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Патент USA US3100780

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United States Patent Of?Ce
3,100,775
Patented Aug. 13, 1963
2
1
at least 1 and as many as several —.O-lower alkyl group
-
i
3 100 71s
ings replace hydrogen. Still ‘further, Ph represents—~in
‘ >
a-PHENYHPYRIDYI: o’R PIPERIDYL)ALKYL ,
particular instances-—a carboxyphenyl, nitrophenyl, or
ESTERS 0F (CHLORO 0R LOWER ALKOXY)- ,
‘BENZOIC ACIDS AND CONGENERS
‘
di(lower alkyl)phenyl radical.
‘
Equivalent to the basic amines of this invention for
the purposes‘ described are non-toxic acid addition and
‘Kurt J. Rorig, Glenview, 111., assi‘gnor to G. ‘D. ,Sear‘le &
(10., Chicago, 111., a corporation of Delaware
N0 Drawing. Filed Apr. 1, 1959,-Ser. No. 803,371‘ .
16 Claims. (Cl. 260-295)
quaternary ammonium salts thereof, the compositions of
which may be symbolized by
This invention relates to aryl(cyclic amino) alkyl esters
of substituted ‘aromatic acids, and to processes for the
manufacture thereof. ‘More ‘particularly, this invention
relates to compounds of the formula ‘
wherein Het, Ar, R, Alk, Alk’, .n, m, and Ph have the
meanings hereinbefore assigned; Q is selected from among
15
hydrogen andlower alkyl, hydroxy?ower'alkyl), and
lower alkenyl radicals, as also such aralkyl radicals as
benzyl, phenethyl, and naphthylmethyl; T is 1 equivalent
of an anion-e-for example, chloride, bromide, iodide,
wherein He‘t designates a nitrogenous heterocyclic radical
optionally alk'ylated, aralkylated, or N-oxygenated; Ar
nitrate, phosphate, sulfate, sulfamate, methyl sulfate, ethyl
benzenesulfonate, toluenesulfonate, acetate,
lactate, succinate, malate; maleate, tartrate, citrate,
‘designates hydrogen or ‘an aromatic carbocyclic radical 20 sulfate,
optionally alkylated, alkoxylated,_or halogenated; R desig- ‘ ‘
nates hydrogen or a phenyl or alkyl ‘radical;‘A1k“and
Alk’ each designate a lower alkylene or alkenylene radical;
n and In each designate Q or‘the positive integer l; and
.gluconate, ascorbate, benzoate, cinnamate, or the like-l
-which, in combination with the cationic portion of a salt
aforesaid, is neither pharmacologically nor otherwise
Ph designates a halogenated, alkoxylated, carboxylated, 25 undesirable inttpharmaceutical dosage; and y is 1 except
carboalkoxylated, nitrated, or dialkylaminated phenyl
"where Ph comprises an amino radical, in which case y is
radical.‘
‘
.
‘either-‘l or 2.
‘Among the cyclic amino radicals represented by Het in
The application for Letters Patent securing the inven
the foregoing formula are pyridyl, piperidyl, pyrrolidyl, 30 tion herein described and claimed is a continuation-in-part
quinolyl, and tetrahydroquinolyl groupings. Of these‘ ‘ of applicant’s prior‘copending application, Serial No.
groupings, those wherein the imino function is present
can, in any given instance, be substituted on the nitrogen
atom by oxygen or especially a lower alkyl‘or aralkyl
radical. The lower alkyl radicals contemplated include
689,273, ?led October 10, 1957, and‘ now forfeited.
-:The compounds hereindisclosed are useful because
“of: their valuable pharmacological properties. Thus, for
example, the subject compositions are selective CNS
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, ‘
tert-butyl, pentyl, isopeutyl, tert-pentyl, neopentyl, hexyl,
isohexyl, heptyl, octyl, and like CSHZSH radicals wherein
depressant, anorectic, spasmolytic, and fungicidal agents;
‘ ‘and especially theitrialkoxybenzoates‘ of this invention
‘are characterized by an unexpectedly potent and diverse
s is an integer amounting ‘to less than 9. Illustrative
of the aralkyl radicals occasionally *present‘are such as 40
tranquilizing effect on the ‘central ‘nervous system.
The compounds to which this inventionmelates are
Ar in the structural formula, these are principally phenyl
or naphthyl‘ groupings which can comprise,‘ in place of
nuclear hydrogen, 1 or more straight- or branched-‘chain 45
alkyl or alkoxy- radicals, ‘or halogen, or combinationsof
Ar-(‘l-Alkn-OH
l.
.benzyl and phenethyl' groupings. ‘
Ypre'parable by a variety‘ of methods, but the preferred
As‘ to thetaromatic carbocyclic radicals designated by 5‘ process proceeds via contact of a carbinol of the formula
these substituents, the alkyl and alkoxy substituents ordi- . "
Het
with an anhydride of the formula
narily being of lower order, which is to say embracive
of fewer than 9 carbon atoms.
The lower alkylene and alkenylene radicals represented
by Alk and Alk' in the formula are. bivalent acyclic
straight- or.branched-chainhydrocarbon moieties, satu
rated or containing not more than 1 double bond, and
typi?ed by methylenejethylene, vinylene, trimethylene,
propylene, 1,3-propenylene, tetramethylene, .Z-methyl-l,
S-propenylene, and 2,2-dimethyl-LES-propylene groupings.
It will be recognized that when n ‘or min the formula
is 0, the apposed term drops out; and when both It and
m are 0, the compounds referred to can be depicted
'
55
Het, Ar, R,‘Alk, Alk', n, m, and Ph being selected
‘from the previously defined groups of radicals in accord
ance with the particular product sought to be prepared.
