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Патент USA US3073829

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3,073,819
United States Patent O??ce
2
1
1 - p -' chlorobenzoyl-l-benayl-Z-(4-pyridy1-methylene)
hydrazine
3,673,819
drazine
The compounds described above are produced by con
Switzerland, assignors to Ho?mann-La Roche Inc”
Nutley, N.li., a corporation of New Jersey
densing a compound of the formula
No Drawing. Filed Apr. 29, 1960, Ser. No. 23,369
Claims priority, application Switzerland Apr. 39, 1959
(I1)
8 ?laims. (Cl. EMF-249)
ltl-N-Nrn
wherein R1 has the same signi?cance as above’ and R5
represents hydrogen, aralkyl or up to 7 carbon atom
aliphatic or alicyclic groups,
with a carbonyl compound of the formula
having the following structural formula:
2112
‘
Ilia
,
This invention relates to hydrazine derivatives. More
particularly, the invention relates to hydrazine derivatives
,
'
1 - pivaloyl - l - benzyl-Z-(a-4-pyridyl-ethylidene)hy
HYDRAZlNL'J DERIVATHVES
Otto Straub, Bottmingen, and Paul Zeiier, Nenallsehwil,
(I)
Patented Jan._15, 1963
in is .
R1-N—N=o—n,
wherein R1 represents hydrogen or acyl, Rz'represents
aralkyl, cycloalkyl or alkyl, R3 represents hydrogen or
1.5
wherein R3 and K, have the same signi?cance as in For
mula
I.
'
'
’
_
alkyl and R, represents pyridyl,
The resulting hydrazone may, if desired, be acylated when
R1 represents hydrogen. If R5 represents hydrogen, a
and to salts of such compounds”
The symbol R1 in Formula I, in addition to hydrogen, 20 group represented by R2 may be introduced into the hy
represents carboxylic acid groups of the aliphatic series,
drazone.
'
'
e.g. both lower and higher fatty acid (alkanoyl) groups
' In the ?rst stage of the process a hydrazine derivative
up to about ‘18 carbon atoms such as acetyl, propionyl,
of Formula II’ is condensed with an aldehyde or ketone
of Formula 111, preferably in an inert solvent such as
butyryl, pivaloyl, palmitoyl and the like, cycloalkanoyl
groups, preferably containing 4 to 7 carbon atoms such as
25 benzene, ethanoh'water or the like at room temperature
cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopen
or above.
tanecarbonyl, cyclohexanecarbonyl and the like, monocy
clic aromatic acyl groups, e.g. phenyl lower alkanoyl
groups such as benzoyl, phenacetyl and’ the like, as well’
as heterocyclic acyl groups, preferably nitrogen, sulfur 30
and oxygen-containing, 5-7 membered monoheterocyclic
acyl groups such as thenoyl, ,furoyl, isonicotinoyl, nico
tinoyl, picolinoyl, andvthe like. The acyl groups may
also contain substituents such as the halogens, hydroxy
and up to 4 carbon atom alkoxy and alkylmercapto
groups.
I
‘
-
»
‘R2 represents e.g. straight or branched chain lower al
kyl'grioups such as methyl, ethyl, propyl, 'isopropyl, butyl,
isobutyl and the like, phenyl loweralkyl groups such as
benzyl, and 3 to 6 carbonrcycioalkyl groups suchas cy
clopropyl, cyclobutyhcyclopentyl
cyclohexyl. ; R3,;
1
‘
If a non-acylated compound is obtained in the ?rst
stage, the hydrazone may then be acylated in the second
stage by means of an acylating agent. Reactive acid de-.
rivativesv such, as acid halides, especially chlorides, esters
or anhydrides may be used. I Symmetrical acid anhydride's
containing‘ two of the same ‘acyl groups or mixed ‘anhy
drides, for example, with lower alkanoic acids or’ car
boxylic acid monoesters, may be used.
,
> i
Freeiacids may also be used as acylating agents, In. I
that case, the condensation is preferably _,e?ected in the v
I ‘presence. of an N, ,Ni-disubstituted ,carbodiimide. The
. carbodiimide may be obtained, for ‘example, by treating
' ‘a disubstituted: urea derivative with p-toluenesulfonyl.
