a deserpidate compound of the formula:
compound may be distilled out of a solution, such as a
diethylether solution, into the suspension or solution of
a deserpidic acid compound or a salt thereof.
An ex
15 cess of the diazo derivative present in the reaction mix
ture may be destroyed, for example, by ‘adding an addi
tional carboxylic acid, e.g. acetic, benzoic acid and the
like. The esteri?cation may be carried out under cooling
or at room temperature, and, if desired, under the at
20 mosphere of an inert gas, e.g. nitrogen.
Or, by treating the necessary amount of an alkali met
in which R1, R2, R4, R5 and R6 have the previously given
al, e.g. lithium, potassium, or particularly sodium, with
meaning, or an N-oxide thereof, with a reactive ester
a lower alkanol, a lower alkoxy-loWer alkanol or a tertiary
of a 2-hydroxy-cyclo-oxa-alkane, which contains at least
amino~lower alkanol and adding a deserpidic acid lactone
?ve atoms as ring members, in the presence of a con
to the resulting alkali metal derivative of the alcohol,
the desired deserpidate compound may be obtained. Al
densing reagent, and, if desired, separating a resulting
mixture of isomeric compounds into the single isomers,
though this reaction may proceed under cooling or at
room temperature, the mixture is advantageously heated,
if necessary, in the atmosphere of an inert gas, e.g. ni
and/ or, if desired, converting a resulting compound into a
salt or an N-oxide thereof.
The reactive ester of a Z-hydroxy-cyclo—oxa-alkane, used
as the reagent in the above reaction, is particularly an
ester with a strong inorganic or organic acid, particularly
a mineral acid, such as a hydrohalic acid, e.g. hydrochlo
ric, hydrobromic acid and the like, as well as a monocyclic
carbocyclic aryl sulfonic acid, eg p-toluene sulfonic acid
and the like. The reagent is represented primarily by a
Z-halogeno-cyclo-oxa-alkane, which contains at least ?ve
atoms as ring members, particularly by a 2-chloro-cyclo
trogen.
N-oxides of the starting material may be prepared ac
cording to known N-oxidation methods; for example, a
solution of the starting material may be treated with a
DJ on
per-acid, such as, for example, peracetic, perbenzoic,
monoperphthalic, p-toluene persulfonic acid and the like,
with hydrogen peroxide or with ozone.
‘Compounds of the present invention may also be pre
pared by reacting a deserpidate of the formula:
oxa-alkane, as well as by a 2abromo-cyclo-oxa-alkane,
which contain from ?ve to seven atoms as ring members.
Speci?c reagents are, for example, 2-chloro-tetra-hydro—
furan (2-chloro-cyclo-oxapentane), Z-chloro-tetrahydro
pyran (2-chloro-cyclo-oxahexane), 2-chloro-cyclo-oxa
heptane, as Well as the corresponding bromo derivatives.
The above cyclo-oXa-alkane compounds may contain hy
drocarbon radicals, such as, for example, lower alkyl, e.g.
methyl and the like, or functional groups, such as addi
tional halogen atoms, e.g. chlorine and the like, or any
other suitable sustituent; substituted reagents are, for ex
ample, 2-chloro-S-methyl-tetrahydrofuran (2-chloro-5
methyl-cyclo-oxapentane), 2-chloro-4-methyl-tetrahydro
pyran (2-chloro-4-methyl-cyclo~oxahexane), 2-chloro-6
in which R1, R2, R4, R5 and R6 have the above-given
meaning, a salt or an N-oxide thereof, with a cyclo~oxa~
alk-Z-ene, which contains at least ?ve atoms as ring mem
methyl-tetrahydropyran (2-chloro-6—methyl-cyclo-oxahex
ane), 2,3-dichloro-tetrahydropyran (2,3-dichloro-cyclo
bers, and which is capable of introducing the desired
radical R3, in the presence of an acid condensing reagent,
oxahexane) and the like.
A condensing reagent may be represented more particu
_ and, if desired, converting a resulting salt into the free
lady by N,N-dimethylformamide; any other suitable
base, and/or, if desired, separating a resulting mixture of
isomeric compounds into the single isomers, and/or, if
reagent may be used. N,N-dimethylformamide may also
desired, converting a resulting compound into a salt or
serve as a solvent; other inert solvents may be used as
an N-oxide thereof.
diluents.
The cyclo-oxa-alk-Z-enes used as the reagents, contain
Ordinarily, the reaction mixture is allowed to stand, 60 no further substituents, or, whenever substituents, such
if necessary, while cooling and with protection from light,
as halogen, lower alkyl and the like, are present, such
until the reaction is completed. The desired compound
substituents are attached to those carbon atoms, which
is isolated from the reaction mixture according to meth
do not involve the 2,3-double bond. Especially suitable
ods known per se, for example, by evaporating the sol
reagents are cyclo-oxa-alk-Z-enes, which contain from
vent and isolating the reaction product from the resi
" ?ve to six atoms as ring members, and which, when sub
due, by diluting the reaction mixture and precipitating or
stituted, contain such substituents attached to carbon
extracting the product, and the like. The reaction prod
atoms not involving the 2,3-double bond, such as, for
uct may be purified by crystallization, adsorption and
elution, recrystallization and the like.
example, 2,3-dihydrofurans (cyclo-oxapent-Z-enes), e.g.
The deserpidate compounds used as the starting ma—
terials are known or, if new, may be prepared accord
hydrofuran (S-methyl-cyclo-oxapent-2-ene), and the like,
2,3-dihydropyrans (cyclo-oxahex-Z-enes), e.g. 2,3-dihy
ing to procedures used for known analogous compounds.
For example, deserpidic acids may be esteri?ed by treat
pyran (4-methyl-cyclo-oxahex-Z-ene), 2-methyl-2,3-dihy~
2,3-dihydrofuran (cyclo-oxapent-Z-ene), 2-methyl-2,3-di
dropyran (cyclo-oxahex-Z-ene), 4-methyl-2,3-\dihydro~
ment with a lower diazoalkane, a lower alkoxy-lower
dropyran (6-methyl-cyclo-oxahex-Z-ene), 2-chloro-2,3-di
diazoalkane or a tertiary amino-lower diazoalkane, or 75 hydropyran (6-chloro-cyclo-oxahex-2-ene) and the like.
3,048,591
9
it)
These reagents are reacted with the deserpidate com
the previously given meaning, particularly a lower diazo
pound in the presence of an acid condensing reagent, rep
resented by a strong Lewis acid. Mineral ‘acids, e.g. hy
drochloric, hydro'bromic or sulfuric acid (used in anhy
alkane, e.g. diazomethane, diazoethane, l-diazopropane,
l-diazo-n-butane, l-diazo-isobutane, l-diazo-n-pentane, 1
diazo-isopentane, 1-diazo-n-hexane and the like, a lower
drous form or as concentrated aqueous solutions), phos
alkoxy-lower diazoalkane, particularly a lower alkoxy
lower diazoalkane, in which lower alkoxy is separated
phoric acid (for example, in the form of polyphosphoric
acid), phosphorous oxychloride, ?uo‘boric acid (in the
from the diazo group by from two to three carbon atoms,
form of a highly concentrated aqueous solution), boron
and lower alkane contains from two to three carbon atoms,
tri?uoride (in the form of its etherate, particularly with
e.g. Z-methoxy-diazoethane, Z-ethoxy-diazoethane, 2-n
diethyl ether), or a carbocyclic aryl sulfonic acid, such 10 propyloxy-diazoethane, 3-methoxy-1-diazopropane, 3-eth
as a monocyclic ‘CEll‘bOCYCllC acid, especially p-toluene sul
oxy-l-diazopropane and the like, or a tertiary amino-lower
fonic acid, or similar reagents having Lewis acid proper
diazoalkane,
particularly an N,N-di-l0wer alkyl-.amino—
ties, such as, for example, cation exchange resins in acid
lower diazoalkane, in which the N,N-di-low=er alkyl-amino
form, e.g. sulfonic acid resins, or any other suitable Lewis
group is separated from the diazo group by from two to
‘acid may serve as a condensing reagent.
three carbon atoms, and lower alkane contains from two
In the presence of the strong Lewis acid the deserpidate
to three carbon atoms, e.g. 2-N,N-dimethylaminoediazo
compound may ?rst form a salt with such acid and react
in the form of an acid addition salt. Therefore, a salt
of the deserpidate compound with an acid may also be
used as the starting material.
The reaction may be carried out in the absence of a
solvent, whereby an excess of a liquid cyclo-oxa-alk-Zene
ethane, 2~N,N-diethylamino-diazoethane, 3-N,N-dimethyl
amino—l-diazopropane and the like. The reaction of the
l8-O-R3-deserpidic acid compounds with such diazo-re
agents is carried out, for example, in the presence of a dil~
uent, such as in a lower alkanol, e.g. methanol, ethanol,
n-propanol, isopropanol and the like, a halogenated lower
alkane, e.g. chloroform, methylene chloride and the like,
or any other suitable solvent; preferably, the diazo~reagent
is used in solution, for example, in an ether solution.
Cooling of the reaction mixture and/or the presence of
may also serve as the solvent, or in the presence of an
inert solvent. Such solvents are, for example, carbocyclic
aryl hydrocarbons, such as monocyclic carbocyclic aryl
hydrocarbons, e.g. lbenzene, toluene and the like, ethers,
e.g. diethylether, tetrahydrofuran, p-dioxane and the like,
lower alkanones, e.g. acetone, ethyl methyl 'ketone and
the like, formamides, e.g. formamide, N,N-dimethyl
an atmosphere consisting of an inert gas, e.g. nitrogen,
may be required.
The starting materials used in the above process for the
preparation of the compounds of this invention are new
and are intended to be included Within the scope of the
formamide and the like, acetonitrile or any other suitable
solvent.
The reaction may be carried out by mixing the reagents
or solutions thereof, whereupon the temperature may
invention. They may be depicted by the formula:
raise, and the mixture may then be allowed to stand or
may be agitated under cooling, at room temperature or at
an elevated temperature. The desired product may be
isolated according to standard procedures, e.g. extraction,
adsorption and elution, crystallization, and the like, pref
erably after having neutralized the acidic reaction mix
ture with an alkaline reagent, for example, ammonia, e.g. 40
aqueous ammonia, ammonia in a lower alkanol such as
methanol, ethanol and the like, aqueous alkali metal car
bonate, e.g. sodium or potassium carbonate or hydrogen
carbonate and the like, aqueous alkali metal hydroxide,
e.g. sodium hydroxide, potassium hydroxide and the like,
in which the radicals R2, R3, R4, R5 and Re have thepre
or any other suitable alkaline reagent.
viously given meaning, salts and N-oxides of such com—
pounds. Particularly useful are ‘the compounds of the
formula:
The reaction may also be carried out in the atmosphere
of an inert gas, e.g. nitrogen and/or, if necessary, with
the exclusion of moisture by adding a dehydrating reagent,
or under pressure in a closed vessel.
The compounds of the present invention may also be
50
prepared by converting in compounds of the formula:
60
I!
on
in which R2, R3, R4, R5 and R6 have the previously given
meaning, a salt or an N-oxide thereof, the free carboxyl
group in 16-position into an esteri?ed carboxyl group of
the formula R1—O—(O=)C-~, in which R, has the pre
viously given meaning, and, if desired, carrying out the
optional steps.
in which R2 represents lower alkyl containing from one to
four carbon atoms, R3 stands for .2-cyclo-oxa-alkylcon
taining from ?ve to seven atoms as ring members, lower
alkyl-substituted Z-cyclo-oxa-alkyl containing from ?ve to
seven atoms as ring members, or halogeno-substituted 2
cyclo-oxa-alkyl containing from ?ve to seven atoms as ring
membersyeachlof the groups R4 and R5 stands for hydro
gen, lower alkyl containing from one to four carbon atoms,
lower alkoxy containing from one to four carbon atoms,
The esteri?cation of the free carboxyl group may be 70 lower alkyl—mercapto containing from one to four carbon
carried out according to methods known per se, which are
atoms or halogeno, and R6, attached to one of theposi
‘used for the preparation of analogous compounds. For
tions 5 and 6, stands for hydrogen or lower alkyl contain
example, the l8-O-Raadeserpidic acid compounds, in which
ing from one to four carbon atoms, salts or the N-oxides
R3 has the previously given meaning, may be treated with
of these compounds, as well as their various isomeric
‘a diazo compound of the formula RINZ, in which R1 has 75 forms.
3,048,591
12
11
V
compounds by treatment, for example, with lower di
azoalkanes, lower alkoxy-lower diazoalkanes, in which
This group of compounds may be represented by re
serpic acid compounds of the formula:
lower alkoxy is separated from the diazo group by from
two to three carbon atoms, and lower alkane contains
from two to three carbon atoms, N,N-di-lower alkyl
amino-lower diazoalkanes, in which the N,N-di-lower
alkyl-amino group is separated from the diazo group by
from two to three carbon atoms, and lower alkane con
tains from two to three carbon atoms.
The deserpidic acid compounds used as the interme
diates may be prepared, for example, by treating a
deserpidic acid compound of the formula:
salts or N-oxides thereof. Speci?c compounds of this type
are, for example, l8-O-(tetrahydro-2-furanyl)-reserpic
acid, 18-0-(tetrahydro-Z-pyranyl)-reserpic acid and the
like. Another group of these compounds may be repre
' sented by the formula:
in which R2, R4, R5 and R6 have the previously given
salts or N-oxides thereof. Speci?c compounds of this type
meaning, or an N-oxide thereof, with a reactive ester of
a 2-hydroxy-cyclo-oxa-alkane, which contains at least ?ve
atoms as ring members, in the presence of a condensation
are, for example, l8~O-(tetrahydro~2-furanyl)Pdeserpidic
acid, 18-0-(tetrahydro-Z-pyranyl)-deserpidic acid and the
30
like.
.
reagent, and, if desired, separating a resulting mixture of
Apart from the above-mentioned reserpic acids and
isomeric compounds into the single isomers, and/or, if
deserpidic acids, other deserpidic acid-type compounds of
desired, converting a resulting salt into a free compound,
and/or, if desired, converting a resulting compound into
the previously given formula, are, for example,
a salt or an N-oxide thereof.
S-methyl-18-O—(tetrahydro-2-furanyl)-deserpidic acid,
S-methyl-l8-0-(tetrahydro-2-furanyl)-reserpic acid,
This reaction may be carried out as shown hereinabove.
2-halogeno-cyclo-oxa-alkanes, primarily 2-chloro-cyclo
6-methyl-1 8-O- (tetrahydro-Z-furanyl) -deserpidic acid,
6-methyl-l 8-0- (tetrahydro-Z-furanyl) -reserpic acid,
9-methyl—18-0-(tetrahydro-Z-furanyl) -deserpidic acid,
lO-methoxy-l 8-0- (tetrahydro-Z-furanyl) -deserpidic acid,
lO-methoxy-l 8-O-(tetrahydro-2-furanyl) —reserpic acid,
oxa-alkanes, which contain from ?ve to seven atoms as
ring members, e.g. Z-chloro-tetrahydrofuran (2-chloro
cyclo-oxapentane), 2-chloro-tetrahydropyran (2-chloro
cyclo-oxahexane) and the like are used as the preferred
reagents, and N,N-dimethylformamide is a very suitable
condensing reagent, which may simultaneously serve as
1 l-ethoxy-l 8-0- (tetrahydro-Z-furanyl) -deserpidic acid,
l2-methoxy-1 8-0- (tetrahydro-2-furanyl) -deserpidic acid,
10-chloro-l 8-0-(tetrahydro-Z-furanyl) -deserpidic acid,
10-bromo-l 8-O—(tetrahydro-2-furanyl) -deserpidic acid,
10-bromo-l 8-0- (tetrahydro-Z-furanyl) -reserpic acid,
a solvent.