An inerthydrocarbon solvent may be used, or not,‘ as
60 desired, except that where a tertiary hydroxyl is to be
esteri?ed, both the solvent and catalytic amounts of,
for example, mineral acid or an acid salt such as zinc
chloride, are advisably present. Solvents‘ commonly but,
in thecase of at least alcohols, unessentially employed
Het, Ar, R, and Ph being de?ned as before.
Pb in the formula unexceptionably depicts a substituted 65 are benzene,- toluene, xylene, and the like; and a variety
of catalysts may be incorporated ad libitum (with the
phenyl radical, as aforesaid, but the nature and number
exception as to, tertiary ‘carbinols above noted), for
of the substituent groupings can vary within rather wide
instance caustic,'alkali metal alkoxide, pyridine orother
limits. Thus, Ph represents a halophenyl radical—as
for example, chlorophenyl, ‘dichlorophenyl, trichloro
tertiary amine, sodium acetate, etc. Water is‘ excluded‘.
phenyl, and the 1ike—an-d, alternatively, it represents an
alkoxyphenyl radical-particularly, a (lower alkoxy)
phenyl radical, which is to say a phenyl radical wherein
The process is generally carried out at elevated tempera
tures in comparatively short periods oftimge, 2-5 hours
' at 125-1 60? being representative.
In addition to its more
3,100,775
3
4
,
.
general, applicability, this preferred procedure‘ leads to
salt may be smoothly effected in butanone solution at
products of greater purity and in higher yield.
70°, the reaction time being approximately 1 hour.
Other means of manufacturing the claimed composi
tions include (1) transesteri?cation in hot hydrocarbon
' The following examplesdescribe in detail certain of
the compounds illustrative of the present invention and
methods which have been devised for their manufacture.
1solvent of the carbinol '
However, the invention is not to be construed as limited
thereby, either in spirit or in scope, since it will be
apparent to those skilled in the art of organic synthesis
that many modi?cations, both of materials ‘and of
I with, ordinarily, a lower alkanoate of the acid
10
methods, may be practicedwithout departing ‘from the
purpose and intent of this disclosure. In the ‘examples
hereinafter detailed, temperatures are given in degrees
under the in?uence of an alkali metal alkoxide, alcoholic
centigrade, pressures in millimeters of mercury or pounds
caustic, or a comparably basic substance, or an acid such
per square inch (psi), and relative amounts of materials
as hydrogen chloride; (2) interaction of the carbinol 15. in parts by weight, except as otherwise noted.
I
'
aforesaid with'an acid chloride
Example 1 '
,
Ph-Alkm,-C:0Cl
ot-Phenyl-4-pyridinem‘ethyl o-chlWobenzoizta-A mix
generally without solvent, but alternatively in benzene,
ture of 25 parts :of qt-phenyl-4-pyridinemethanol and 60
toluene, xylene, or the like, and with anhydrous caustic, 20 parts of o-chlorobenzoyl chloride is heated with agitation
.alkali, or alkaline carbonate, pyridine or other tertiary
at 130-150° for 11 hours under-nitrogen. The mixture
base, or sodium hydride optionally present as‘ an acid
is then cooled to about 30°, at which point an excess of
acceptor; and (3) interaction of the c‘arbinol aforesaid
1aqueous 10% caustic is introduced. The resulting mix
with an acid
.
'
.
ture is thoroughly extracted with ether, and the ether ex
Ph--Alkm—COOH
25 tract in turn is extracted with dilute mur-iatic acid. The
acid extract is made basic with lye, the resulting precipitate
in the presence of pyridine or equivalent solvent and'
of aaphenyl-4-pyridineme1thyl o-chlorobenzoate being
'mediated by a hydrocarbonsulfonyl chloride, as for exam
taken'up in ether. 'Ilhis‘ether extract is dried over anhy
ple, benzenesulfonyl chloride, toluenesulfonyl chloride,
drous potassium ‘carbonate, ?ltered, and stripped of sol
etc. The preparation from carbinol and acid chloride
vent by evaporation, fol-lowing which the residual oil is
usually requires from 3 to 24 hours at temperatures rang
distilled in vacuo. The pale yellow fraction coming over
ing from 35 to 165°, -1 to 6 hours at 100-140“ being
at l75-l9=5.° ‘under 0.15 mm. pressure is OL-P'heHYI-4-PYI
preferred where no Solvent or catalyst is employed.
idinem'ethyl o~chlorobenzoate, of the formula '
.The claimed N-alkyl and N-aralkyl compositions are
.derived from 4-benzoylpyridine, which is converted to the
35
appropriate pyridinium compound by quaternization with
, a selected alkyl or aralkyl'halide, the resultant pyridinium
compound being catalytically hydrogenated tothe cor
responding piperidinealkanol, and this material thereupon
O
being esteri?ed by one of .the procedures hereinbefore set
forth. As variations on the foregoing preparative pro-_ 4.0
I
Cl
cedures, the N-oxido‘ compounds hereof can be obtained
Example 2 V
by the action of an appropriate peracid on an ester of
choice, as illustrated by'Example 21 hereinafter; and the
a - Phenyl-4-pyridineme'zhyl p-chlorobenzoate.-Using
alkoxycarbonyl esters of the invention can be derived
essentially the technique set forth in Example 1,‘ but sub
from corresponding‘carboxy compounds by esteri?cation 45 stituting 60 parts of p-chlorobenzoyl chloride :for the o
' catalyzed with mineral acid (see Example 32).
Com~
chlorobenzoyl chloride prescribed therein, one obtains
mercially unavailable carbinol intermediates wherein the
asphenyl-ildpyridinemethyl p-chlorobenzoate as a solid
melting at approximately 68-69 ° when recrystallized from
phenyl radical‘ is alkylated or halogenated can ‘be syn-, 1
thesized by combining the corresponding Grignard
reagents
‘
50
_
petroleum ether. The product has the formula
N
‘
.