40
‘chloride in pyridine. In thevvcondensationyreaction the _
correspondingurea derivatives are reformed‘.v By using-“'5
similar to those represented byRz. h R4 represents the _2-, - v‘ hexylacrbodiimide, urea‘ derivatives are obtained asby- ’
productslwhich are ‘readily separated from the desired re- .
3a or .4-pyridyl radical.
45v
Representative of the compounds contemplated by
invention are the following:
'
preferred substituted carbodiirnides, cg. N,N1-dicyclo-_ iv
in addition to hydrogen, represents lower vialkyl "groups
perature
action. product.
within thereactionmay
the rangeof 0jto‘ beeffected
50F’. C.,-ppr‘eferably
[at atemt.
at
1.
,
room temperature or slightly _abpve.-.
' "
> When a starting material of Formula,“
‘ '
wherein R5, "
'
.50 ‘1 represents hydrogen’. isl'used'inr'the' ‘?rst stage, thehy: I
r: ‘ draz‘one‘ obtainedjas a resultof the condensation with]
f “the carbonyl; compoundis treated‘with an agent'supplying ,1
-' l-benzyl-2- ( 4-pyridyl-methylene) hydrazine ' ' '
1-isopropyl-2¢(a-4-pyridyl-ethylidene)hydrazine,
1-benzyl-2-(a¢4lpyridylrethylidene)hydrazineY
I
’
,the group Rzrffl‘he introduction of. this .substituent“oc'~i
‘curs upon'reaction withaii'halide of theformulal'Rgéhal
'
l-benzoyl-l-isopropyl-2-(4-pyridylémethylene)hydrazine
'
ene),-,hydr.azine
.
.,
in the presence- of an" alkali metal alcoholate, ‘preferably!
_. "1 lqform
,
, acid ‘additionj__salts
,.
a‘sodium-ethoir'ide,
v The compounds ’of Formula
.
upon reactionwith-inorganic.ororganic acids‘ and these " '
'._1 - (2 - thenoyli-1-isopropyl-Z#(dipyridyl-methylene)hy-Q
' ,
drazine.v
,salts are also within_thei"'s¢qpeaof..the invention"
' '
'1: ,- (2 - furoyl)f-1-isopropylJ2:(v47pyridyl-methylene)hy-‘I ‘salts, include mineraliacidgsalts, .e.g. hydr'ohalid tire; ‘
.GPIiiYdmCmOnde,
'. nitrate, phosphate
hydrobroinide,
and thelike,
hydroicdide,".etc.,'-su1fate;1i
and organiclsal'ts, =e'.g.=' 3 ,,
*drazine
-
>
' ‘ ;_ryoxalate,:tartrate,citratepet
e ' 'Tl1e,pr'oducts described;
1 - p vJchlorohenzoyl-1-isopropylq2-(3:pyridyl-rnethylene)
1
v
>
,
Viie are monoaminefoiridase' -' i '
‘ inhibitors. They arelusefulv in ‘ psychotherapy . for treat?"
ment of depressed ,iorvdistu'rbe'd states. Theyareals'o use;
benzen
fill in caseslofcachexia. The base or: pharmaceuticall
. accetable acidiadditiornv salt "may"? be] 'adrnini‘steredierin' ten:
.pyadyiatyudaaty;I
glfbenzoyl-l-benzyl-21(‘2-pyridylmethylene2hydrazine
idra'zi'ne
~;
g
y
__
,
a,
V
-
V ,
' suspena; ‘
‘ - ventio’nal'
‘fsionhinjectables
dosageandthelike.
forms;'suchias’tablets,
I"
, " eli-X‘
’ if
"
.-
,
,
'
, The following exarnples'are illustrativeof the inventiona '
vTerriperatures:are stated in degrees 'ce'ntigrade'. . v “I
3,073,819
3
4
Example 1
the resulting suspension was thoroughly extracted with
ether. The ether solution was washed with sodium car
bonate and sodium chloride solutions and dried. The
ether was then distilled 00?. The residue was crystallized
5.54 g. of 1-benzoyl-1-isopropylhydrazine were sus
pended in 15 ml. of 50% aqueous ethanol and treated
with a solution of 3.53 g. 4-pyridine aldehyde in 20 ml.
of 50% ethanol. The suspension was heated slowly at
from water and methanol (2:1) to obtain l-benzoyl-l
a temperature slightly under the boiling point, then per
isopropyl-Z-(4-pyridylmethylene)hydrazine, M.P. 76.5
methanol (1:1).
described in Example 2 to obtain 1-acetyl-l-isopropyl-2
(4-pyridylmethylene)hydrazine, M.P. 92.5-95.5 ‘' (crys
77.5°.
mitted to cool. After 24 hours, 100 ml. of water were
Example 3
added to the reaction mixture. The aqueous solution was
extracted with ether, the ether solution was dried, con
1 - isopropyl - 2 - (4 - pyridylmethylene)hydrazine was
centrated, and the residue was crystallized from water 10 treated with acetyl chloride according to the procedure
The l-benzoyl-1-isopropyl-2-(4-pyri
dylmethyleue)hydrazine melted at 73-75“.