The starting materials may also be prepared by treating
a deserpidic acid compound of the formula:
' 17 - desmethoxy - 17 - ethoxy - 18 - O - (tetrahydro - 2
furanyl) -reserpic acid,
5 ~methyl-1 8-O~(tetrahydro-2-pyranyl) -deserpidic acid,
S-methyl-1S-O-(tetrahydro-Z-pyranyl) -reserpic acid,
6-methyl-18-O-(tetrahydro’2-pyranyl) -reserpic acid,
6-methy1-1 8-O-(tetrahydro-2-pyranyl) -deserpidic acid,
9-metl1yl-18-O-(tetrahydro-Z-pyranyl)-deserpidic acid,
1 1-methy1-18-O-(tetrahydro-Z-pyranyl)-deserpidic acid,
9-methoxy-18-0-(tetrahydro-Lpyranyl) -deserpidic acid,
10~methoxy-18-O-(tetrahydro-2-pyranyl)deserpidic acid,
l0-methoxy-18-O-(tetrahydro-2-pyranyl)-reserpic acid,
1 l-ethoxy-1S-O-(tetrahydro-Z-pyranyl) -deserpidic acid,
11 - n - propyloxy - 18 - O - (tetrahydro - 2 - pyrany1)
deserpidic acid,
12-methoxy-18-0-(tetrahydro-2-pyranyl) -deserpidic acid,
60
alk-2—ene containing at least ?ve atoms as ring members,
in the presence of an acid condensing reagent, and, if
rany1)-deserpidic acid,
1.1 - ethyl - mercapto - 18 - O - (tetrahydro - 2 - pyranyl)
‘deservpidic acid,
desired, carrying out the optional steps.
65
’ 10,11 - methylenedioxy - 18 - O - (tetrahydro - 2 - py
ing from ?ve to six atoms as ring members, such as the
' 10-chloro-l8-0-(tetrahydro-Z-pyranyl)-deserpidic acid,
previously described 2,3-dihydrofurans (cyclo-oxapent-Z
10-bromo- 1 8-0- (tetrahydro-Z-pyranyl ) -deserpidic acid,
' 10-bromo-18-0-(tetrahydro-Z-pyranyl)-reserpic acid,
‘ 17 - desrnethoxy - 17 - ethoxy - 18 - O‘ - (tetrahydro - 2
pyranyl)-reserpic acid
_ and the like, as well as salts or N-oxides thereof.
The above reaction is carried out according to the pre
viously shown procedure; a cyclo-oXa-alk-2-ene contain
ranyl) -deser-pidic acid,
'
in which R2, R4, R5, R6 and R7 have the above-given
meaning, a salt or an N-oxide thereof, with a cycle-oxa
11 - methyl - mercapto - 18 - O - (tetrahydro - 2 - py
As
,- shown hereinabove, these deserpidic acid compounds or
salts thereof may be converted into the desired deserpidate
70
enes), 2,3-dihydropyrans (cyclo-oxa-hex-Z-enes) and the
like, are used as the preferred reagents, and an acid con
densing reagent, such as a mineral acid, p-toluene sulfonic
acid and the like, is used to promote the reaction.
The deserpidic acids used as starting materials may also
be prepared, for example, by replacing in deserpidate
3,048, 591
l3
14
compounds or N-oxides thereof, these compounds having
the formula:
Other intermediates useful in the above preparation of
starting materials are the compounds of the formula:
R4
10
15
in which R2, R3, R4, R5, R6, Ph and Z have the previously
given meaning, and salts thereof; they are new and are
intended to be included within the scope of this invention.
Particularly useful as intermediates in the above'reaction
20 are the compounds of the formula:
in which R2, R3, R4, R5 and R6 have the previously given
meaning, and R1’ represents lower alkyl, lower alkoxy
lower alkyl, tertiary amino-lower alkyl or the group of
the formula Ph—(Z) CH-—, in which Ph represents mono
cyclic carbocyclic aryl and Z stands for hydrogen or lower
alkyl, the esteri?ed carboxyl group in 16-p0sition by a
free carboxyl group, and, if desired, carrying out the
optional steps.
Lower alkyl, lower alkoxy-lower alkyl and tertiary 30
amino-lower alkyl, representing R1’, are identical with the
radicals standing for the previously de?ned R1. The
monocyclic carbocyclic .aryl radical Pb in the formula
Ph—(Z)CH— stands primarily for phenyl; it may also
be represented by substituted phenyl, whereby substituents
may be lower alkyl, e.g. methyl and the like, lower alkoxy,
in which R2 represents lower alkyl containing from one
35 to four carbon atoms, R3 stands for 2~cyclo-oxa-alkyl con
e.g. methoxy and the‘like, or halogen, e.g. chlorine, bro
mine aud the like, or any other substituents, which do not
taining from ?ve to seven atoms as ring members, lower
alkyl-substituted 2-cyclo-oxa-alkyl containing from ?ve
to seven atoms as ring members, or halogeno-substituted
2-cyclo-oxa-alkyl containing from ?ve to seven atoms as
hinder the departure of the monocyclic carbocyclic aryl
methyl radical. Although Z may represent lower alkyl, 40 ring members, each of the groups R, and R5 stands for
hydrogen, lower alkyl containing from one to four car
e.g. methyl, ethyl, n-propyl and the like, it stands primarily
for hydrogen.
bon atoms, lower alkoxy containing from one to four
carbon atoms, lower alkyl-mercapto containing from one
The radical R1’ in the above-depicted formula for the
to four carbon atoms or halogeno, R6 stands for hydrogen
intermediate may be replaced by hydrogen by way of
hydrolytic cleavage. This reaction may be carried out 45 or lower alkyl containing from one to four carbon atoms,
or the N-oxides of these compounds, as well as their var
according to known methods, for example, by treatment
with an alkaline reagent, such as, for example, with a
ious isomeric forms. This group of compounds may be
solution of an alkali metal hydroxide, e.g. lithium hy
represented by benzyl 18—O-(2-cyclo-oxa-alkyl)~reserpates
droxide, sodium hydroxide, potassium hydroxide and the
compounds 2-cyclo-oxa-a1kyl contains from ?ve to seven
like, in an appropriate solvent such as a lower alkanol, e.g.
methanol, ethanol and the like, water, an aqueous lower
alkanol and the like.
The group Ph—(Z)CH-, in which the Ph and Z have
the previously given meaning, may also be removed by
hydrogenolysis, i.e. by reacting the intermediate, prefer
ably a solution thereof, for example, in a lower alkanol,
or benzyl l8-O-(2-cyclo-oXa-alkyl)-deserpiclates, in which
atoms as ring members, e.g. benzyl IS-O-(tetrahydro-Z
furanyl) -reserpate, benzyl l8-O-( tetrahydro-Z-furanyl ) -
deserpidate, benzyl 18-0- (tetrahydro-Z-pyranyl)-reserpate,
benzyl 18-0-(tetrahydro-Z-pyranyl)-deserpidate and the
like.
These compounds may be prepared, for example, by
alcoholyzing a lactone of the formula:
e.g. methanol, ethanol and the like, with hydrogen in the
presence of a catalyst. Such catalyst contains a metal of
the eighth group of the periodic system, for example, 60
palladium and the like, and may be represented by palla
dium black or any other suitable catalyst. If necessary,
increased pressure and/or elevated temperature may be
employed, although normally the reaction proceeds under
atmospheric pressure and at room temperature. In order
to secure a complete hydrogenolysis, the reaction vessel
is agitated to expose the catalyst to the hydrogen.
The intermediates, which are used in the above reaction
and in which R1’ represents lower alkyl, lower alkoxy
lower alkyl or tertiary amino-lower alkyl, are identical 70
in which R2, R4, R5 and R6 have the previously given
with the previously described products, in which R1’ is
meaning, salts or N-oxides thereof, with analcohol of the
replaced by the radical R1; those compounds may be used
formula Ph-—(Z) CH—OH, in which Ph and Z have the
as intermediates in the preparation of ?nal products, in
which R,’ and R1 have different meanings.
previously given meaning, preferably in the presence of
an alcoholysis catalyst, such as an alkali metal, e.g. sodium
3,048,591
15
16
and the like, compound of such alcohol, and reacting a
resulting compound of the formula:
The transesteri?cation reaction may be carried out, for
example, by treating the‘ starting material with an alcohol
of the formula R1—OH, in which R1 has the above-given
meaning, and stands primarily for lower alkyl, particularly
lower alkyl containing from one to four carbon atoms,
e.g. methyl, ethyl, n-propyl, n-butyl, isobutyl and the like;
alcohols of the formula R1--OI-I ‘are, therefore, primarily
lower alkanols such as methanol, ethanol, n-propanol, n
ibutanol, isobutanol and the like. Other alcohols of the
“It
10 formula R1-—OH ‘are those, in which R1 represents lower
alkoxy-lower alkyl or tertiary amino-lower alkyl, whereby
the lower alkoxy and tertiary amino groups are separated
from the hydroxyl group by from two to seven, primarily
by from two to three, carbon atoms; such alcohols are,
15
in which R2, R4, R5, R6, Ph and Z have the previously
for example, Z-methoxyethanol, 2-ethoxyethanol, 3
methoxypropanol, 2-N,N-dimethylaminoethanol, 2-N,N
indicated meaning, with a reactive ester of a Z-hydroxy
diethylaminoethanol and the like.
cyclo-oxa-alkane, which contains at least ?ve atoms as
The reaction is carried out in the presence of a trans
ring members, in the presence of a condensing reagent, or
esteri?cation catalyst, particularly a basic transesteri?ca
'With a cyclo-oxa-alk-Z-enc, which contains at least ?ve 20 tion catalyst. Such catalysts are, for example, alkoxide
atoms as ring members, in the presence of an acid condens
ions, as, for example, furnished by alkali metal lower
ing reagent, and, if desired, converting a resulting salt into
the free compound, and/ or, if desired, converting a result
alkanolates, e.g. lithium, sodium or potassium methano
late, ethanolate, n-propanol-ate, n-butanolate or iso~
butanolate and the like, alkaline earth metal lower
ing compound into a salt or an N-oxide thereof.
The alcoholysis of the (16—> l8)-lactone of a deserpidic
acid compound may be carried out according to known
methods.
alkanolates, e.g. barium or strontium methanolate, ethano
late, n-propanolate, n-butanolate or isobutanolate and
the like, or aluminum lower alkanolates, e.g. aluminum
For example, a small amount of an alkali
metal, e.g. sodium, potassium and the like, is dissolved
‘methanolate, ethanolate, n-propanolate, isopropanolate,
in an alcohol of the formula Ph—(Z)CH—OH, in which
n-butanolate or isobutanolate and the like. The indivi
Ph and Z have the previously indicated meaning, or a 30 dual alkanolate compounds are employed together with
solution thereof in an inert solvent; the resulting reagent
the corresponding lower alkanol used as the transesteri
is then reacted with the lactone or a solution thereof.
?cation reagent. Other alcohols of the formula R1—OH,
The reaction may proceed under cooling or at room tem
in which R1 represents, for example, lower alkoxy-lower
perature, but may be more readily completed by heating,
valkyl or tertiary amino-lower alkyl, may be used in the
if necessary, in the atmosphere of an inert gas, e.g. nitro 35 presence of the corresponding alkali metal, alkaline earth
gen.
metal or aluminum alcoholates. Other basic transesteri
Treatment of the resulting deserpidic acid ester com
, ?cation catalysts are, for example, alkali metal cyanides,
pound with a reactive ester of a Z-hydroxy-cyclo-oxa
e.g. potassium cyanide and the like, or strong quaternary
alkane, which contains from ?ve to seven atoms as ring
ammonium hydroxides, e.g. benzyl-trimethyl-ammonium
members, particularly a corresponding 2-halogeno-cyclo~
oxadalkane, e.g. Z-chloro-tetrahydrofuran (2-chloro-cyclo
hydroxide and the like.
Apart from the alcohols of the formula R1—OH, which
oxapentane), 2-chloro-tetrahydropyran (2-chloro-cyclo
may simultaneously serve as diluents, other inert solvents
oxahexane) and the like, in the presence of a condensing
reagent, especially N,N-dimethylforma-mide, or with a
cyclo-oxa~alk-2-ene, which contains from five to six atom-s
may be used in the above-mentioned reactions; carbocyclic
aryl hydrocarbons, e.g. benzene, toluene and the like, are
examples of such inert solvents. If necessary, the reac
tion may be carried out at an elevated temperature, under
increased pressure ‘and/or in the atmosphere of an inert
as ring members, e.g. 2,3-dihydrofuran (cyclo-oxapent-Z
ene), 2,3-dihydropyr'an (cyclo-oxahex-Z-ene) ‘and the like,
in the presence of an acid condensing reagent, e.g. hydro
gas, e.g. nitrogen.
gen chloride, p-toluene sulfonic acid and the like, is car
This method is, therefore, suitable for preparing from
ried out according to previously described methods.
50 compounds of this invention other compounds which are
The compounds of the present invention may also be
embraced by the generic formula given for the compounds
prepared by transesterifying in deserpidate compounds
of this invention, and which may not be readily accessible
of the formula:
by the other procedures.
The compounds of the present invention may also be
obtained by isomerizing in a compound of the formula:
as
60
in which R1’, R2, R3, R4, R5 and R6 have the above-given
meaning, or an N-oxide thereof, the esteri?ed carboxyl
group, having the structural formula R1'—-O—-(O=)C—,
in which R1’ has the above-given meaning, into the esteri
?ed carboxyl group R1—O—-(O=)C-—, in which R1 has
the previously given meaning, by treatment with an alcohol
of the formula R1-OH in the presence of a transesteri
in which R1, R2, R3, R4, R5 and R6 have the above-given
.?cation agent, and, if desired, carrying out the optional
steps.
meaning, a salt or an N-oxide thereof, the hydrogen atom
attached to the 3-position in the presence of an acid
3,048,591
17
18
reagent and isolating the desired compound of the
Particularly useful are the intermediates of the for
mula:
formula:
10
15
in which R1, R2, R3, R4, R5 and R6 have the previously
in which R1 represents lower alkyl containing from one
to four carbon atoms, lower alkoXy-lower alkyl, in which
given meaning, va salt or an N-oxide thereof, and, if de
sired. carrying out the optional steps.
lower alkoXy contains from one to four carbon atoms and
lower alkyl, containing from two to three carbon atoms,
separates lower alkoxy from the carboxy group by from
two to three carbon atoms, or N,N-di-lower alkyl-amino
pionic acid and the like, primarily glacial acetic acid,
lower alkyl, in which lower alkyl of the N,N-di-lower
monocyclic carbocyclic aryl sulfonic acids, e.g. p-toluene 25 alkyl amino portion contains from one to four carbon
Acid reagents used in the above isomerization pro
cedure are more especially lower aliphatic carboxylic
acids, such as lower alkanoic acids, e.g. acetic acid, pro
sulfonic acid and the like or any other suitable acidic re
atoms and lower alkyl, separating N,N-di-lower alkyl
agent or mixtures of acids. Thus, aromatic sulfonic acids
are advantageously used together with one of the lower
aliphatic carboxylic acids mentioned above; a suitable
amino from the carboxy group by two to three carbon
atoms, contains from two to three carbons, R2 represents
lower alkyl containing from one to four carbon atoms,
R3 stands for 2-cyclo-oxa-alkyl containing from ?ve to
seven atoms as ring members, lower alkyl-substituted
2-cyclo-oXa-alkyl containing from ?ve to seven atoms as
mixture is, for example, p-toluene sulfonic acid in glacial
acetic acid. The reaction may be carried out in the ab
sence or presence of an additional solvent; for example,
p-toluene sulfonic acid may be used in the presence of
ring members, or halogeno-substituted 2~cyclo-oxa-alkyl
an organic base, e.g. pyridine, collidine and the like, as 35 containing from ?ve to seven atoms as ring members,
well as in the presence of another acid, e.g. glacial acetic
each of the groups R, and R5 stands for hydrogen, lower
acid and the like. Isomerization may be effected at room
alkyl containing from one to four carbon atoms, lower
temperature or, if necessary, at an elevated temperature,
alkoxy containing from one to four carbon atoms or
in an open vessel or under pressure, preferably in the
halogeno, and R6, attached to one of the positions 5 and
atmosphere of an inert gas, e.g. nitrogen.