Ph-,-Mg—X
,with a suitable amino aldehyde in ethereal medium and, ,
hydrolyzing the magnesium adduct so produced in aque
ous acid or the equivalent.
Conversion of the amine bases of this invention to
equivalent acid addition salts isaccomplished by simple
Example 3
admixture of these compounds with any of various
inorganic or strong organic acids, the anion portion of
a ‘ - Phenyl-2-pyridinenrethylr p-chlarobenzoata-Using
which conforms to T as hereinabove de?ned.
‘ essentially the technique set forth in Example 1, but sub
The quaternary ammonium compounds comprehended
stituting for the u-phenyl-4-pyridinemethanol and o-chlo
robenzoyl chloride therein 37 parts of a-phenyI-Z-pyr
idinemethanol land ‘60 parts of p-chlorobenzoyl chloride,
by‘ this ‘invention are those derived by contacting a
claimed'base with an organic ester of the formula
respectively, one obtains a-phenyI-Z-pyIidinemethyl p
Q——T
.
a
Q and T being limited by the meanings hereinbefore
assigned, and it being additionally provided that Q is
not hydrogen. Quaterniz-ation takes place in the tem
65 chlorobenzoate as a colorless sol-id ‘melting at approxi
' peraturerange between 45 and 100°, using an inert
solvent such as chloroform, acetone, butanone, methanol, 70
butanol, or the like as reaction medium. Quaternization
is ordinarily, completed in from 1 to 48 hours and is
' generally carried out in a closed system if a lower alkyl
‘halide—‘such as methyl chloride-is one of the reagents.
Using methyl bromide,vthe manufacture of quaternary
mately 7 6-77” when recrystallized from: petroleum ether.
The product has the formula .
3,100,775 -
Example 4
A. 3,4,5-lrichlor0benzoz'c anhydride.-A solution con
sisting of 70 parts of thionyl chloride and 25 parts of
3,4,5striohlorobenzoic acid is heated at. the boilingpoint
-
under re?ux for 3 hours. ‘Excess thionyl chloride is then
removed by vacuum distillation, 'and-the'residual 3,4,5
trichlorobenzoyl chloride-is taken up in- 100 ‘parts of-an
hydrous ether. To this solution is added 25 parts of13‘,4,5—
trichlorobenzoiclacid dissolved in 3 OOparts er anhydrous
v
t
..
v
l |
t
.
Example‘?
_
‘ l a‘ ‘ - iPh‘enyil~4-pyridinemethyl p¥eth0xybenzoate.-—Using
essentially the technique setforth inlExample l, but sub,
ether, followed cautiously and with agitation at room tem
stituting 60parts of p-ethoxybenzoyl chloride for the 0
peratures by 15 parts of pyridine. The desired 3,4,5-tri
chlorobenzoyl chloride therein, and cutting the reaction
time to3 hours, one ‘obtains w-phenyl-‘l-pyridinernethyl p
chlorobenzoic anhydride precipitates ‘almost instantly ‘ and
is isolated by ?ltration. Digested with saturated aqueous
sodium bicarbonate and then consecutively washed with
ethoxybenzoate, which =boils in therange 195-200° at 0.3
‘mm. pressure. The ‘product‘solidi?es on ‘standing l. and
water, methanol, and ether, the colorless product melts 15 mama 96-99". It has the formula
in the range 206-210".
‘
B. a - Phenyl-4-pyridinemethyl 3,4,5-trichl0r0benz0
ate.—A mixture of 21 parts of 3,4,5-trichl0robenzoic an
hydride, 9 ‘parts of u-phenyl-4-pyridinemethanol, and 450
parts of xylene is heated to boiling and sufficient solvent 20
distilled off to remove‘anyitraces of moisture present.
Boiling is then maintained under re?ux for approximately
6 hours, at which point the reaction mixture is ?ltered,
.
i ‘ Example. 8
and the ?ltrate ‘thereupon washed with aqueous alkali. 25
m-Phenyl-4-pyridinemethyl lp-methoxyphenylac'etate.—
Solvent is evaporated under reduced pressures,‘ ‘afford
Using essentiallyth‘e technique set iforthin Example 5,
‘ing as the residue a-phenyl-4-pyridinemethyl 3,4,5-tri
but substituting 120 parts of p-methoxyphenylacetyl.ch10:
ohlorobenzoate. The product has the formula ‘
ride for the o-methoxybenzoyl chloride therein, one Oh
tains a~phenyl-4-pyridinemethyl p-methoxyphenylacetate,
boiling in the-range 185-215 ° ‘under 0.4 mm. pressure.
The product has the formula.
‘
l
.
35
l
lzydrochloride.-An anhydrous ether solution of zit-phenyl
4-pyridinemethyl 3,4,5-trichlorobenzoate is acidi?ed with
a slight excess of hydrogen chloride dissolved in absolute
drochloride 50 produced melts at 205-207".
‘
Example 5
i
‘
a-phenyl-4-py1'idinemethyl 3,4-dimethoxybenzoate, which
45 is converted to thehydrochloride as detailed in Example
4C. U a-Phenyl-4-pyridinemethyl -3,4-dimethoxybenzoate
hydrochloride melts at 210-212“ and has the formula
essentially the technique set forth in Example, 1, but sub,
stituting ‘for the 25 parts of a-phenyl-él-pyr-i'dinemethanol
and 60 parts of o-chlorobenzoyl chloride therein 45ipar-ts
of a-phenyl-tpyridinemethanol and approximately 73
c
cutting the reaction time to _2 hours, there is obtained zx- , _
phenyl-4-pyridinemethyl roemethoxybenzoate, boiling in
the range 180-215 ° under 0.8
’
"
f
I
e011;
Q-hno-ii-Q-oom
i
a‘
.HCI
Example 10
pressure.‘ The prod
uct has the formula
/N
0
parts of o-methoxybenzoyl chloride, respectively, and
.