The starting material, l-benzoyl-l-isopropylhydrazine,
was prepared as follows:
To a solution of 65.6 g. of anhydrous sodium acetate 15
in 1 liter of 50% aqueous ethanol were added 88 g. of
isopropylhydrazine hydrochloride and then 84.8 g. of
tallized from petroleum ether, boiling range 80-105 °).
Example 4
1 - isopropyl - 2 - (4 - pyridylmethylene)hydrazine was
acylated with p-chlorobenzoyl chloride according to the
procedure described in Example 2 to obtain l-(4-chloro
benzaldehyde. The solution which was clear at ?rst soon
became turbid. The reaction mixture was agitated for
benzoyl) - 1 - isoproyl-2-(4-pyridylrnethylene)hydrazine,
1 hour, and after standing for a short period of time was 20 M.P. 85-875” (crystallized from petroleum ether, boil
then extracted with ether. The ether extract was washed
ing range 80-105").
with sodium bicarbonate solution and with water, then
Example 5
dried and concentrated. The oily residue was distilled
1 - isopropyl - 2 - (4 - pyridylmethylene)hydrazine was
under high vacuum to obtain 1-isopropyl-Z-benzylidene
25 acylated with Z-thenoyl chloride according to the pro
hydrazine, B.P. 80~84°/0.07 mm.
cedure described in Example 2 to obtain 1-(2-thenoy1)-l
A solution or” 14 g. of benzoyl chloride in 25 ml. of ab
isopropyl-2-(4-pyridylmethylene)hydrazine which was re
solute benzene was dropped into a solution containing
peatedly precipitated from ethanol‘water and then crys
16.2 g. of 1-isopropyl-2-benzylidenehydrazine in 100 ml.
tallized from petroleum ether, M.P. 79.5—81°.
of absolute benzene and 50 ml. of absolute pyridine with
the exclusion of moisture. The mixture was heated at 30
Example 6
80° for about 2 hours and then concentrated at a tem
perature of about 40° and a pressure of about 15 mm.
1 - isopropyl - 2 . (4 - pyridylmethylene)hydrazine was
acylated with isonicotinoyl chloride hydrochloride by the
The residue was digested with a large quantity of water
and the partially solidi?ed product was dried on clay.’
The product, l-benzoyl-1-isopropyl-2-benzylidenehydra
procedure of Example 2 to obtain 1-isonicotinoyl-1~iso
35
zine, was crystallized from methanol-water (2:1), M.P.
propyl-Z-(4-pyridyl-methylene) hydrazine, M.P. 108
110° (crystallized from‘ petroleum ether-ethyl acetate,
2: l ) .
75.5-77".
A suspension of 53.2 g‘. of 1-benzoyl-l-isopropyl-Z-ben
Example 7
zylidenehydrazine in 300 ml. of water, 100 ml. of
A solution of 26.1.g. of 2-furoyl chloride in 50 ml. of
ethanol and 10 ml. of glacial acetic acid and 12 g. of 80% 40 absolute benzene was dropped with stirring and exclu
hydrazine hydrate were boiled under re?ux for 60 hours,
sion of moisture into a solution of 32.6 g. of 1~isopropyl
then cooled’with ice and ?nally treated with 67 ml. of 3 N
2-(4-pyridylmethylene)hydrazine in 200 ml. of absolute
hydrochloric acid. The precipitated benzalazine was ?l
benzene and 100 ml. of absolute pyridine. The mixture
tered off under suction. The aqueous ?ltrate was then
treated with 50 ml. of concentrated ammonia solution.