6, stands for hydrogen or lower alkyl containing from
Optimum yields in such isomerization reactions may be
obtained by removing the desired product from the re
action medium, thus displacing the reaction equilibrium
one to four carbon atoms, or the N-oxides of these
compounds, as well as their various isomeric forms. This
group may be represented by lower alkyl l8-O-(2-cyclo
in favor of the product. The removal may be accom 45 oXa-alkyl) -3-iso-reserpates, in which cyclo~oXa-alkyl con
plished by separating the product, a salt or an N-oxide
tains from ?ve to seven atoms as ring members, e.g.
thereof from the starting material by exploiting their rela
tive solubilities in solvent systems. For example, the
methyl 18-0-(tetrahydro-Z-furanyl)-3_iso-reserpate, ethyl
product, a salt or an N-oxide thereof, may be separated
from the starting material either by adsorption on a suit
able material, such as alumina or paper, and subsequent
fractional elution, or by fractional crystallization from a
(tetrahydro-Z-pyranyl)-3-iso-reserpate, ethyl IS-O-(tetra
hydro-Z-pyranyl)-3-iso-reserpate, n-propyl 18-O-(tetrahy
dro-2-pyrany1)-3-iso-reserpate, isopropyl 18-O-(tetrahy
dro-Z-pyranyl)-3-iso-reserpate, methyl 18-O-(2-cyclo-oxa
18—O-(tetrahydro-Z-furanyl) -3-iso-reserpate,. methyl 18-O
solvent. The starting material separated from the de
heptyl)-3-iso-reserpate and the like, and by lower alkyl
sired product may then be recycled into the isomerization
18-O-(2-cyclo-oXa-alkyl)-3-iso-deserpidates, in which cy
55 clo-oXa-alkyl contains from ?ve to seven atoms as ring
process, enhancing the over-all yield of the reaction.
The intermediates used in the above procedure and
members, e.g. methyl 1S-O-(tetrahydro-Z-furanyl)-3-iso
having the formula:
60
deserpidate, ethyl 18-O-(tetrahydro-Z-furanyl)-3-iso-de
serpidate, methyl l8-O-(tetrahydro-Z-pyranyl)-3-iso-de
serpidate, ethyl 18~O-(tetrahydro-2~pyranyl)-3-iso-deser
pidate, n-propyl 1S-O-(tetrahydro-Z-pyranyl)-3~iso-deser
pidate, isopropyl 18-O-(tetrahydro-Z-pyranyl)-3-iso-de
serpidate, methyl 18-O-(Z-cyclo-oxaheptyl)-3-iso-deserpi
65
particularly lower alkyl 18-O-(2-cyclo-oxa-alkyl)-deserpi
date and the like, as well as by analogous compounds,
date compounds, in which cyclo-oXa-alkyl contains from
?ve to seven atoms as ring members, and in which the
5—position and/or the 6-position may be substituted by
lower alkyl, e.g. methyl and the like, or in which the
70 9-position, the l0-position, the ll-position and/or the
ll-position may contain lower alkyl, e.g. methyl and the
like, lower alkoxy, e.g. methoxy and the like, or halogen,
in which R1, R2, R3, R4, R5 and R6 have the previously
e.g. chlorine, bromine and the like as substituents, and/ or
given meaning, their salts or N-oXides, are new and are
in which the l7-position contains a lower alkoxy sub
intended to be included within the scope of this invention. 75 stituent other than methoXy, e.g. ethoxy and the like.
3,048,591
‘19
20
,
dioxalanyl (cycle-1,3-dioxapentyl) radicals, e.g. 2-(1,3
dioxalanyl) (or 2-cyclo-1,3-dioxapentyl), 4-('1,3-diox
alanyl) (or 4-cyclo-1,3-dioxapentyl), 2-methyl-4-(l,3
The above-mentioned starting material may be pre
pared by reacting compounds of the formula:
dioxalanyl) (or 2-methy1-4-cyclo-1,3-dioxapentyl) and
the like, 1,3-dioxany1 (or cyclo-1,3-d.ioxahexyl) radicals,
e.g. 2-(1,3-dioxanyl)
(or 2-cyclo~1,3-dioxahexyl), 4~
(1,3-dioxanyl) (or 4-cyclo-l,3-dioxahexyl), 2-methyl-4
(1,3-dioxanyl) (or 2-methyl-4-cyclo-1,3-dioxahexyl), 5
chloro-4-(1,3-dioxanyl) (or 5-chlor0-4-cyclo-1,3-dioxa
10 hexyl) and the like, 1,4-dioxanyl (or cyc1o-1,4-dioxahexyl)
radicals, e.g. 2-(1,4-dioxanyl) (or 2-cyclo-1,4-dioxahexyl),
5-methyl-2-(1,4-dioxanyl) (or S-methyl-Z-cyclo-1,4-dioxa
hexyl), 6-methyl-2-(1,4dioxanyl) (or 6-methyl-2-cyclo
1,4-dioxahexyl) and the like, cyclo-1,4-dioxaheptyl radi
cals, e.g. 2-cyclo-l,4-dioxaheptyl and the like, 1,3-oxa
in which R1, R2, R3, R4, R5 and R6 have the above-given
meaning, a salt or an N-oxide thereof, with a reactive
ester of a Z-hydroxy-oxa-alkane, which contains at least 15
thialanyl (or cyclo-1,3-oxathiapentyl) radicals, e.g. 2
?ve atoms as ring members, in the presence of a con
(1,3-oxathialanyl) (or 2-cyclo-1,3-oxathiapentyl), 5-(1,3.
densing reagent, or with a cyclo-oxa-alk-Z-ene, which
contains at least ?ve atoms as ring members, in the pres
ence of an acid condensing reagent, and, if desired, con
verting a resulting salt into a ‘free base, and/ or, if de
sired, separating a resulting mixture of isomeric com
oxathianyl) (or S-cyclo-1,3-oxathiapentyl) and the like,
1,3-oxathianyl (or 2-cyclo-1,3-oxathiahexyl) radicals,
e.g. 2-(1,3-oxathianyl) (or 2-cyclo-l,3-oxathiahexyl), 6
(1,3-oxathianyl) (or 6-cyclo-1,3-oxathiahexyl), Z-methyl
6-(1,3-oxathianyl) (or 2-methyl-6-cyclo-1,3-oxathiahexyl)
pounds into single isomers, and/ or, if desired, converting
and the like, 1,4-oxathianyl (or cyclo-1,4-oxathiahexyl)
radicals, e.g. 2-(1,4-oxathianyl) (or 2-cyclo-1,4-oxathia
a resulting compound into a salt or an N-oxide thereof.
The reaction of the 3-iso-deserpidate compounds with
hexyl), 5-methyl-2-(1,4-oxathianyl) (or S-methyl-Z-cyclo
the above reagents is carried out as previously shown.
Reactive esters of 2~hydroxy-cyclo-oxa-alkanes are pri
1,4-oxathiahexyl) and the like.
These compounds, as Well as their salts and N~oxides,
marily 2-halogeno-cyclo-alkanes, especially 2-chloro-cyclo
show antihypertensive and/or sedative and tranquilizing
eifects, and can, therefore, be used to relieve hypertensive
alkanes, which contain from ?ve to seven atoms as
ring members, e.g. 2-chloro-tetrahydrofuran (2-chloro
conditions and/or states of overactiveness, nervousness
and tensions, such as the conditions mentioned herein
above.
cyclo-oxapentane), 2-chloro-tetrahydropyran (Z-chloro
cyclo-oxapentane) and the like; these reagents are used in
the presence of a condensing reagent, particularly N,N
dimethylformamide and the like.
The above compounds may be illustrated by the de
Cyclo-oxa-alk-Z-enes,
serpidate compounds of the formula:
particularly those which contain from ?ve to six atoms
as ring members, e.g. 2,3-dihydrofuran (cyclo-oxapent 35
Z-ene), 2,3-dihydropyran (cyclo-oxahex-Z-ene) and the
like, are used in the presence of a Lewis acid, particu
larly of hydrogen halide, e.g. hydrogen chloride and
the like, p-toluene sulfonic acid, ?uoboric acid and the
40
like.
The intermediates used in the preparation of the start
ing materials are known, or, if new, may be prepared
according to procedures used for analogous compounds.
Also included within the scope of the invention are
compounds of the formula:
in which R1 represents lower alkyl containing ‘from one
to four carbon atoms, lower alkoxy-lower alkyl, in which
lower alkoxy contains from one to four carbon atoms
and lower alkyl, containing from two to three carbon
atoms, separates lower alkoxy from the carboxyl group
‘by ‘from two to three carbon atoms, or N,N-di-lower
in which R1, R2, R4, D5 and R6 have the previously given
meaning, and R3’ stands for cyclo-dioxa-alkyl or cyclo
alkyl-amino lower alkyl, in which lower alkyl of the
N,N-di-lower alkyl-amino portion contains from one to
55 four carbon atoms and lower alkyl, separating N,N-di
lower alkyl-amino from the carboxyl group by two to
three carbon atoms, contains from two to three carbons,
R2 represents lower alkyl containing ‘from one to four
carbon atoms, R3’ stands for 2-(1,4-dioxanyl) (or 2
oxathia-alkyl, which radicals contain at least ?ve atoms
as ring members, and ‘which are attached to the oxygen
atoms of the l8-position through one of the carbon at
cyclo-1,4-diox-ahexyl), lower alkyl-substituted 2-( 1,4-di
oxanyl) (or lower alkyl-substituted 2-cyclo-1,4-dioxa
hexyl), halogeno-substituted 2-(1,4-dioxanyl) (or halo
oms adjacent to a ring oxygen atom, salts or N-oxides
thereof, as Well as the various isomeric ‘forms of these
compounds, and process for the preparation of these
compounds.
The radicals R3’ contain primarily ‘from ?ve to seven
atoms as ring members and, as mentioned hereinbefore,
are attached to the oxygen atom of the 18-position through
one of the carbon atoms adjacent to a ring oxygen atom.
65
geno-substituted 2-cyclo-1,4-dioxahexyl), 2-(1,4-0xathia
nyl) (or 2-cyclo-l,4-oxathiahexyl), lower alkyl-substitut
ed 2-(1,4-oxathianyl) (or lower alkylesubstituted 2-cyclo
1,4-oxathiahexyl), or halogeno-substituted 2-(1,4-oxa
thianyl) (or halogeno-substituted 2-cyclo-1,4-oxathiahex
yl), each of the groups R, and R5 stands ‘for hydrogen,
lower alkyl containing from one to four carbon atoms,
70 lower alkoxy containing from one to 'four carbon atoms
tional substituents lower aliphatic hydrocarbons, particu
or halogeno, and R6 attached to one of the positions 5
larly lower alkyl, e.g. methyl, ethyl and the like, or
and 6, stands ‘for hydrogen or lower alkyl containing from
functional groups, particularly halogen atoms, e.g. chlo
one to ‘four carbon atoms, therapeutically acceptable min
rine, bromine and the like, or other suitable groups.
eral acid addition salts or the N-oxides of these com
Speci?c radicals representing R3’ are, for example, 1,3 75 pounds, as Well as their various isomeric forms.
I
The radicals are unsubstituted or may contain as addi
3,048,591
21
22
This group may be illustrated by the reserpate com
lower alkyl IO-methoxy-l8-O-R3'-reserpate, lower alkyl
pounds of the formula:
1l-ethoxy-l8~O-R3’- deserpidate, lower alkyl ll-isopropyl
oxy-l8-O-R3'-deserpidate, lower alkyl lZ-methoxy-lS-O
R3'-deserpiclate, lower alkyl 1O-chloro-l8-O-R3'-deserpi
date, lower ‘alkyl l0-bromo-18-O-R3'-reserpate, lower alkyl
lO-bromo-18-O-R3'-reserpate, lower alkyl 10-bromo-18-O
R3’ deserpidate, lower alkyl 1l-methylmercapto-18-O-R3’
deserpidate, lower alkyl 1l-ethylmercapto-l8-O-R3'-de
serpidate, lower alkyl l7-desmethoxy-17-ethoxy-18-O-R3'
reserpate and the like, in which compounds R3’ repre
sents 2-(1,4-dioxanyl) or 2-(l,4-oxathianyl), their N-ox
ides and various isomeric forms.
The compounds described hereinbefore may be pre
pared by treating a compound of the formula:
in which R1 represents lower alkyl containing from one
to four carbon atoms, and X stands for oxygen or sulfur,
or N-oxides of such compounds. Members of this group
are, for example, methyl 1\8—O-[2-(l,4-dioxanyl)]-reser
pate, ethyl 18-O—[2-(l,4-dioxanyl) ]-reserpate, n-propyl
R5
18-O-[2-(1,4-dioxanyl)J-reserpate, isopropyl 18-0-[2-(1,
4-dioxanyl)]~reserpate, n-‘outyl l8-O-[2-(1,4-oxathianyl)]
reserpate, methyl 18-0-[2-(1,4-oXathianyl)]-reserpate, ethyl
18-O-[2-(1,4-oxathianyl)]-reserpate, n-propyl 18-0-[2
(1,4-oxathianyl)]~reserpate, isopropyl 18-O-[2-(l,4-oxa
20
B14
thianyl)]-reserpate and the like, as well as N-oxides of
such compounds, whereby these compounds may be pres
ent in various isomeric forms.