A. a - Phenyl-4-pyridinemethyl 3,4,5-trimeth0xybenz0
ate hydrochloride.—A mixture of 45 parts of methyl 3,4,5 a
‘
O
1‘
0110-0-
Q'
i
4B, but substituting 17 parts of veratric anhydride for
the 3,4,5-trichlorobenzoic .anhyd-ride therein, one obtains
u-Phenyl-4-pyridinemethyl 0-meth0xybenz0ate.-Using
/N‘
i
a-Phenyl-4-pyridinemethyl 3,4-dimeth0xybenz0ate hy
drochl0ride.—Using essentiallythe technique of Example
2-propanol. The precipitate thrown down is recovered
on a ?lter, washed thereon with ether, and ?nally dried
in air. crystallized ‘from a mixture of ethanol and ether, 4
the a-phenyl-4-pyridinemethyl 3,4,5-trichlorobenzoate hy
O
@ono-iiorn-Q-oom
Example 9
C. 06 - Phenyl-4-pyridinem‘ethyl 3,4,5-trichl0robenzoate
"iQ
I
‘
$GH3
‘
‘60
a
'
4.
trimethoxybenzoate, 37 parts of a-iphenyl-4-pyridinemetha
1101, and 2900 parts‘ of anhydrous xylene in the presence of
excess sodium is concentrated to 1% volume bydistillation
under a nitrogen atmosphere during j approximately 7
hours. From the reaction mixture, at room temperatures,
‘
is ?ltered a brown lgranular solid. 'Ilhe?ltrate is diluted
‘
Example 6
with 350 parts of anhydrous ‘ether and then made acid
with abare excess of hydrogenchloride dissolved in ab
‘
essentially the technique set forth in Example 5, but sub
stituting 73 parts of phmethoxybenzoyl chloride ‘for the
o-methoxybenzoyl chloride called for therein,‘ there is ob
solute, 2-propano1. The white precipitate which is thrown
down is recoveredon a ?lter, washed thereon with ether,
next washed‘ by suspension‘ in cold water, and ?nally dried
inair at approxiniatelyjSOK This material‘ is a-phenyl-4-.
tained at - pheuyl-4-pyridinen1ethyl p-methoxybenzoate,
which boils in the range 185-205 ° at 0.3 mm. pressure.
crystallizable from a mixture of ethanol. and anhydrous
a-Plzenyl-4-pyridinemethyl p-methoxybenzoate.-Using
pyridinemethyl ‘ . 3,4,5 -.trimethoxybenzoate . hydrochloride,
ether, and which melts at approximately 219-220°. The
The product solidi?es on standing and melts at 94-96".
It has the ‘formula
.
75
product has‘ the vformula
‘ '
‘
3,100,775
8
water mixture which is extracted with ether. The ether
extract is dried over anhydrous sodium sulfate, treated
. /,N.
I
with decolorizing charcoal, and ?nally evaporated-to a
OCH:
'viscous dark brown oil. Distillation of the oil at 0.3 mm.
pressure’ and 160° vapor temperature serves to remove
4-benzoylpyridine present as a hy-product. The residue is
taken up in hot absolute ethanol, and the resultant solu
, ®ono-o-®—oom .1101
'
I
.OCHa
tion is made acid with hydrogen chloride dissolved in
a - Phenyle4-pyrjidinentethyl 3,4,5-trirrtethoxybenz0
Lll€.-—;AI1> aqueous solution of a-phenyl-4~pyridinemethyl
’3,4,5-trin1ethoxybenzoate hydrochloride is made alkaline.
absolute Z-propanol. Upon addition of anhydrous ether,
10 a granular ivory precipitate is thrown down.
This ma
terial‘ is a-phenyl-4-pyrid-inemetliyl 3,4,5-triethoxybenzo
ate hydrochloride, the melting point of whichis202-204".
‘ vExtraction of the resultant mixture with ether and drying
of the ether extract'over anhydrous potassium carbonate,
The product has the formula
' followed vbyevaporation of the solvent, affords a-phenyl- .
'
4-pyridinemethyl 3,4,5-trimethoxybenzoate as -a colorless
oil which crystallizes to awaxen solid on standing. The 15
water-free product melts at approximately 118-120°.
C. a-Phenyl-4-pyridinemethyl 3,4,5-trimethoxybenzo
ate maleate.-Approxirnately 3 parts of inaleic acid and
10 parts of a-phenyl-4-pyridineme-thyl 3,4,5-trimejthoxy~
henzoate are ‘dissolved in 120 parts of 2-propanol by
heating. The resultant solution is chilled and seeded
(BCzHs -
Example 14
with a crystal of pure,a-phenyl-4pyridinemethyl 3,4,5
A. oc-Phenyl-Z-pyridinemethyl 3,4’-,5-trimethoxybonzo
trimethoxybenzoate maleate obtained by diluting a sample
of the hot solution with cyclohex-ane and maintaining 25 ate.-—'A mixture of .20 parts of 3,4,S-trimethoxyb0nzoic
anhydride, 9 parts of a-phenyl-Z-pyridinemethanol, and
1 this mixture inthe'co‘ld. Copious precipitation of the
450 parts of xylene is heated to boiling and su?‘icient sol
maleate occurs. The desired salt is isolated by ?ltration.
It melts at 117-1 19° with gas evolution.
i
‘
vent distilled off to remove any traces of moisture present.