was gently boiled for 11/2 hours and cencentrated as
much as possible at 40° under water vacuum. The resi
due was taken up in a small amount of ethanol‘and stirred
This was thenconcentrated under water vacuum at 40
50° and the residue was taken up in chloroform. The
with a'large amount of ice‘water. The precipitate which
formed
was ?ltered under suction, dissolved in ethanol
tered, and the ?ltrate was evaporated to dryness. The
and reprecipitated by the addition of water, then ?nally
residue was dried over sulfuric acid for 24 hours in vacuo 50 crystallized from water-ethanol (2:1). The 1-2~furoyl)
and crystallized from low boiling petroleum ether to ob
l-isopropyl-Z-(4-pyridylmethylene)hydrazine melted at
resulting suspension was dried with sodium sulfate, ?l
tain l-benzoylal-isopropylhydrazine, M.P.. 56—58°.
Example 2
84-85 °..
.
.
‘ Example 8
1 - isopropyl r 2 - (4 7 pyridylmethylene)hydrazine was
V A solution of 82 g. of anhydrous acetate in 220 ml. of 55
acylated with palmitoyl chloride by the procedure of Ex
water was added to a solution of 110.5 ‘g. of-isopropylhy
drazine hydrochloride in 150 ml. of water.- 101.7 g. of
4-pyridine aldehyde 'were added dropwise, After stir
ring for 4 hours at a moderately elevated. temperature,
ample 7 to 1 obtain 1-palmitoyl—1-isoproyl-2-(4-pyridyl
Vmethylene)hydrazine which was r'epeatedlytcrystallized
from‘ a water-ethanol mixture'and melted at 50-54°.
the mixture was permitted to stand for several hours and 60
then extracted with ether.
The ether extract was washed ‘ ‘
with‘sodium ‘bicarbonate and sodium chloride solution,
M.P. 61-65";
To a solution of 98 of ‘1-isopropyl-2~(4-pyridylmeth-‘
ylene) hydrazine in 600 ml. of absolute benzene and 300‘
ml. of absolute pyridine was added’dropwise a solution of
84.3 g. of benzoyl chloride in 150 ml. of absolute benzene"
overa period 'of. 1 hour with stirring with the exclusion
of moisture.- The mixture was then heated to'boiling -
for about 11/: hours. Thepyridine and benzene solvents
present were distilled oif under water vacuum at 40°.‘
‘
1. A member
selected from_
V
compounds of the formula .
dried and concentrated. ‘The residue was puri?ed by dis
tillation under a high vacuum to obtain} 1-isopropyl-2~(4
pyridylmethylene)hydrazine, B.P. l'10~l13°/0.1 mm.,
We claim:
.
65
‘
it:
the group consisting of
‘
t
‘ Ilia ‘.
‘nr-N- =o-R.
wherein R1 represents a member of the group consist-.
ing‘v of alkanoyl of up ‘to 18 carbon atoms, 4 ‘to“7 ‘
carbon atom‘. cycloalkanoyl,‘ phenyl ‘lower alkanoyl,
thenoyl and‘ furoyl, R2 represents amember of the
‘ ‘group consisting. of lower alkyl, phenyl lower alkyl‘
and 3v to 6 carbon c'ycloalkyl, R3 represents a mem- .
ber of. the group consisting of hydrogen and lower
alkyl, and _R.;_repres‘e_uts pyridyl, v
narmaceutically
The residue was taken up ‘in a large amountjof‘water and 75 said compounds.
. and ‘p
acceptable acid.‘ addition salts of“,
3,073,819
5
O 6
. A compound of the formula
7. A compound of the formula
lower alkyl
0
Q0 O—N—N=OH-pyridyl
CFFKOHM ’
o O-—N——N=OH@
5
. A compound of the formula
omoum
8. A compound of the formula
. A compound of the formula
cfmc?m
10
-—\\N
____
Refetences Cited in the ?le of this patent
OH3O°_N_1‘=CH_<__ /
FOREIGN PATENTS
. A compound of the formula
CHwHm
IT
C1‘®C°_I“N=OH*<
1..
a
187,112
724,699
Austria ______________ __ Oct. 25, 1956
Great Britain _________ __ Feb. 23, 1955
\
729,348
Great Britain __________ __ May 4, 1955
\N/
729,967
Great Britain _____ __>____ May 11, 1955
. A compound of the formula
CH(OHa)z
S
OTHER REFERENCES
20
Wiley et al.: I. of Org. Chem, volume 22, pages
t
/ FCMLLMCHQ
2044 (1957),
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