Another outstanding group of compounds are the deser~
pidate compounds of the formula:
in which R1, R2, R4, R5 and Re have the previously given
meaning, or an N-oxide thereof, with a reactive ester of
a hydroxy-cyclo-dioxa-alkane or a hydroxy-cyclo-oxa
thia-alkane, which contains at least ?ve atoms as ring
members, and in ‘which the hydroxyl group is attached to
one of the carbon atoms adjacent to a ring oxygen atom,
in the presence of a condensing reagent, or converting in
35 a compound of the formula:
in which R1 represents lower alkyl containing ‘from one
to four carbon atoms, and X stands for oxygen or sulfur,
or N-oxides of such compounds. This group may be
illustrated, for example, by methyl 18-O-[2-( 1,4-dioxa
nyl) ]-deserpidate, ethyl 18~G-[2-( 1,4-dioxanyl) ]-deser
pidate, n-propyl l8-O-[2-(l,4-dioxanyl)l-deserpidate, iso
propyl 18~‘O-[2-(l,4-dioxanyl)]-deserpidate, nabutyl l8
O—[2-(l,4-dioxanyl)]-deserpidate, methyl 18-O-[2-(L4
45
oxathianyl) ] -deserpidate, ethyl 18-O-[2-(1,4-0xathianyl) ]
desenpidate, n-propyl l8~O-[2-(1,4-oxathianyl)]-deserpi
date, isopropyl l8-O~[2-(1,4-oxathianyl)]-deserpidate and
the like, as well as N-oxides of such compounds, and the
in which R2, R3’, R4, R5 and R6 have the previously given
various isomeric forms of these compounds.
Additional compounds, which illustrate the above group,
are lower alkoxy-lower alkyl, ‘in which lower alkoxy con
meaning, a salt or an N-oxide thereof, the ‘free carboxyl
group of the formula HO—~(O=)C— into an esteri?ed
tains from one to four carbon atoms and lower alkyl,
containing from two to three carbon atoms, separates
carboxyl ‘group of the formula R1—O—(O1=)C-, in
which R1 has the previously given meaning, or converting
in a compound of the formula:
lower alkoxy from the carboxy group by from two to
three carbon atoms, e.g. Z-methoxyethyl, Z-ethoxyethyl,
3-rmethoxypropyl and the like, 18-O-R3’-reserpate or 18
O-R3’-deserpidate, in which R3’ represents 2-(1,4-di
oxanyl) or 2-(l,4-oxathianyl), N,N~di-lower alkyl-amino
lower alkyl, in which lower alkyl of the N,N-di-lower
alkyl-amino group contains from one to four carbon
atoms, and lower alkyl, separating the amino group from
the carboxy ‘group by from two to three carbon
atoms, contains from two to three carbon atoms, eg.
2 - N,N - dimethylaminoethyl,
2 - N,N - diethylarnino
ethyl, 3 - N,N - dimethylaminopropyl and the
like,
18-O~R3'-reserpate or 18-O-R3’-deserpidate, in which
R3’ represents 2-(1,4-dioxanyl) or 2-(1,4-oxathianyl), or
lower alkyl, erg. methyl, ethyl, n-propyl and the like, 5
in which R2, R3’, R4, R5 and R6 have the previously
given meaning, ‘and R1’ represents lower alkyl, lower
methyl-l8-O-R3'-reserpate, ‘lower alkyl 5-methyl~l8-O 70 alkoxy-lower alkyl, tertiary amino-lower alkyl, or a group
R3’-deserpidate, lower alkyl 6-methyl-18-O-R3’-reserpate,
of the formula Ph—(Z)CH—, in which Ph and Z have
lower alkyl 6-n1ethyl~18-O-R3'-deserpidate, lower alkyl
the previously given meaning, or an N-oxide thereof,
9-rnethyl-l8—O-R3’-deserpidate, lower alkyl ll-rnethyl
the radical R1’ into the desired radical R1 by transesteri?
l8-O-R3'-deserpidate, lower. alkyl 9-methoxy-18-O-R3'
cation with an alcohol of the formula Bil-OH, in which R1
deserpidate, lower alkyl ltl-methoxy-l8-O-R3’-deserpidate, 75 has the previously given meaning, in the presence of a
24
2-N,N-dirnethylamino-diazoethane and the like. These
‘transesteri?cation reagent, or isomerizing in a compound
of the ‘formula:
reagents may be used as previously shown.
The starting materials used in this modi?cation of the
procedure having the formula:
R14
10
‘0112
in which R1, R2, R3’, R4, R5 and R6 have the previously
given meaning, a salt or an N-oxide thereof, the hydro
gen atom attached to the 3-position in the presence of an
F in which R2, R3’, R4, R5 and R6 have the previously
acid reagent, and isolating the desired compound having
the previously given formula, and, if desired, converting
given meaning, salts or N-oxides thereof, are new and
a resulting salt into the free compound, and/or, if de
sired, separating a mixture of isomeric compounds into
vention. Particularly useful are the deserpidic acid com
pounds of the formula:
are intended to be included within the scope of the in
the single compounds, and/or, if desired, converting a
resulting compound into a salt or into an N~oxide there
of.
The reactions in the above procedures are carried out
according to the general methods given hereinbefore.
For example, a reactive ester of a hydroxy-cyclo-dioxa
alkane or a hydroxy-cyclo-oxathia-alkane is an ester with
25
one of the previously mentioned acids, particularly with
a hydrohalic acid, e.g. hydrochloric, hydrobromic acid
and the like; speci?c reagents are, for example, halogeno 30
1,3-dioxalanes (or halogeno-cyclo-1,3-dioxapentanes), in
in which R2 represents lower alkyl containing from one
to four carbon atoms, R3’ represents 2-cyclo-1,4-dioxa
hexyl or 2-cyclo-1,4-oxathiahexyl or the corresponding
lower alkyl-substituted or halogeno-substituted radicals,
which halogen is attached to one of the carbon atoms
adjacent to the ring oxygen atoms, e.g. 2-chloro-1,3
dioxalane (or 2-chloro-cyclo-1,3-dioxapentane), 4-chloro
1,3-dioxalane (or 4-chloro-cyclo-1,3-dioxapentane) and
the like, halogeno-l,3-dioxanes (or halogeno-cyclo-l,3
dioxahexanes), in which halogen is attached to one of
the carbon atoms adjacent to- the ring oxygen atoms, e.g.
2-chloro-1,3-dioxane (or Z-chloro-cyclo-1,3-dioxahexane),
4-chloro-1,3-dioxane (or 4-chloro-cyclo-1,3-dioxahexane)
and the like, halogeno-l,4-dioxanes (or halogeno-cyclo
1,4-dioxahexanes), in which halogen is attached to one
of the carbon atoms adjacent to the ring oxygen atoms,
e.g. 2-chloro-l,4-dioxane (or 2-chloro-cyclo-1,4-dioxahex
ane), 2-c'nloro-5-rnethyl-1,4-dioxane (or 2-chloro~5
methyl-cyclo-1,4-dioxahexane) and the like, halogeno~1,3
oxathialanes (or halogenowyclo-1,3-oxathiapentanes), in
“ each of the groups R; and R5 stands for hydrogen, lower
alkyl containing from one to four carbon atoms, lower
alkoxy containing from one to four carbon atoms, lower
alkyl-mercapto containing from one to four carbon atoms
or halogeno, and R6, attached to one of the positions 5
40 and 6, stands for hydrogen or lower allryl, or N-oxides
of such compounds, as well as the various possible iso
meric forms thereof. Speci?c compounds of this group
are 18~O-[2-(l,4-dioxanyl)]-reserpic acid, 18-O-[2-(l,4
oxathianyl)]~reserpic acid, l8-O-[2-(1,4~dioxanyl)]-de
_ serpidic acid, 18-O~[2-(l,4-oxathianyl)]-deserpidic acid,
which the halogen atom is attached to a carbon atom
adjacent to the ring oxygen atom, e.g. 2-chloro-1,3-oxa
thialane (or 2-chloro-cyclo-1,3-oxathiapentane), S-chloro- Cu' 0
1,3-oxathialane (or S-chloro-cyclo-1,3-oxathiapentane)
and the like, halogeno-1,3-oxathiahexanes (or halogeno
cyclo-l,3-oxathiahexane), in which the halogen atom is
attached to a carbon atom adjacent to the ring oxygen
atom, e.g. 2-chloro-1,3-oxathiane (or 2-chloro-cyclo-l,3
oxathiahexane), 6-chloro-l,3-oxathiane (or 6-chloro<
6-methyl-l8-O- [2-( 1,4-dioxanyl) ]-reserpic acid, IQ-meth
oxy-l8-O-[2-( 1,4-dioxanyl) ]-deserpidic acid, l2-meth
oxy- l 8~O- [2-( 1,4-dioxanyl) ] -deserpidic acid, l0‘-chloro
l8-O-[2-(L4-dioxan31l) l~deserpidic acid, lO-bromo-18-O
[2-(1,4-dioxanyl)]-deserpidic acid, 17-aesmethoxyl17
ethoxy-l8-O-[2-(l,4-dioxanyl)]-reserpic acid and the
like.
These starting materials may be obtained according to
the methods previously outlined for the preparation of
analogous deserpidic acid compounds.
Transesteri?cation of the esteri?ed carboxyl group of
the
formula R1’—-O——(O=)C——, in which R1’ has the
oxathianes (or halogeno-cyclo-l,3-oxathiahexanes), in
previously given meaning, into the desired esteri?ed car
which the halogen atom is attached to a carbon atom
boxyl group of the formula R1—-O—(O=)C~—, in which
adjacent to the ring oxygen atom, e.g. 2-chloro-1,4-oxa 6 0 R1
has the previously given meaning, may be carried out
thiane (or Z-chloro-cyclo-1,4-oxathiahexane), 2-chloro-5
as previously shown; for example, the compound previ
methyl-1,4-oxathiane (or Z-chloro-S-methyl-cyclo-l,4—
ously shown by way of the above-depicted structural
oxathiahexane) and the like. These reagents are used
formula, when reacted with an alcohol of the formula
in the presence of a condensing reagent, particularly N,N
R1—OH, in which R1 has the previously given meaning,
dimethylformamide and the like.
cyclo-1,3-oxathiahexane) and the like, or halogeno-1,4—
Or, the free carboxyl group in a deserpidic acid corn—
pound of the previously given structural formula may
be converted into the desired esteri?ed carboxyl group
by treatment with a diazo compound of the formula RlNz,
in the presence of a trans-esteri?cation catalyst, such as,
for example, an alkali metal compound of the alcohol
R1—OH, yields an ester compound, in which the esteri?ed
carboxyl group has the formula R1—-O—(O=)C-—, in
R1 has the previously given meaning. Alcohols
in which R1 has the previously given meaning, particu 70 which
of the above-given formula are particularly lower al
larly with a lower diazo-alkane, e.g. diazomethane, diazo
kanols, e.g. methanol, ethanol, n-propanol, isopropanol,
ethane, l-diazopropane and the like, with a lower alkoxy
n-butanol and the like, lower alkoxy-lower alkanols, e.g.
diazo-lower alkane, e.g. Z-methoxy-diazoethane, 2-ethoxy
Z-methoxyethanol, 2-ethoxyethanol, 3-methoxypropanol
diazoethane, 3-methoxy-1-diazopropane and the like, or
and the like, or N,N-di-lower alkyl-amino-lower alkanols,
with an N,N-di-lower alkyl-amino-lower diazoalkane, e.g. 75 e.g. 2-N,N-dimethylaminoethanol and the like; trans-v
3,048,591
25
26
esteri?cation catalysts may be, for example, the alkali
metal, e.g. lithium, sodium, potassium and the like, com
sodium ‘and the like, compound of such alcohol, and
recating a resulting compound of the formula:
as
pounds of these alcohols, or other suitable basic catalysts,
such as those mentioned hereinbefore, e.g. potassium
cyanide, benzyl trimethyl ammonium hydroxide and the
I
like. The reaction is carried out as previously shown.
Starting materials, which are used in the above proce
4%
dures and have the previously ‘given structural formula,
in which R2, R3’, R4, R5 and R6 have the aforementioned
meaning, and R1’ stands for the group of the formula 10
Ph—-(Z)CH-—-, in which Ph and Z have the above-given
meaning, are new and are intended to be included within
the scope of the invention. Particularly useful are the
compounds of the formula:
in which R2, R4, R5, R6, Ph and Z have the previously
15 given meaning, with the reactive ester of a hydroxy-cyclo
dioxa-alkane or of a hydroxy-cyclo—oxathiaaalkane, which
contain at least ?ve atoms as ring members, and in which
the hydroxyl group is attached to one of the carbon
atoms adjacent to a ring oxygen, in the presence of a
20 condensing reagent, and, if desired, converting a result
ing compound into a salt or an N-oxide thereof.
The alcoholysis of the lactone can be performed as
previously shown; a deserpidate compound reacts with
the reactive ester of a hydroXy-cyclo-dioXa-alkane or a
25
hydroxy-cyclo~oxathia~alkane according to the above-de~
scribed method, particularly in the presence of N,N-di
methylformamide as a condensing reagent.
Isomerization of 3-iso-deserpidate compounds having
in which R2 represents lower alkyl containing from one
to four carbon atoms, R3’ stands for 2-(l,4-dioxany1)
the previously shown structural formula may be carried
‘as previously shown; acids, such as glacial acetic
(or 2-cyclo-1,4~dioxahexyl), lower alkyl-substituted 2-(1, 30 out
acid,
p-toulene sulfonic acid or a mixture of such acids,
4-dioxanyl) (or lower alkyl-substituted 2-cyclo~1,4- di
are suitable isomerization reagents.
oxahexyl), halogeno-substituted 2-(1,4-dioXanyl) (or hal
The starting materials used in the latter modi?ca
ogeno-substituted 2-cyclo-l,4-dioxahexyl), 2-(1,4-ox
tion, which has the previously given structural formula,
athianyl) (or 2~cyclo-1,4-oxathiahexyl), lower a1kyl~sub
are new and are intended to be included within the scope
stituted 2-(1,4-oxathianyl) (or lower alkyl-substituted 2 35 of
the invention. Especially valuable starting materials
cyclo_l,llaoxathiahexyl), or halogeno-substituted 2-( 1,4
are the compounds of the formula:
oxathianyl) (or halogeno-substituted 2 - cyclo - 1,4 - ox
athiahexyl), each of the groups R, and R5 stands for
hydrogen, lower alkyl containing from one to four car
bon ‘atoms, lower alkoxy containing from one to four 40
carbon atoms or halogeno, and R6, attached to one of
the positions 5 and 6, stands for hydrogen or lower alkyl
containing from one to four carbon atoms, acid addi
tion salts or the N-oxides of these compounds, as well 45
as their various isomeric forms.
This group of compounds may be represented by benzyl
l8-O-R3'-resperate and benzyl l8-O-R3’-desperpidate, in
which R3’ stands for 2-(l,4-dioxanyl) or 2-(1,,4-0X
athianyl), or N-oxides thereof; speci?c compounds are,
for example, benzyl 18-O-[2-(l,4-dioxany1)]-resperate,
benzyl 18-O-[2-(1,4a0xathianyl)]-resperate, benzyl 18-O
in which R1 represents lower alkyl containing from one
to four carbon atoms, lower alkoXy-lower alkyl, in which
lower alkoxy ‘contains from one to four carbon atoms
and lower alkyl, containing from two to three carbon
atoms, separates lower alkoiry from the carboXy group
athianyl)]~deserpidate and the like.