'
Boiling is then maintained under ‘re?ux for approximately
6 hours, at which point the reaction mixture is ?ltered, and
Example 11 '
a-Phenyl-4-pyridinemethyl
2,3,4-trimethoxybenzoate
30
, the ?ltrate thereupon washed with aqueous alkali.
hydrochloride.—Using the technique of Example 10A, but
substituting 45 parts of methyl 2,3,4~trirnethoxybenzoate
for the methyl 3,4,5-trimethoxybenzoate therein, there is
obtained a-phenyl-4-pyridinemethyl 2,3,4-trimethoxyben
zoate hydrochloride, of the formula
/N7I
.
(FCHa OCH:
.
r!)
.
.
Sol
vent is evaporated under reduced pressures, a?ording a
solid residue which, recrystallized from 2-propano1, melts
at 115-116‘. The pure white material thus obtained is
a-phenyI-Z-pyridinemethyl 3,4,5-trimethoxybenzoate, of
35
the formula
40
N
v
I
00113.
O
/ TCHO-lé-Q-eOCHa
l
OOH3
.1301
Example 12
45
B. a-Phenyl-2-pyridinemethyl 3,4,5-trimethoxybenzoate
hydrochloride-An anhydrous ether solution of “phenyl
' a-Pherjlyl-4-pyridinemethyl 2,4,6-trimethoxybenzoa‘te hy
drochloride.—-Using the technique of Example 10A, but
substituting 45 parts of methyl 2,4,6-trimethoxybenzoate
2-pyridinemethyl 3,4,5-trime'thoxybenzoate is acidi?ed with
a slight excess of hydrogen chloride dissolved in absolute
for the methyl 3,4,5-trimethoxybenzoate therein, there is ’
2-propanol. The precipitate thrown down is recovered
obtained a-phenyl-4-pyridinemethyl 2,4,6-trimethoxyben
on a ?lter, washed thereon with ether, and ?nally dried
in air.- crystallized from a mixture of ethanol and other,
zoate hydrochloride, of the formula
/N
the a-phenyl-2-pyridinemethyl 3,4,5-trimethoxybenzoate
hydrochloride so produced melts at 172,5—174°.
I
00113
- it’
®~CHO—G—
~OCH3
‘
l
Example‘ 15
55
a-'Phenyl - 3 - pyridineme'thyl 3,4,5-frimeth0xybenz0ate
.1101
OCH3
Example 13
a-Phenyl-il-pyridz'nemethyl 3,4,5-trieth0xybenzoate hy
hydrochloride-Using essentially the technique set forth
in Example 14A, ‘but substituting 10 parts of a-phenyl-3
pyridinemethanol for the a-phenyl-2-pyridinemethanol
60
prescribed therein, one obtains a-phenyl-3~pyridinemethyl
3,4,5-tIimethoxy-benzoate which, converted to the corre
benzoyl chloride, 37 parts of a-phenyl-4-pyridinernethanol,
sponding hydrochloric acid addition salt as detailed in
‘Example 14B and recrystallized from ethanol, affords
re?ux‘ in an atmosphere of nitrogen for 22 hours." The
has the formula
dr0chloride.—A mixture of 55 parts of 3,4,5-triethoxy
.20 parts of triethylamine, ‘and 1350' parts of anhydrous 65 colorless a-phenyl-3-pyridinemethyl 3,4,5-trimethoxyben
zoate hydrochloride melting at 192—194°. The product
xylene is heated with agitation at the boiling point under
-
mixture is then cooled, freed of precipitate by ?ltration,
and made acid with hydrogen chloride dissolved in an
hydrous 2~propanoL A second precipitate is thrown 70'
down, this material likewise being removed by ?ltration.
The ?ltrate from this operation is stripped of solvent by
evaporation, whereupon the residue is taken up in dilute
aqueous muriatic acid. The resultant solution is washed
, with ether and then made alkaline, producing an oil-and 75
OCHa
l
OCH;
.1161
3,100,775
10
one obtains a-phenyl-4-pyridinernethyl 3,4,5-trimethoxy
cinnamate hydrochloride, which melts at approximately
ZOO-201° (with gas evolution). The product has the
Example 16
,3-Phenyl-4-pyridineethyl 3,4,5 - trimethoxybenzoate.-—
Using the technique of Example 14A, but substituting 10
parts of /8-pheny1-4»pyridineethano1 [prepared according
{formula
to’Tschitschibabin, J. pr-akt. Chem, 69, ‘315] for the a
/N
phenyl-Z-pyridinemethanol prescribed therein, one obtains
‘?~phenyl-4-pyridineethyl 3,4,5-trimethoxybenzoate,‘ which
has the formula
_
‘
‘
i
'10
/N
|
i
‘l
@onomo-o
.
0am
I
15
0 0113
0 on;
®CHO~C CH=GH—
0 CH5
I
.
‘u’
.
0on3
.
I
CH3
Example 21
a-Phenyl-4-pyridinemethyl 3,4,5 -trimeth0xybenz0ate N
oxide-A mixture of 100 parts of a-phenyl-4-pyridine—
‘methyl 3,4,5-trimethoxybenzoate with 5 6 parts of perben
Example 1 7
zoic acid dissolved in 400 parts of benzene, protected
'y-Phenyl-4-pyridinepr0pyl 3,4,5-trimeth0xybenz0ate.—
Using essentially the technique of Example 14A, but sub
stituting 11 parts of 'y-phenyl-4~pyridinepropano1 for the
20
from light, is maintained .at room temperatures for 24
‘hours. The resulting solution is washed free of organic
‘acids with aqueous 5% caustic, dried over anhydrous
a-phenylQ-pyridinemethanol prescribed therein, one ob
potassium carbonate, and stripped of solvent by vacuum
'tains 'y-phenyl-‘4-pyridinepropyl 3,4,S-trirnethoxybenzoate,
‘distillation.
The pale yellow viscous oil which remains
of the formula
is the desired a-phenyl-4-pyridinemethyl 3,4,5-‘trirnethoxy~
2 Cil
benzoate N-oxide, which is characterized by an absorp
tlon band in the infrared spectrum at 6.72,a. The prod
not has the formula
OCHs
‘l
®-oaomomo—c—
com
'
‘
o
30
1‘
on, ‘
0on3
Example 1 8
a-Phenyl-4-pyridinemezhyl 3,4,5-trimethoxyphenylace~
tate hydrochloride-Using the technique of Example
10A, but substituting 47 parts of methyl 3,4,5-trimethoxy
phenylacetate for the methyl 3,4,5-trimethoxybenzoate
therein, one obtains a-phenyl-4-pyridinemethyl 3,4,5-tri
methoxyphenylacetate hydrochloride, melting at approxi
mately 182° (with gas evolution). The product has the
formula
iN
‘
fl)
'
|
‘l
Q-ono-o'
OOH:
Example 22 .5011.
A. a-m‘Tolyl-4-pyridinemethanoL-To a suspension of
243'parts of magnesium in 140 parts of anhydrous ether
is added, with agitatioma solution of 171 parts of m
‘bromotoluene in 560 parts of anhydrous ether. The
45 resultant mixture is heated at the boiling point under
‘reflux for one hour, whereupon a solution of 107 parts
0 cm
|
®_ono-o CHz-—®—O0Ha
1
.HCl
0 CH3
of pyridine-4-aldehyde in 140 parts of anhydrous ether
is cautiously introduced. Boiling under re?ux is main
tained overnight, after which the reaction mixture is de
50 composed with saturated aqueous ammonium chloride.
Extraction with dilute aqueous muriatic acid serves to
remove the desired amino alcohol in the form of the
Example 19
acid salt, which is converted to the free
a-Phenyl-ll-pyridinemethyl 3-(3,4,5-trimethoxyphenyl)~ _' hydrochloric
base by alkalization with potassium carbonate. The a-m
pr0pi0nate.-—Using essentially the, technique set forth in
thus thrown down is puri?ed by
Example 1,- but substituting 52 parts of 3-(3,4,5-trimeth 55 tolyl-4-pyridinernethanol
recrystallization
fnom
benzene.
The product melts at
oxyphenyl)propionyl chloride [prepared ‘according to
147-150”.
Slotta and Heller, Ber., 63, 3042 (1930)], for the o—
B. a é- m - Tolyl - 4 - pyridinemethyl 3,4,5 - trimeth
chlorobenzoyl chloride prescribed therein, one; obtains
oxybenzoate ‘hydrochloride-A mixture of 20 parts of
a-phenyl - 4 - pyridinemethyl 3-(3,4,5-trirnethoxyphenyl) 60 a-m-tolyl-4-pyridinemethanol and 28 parts of 3,4,5-‘tri
propionate, of the formula
methoxybenzoyl chloride is heated with agitation at 130—
140° [for 31/2 hours‘under nitrogen. The mixture is then
cooled to about 60°, at which point an excess of aqueous
OCH:
‘l
®GHO~O omom-
-0 on:
I
OCHa
Example 20
a-Phenyl-ll-pyridinemethyl 3,4,5 - trimethoxyainnamate
10% caustic is introduced.
The resulting mixture is
65 thoroughly extracted with ether, and the ether extract in
turn is extracted with dilute muriatic acid. This acid
solution is made basic with‘ potash, the resulting pre
cipitate of mm-tolyl-4-pyridinemethyl r3,4,S--trime'thoxy
benzoate being taken upin ether. To the ether extract is
70 added a‘ slight excess of hydrogen chloride dissolved in
Z-propanol. ' The a=m-tolyl-4~pyridinemethyl- 3,4,5-tri
methoxybenzoate hydrochloride which is thrown down ‘is
hydrochloride-Using the technique of Example 10A,
?ltered 0E and further puri?ed by recrystallization from
but substituting 51 parts of methyl 3,4,5-trirnethoxycin~
a mixture of absolute ethanol and ether. The product
namate for the methyl 3,4,5-trirnethoxybenzoate therein, 75 melts at 200-202 ° and has the formula
3,100,775
11'
.
.
'
12
cautiously added to destroy excess hydride. After being
a W '
washed with su?i'cient dilute aqueous muriatic acid to
U '0
remove unreacted amino alcohol, the mixture is dried‘over
oornv
|
calcium sulfate and evaporated to dryness. The residue
@-<'m~l—@-m
(‘1H3
éCHa
is extracted with hot benzene, from which on cooling a
vfurther amount of unreacted amino alcohol is precipi
tated. This is ?ltered 01f, and an excess of hydrogen
chloride dissolved in 2-propanol is added to the hot ?l~
trate. From the ?ltrate, on cooling, the desired u-m
.HCI
Example23
10 chlorophenyl - 4 - pyridinemethyl 3,4,5 - trimethoxyben
zoate hydrochloride precipitates. Recrystallized ‘from ab
zoate hydrochloride-A mixture of 15 parts of u-rn-tolyl
solute ethanol, the material melts at 204-2061 The
4-pyridinernethanol, 22 parts of 3,4,5-triethoxybenzoyl
product has the formula
.