These compounds may be prepared, for example, by 55 by from two to three carbon atoms, or N,N-di-lower
alkyl-amino-lower ‘alkyl, in which lower ‘alkyl of the N,
alcoholyzing a lactone of the formula:
[2-(l,4-dioxanyl)]~desperidate, benzyl 18-O-[2-(1,4-ox
5
1R6
N-di-lower alkyl amino portion contains from one to
four carbon atoms and lower alkyl, separating N-N-di
lower alkyl-amino from the carboxy group by two to
three carbon atoms, contains from two to three carbons,
60 R2 represents lower alkyl containing from. one to four
carbon atoms, R3’ stands ‘for 2-(1,4-dioxanyl) (or 2
cyclo-l,4-dioxahexyl), lower alkyl-substituted 2-(1,4- di
oxanyl)
(or lower alkyl - substituted 2. - cyclo - 1,4 - di
oxahexyl), halogeno-substituted 2-(1,4-dioxanyl) (or
' halogeno-substituted 2-cyclo-l,4-dioxahexyl), 2-(1,4-ox
athianyl) (or 2~cyclo-1,4-oxathiahexyl), lower alkyl-sub
stituted 2-(l,4-oxathianyl) (or lower valkyl-substituted 2
cyclo-1,4-oxathiahexyl), or halogeno-su-bstituted 2-(1,4—
oxathianyl)
in which R2, R4, R5 and R6 have the previously given
meaning, salts or N-oxides thereof, with an alcohol of
the formula Ph—(Z) CH—OH, in which Ph and Z have
the previously given meaning, preferably in the presence
(or halogeno~substituted 2.-cyclo-l,4-oX
athiahexyl), each of the groups R; and R5 stands for
hydrogen, lower alkyl containing from one to four car
bon atoms, lower al'koxy containing from one to four
carbon atoms or halogeno, and R6, attached to one of
the positions 5 and 6, stands for hydrogen or lower alkyl
of an alcoholysis catalyst, such as ‘an alkali metal, e.g. 75 containing from one to four ‘carbon atoms, acid addition
3,048,591
28
27
salts or the N-ox-ides of these compounds, as well as their
various isomeric forms.
This group of compounds may be represented by lower
alkyl 18-O-R3’-3-iso-reserpate or lower alkyl 18-O-R3'-iso—
deserpidate, in which R3’ stands for 2-(1,4-dioxanyl) or
2-(1,4-oxathianyl)', or N-oxides thereof.
Speci?c com
pounds are, for example, methyl 18-O-[2—(1,4-dioxanyl) ]
3-iso-reserpate, ethyl l8~O-[2-(1,4-dioxanyl)]-3-iso-reser
pate, n-propyl 18-O-[2-(1,4-dioxanyl)]-3-iso-reserpate,
methyl 18-0-[2-(1,4-oxathianyl)]-3-iso-reserpate, meth
yl 18-O'-[2-(1,4-dioxanyl)]-3-iso-deserpidate, methyl l8
O-[2~(1,4-oxathianyl)]-3-iso-deserpidate and the like.
These compounds may be prepared, for example, by
reacting a compound of the formula:
ticularly when derived from natural sources. Resulting
racemates may be resolved into the optically active forms,
the laevo~rotatory l-form and the dextro-rotatory d-form.
Resolution procedures may be carried out according to
known methods suitable for the separation of racemates.
For example, to a solution of the free base of a racemate
(a d, l-compound) in a solvent, such as a lower alkanol,
e.g. methanol, ethanol, isopropanol and the like, a lower
alkanone, e.g. acetone, ethyl methyl ketone and the like,
10 or any other suitable solvent, or a mixture of solvents, is
added one of the optically active forms of an acid con
taining an asymmetric carbon atom, or a solution thereof,
for example, in the same lower alkanol, lower alkanone,
other solvent, or solvent mixture mentioned hereinabove.
Salts, which are formed by the optically active forms of
the base With the optically active form of the acid may
then be isolated, primarily on the basis of their different
solubilities.
Useful as optically active forms of salt
forming acids having an asymmetric carbon atom, are,
for example, the d-tartaric acid (L-tartaric acid)‘ and the
l-tartaric acid (D-tartaric acid), as well as the optically
active forms of dibenzoyl tartaric, di-p-toluyl-tartaric,
malic, mandelic, IO-camphor sulfonic acid, quinic acid
in which R1, R2, R4, R5 and R6 have the above-given
meaning, or an N-oxide thereof, with the reactive ester
of a hydroxy-cyclo-dioxa~alkane or of a hydroxy-cyclo
oxathia-alkane, which contain at least ?ve atoms as ring
members, and in which the hydroxyl group is attached
to one of the carbon atoms adjacent to a ring oxygen
atom, in the presence of a condensing reagent, and, if
desired, converting a resulting compound into a salt or
an N-oxide thereof.
and the like. The free and optically active base may be
obtained from a resulting sal-t according to methods
known for the conversion of a salt into a base as, for
example, is outlined hereinbefore. An optically active
base may be converted into a therapeutically useful acid
addition salt with one of the acids mentioned hereinbefore,
or may be converted into an N-oxide described hereinbe
fore. The optically active forms may also be isolated by
‘biochemical methods.
Or, by reacting a deserpidate compound with a cyclo
alk-Z-ene as mentioned hereinbefore, two isomeric com
The reaction of the deserpidate compound with the 35 pounds may be formed, which may be separated on the
basis of differences of physico-chemical properties, e.g.
oxathia-alkane can be carried out according to the previ
solubility, adsorbability and the like.
ously described ‘method, particularly in the presence of
The invention also comprises any modi?cation of the
ester of a hydroxy-cyclo-dioxa-alkane or a hydroxy-cyclo
N,N-dimethylformamide as ‘a condensing reagent.
process wherein a compound obtainable as an intermedi
The compounds prepared according to the process of 40 ate at any stage of the process is used as starting material
this invention may be obtained in the form of the free
and the remaining step(s) of the process is (are) carried
bases or the salts thereof. A salt may be converted into
the free base by reacting the former with an alkaline re
out. It also includes any new intermediates, which may
be formed in one of the procedures outline hereinbefore.
agent, such as, for example, aqueous silver oxide, aqueous
In the process of this invention such starting materials
ammonia, or any other suitable alkaline reagent. A free 45 are preferably used which lead to ?nal products mentioned
base may be converted into its therapeutically useful acid
in the beginning as preferred embodiments of the inven
addition salts by reaction with one of the acids mentioned
tion.
hereinbefore; such reaction may be carried out, for ex
The present application is a continuation-in-part ap
ample, by treating a solution of the base in a solvent,
plication of my applications Serial No. 837,351, ?led Sep
such as a lower alkanol, e.g. methanol, ethanol, propanol, 50 tember l, 1959, and Serial No, 837,352, ?led September 1,
isopropanol and the like, with the appropriate acid or a
1959, each of which in turn is a continuation-in-part ap
solution thereof, and isolating the formed salt.
N-oxides of the compounds of the present invention
may be formed according to known methods; for ex
plication of my application Serial No. 818,511, ?led June
8, 1959, which in turn is a continuation-in-part of my ap
solution thereof in an inert solvent, may be reacted with
an N-oxidizing reagent, such as, for example, hydrogen
peroxide, ozone, persulfuric acid, or more especially, or
ganic peracids, such as organic percarboxylic acids, e.g.
No. 793,959, ?led February 18, 1959, all now abandoned.
The following examples illustrate the invention and are
plication Serial No. 803,360, ?led April 1, 1959, which
ample, .the resulting deserpidate compound, preferably a 55 in turn is a continuation-impart of my application Serial
peracetic, perbenzoic, monoperphthalic acid and the like,
or per-sulfonic acids, e.g. p-toluene persulfonic acid and
the like. Inert solvents are, for example, monocyclic car
‘boxylic aryl hydrocarbons, e.g. benzene, toluene and the
like, halogenated lower alkanes, e.g. chloroform, ethylene
not to be construed as being limitations thereon. Tem
peratures are given in degrees centigrade.
Example 1
1 g. of methyl reserpate is suspended in 25 ml. of 2,3
dihydropyran and 7 drops of concentrated aqueous hy
drochloric acid (37 percent) is added, while agitating.
chloride and the like, lower alkanols, e.g. methanol, 65 The ?ask is closed with a glass stopper, shaken and then
ethanol and the like, or any other suitable solvent. In
allowed to stand for three days at room temperature. 10
the N-oxidation reaction an excess of the oxidation re
ml. of aqueous ammonia (28 percent) is added while
agent and/ or an increase in temperature should be avoided
stirring, and an excess of benzene is then given to the re
in order to prevent oxidative degradation.
action rnixture to form two layers. The organic layer
Depending on the form of starting materials used in 70 is separated, dried over sodium sulfate and evaporated
the formation of the compounds of the present invention,
under reduced pressure. The residue is dissolved in ace
the latter may be obtained in the form of different iso
tone, the solvent is evaporated and the residue is again
mers. Thus, racemic or optically active deserpidic acid
taken up in acetone, whereupon crystals are formed which
derivatives may be used as starting materials whereby the
are ?ltered off. The mother liquor is diluted with ether
latter is preferably used in the optically active form, par 75 and a second crop of crystals are obtained which are
29
3,048,591
combined with the ?rst crystallization product. The
tion of sodium hydroxide and a second portion of 54 g.
of ethyl chloroformate are given to the mixture, which is
stirred for one hour. The ether layer is separated, the
aqueous phase is extracted with 100 ml. of diethyl ether,
methyl 18-0-(tetrahydro-Z-pyranyl)-reserpate melts at
262-265" (decomposition); yield: 0.29 g.
Example 2
and the two ether solutions are combined and dried over
To a mixture of 1 g. of methyl reserpate and 15 ml.
potassium carbonate. The solvent is evaporated under
reduced pressure and the ethyl N—(2~methoxyethyl)-car—
of 2,3-dihydropyran is added 35 ml. of benzene, which
has been saturated at room temperature with gaseous
bamate is distilled at 105—106‘’/ 17-20 mm.
To a solution of 33 g. of ethyl N-(2-methoxyethyl)
thoroughly shaken and allowed to stand for two hours at
10 carbamate in 200 ml. of diethyl ether are added 25 g. of
room temperature to form a complete solution. 20 ml.
cracked ice and a solution of 81 g. of sodium. nitrite in
of 10 percent aqueous sodium ‘hydroxide is added while
125 ml. of water. While keeping the temperature below
shaking, the benzene layer is separated, washed once with
15 °, 150- ‘g. of 35% aqueous nitric acid is added care
water and dried over sodium sulfate. The solvent is
evaporated under reduced pressure and ether is added to 15 fully over a period of one hour. The ether layer is sepa
rated, washed with water and aqueous potassium car
the residue. The crystalline material is ?ltered oil‘ and
bonate and then dried over potassium carbonate. The
washed with ether to yield the methyl 18~O-(tetrahydro
hydrogen chloride. The reaction vessel is then closed,
2-pyranyl)-reserpate, M.P. 265-267"; yield: 0.55 g.
The resulting product is identical in every respect with
the compound obtained according to the procedure of 20
Example 1.
Example 3
residue, obtained after evaporation of the solvent under
reduced pressure, represents the ethyl N-(2-methoxyeth
yl)-N-nitroso-carbamate, which is used without further
puri?cation.
A gently re?uxing solution of 5 g. of potassium hy
droxide in 15 g. of methanol and 150 ml. of diethyl ether
is treated with a solution of 15.5 g. of ethyl N-(2-meth~
To 5 g. of n-propyl reserpate in 100 ml. of 2,3-dihydro
pyran is added 100 ml. of benzene, which has been satu
oxyethyl)~N-nitroso-carbamate in 50 ml. of diethylether,
rated with hydrogen chloride at room temperature; the 25 which is added dropwise over a period of one hour.
reaction mixture is placed in a ?ask and the closed ?ask
After re?uxing for 5 minutes, 100 ml. of water is added
is allowed to stand at room temperature for about thirty
and the yellow ether solution, containing the 2-methoxy
minutes. 80 ml. of a cold 10 percent aqueous solution
diazoethane, is separated.
of sodium hydroxide, containing a small amount of am
The above ether solution of Z-methoxy-diazoethane is
monia, is added while shaking. The benzene layer is 30 reacted with small portions of a slurry of reserpic acid in
separated, washed twice with ice water, ‘containing a small
methanol until no further reaction can be observed. A
amount of ammonia, dried over sodium sulfate, ?ltered
few drops of acetic acid are added, the solution is evapo
and evaporated under reduced pressure. The oily residue
rated under reduced pressure and the residual oil is dis
is dissolved in petroleum ether and crystallizes after cool
solved in ethyl acetate. Upon addition of petroleum
ing. The crystalline material is ?ltered oli, and dissolved 35 ether a precipitate is formed, which is ?ltered off, dis
in methylene chloride; the solution is ?ltered through a
column containing magnesia-silica gel, the solvent is
solved in methylene chloride, which solution is washed
with aqueous ammonia and ?ltered through a small col
umn containing a diatomaceous earth. The residue, ob~
evaporated, and the residue is crystallized from a mix
ture of petroleum ether and ether to yield 3.49 g.
of n-propyl 18-0-(tetrahydro-2-pyrauyl)-reserpate, M.P.
40
190~192°.
The starting material may be prepared as follows:
The gaseous n-diazopropane is distilled from its ether
tained after evaporation of the solvent, is crystallized
from ethyl acetate to yield the 2-methoxyethyl reser-pate,
M.P. 183-185".
Other deserpidates which may be prepared according to
the previously given procedure by replacing the starting
solution into a suspension of 20 g. of reserpic acid in a
material by other intermediates are, for example,
1:1 mixture of chloroform and ethanol. Any excess of 45
2-ethoxyethyl 18-O~(tetrahydro-2-pyranyl)-reserpate,
2-n-propyloxyethyl 18-O-(tetrahydro-2-pyranyl)~reserpate,
2-isopropyloxyethyl 18-O-(tetrahydro-Z-pyranyl)
reserpate,
3-methoxypropyl l8~O-(tetrahydro~2-pyranyD-reserpate,
2~rnethoxyethyl 18-O-(tetrahydro-2-pyranyll-deserpidate,
2-ethoxyethyl 18-O-(tetrahydro-2-pyranyD-deserpidate,
n-diazopropane is decomposed with acetic acid, the sol~
vents are evaporated under reduced pressure and the
residue is poured into 8100 ml. of water containing 20 ml.
of concentrated aqueous ammonia. A white crystalline
precipitate is obtained, which is washed with water to
yield the n-propyl reserpate, M.P. 164-166".
Z-methoxyethyl 5 -methyl- 1 S-O-(tetrahydro-Z-pyranyl)
Example 4
reserpate,
To 1 g. of Z-methoxyethyl reserpate in 25 ml. of 2,3
2-methoxyethyl
S-methyl-l8-O-(tetrahydro-2—pyranyl)
dihydropyran is added 25 ml. of benzene, which has 55 deserpidate,
been saturated at room temperature with hydrogen chlo
ride; the mixture is allowed to stand ‘at room temperature
for two hours. To the homogeneous solution is then
added 20 ml. of 10 percent aqueous sodium hydroxide
2-meth0xyethyl 6-methyl-18~O»(tetrahydro—2-pyranyl)
reserpate,
Z-methoxyethyl 9~methyl'18-O-(tetrahydro-Z-pyranyl)
deserpidate,
while shaking. The organic layer is separated, washed 60 2-methoxyethyl 1 l-methyl- 1 S-O-(tetrahydro-Z-pyranyl)
twice with water containing a few drops of concentrated
aqueous ammonia and then dried over sodium sulfate. A
yellow oil is obtained after evaporating the solvent under
reduced pressure. It is dissolved in acetone; petroleum
ether is added to this solution, the supernatant liquid is 65
decanted from the gummy precipitate, which is allowed
to stand overnight in the refrigerator. The gel-like solid
is dried on a ?lter to yield a tan powder, representing
2-methoxyethyl 18 - O - (tetrahydro-Z-pyranyl)~reserpate,
Ml’. 78—85°.
70
The starting material may be prepared as follows: To
a mixture of 226 g. of a 33 percent aqueous solution of
2-methoxyethylamine and 150 ml. of diethyl ether, kept
at 5° to 10° in an ice bath, is added dropwise 54 g. of
ethyl chloroformate. 100 g. of a cold 40% aqueous solu 75
deserpidate,
Z-methoxyethyl
deserpidate,
Z-methoxyethyl
deserpidate,
Z-methoxyethyl
reserpate,
Z-methoxyethyl
deserpidate,
Z-methoxyethyl
deserpidate,
9-methoxy-18-O-(tetrahydro-Z-pyranyD
IO-methoxy-l8-O-(tetrahydro-Z-pyranyh
10-methoxy-18—O-(tetrahydro-2-pyranyl)—
12-methoxy-18-O-(tetrahydro-2-pyranyl)
11-ethoxy-18-O-(tetrahydro-Z-pyranyl)—
Z-methoxyethyl 1 l-n-propyloxy-l 8-O-(tetrahydro-2
pyranyl)~deserpidate,
Z-ethoxyethyl 1l-isopropyloxy-18-O-(tetrahydro-2
pyranyD-deserpidate,
spa-8,591
32
31
ethyl acetate to yield ethyl N-(Z-dimethylaminoethyD-N
2-methoxyethyl 1 1-n-buty1oxy-18-O-(tetrahydro~2~
nitroso-carbamate hydrochloride, MP. 133-135".
A suspension of 11.3 g. of ethyl N—(2-dimethylamino->
ethyD-N-nitroso-carbamate hydrochloride in 100 ml. of
pyranyl)-deserpidate,
Z-methoxyethyl 10,1 l-methylenedioxy-18-O-(tetrahydro
2—pyranyl)-deserpidate,
ether is added to a mixture of 40 g. of a 25 percent meth
Z-methoxyethyl 1 O-benzyloxy-l 8-O-(tetrahydro-2
pyranyl)-deserpidate,
anol solution of potassium hydroxide and 300 ml. of ether
while gently re?uxing. After ?fteen minutes of addi
deserpidate,
tional heating the ether layer, containing the 2—dimethyl—
amino-diazoethane, is decanted and immediately used.
2-ethoxyethyl 1 l-benzyloxy- 1 8-O-(tetrahydro-2-pyranyl)
Z-methoxyethyl 1 l-methylmercapto- l 8-O-(tetrahydro-2
To the above described ether solution is added por
pyranyl)~deserpidate,
3-methoxypropyl 1 l-ethylmercapto-l8-O-(tetrahydro-2
10 tionwise 12.0 g. of reserpic acid in methylene chloride and
methanol.
pyranyl)-deserpidate,
2-methoxyethyl 10-chloro-1 8-O-(tetrahydro-2-pyranyl)
The mixture is allowed to stand overnight at
room temperature, the solvents are evaporated under re
duced pressure, and the residue is added to 400 ml. of
deserpidate,
water containing 20 ml. of ammonium hydroxide. The
water solution is extracted with methylene chloride, the
2~methoxyethyl 10-bromo-l 8-O-(tetrahydro-Z-pyranyl)
deserpidate,
Z-methoxyethyl 17-desmethoxy-17-ethoxy-18-O-(tetra
hydro-2-pyranyl)~reserpate,
2-methoxyethyl 17~desmethoxy~17-11-propyloxy-18-O
(tetrahydro-2-pyranyl)-reserpate,
2-methoxyethyl 17-desmethoxy-17-isopropyloxy-18nO
tetrahydro-2-pyranyl)-reserpate
organic solution is ?ltered through a column containing a
diatomaceous earth and evaporated. The Z-dimethyl-i
aniinoethyl reserpate is recrystallized from a mixture of
ethyl acetate and petroleum ether, MP. 110~114°.
20
Other deserpidates may be prepared according to the
and the like.
Example 5
previously given procedure by replacing the starting ma
terial by other deserpidates; such compounds are, for
example,
2-N,N-diethylaminoethyl 18-O-(tetrahydro-Z-pyranyD
To a solution of 4.3 g. of crude methyl deserpidate and
4.6 ml. of 2,3-dihydropyran in 40 ml. of acetone is grad—
reserpate,
ually added 2.82 g. of p-toluene sulfonic acid in 12 ml. of
2-(1-piperidino)-ethyl 18~O-(tetrahydro-2-pyranyD
acetone while stirring. The solution is agitated for an
reserpate,
additional thirty minutes, ethyl acetate is added and the
2-(4-methyl-1-piperazino)-ethyl 1 S-O-(tetrahydro-Z
resulting solution is washed twice with 10 percent aqueous 30
pyranyl)-reserpate,
sodium hydroxide and then with water. The organic
3-N,N-dmethylaminopropyl 18~0-(tetrahydro-2-pyranyl)
layer is dried over sodium sulfate, the solvent is removed
reserpate,
under reduced pressure and the residue is crystallized
2-N,N-dimethylaminoethyl 18-O—(tetrahydro-2-pyranyl)
from a mixture of ethyl acetate and petroleum ether.
deserpidate,
The resulting methyl 18-O-(tetrahydro-2-pyranyl)-deserpi
date is recrystallized from ethyl acetate, M.P. 255-257";
yield: 0.57 g.
Methyl deserpidate may be replaced by other lower
alkyl deserpidates in the above example, and compounds,
such as ethyl 18-O-(tetrahydro - 2 - pyranyl) - deserpidate, 40
n-propyl 18-O-(tetrahydro-2-pyranyl)-deserpidate, isopro
pyl-l8-O-(tetrahydro-2-pyranyl)-deserpidate, n-butyl 18-O
(tetrahydro-2-pyranyl)-deserpidate, isobutyl 18—O-(tetra
3~N,N-diethylaminopropyl 18-O-(tetrahydro-2-pyranyl)
deserpidate,
2-N,N-dimethylaminoethyl S-methyl- 1 8-O-(tetrahydro-2
pyranyl)-reserpate,
2—N,N-dimethylaminoethyl 5-methyl~1 8-O-(tetrahydro-2
pyranyl)-deserpidate,
2-N,N-dimethylaminoethyl 6-methyl-l 8-O-(tetrahydro-2
pyranyl)-reserpate,
2-N,N-dimethylaminoethyl 9-methyl-18-O-(tetrahydro-2
pyranyl)-deserpidate,
hydro-2-pyranyl)-deserpidate and the like, are formed
upon treatment with 2,3-dihydropyran according to the 4.5 2-N,N-dimethylaminoethyl 1 l-methyl-18-O-(tetrahydro
above procedure.
2-pyranyl)-deserpidate,
2-N,N-dimethylaminoethyl 9-methoxy-1S-O-(tetrahydro
Z-pyranyD-deserpidate,
Example 6
A mixture of 1.0 g. of Z-dimethylaminoethyl reserpate
2-N,N~dimethylaminoethyl 10-methoxy- 1 8-O-(tetrahydro
and 25 ml. of 2,3-dihydropyran, When treated with 25 m1. 50
2-pyranyD-deserpidate,
of benzene, which has been saturated with hydrogen chlo
2-N,N-dimethylaminoethyl 10-methoxy-l S-O-(tetrahydro
ride, according to the procedure outlined in Example 2,
2-pyranyl)-reserpate,
yields the desired Z-dirnethylaminoethyl 18-O-(tetrahydro
2-pyranyl)-reserpate.
The starting material used in the above reaction may be 55
prepared as follows: A mixture of 88 g. of a 33% aque
2-N,N-dimethylaminoethyl 12-methoxy-1 S-O-(tetrahydro
2-pyranyl)-deserpidate,
2-N,N-dimethylarninoethyl 1 l-ethoxy-18-O-(tetrahydro-2
pyranyl)-deserpidate,
ous N,N-dimethylethylenediamine solution and 150 ml.
2-N,N-dimethylaminoethyl 1 1-n-propyloxy~18-O-(tetra
of ether is cooled to 5° and a total of 108.5 of ethyl
hydro-Z-pyranyl)-deserpidate,
chloroformate is added in portions. A solution of 40 g.
2-N,N-diethylaminoethyl
1 1-isopropyloxy~18-O—(tetra
of sodium hydroxide in 60 ml. of water is given to the 60
hydro-Z-pyranyD-deserpidate,
reaction mixture simultaneously with the second half of
2-N,N-dimethylaminoethyl 1 l-n-butyloxy- 1 S-O-(tetra
the ethyl chloroformate; stirring is continued for an addi
hydro-2-pyranyl)-deserpidate,
tional hour. The ether layer is separated, the aqueous
2—N,N—dimethylaminoethyl 10,1 1-methylenedioXy-18-O
portion is extracted with ether and the ether extracts are
(tetrahydro-Z-pyranyl)-deserpidate,
combined and dried over anhydrous potassium carbonate. 65 2-N,N-dimethylaminoethyl 10-benzyloxy-1B-O-(tetra
The ether is evaporated, the residue is distilled, B.P. 118
hydro-Z-pyranyD-deserpidate,
122° at 17-20 mm., to yield the ethyl N-(Z-dimethyl
aminoethyD-carbamate.
2-N,N-dimethylaminoethyl 1 1-benzyloxy-18-O-(tetra
A solution of 40 g. of ethyl N-(2-dimethylaminoethyl)—
carbamate in 125 ml. of methylene chloride is cooled to
0°, and 19.5 g. of nitrosyl chloride in 300 ml. of methyl
2-N,N-dirnethylaminoethyl 1 1-methylmercapto-18-O
ene chloride is added over a period of approximately one
hour while stirring and keeping the temperature between
0° to 5°.
Stirring is continued for an additional two
hours, the precipitate is ?ltered o? and recrystallized from 75
hydro-2-pyranyl)-deserpidate,
(tetrahydro~2-pyranyD-deserpidate,
3-N,N-dimethylaminopropyl 1 l-ethylmercapto-18-O
(tetrahydro-2-pyranyl)-deserpidate,
2-N,N-dimethylaminoethyl lO-chloro- 1 8-O-(tetrahydro-2
pyranyl)-deserpidate,
3,048,591
33
2-N,N-dirnethylaminoethyl 10-bromo-18-0-(tetrahydro-2
pyranyD-deserpidate,
2-N,N-dimethylaminoethyl I ledesmethoxy-l7-ethoxy-18
O-(tetrahydro-2-pyranyl)-reserpate,
2-N,N—dimethylaminoethyl l7-desmethoxy-l7-n-propyl
oxy-l8~0-(tetrahydro-Z-pyranyD-reserpate,
2-N,N-dimethylamiuoethyl l7-desmethoxy-l7-isopropyl
34
added dropwise while vigorously stirring a solution of 12.0
g. of p-toluene-sulfonic acid in 50 ml. of acetone.
The
temperature is kept below 35—50° by external cooling.
A clear amber solution forms during the addition of the
p-toluene sulfonic acid. The reaction mixture is allowed
to stand at room temperature for thirty minutes and is
then diluted with 250 ml. of ethyl acetate; the mixture is
oxy- l 8-O-(tetrahydro-Z-pyranyl)-reserpate
repeatedly washed with 10 percent aqueous ammonia to
and the like.
completely remove any remaining acid. The ethyl ace
Example 7
10 tate solution is washed with water, dried over anhydrous
To 1 g. of ethyl reserpate in 25 ml. of 2,3-dihydropyran
sodium sulfate and concentrated to the small volume,
is given 25 ml. of benzene, which has been freshly satu
when crystallization occurs. The crystalline material is
rated with hydrogen chloride. The mixture is allowed to
?ltered oil and washed with ether to yield the desired
stand at room temperature for 45 minutes. After cooling
methyl l8-O~(tetrahydro-Z-pyranyl)-reserpate, M.P. 262
in ice-water 20 ml. of cold 10 percent aqueous sodium 15 264°. The product is identical in every respect with the
hydroxide containing a small amount of ammonia is added
compound obtained according to the procedure of Exam
ple 1.
to the mixture while shaking. Two layers separate quick
ly; the organic portion in washed twice with ice-water
Instead of hydrogen chloride or p-toluenesulfonic acid,
containing a small amount of ammonia and then dried
?uoboric acid may be used as the Lewis acid in the pre
over sodium sulfate while cooling. The solution is ?ltered 20 viously described procedures.
and evaporated under reduced pressure at less than 55°.
Example 1]
An amber oil is recovered, petroleum ether is added and
A
mixture
of
1.0
g.
of methyl S-methyl-reserpate and
evaporated again and the resulting residue is dissolved in
2
ml.
of
2,3—dihydropyran,
when reacted according to the
fresh petroleum ether. After cooling the solution over
procedure
of
Example
10,
i.e.
in the presence of 0.6 g. of
night in the refrigerator, 1 g. of solid material is ?ltered 25
p-toluene sulfonic acid and 20 ml. of acetone, yields the
oil, washed with petroleum ether and dissolved in 25 ml.
methyl S-methyl- l 8-O-(tetrohydro-2-pyranyl)-reserpate.
of methylene chloride containing two drops of aqueous
Example 12
ammonia. The solution is ?ltered through a synthetic
magnesia-silica gel preparation, which is washed with an
Treatment of an acetone solution of 0.5 g. of methyl
6-methyl-deserpidate with 0.8 ml. of 2,3-dihydropyran in
additional amount of methylene chloride, until a total of
the presence of 0.4 g. of p-toluene sulfonic acid according
100 ml. is collected. The solvent is evaporated under
to the procedure of Example 10, yields the methyl 6
reduced pressure; the resulting foam crystallizes upon
methyl-l 8-O-(tetrahydro-2—pyranyl)-deserpidate.
adding a small amount of diethyl ether. The ethyl 18-O
(tetrahydro-Z-pyranyl)-reserpate is ?ltered and washed
Example 13
with diethyl ether, then with petroleum ether, M.P. 210 35
Methyl
6-methyl-18-O-(tetrahydro-2~pyranyl)-reserpate
218°; yield: 0.6 g.
can be formed by reacting an acetone solution of 1.0 g. of
Example 8
methyl o-methyl-reserpate with 2 ml. of 2,3-dihydropyran
A mixture of 1 g. of n—butyl reserpate (M.P. ll6—ll8°,
in the presence of 0.5 g. of p-toluene sulfonic acid accord—
prepared by treating reserpic acid with an ether solution
ing to the procedure described in Example 10.
of n-diazobutane) in 25 ml. of 2,3-dihydropyran, to which 40
Example 14
is added 25 ml. of benzene, which has been freshly satu
rated With hydrogen chloride, is allowed to stand for 30
0.5 g. of n-propyl 6-methyl-reserpate, when treated
minutes and is then worked up as shown in Example 7.
with 1 ‘ml. of 2,3-dihydropyran in the presence of 0.3 g.