>
chloride, and 8 parts of triethylamine in 900 parts of an
hr
hydrous xylene is heated at-the boiling point of the sol 1.5
went under re?ux in an atmosphere of nitrogen during
_24 hours. The reaction mixture is then cooled to room
0 CH3
temperatures and‘?ltered. To the ?ltrate is added an
fl)
|
excess of ‘hydrogen chloride dissolved in 2-propanol.
a - m - Tolyl - 4 - pyridinem'ethyl
3,4,5-triethoxyben
®-ono~o—®-oorn
.HCI
I
‘Evaporation of solvent by vacuum. distillation leaves a
residue which is taken up in hot benzene. Upon cool
ing of the benzene solution, there is precipitated a mix
turev of salts which is recovered by ?ltration and resolved
01
'
'
by suspension in hot water. The material which remains
60H.
Example 26
oz - o - Chlorophenyl - 4 - pyridinemethyl
3,4,5 - tri
lundissolved is the desired a-m-tolyl-4-pyridinemethyl 25 cthoxybenzoate hydrochloride.-—Using the technique of
Example 25B, but substituting ‘for the a-rnrohlorophenyl
3,4,5-triethoxybenzoate hydrochloride which, recrystal
4-pyridinemethanol and 3,4,5-trimethoxybenzoyl chloride
liz'ed from absolute ethanol, melts at 207~210°. The
therein 33 parts of a-o-chlorophenyl-4-pyridinemethanol
product has the formula
and 45 parts of 3,4,5-triethoxybenzoyl chloride, respec
/N
tively, there is obtained a-o~chlorophenyl-4-pyridine
methyl 3,4,5-triethoxybenzoate hydrochloride, which has
I
<
I O C 2H5
(H)
I
,
,
~
I
>-_oHo-o_®-0om,
‘
CH3
the formula
I
/N
35
.1101
i '
0 C 2H5
002135
‘I?
Example 24
A. at - p - Ethylphenyl - 4 - pyridinemethanoL-Using
I
the technique of Example 22A, but substituting 184 parts
‘of psbromoethylbenzene for the m~bromotoluene therein,
there is obtained a-peethylphenyl-4-pyridinemethanol.
Cl
I
l
'
.1201
0 CnHa
Example 27
A. a-Phenyl-4-piperidinemethan0l.--A solution of 110
B. a - p - Ethylphenyl - 4 - pyridinemethyl 3,4,5 - tri
parts of a-phenyl-4-pyridinemethanol in a mixture of 660
parts of acetic acid and 220 parts of water is agitated
ethoxybertzoate hydrochl0=rid'e.—Using the technique of
Example 23, but substituting 16 parts of a-p-ethylphenyl
during 9 hours under 45 psi. of hydrogen in the pres
ence of platinum oxide catalyst. Approximately 4 parts
of the catalyst is incorporated at the start of the reduc
tion, another 4 parts being introduced at the end of the
v4-pyridinemethanol for the ot-m-tolyl-‘4-pyridinemethano1
therein, there is obtained u-p-ethylphenyl-4-pyridine~
methyl 3,4,5-triethoxybenzoate hydrochloride, of the
ctormula
?rst 3 hours.
Temperatures rise to around 35° in proc- '
ess. When the uptake of hydrogen indicates that reduc
.
.,
AW
I
tion is complete, hydrogenation is stopped, catalyst is
?ltered ad, and acetic‘ acid is stripped vfrom the ?ltrate
by vacuum distillation. The residue is taken up‘ in water,
O C 2H6
55 ‘and the resultant solution made alkaline with caustic soda.
1
002115 '
Example 25
A. a -‘m - Chlorophenyl - 4 -- pyridinem'ethanoL-Using 60
the technique of Example 212A, but substituting 192 parts
of 'm-bromochlorobenzene for the m~bromotoluene
therein, there is obtained afm-chlorophenyl-4-pyridine
methanol.
This material melts at 133-135".
B. a >- m - Chlorophenyl - 4 - pyridinemethyl 3,4,5-tri
methoxybenzoate hydr0chl0ride.-—To a solution of 33
~parts of a~m-chlorophenyl-4-pyridinemethanol in 450
‘parts of anhydrous toluene is added, portionwise with
agitation at ISO-90° under a nitrogen atmosphere, 4 parts
of sodium hydride. Heating at the prescribed tempera 70
tures is continued rfor 1 hour, whereupon a solution of
approximately 43 parts of 3,4,5-trimethoxybenzoyl chlo
ride in 180 parts of anhydrous toluene is introduced dur
ing 10 minutes. fIhe resulting mixture is maintained at
80° overnight, at which point 16 parts of methanol is
The solid precipitate thrown down is isolated by ?ltration‘
and further puri?ed by recrystallization from absolute
ethanol; The desired a~phenyl-4-piperidinemethanol is
obtained by this means as a white powder melting at
approximately 168-169°.
B. 0; ~ Phenyl - 4 - piperidinemethyl
'
3,4,5 - trimetlrz
oxybenzoate hydr0chl0ride.-—A mixture of 23 parts of
methyl 3,4,5-trimethoxybenzoate, 19 parts of a-phenyl-4
piperidinemethanol, and 2 parts of sodium in Xylene me
dium is processed substantially as described in Example
10A to give u-phenyl-4-piperidinemethyl 3,4,5-trimeth
oxybenzoate hydrochloride, which has the formula
‘$100,775
13
i i C. a,- Phenyl - 4
14
Example 30
p‘iperidineniezhyl‘ ‘3,4;5 - t‘r‘i'meth
‘0xybenz0ate.-—~The hydrochloric acid saltrof the forego
ing Part B of this‘ example ispconvertedto: the correspond
.ing baseby alkalization in aqueous solution, the u-phenyl
4-piperidinemethyl ‘3,4,5-trimethoxybenzoate“ thus qpro
A. 4-benzo‘yl-1-benzylpyridinium chloride.—-A solution
of 37'parts of 4-benzoylpyridine and 65 parts of benzyl
chloride in 750 parts of chloroform is heated at the boil
ing point underre?ux for 26 hours. The solvent is then‘
“ duced being isolated by‘ extraction ‘into ‘ether and;r subse
evaporated by vacuum ‘distillation, whereupon the residue
quent evaporation of solvent as described in ExamplelOB.
is crystallized from butanone to‘ give pure white 4-bcn
Example 28
rzoyl-l-benzylpyri-dinium chloride,‘ the 'melting 1point of
which is approximately 193-11949.