0.08 g. of n-butyl 18-O-(tetrahydro-2-pyranyl)-reserpate,
of p-toluene sulfonic acid and acetone according to the
45 procedure of Example 10, yields the desired n-propyl 6
M.P. 190—l92°, is obtained.
methyl- 1 8-O-(tetrohydro-2-pyranyl)-reserpate.
Example 9
Example 15
To a solution of 2 g. of n-hexyl reserpate in 15 ml. of
acetone and 2 ml. of 2,3~dihydropyran is added dropwise,
A mixture of 1.0 g. of methyl 9-methyl-dcserpidate, 1
at room temperature and while stirring a solution of 1.2 50 ml. of 2,3~dihydropyran and 0.6 g. of p-toluene sulfonic
g. of p-toluene-sulfonic acid in 5 ml. of acetone. The
acid in acetone, when treated ‘according to the procedure
mixture is allowed to stand at room temperature for thirty
of Example 10, yields the methyl 9-methyl-l8-O-(tet1'a
minutes, and is then diluted with an excess of ethyl acetate.
hydro-Z-pyranyl) -deserpidate.
The organic solution is washed with 10 percent aqueous
Other compounds, which may be prepared according
ammonia to remove all traces of the acid, the ethyl ace~ 55 to the previously described method by selecting the ap
tate solution is dried, evaporated to dryness, and the oily
residue is crystallized from a mixture of ether and petro'
leum ether. The crystalline material is ?ltered 01f and
Washed with a small amount of petroleum ether to yield
the desired n-hexyl l8-O-(tetrahydro-2-pyranyl)-reserpate,
M.P. l67-170°.
An additional amount can be recovered
propriate starting materials are, for example, ethyl 9
methyl - l8-O-(tetrahydroQ-pyranyl)-deserpidate, methyl
ll - methyl - l8-0-(tetrahydro-Z-pyranyl)-dcserpidate, n
propyl 1 1~methyl-18-O-(tetrahydro-2-pyranyl) -deserpidate
60 and the like.
Example 16
from the ?ltrate; total yield: 0.70 g.
By reacting 1.0 g. of methyl l0~methoxy-deserpidate
The n-hexyl reserpate, M.P. 1l7—l18°, may be pre
with
2 ml. of 2,3-dihydropyran according to the method
pared by treating reserpic acid with an ether solution of
n-diazohexane. The latter can be obtained by reacting 65 described in Example 10, i.e. in an acetone solution and
in the presence of 0.6 g. of p-toluene sulfonic acid, the
n-hexylamine with ethyl chloroformate, nitrosating the
resulting ethyl N-n-hexyl-carbamate with sodium nitrite
in the presence of nitric acid, treating the ethyl N~n~hexyl
N-nitroso-carbamate with a 25 percent solution of potas
sium hydroxide in methanol in the presence of ether and
methyl IO-methoxy- 1 8-0- (tetrahydro-2~pyranyl) -deserpi
date can be prepared.
Analogous compounds, such as, for example, methyl
9-methoxy- 1 8-0- ( tetrahydro-Z-pyranyl ) -deserpid-ate, ethyl
separating the ether solution of n-diazohexane; these reac 70 10 ~ meth0xy-18-O- (tetrahydro-Z-pyranyl) ~deserpidate, n
propyl 10 - methoxy-18-O-( tetrahydro-Z-pyranyl) ~deserpi
tions are carried out as previously shown.
Example 10
date, methyl l0 -methoxy-l8-O-(tetrahydro-Z-pyranyl)
reserpate, n-propyl lO-methoxy-l8-O-(tetrahydro-2-pyr
To a suspension of 20.0 g. of methyl reserpate in 150
anyD-reserpate and the like, may be prepared accordingly
ml. of acetone containing 20 ml. of 2,3-dihydropyran is 75 by using appropriate starting materials.
3,048,591
35
36
g. of p-toluene sulfonic acid and in an acetone solution
Example 17
according to the procedure described in Example 10,
The methyl 12-methoxy-l8-O-(tetrahydro-Z-pyranyl)
yields the desired methyl l0-chl-oro—18-O-(tetrahydro-2
deserpidate may be prepared by reacting an acetone solu
tion of 0.5 g. of methyl l2-methoxy-deserpidate with 1
pyranyl) -deserpidate.
Analogous compounds, which may be prepared accord
ing to the procedure of Example 10 vby selecting the ap~
ml. of 2,3-dihydropyran in the presence of 0.3 g. of p
toluene sulfonic acid according to the procedure of Ex
propriate starting materials, are, for example, ethyl l0
ample 10.
chloro-18-O-(tetrahydro-Z-pyranyl)-deserpidate, n-propyl
Ethyl IZ-methoxy-l 8-O-(tetrahydro-Z-pyranyl) -de:serpi
date, n-propyl 12-methoxy-18-O-(tetrahydro-2-pyranyl)
10 - chloro - 18 - O - (tetrahydro-Z-pyranyl)-deserpidate,
methyl l0~?uoro-18-O-(tetrahydro-2-pyranyl)-deserpidate,
deserpidate and the like may be prepared according to 10 methyl 11 - chloro - 18-O-(tetrahydro-Z-pyranyl)-deserpi
the previously described procedure by treating the ap
propriate starting materials with 2,3-dihydropyran in the
presence of an acidic condensing catalyst, for example,
p-toluene sulfonic ‘acid as described in Example 10.
Example 18
date, methyl 10 - bromo - 18 - O-(tetrahydro-2-pyranyl)
reserpate, methyl lO-bromo-IS-O-(tetrahydro-Z-pyranyl)
15
Methyl 17-desmethoxy-17-ethoxy-reserpate (0.5 g.),
A mixture of 1.0 g. of methyl ll-ethoxy-deserpidate,
2 ml. of 2,3-dihydropyran and 0.6 g. of p-toluene sulfonic
when reacted with 1 ml. of 2,3-dihydropyran in the pres
ence of 0.3 g. of p-toluene sulfonic acid according to the
acid in acetone, when reacted as described in Example
procedure of Example 10, yields the methyl l7-desme
10, yields the desired methyl ll-ethoxy-lS-O-(tetrahydro
thoxy-17-ethoxy-l 8-O~(tetrahydro-Z-pyranyl) -reserpate.
Z-pyranyl) -deserpidate.
Other ‘compounds which may be prepared according to
the procedure of Example 10 by selecting the appropriate
starting materials, are, for example, ethyl 17-desmethoxy~
Other compounds, which may be prepared according to
the procedure of the ‘above example by selecting the ap
propriate starting materials are, for example, ethyl 11
l7-ethoxy- 1 8-O- ( tetrahydro-Z-pyranyl ) -reserpate, methyl
ethoxy-18-0-(tetrahydro-Z-pyranyl) -deserpidate, n-propyl
17 - desmethoxy - l7-n-propyloxy-18-O-(tetrahydro-2-pyr
anyl)-reserpate, methyl 17-desmethoxy-17-isopropyloxy
11 - ethoxy - 18 — O - (tetrahydro~2-pyranyl)-deserpidate,
methyl 11 - n - propyloxy - 18 — O-(tetrahydro-Z-pyranyl)
ideserpidate, methyl ll-isopropyloxy-18-0-(tetrahydro-2
pyranyl)-deserpidate, methyl 1l—n-butyloxy-lS-O-(tetra
hydro-Z-pyranyl)-deserpidate and the like.
18-0-(tetrahydro-Z-pyranyl)-reserpate, methyl 17-desme
thoxy - 17 -ethoxy-1 8-O- (tetrahydro-Z-pyranyl) -deserpidate
and the like.
3O
Example 24
Example 19
To 2.0 g. of methyl reserpate and 2 ml. of 2,3-dihydro
furan in 15 ml. of acetone is added slowly a solution
of 1.2 g. of p-toluene sulfonic acid in 5 ml. of acetone
Methyl 10,11 - methylenedi-oxy-l8-O-(tetrahydro-2-pyr
anyl)-deserpidate may be prepared by reacting 0.5 g. of
methyl 10,11—methylenedioxy-deserpidate with 0.8 ml. of
2,3-dihydropyran in the presence of 0.3 g. of p-toluene
sulfonic acid according to the procedure of Example 10.
at room temperature while stirring. After the addition
is completed, the solution is allowed to stand at room
temperature for 25 minutes, 100 ml. of ethyl acetate is
The ethyl 10,1l~methylenedioxy-l8-O-(tetrahydro-2
added, the solution is washed with 10 percent aqueous
ammonia, then with water and dried over sodium sul
fate. The solution is concentrated under reduced pres
sure until crystals appear. The crystalline material is
?ltered oh? and washed with ether to yield 0.7 g. of
pyranyl)-deserpidate, n-propyl 10,1l-methylenedioxy-l8
O-(tetrahydro-Z-pyranyl)-deserpidate and the like may be
prepared by substituting in the previous example ethyl
10,11-methylenedioxy-deserpidate, n-propyl 10,11-methyl
enedioxy-deserpidate and the like for the methyl 10,11
rnethylenedioxy-deserpidate and reacting the former with
2,3-dihydropyran according to the procedure described in
Example 10.
Example 20
Upon treatment of methyl 1.0 g. of 10-benzyloxy
deserpidate with 1.5 ml. of 2,3-dihydropyran in the pres
methyl 18-0-(tetrahydro-Z-furanyl)-reserpate, M.P. 256~
258° (decomposition).
Other lower alkyl ‘18-O-(tetrahydro-Z-furanyl)-de
serpidate compounds, which may be prepared according
to the above-described procedure by selecting the appro
priate starting materials are, for example, ethyl 18-O
(tetrahydro-Z-furanyl)~reserpate, n-propyl 18-O-(tetra
hydro-Z-furanyl)-reserpate, isopropyl 18-O-(tetrahydro
Z-furanyD-reserpate, n-butyl l8-O-(tetrahydro-2-furan
yl)-reserpate, isobutyl 18-O-(tetrahydro-Z-furanyl)-reser
ence of 0.6 g. of p-toluene sulfonic acid according to the
procedure of Example 10, the methyl lO-benzyloxy-lS-O
(tetrahydro-Z-pyranyl)-deserpidate can be obtained.
The ethyl 10-benzyloxy-l8-O-(tetrahydro-2-pyranyl)
deserpidate, methyl 11 - benzyloxy - 18-O-(tetrahydro-2
pyranyl)-deserpidate and the like may be prepared by re
55
0.5 g. of methyl 11-methylmercapto-deserpidate, when
treated with 0.9 ml. of 2,3-dihydropyran in the presence
of 0.3 g. of p-toluene sulfonic acid according to the
procedure of Example 10, yields methyl ll-methylmer
capto- 1 8-O-(tetrahydro-2-pyranyl ) -deserpidate.
Ethyl 11-methylmercapto-deserpidate or methyl l1
ethylmercapto-deserpidate, when reacted with 2,3-dihydro
pyran according to the procedure of Example 10, yield the
ethyl 11 - methylmercapto - l8-O-(tetrahydro-2-pyranyl)
deserpidate and the methyl 11-ethy1mercapto-l8-O-(tetra
hydro-2-pyranyl) -deserpidate, respectively.
Example 22
The reaction of 0.6 g. of methyl 10-chlor0-deserpidate
with 1 ml, of 2,3-dihydropyran in the presence of 0.4
pate, methyl l8-O-(tetrahydro-Z-furanyl)-desirpidate, eth
yl 18-O-(tetrahydro-Z-furanyl)-desirpidate, methyl 6
methyl-l8-O-(tetrahydro-2-furanyD-reserpate, methyl 9
methyl - 18 - O - (tetrahydro - 2 - furanyl) - desirpid'ate,
acting the appropriate starting materials with 2,3-dihydro
methyl 10~methoxy-18—O-(tetrahydro-Z-furanyl)-deserpi
pyran ‘according to the procedure of Example 10.
Example 21
deserpidate and the like.
Example 23
60
date, methyl 11-ethoxy-l8-O-(tetrahydro-Z-furanyl-de
serpidate, methyl 12-methoxy-18-O-(tetrahydro-Z-furan
yl ) -deserpidate, methyl 10-bromo- l 8~O~ (tetrahydro-Z-fu
ranyl)-deserpidate, methyl lO-methylmercapto-lS-O-(tet
rahydro-Z-furanyl)-deserpidate, methyl 17-desmethoxy
17-ethoxy-l8-O-(tetrahydro~2-furanyl)-reserpate and the
like.
Example 25
A mixture of 2.0 g. of methyl reserpate and 2 ml. of
4-methyl-2,3-dihydropyran in 15 ml. of acetone is stirred,
while a solution of 1.2 g. of p-toluene sulfonic acid in
5 ml. of acetone is added slowly. The reaction mix
ture is allowed to stand at room temperature for 11/2
hours, 100 ml. of ethyl acetate is added and the diluted
mixture is washed with 10 percent aqueous ammonia and
then with water. The organic layer is dried over sodium
sulfate and concentrated to dryness under reduced pres
3,048,591
37
33
sure; the oily residue crystallizes when stirred with di
ethyl ether. The solid material is recrystallized from
ethanol to yield the desired methyl 18-O-(4-methyl-tetra
hydro-2-pyranyl)-reserpate, M.P. 250-252° (with de
potassium hydroxide in methanol, and 300 m1. of ether.
The mixture is re?uxed for an additional thirty minutes,
an excess of water is added and the organic phase is
separated, washed with water and dried over anhydrous
sodium sulfate. The ether solution of the resulting di
azoisobutane is used in the next step.
A total of 6 g. of reserpic acid is added in small
amounts to the ether solution of diazoisobutane over a
composition) .
Analogous deserpidate compounds, such as, for exam
ple, ethyl 18-O-(4-methyl-tetrahydro-Z-pyranyl)-reser
pate, n-propyl 18-O-(4-methyl-tetrahydro-2-pyranyl)-res
erpate, methyl l8-O-(4-methyl-tetrahydro42-pyranyl)~de
serpidate, methyl 10-methoxy-18-O-(4~methyl-tetrahydro
2 - pyranyl) - deserpidate,
methyl
period of four hours.
The ether is then evaporated
10 under reduced pressure, the residue is added to a solu
12 - methoxy - 18 — O
tion of 20 ml. of concentrated aqueous ammonia in 600
ml. of water. The aqueous solution is extracted with
(4-methyl-tetrahydro-Z-pyranyl)-deserpidate and the like,
may be prepared by reacting the appropriate starting
methylene chloride, the organic layer is separated, passed
materials with 4-methyl-2,3-dihydropyran as shown in the
through a short column containing a synthetic magnesium
silicate adsorbent preparation and then evaporated. The
above example.
Example 26
residue is distilled under reduced pressure to remove un
reacted ethyl N—isobutyl-carbamate (B.P. 93_94°/ 15
To a solution of 2.0 g. of isopropyl reserpate and
mm.), and the non-distillable material is recrystallized
5 ml. of 2,3-dihydropyran in 15 ml. of acetone is added
from ether to yield isobutyl reserpate, M.P. 145-148";
dropwise and at room temperature while stirring a solu
tion of 1.2 g. of p-toluene sulfonic acid in 5 ml. of 20 yield: 3.0 g.
Example 28
acetone. The solution warms up towards the end of the
addition of the acid and darkens in color;.it is stirred
To a mixture of 2.0 g. of isopentyl reserpate and 2 m1.
for an additional thirty minutes. To the reaction mix
of 2,3-dihydropyran in 25 ml. of acetone is added grad
ture is added an excess of ethyl acetate, the solution is
ually 1.2 g. of p-toluene sulfonic acid in 5 ml. of acetone.
washed with 10 percent aqueous sodium hydroxide and
water and then dried over anhydrous sodium sulfate.
The solvent is evaporated to yield an oil, which crystal
lizes upon adding diethyl ether to yield the desired iso
propyl 18-0-(tetrahydro-Z-pyranyl)-reserpate, M.P. 250
253°; yield: 0.475 g.
The starting material used in the above reaction may
be prepared as follows: A mixture of ‘10 g. of methyl
reserpate, 500 ml. of isopropanol and 20 drops of benzyl
trimethyl ammonium hydroxide is re?uxed for 21/2 hours.
After standing at room temperature for several hours,
a white precipitate (needles) is formed, which is removed
30
After standing at room temperature for thirty minutes
an excess of ethyl acetate is added; the resulting mixture
is then washed twice with 10 percent aqueous sodium hy
droxide. The organic layer is dried over sodium sulfate
and evaporated under reduced pressure; the oily residue
is heated in a distillation apparatus to about 120° under
reduced pressure. Ethyl acetate is added to the non
by ?ltration. The ?ltrate is evaporated to dryness, the
distillable residue, a crystalline material precipitates,
which is ?ltered off and dissolved in methylene chloride.
The solution is passed through a column containing a
synthetic magnesium silicate adsorbent preparation; the
residue obtained after evaporating the solvent from the
eluate is crystallized from ethyl acetate to yield isopentyl
foamy residue is taken up in 500 ml. of water contain
ing 5 ml. of concentrated aqueous ammonia. The aque
ous mixture is extracted with methylene chloride, the
organic solvent is passed through a column containing a
yield: 0.12 g.
The starting material may be prepared as follows: To
a solution of 60 g. of ethyl N-isopentyl-carbamate, B.P.
diatomaceous earth preparation and is then evaporated
to dryness under reduced pressure. The residue is crystal
lized by the addition of diethyl ether, the crystalline ma
terial is ?ltered otf, dried and identi?ed as isopropyl
reserpate, M.P. 214—216°.
amine with ethyl chloroformate in the presence of sodium
hydroxide ‘and in a mixture of water and ether) in 150 m1.
of ether is added 50 g. of ice and then 163 g. of sodium
18-0-(tetrahydro-Z-pyranyl)-reserpate, M.P. 130—135°;
107—108°/17-20 mm. (prepared by reacting isopenthyl
nitrite in 250 ml. of water. A solution of 1.50 g. of con
centrated nitric acid and 150 g. of ice is gradually given
to the reaction mixture over a period of 11/2 hours, keep
A solution of 1.2 g. of p-toluene sulfonic acid in 5 ml. 50 ing the temperature below 15° by adding more ice. The
separated ether layer is Washed twice with water and
of acetone is added dropwise to 2 g. of isobutyl reserpate
cold aqueous potassium carbonate, and is then dried over
and 2 ml. of 2,3-dihydropyran in 15 ml. of acetone. The
potassium carbonate. The solvent is removed on the
reaction mixture is stirred and kept at room temperature
steam bath, leaving ethyl N-isopentyl-N-nitroso-carba
during the addition and is then allowed to stand at the
same temperature for an additional thirty minutes. An 55 mate, yield: 78 g.
A mixture of 40.0 g. of ethyl N-isopentyl-N-nitroso
excess of ethyl acetate is added, the organic portion is
carbamate in 75 ml. of ether is added dropwise to 80.0
washed with 10 percent aqueous ammonia to neutralize
g. of a 25 percent solution of potassium hydroxide in
the acid and is then dried and evaporated to dryness.
methanol and 400 ml. of ether while re?uxing. Boiling
The residue is crystallized from a mixture of ether and
petroleum ether to yield the desired isobutyl 18-O-(tetra~ 60 is continued for an additional twenty minutes. An excess
of Water is added, the ether layer is separated, washed
hydro-2-pyranyl)-reserpate, which, after washing with a
with water and dried over sodium sulfate.
small amount of petroleum ether, melts at 206-208";
To the ether solution, containing the diazoisopentane,
yield: 0.75 g.
is added reserpic acid hydrochloride portionwise until no
The isobutyl reserpate may be prepared as follows:
To a stirred solution of 34 g. of ethyl N-isobutyl-car 65 further liberation of gas is observed. The reaction mix
ture is stirred overnight at room temperature, the ether
bamate in 120 ml. of methylene chloride, kept at 0°, is
is
removed under reduced pressure, the residue is dis
added dropwise 15 g. of nitrosyl chloride, whereby the
Example 27
temperature is not allowed to raise to more than 5°.
solved in methylene chloride, the organic phase is washed
with water containing ammonium hydroxide and then
The mixture is stirred for an additional hour, the solvent
is evaporated under reduced pressure and the resulting 70 passed through a short column containing a synthetic
magnesium silicate adsorbent preparation. The residue,
ethyl N-isobutyl-N-nitroso-carbamate is used in the fol
obtained after evaporating the solvent of the eluate, crys
lowing step without any further puri?cation.
tallizes from a mixture of ethyl acetate and petroleum
A mixture of 30 g. of ethyl N-isobutyl-N-nitroso
ether after an initially precipitating gum has been re
carbamate and 75 ml. of ether is added dropwise to a
moved. The crystalline isopentyl reserpate melts at 135
re?uxing mixture of 50 g. of a 25 percent solution of 75 138°; yield: 4.13 g.
3,048,591
39
N,N-dimethylformamide as shown in Example 33, yields
the desired 18-O~(tetrahydro-Z-pyranyl)-deserpidic acid
compound, e.g. 18-O-(tetrahydro-Z-pyranyl)-reserpic acid,
18-0-(tetrahydro-Z-pyranyl)-deserpidic acid and the like
Example 29‘
1.0 g. of 18-O-(tetrahydro-2-pyranyl)-reserpic acid is
added in small amounts to an ether solution of diazo
ethane until evolution of nitrogen ceases.
The reaction
can be formed.
mixture is allowed to stand at room temperature, an
'18-O-(tetrahydro - 2 - furanyl)-deserpidic
excess of benzoic acid in ether is added and the solvent
is evaporated. Dilute aqueous ammonia is given to the
residue, and the aqueous mixture is extracted with meth
acid
com
pounds, such as for example, 18-0-(tetrahydro-2-furanyl)
ylene chloride. The organic solvent is evaporated after
drying and the residue is worked up to yield the desired 10
ethyl 18-0-(tetrahydro-Z-pyranyl)-reserpate, M.P. 210
reserpic acid, 18-O-(tetrahydro-2-furanyl) -deserpidic
acid, 1*0-methoxy-18-O-(tetrahydro-Z-furanyl)-deserpidic
acid, 12-methoxy-18-O-(tetrahydro-Z-furanyl)-deserpidic
acid and the like, can be obtained by hydrolyzing a cor
responding lower alkyl 18-O-(tetrahydro-Z-furanyl)-de
218°.
serpidate compound or by reacting a mixture of the cor
The starting material may be prepared as follows: A
responding 18-unsubstituted deserpidic acid compound and
solution of 3.6 g. of methyl 18-O-(tetrahydro-2-pyranyl)
reserpate in 45 ml. of 1 N aqueous sodium hydroxide is 15 2,3-dihydrofuran in an N,N-dimethylformamide solution
with p-toluene sulfonic acid as ‘shown in the above ex
refluxed for 2% hours. The resulting solution is concen
ample.
trated under reduced pressure, and the residue is diluted
Example 30
with Water. The solution is adjusted to pH=7 with acetic
A solution of 0.5 g. of methyl 18-O-(tetrahydro-2
acid and then extracted with methylene chloride. The or
ganic solution is dried over sodium sulfate, the solvent 20 pyranyl)-reserpate, prepared, for example, according to
the procedure of Example 10, in ethanol containing
is evaporated under reduced pressure and the residue is
sodium ethanolate, when heated to re?ux over a short
crystallized from a mixture of ethyl acetate and ethylene
period of time, yields the desired ethyl 18-O-(tertahydro
chloride to yield 1.5 g. of 18-O-(tetrahydro-2-pyranyl)
Z-pyranyD-resperpate, M.P. 210—218°.
reserpic acid, M.P. 215~218° (with decomposition).
Example 31
The 18-0-(tetrahydro-2-pyranyl)-reserpic acid may al 25
so be prepared as follows: To 0.5 g. of reserpic acid hy
To a solution of 1.29 g. of methyl reserpate N-oxide and
1.25 ml. of 2,3—dihydropyran in 10 ml. of acetone is
drochloride in 10 ml. of N,N-dimethylforma1nide and
5 m1. of 2,3-dihydropyran is added dropwise 0.3 g. of p
toluene sulfonic acid in 5 ml. of N,N-dimethylformamide
gradually added, while stirring, 0.76 g. of p-toluene sul
fonic acid in 3.2 ml. of acetone. Stirring is continued
for an additional thirty minutes and ethyl acetate is added;
while stirring at room temperature. The solution is
stirred for an additional thirty minutes, and is then poured
the organic layer is washed twice with 10 percent aqueous
into water; the mixture is extracted with methylene chlo
sodium hydroxide and with water. The organic solution
ride, the organic layer is dried over anhydrous sodium
is dried over sodium sulfate, the solvent is removed
sulfate and evaporated under reduced pressure. The
under reduced pressure, ‘and the residue is precipitated
35
residue is crystallized by adding diethyl ether and stirring
from a mixture of acetone and diethyl ether and crys
until crystals appear. The solid material is ?ltered off,
tallized from ethyl acetate. The resulting methyl 18-0
washed with ether, dried and recrystallized from a mix
(tetrahydro-Z-pyranyl)-reserpate N-oxide melts at 226
ture of ethyl acetate and methylene chloride, M.P. 200—
227°; yield: 0.11 g.
205“; yield: 0.3 g.
Other N-oxides, such as, for example, ethyl 18-O-(tetra
Other 18-0-(tetrahydro-Z-pyranyl) ~deserpidic acid com
hydro-Z-pyranyl)-reserpate N-oxide, n-propyl 18-O-(tetra
pounds, such as for example, 18-O-(tetrahydro-Z-pyra
hydro-Z-pyranyl)-reserpate N-oxide, methyl 18-O-(tetra
nyl)-deserpidic acid, S-methyl-lS-O-(tetrahydro-Z-pyra
nyl)-reserpic acid, 5-methyl-18-O-(tetrahydro-2-pyranyl)
deserpidic acid, 6-methyl-18-Oe(tetrahydro-2-pyranyl)
reserpic acid, 9-methyl-18~O-(tetrahydro-Z-pyranyl)-de
serpidic acid, 1l-methyl-l8-O-(tetrahydro-2-pyranyl)-‘de—
serpidic acid, 9-methoxy-18-O-(tetrahydro-Z-pyranyl)-de
serpidic acid, 10-methoxy~18-O-(tetrahydro-Z-pyranyl)
deserpidic acid, 10-meth0xy-18-O-(tetrahydro-2-pyranyl)—
reserpic acid, 12-methoxy~(tetrahydroQ-pyranyl)-deser
pidic acid, 1l-ethoxy-l8-O-(tetrahydro-Z-pyranyl)-deser
pidic acid, 11~n-propy1oxy-18-O>(tetrahydro-2-pyranyl)
deserpidic acid, 1l-isopropyloxy-lS-O-(tetrahydro-Z-pyr
anyl) -deserpidic acid, 1l-n-butyloxy-18-O-(tetrahydro-2
pyranyl) -deserpidic acid, 10,1l-methylenedioxy-18-O-(tet
rahydro-Z-pyranyl)-deserpidic acid, 10-benzyloxy-18-O
(tetrahydro-Z-pyranyl)-deserpidic acid, 11-benzyloxy-18
O-(tetrahydro-Z-pyranyl)-deserpidic acid, 11~methylmer
hydro-Z-pyranyl)-deserpidate N-oxide, methyl IO-meth
oxy-18-0-(tetrahydro-2-pyranyl) - deserpidate
45
N - oxide,
methoxyethyl 18-0-(tetrahydro-Z-pyranyl)-reserpate N
oxide, methyl l8-O-(4-methyl-tetrahydro-Z-pyranyl)-re
serpate N-oxide, methyl 18-0-(tetrahydro-Z-furanyl)-re
serpate N-oxide and the like, may be obtained by reacting
the appropriate lower alkyl or lower alkoxy-lower alkyl
deserpidate N-oxide compounds with 2,3-dihydropyran,
50 4-me'thyl-2,3-dihydrcpyran, 2,3-dihydrofuran and the like
according to the above procedure.
Example 32
A suspension of 249.3 g. of methyl reserpate in 1870
55 ml. of acetone and 250 ml. of 2,3-dihydropyran is stirred
at room temperature; a solution of 129.3 g. of p-toluene
sulfonic acid monohydrate in 620 ml. of acetone is added
over a period of nine minutes. The resulting solution is
capto-l8-0-(tetrahydro-2-pyranyl)-deserpidic acid, 11
stirred for thirty minutes, the acetone is removed by dis
ethylmercapto - 18 - O - (tetrathydro - 2 - pyranyl)-de
60 tillation and the residue is suspended in 2500 ml. of ethyl
serpidic acid, 10-chloro-18-O-(tetrahydro-Z-pyranyl)-de
serpidic acid, 10-bromo-18-O-(tetrahydro-Z-pyranyl)~de
serpidic acid, 17’desmethoxy-17-ethoxy-1S-O-(tetrahydrd
2-pyranyl)-reserpic acid, 17-desmethoxy-17-n-propyloxy
acetate. The organic solution is washed with a mixture of
602 ml. of 10 percent aqueous sodium carbonate and
780 ml. of water, and then three times with 300 ml. of
18-O-(tetrahydro-2-pyranyl)-reserpic acid, 17-desmeth
water.
oxy-17~isopropyloxy-18-0-(tetrahydro-2-pyranyl) -reserpic
acid and the like, may either be prepared by hydrolysis,
for example, of the corresponding lower alkyl IS-O-(tetra
hydro-2-pyranyl)-deserpidate compounds, or by treatment
of the corresponding deserpidic acid compounds with 2,3 70
dihydropyran as shown hereinabove.
2,3-dihydropyran may be replaced by a 2-halogeno
tetrahydropyran, such as 2-chloro-tetrahydropyran, which
upon reaction with a deserpidic acid compound, e.g. re
1000 ml. of chloroform is added, the remaining
65 water is distilled azeotropically and the solution is cooled.
A precipitate is formed, is ?ltered off and washed with
ethyl acetate and then with ether. The isolated product
is identical in every respect with the methyl IS-O-(tetra
hydro-2-pyranyl) -reserpate obtained according to the pro
cedure of Example 10; its rotation is [a]D25=———l48.75°
(in chloroform); yield: 107.6 g.
The ?ltrate, obtained after separating the solid material,
is concentrated to 400 ml. and the oily residue is dis
solved in 500 ml. of isopropanol. On cooling at 5” over
serpic, deserpidic acid and the like, in the presence of 75 night, a precipitate is formed, which is ?ltered off, washed
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