A. 4-benz0yl-1-methylpyridinium iodide-A mixture‘
of 18 parts of 4-benzoylpyridine and 30 parts of methyl
iodide in 400 parts of water-washed chloroform is heated
at the boiling point under reflux overnight. Solvent is
then stripped in vacuo at elevated temperatures, leaving as
a residue 4-benzoyl-l-methylpyridiniurn iodide.
‘
‘
‘
i
'
' B; 'J-benzyl-u-phertyl-épiperidinemethanol hydrochlo
-ride.-—A mixture‘of 16 parts of 4-benzoyl-l-benzylpyri
din'ium chloride, lpart of platinum oxide and 160.parts
of . absolute ethanol 3-is rhy'clrogenated'under pressures of
15 the Ol'dEI'LOf‘ 50ip;s.i."~When.;th‘e uptake of hydrogen indi
catés’that lthe ‘ ‘desired, reduction. is ‘achieved, "hydrogena
B. 1 - methyl - cc - phenyl '- 4 '--piperidinemethanol.-A
'tion:is stopped andth’ereactionmixture is ?ltereditore
,mixture‘ of, 15 parts ‘ of ~4-ben‘zoyl-l-methylpyridinium
wrnoves'catalyst; ‘Stripping of solventtfrom.thei?ltratefby
.iodide, l‘part of platinum oxide, and 175 parts ‘of absolute
vacuum distillation leaves a light brown oil whichlsolidi
:ethanol is ‘hydrogenated ;ur1der pressures ‘oftheeorder-of it20 ?es to ‘an ec‘ru crystalline solid on standing. This solid
.50 psi. until the uptake of hydrogen-gas‘is consistent
is recrystallized from a mixtureiof‘absolute ethanol and
with the‘ reduction in ‘prospect. .1. Catalyst is‘then ?ltered
anhydrous ether to give‘ a pure white material. melting at
“loft and, the ?ltrate distilled to remove ‘sol-vent: present‘.
l90-193°. The? product thus “obtained is l-benzyl-a
_The residue is _.;17methyl-mphenyl-fi-piperidinemethanol
phenyl-4—piperidinemethanol hydrochloride.
.
.hydroiodide, which is converted to the‘ correspondingrbase (
C. 1-beh2yl-a-phen;yl-4-piperidinemethyl 3,4,5-trimeth
.by dissolution in ‘water tandineutralization of this solu
tion with aqueous sodium bicarbonate“ The base 'isgiiso
‘lated by extraction into ether anddistillation of solvent
from the ether extract.
.200 parts of benzeneis thoroughly‘ mixed with an. excess of
The benzene phase
piiperidinemetltyl 3,4,5-‘ isdilutejaqueouszpotassiumicarbonate.
then1 ‘separated and dried by azeotropic distillation.
'
C. 1 - methyl - a - phenyl - 4 -
oxybenzoate hydr0br0mr'de.-—A suspension of 25 parts of
1=benzyl-a-phenyl-4-piperidinemethanol hydrochloride in
i
i
zfrimethoxybenzoate.-—A mixture of '21 parts of l-methyl
a-phenyl-4-piperidinernethanol, 23 parts of 3,4,5-trimeth
oxybenzoyl .chloride, and 165‘ parts of dry benzene is
heated at the boiling point under re?ux tor 24 hours,
.‘Ihewe'ight of benzene. present is adjusted to approximate
‘ .8 times ithatiriof amino ‘alcohol, whereupon 19. parts of
3,4,l5_-trimethoxybenzoyl chloridedissolved in 200 ‘parts
:ofj-benzenejis incorporated. Themixtureis heated at
thehoiling 3 point under ‘re?ux vforj26u hours. Precipita
then cooled and?ltered. The ?ltrate is thoroughly mixed @ 35
with an excess of dilute aqueous mur’iatica-acid, following
tioueoccurslwithin. afew 1 minutes. . flhe reaction mixture
which the ‘benzene phase is discarded and excess aqueous
iiscooled and‘ ‘?lteredxiandlthei ?ltrate is thoroughly mixed
caustic sodaris stirred‘in.‘ Su?icient ‘potassium carbonate
‘avithaan. excess ‘of. dilute .aqueous;muriatic acid. .A, heavy
‘to insure saturation is next incorporated; following which
water-insbluble siltis-throivnrdawn; and. this 9i1,:t<.>g@th¢r
the mixture is extracted withfe‘the’r.‘ jEvaporationfof.‘ sol 40 with
‘theaqueous ,phase is‘. made ibasicgwith caustic. soda.
vent ‘from the ether‘ext‘ract aifords'as aI-residue‘the de
The'resultant
niixturenis.‘saturated‘iwith potassium car
sired 1rmethyl-u-phenyl-llépiperidinemethyl. ‘3,4,‘5-‘trimeth
bonate and then extracted with ether. The ether extract
‘oxybenzoate, which has‘the‘lformula‘ ‘
‘ "
r
is dried over anhydrous potassium carbonate and then ?l
tered and evaporated. There remains a “glass” which is
e
4.5
NW
‘
‘OCHa ‘
‘i’
‘
‘ '
‘
‘f
OCH;
50
i. . 1 -0ctyl-arphenyl-4-piperidineinethyli.
move small amountspfinsoluble ?occulentmaterial, fol
lowing which it is‘ ‘made acid‘ with} alcoholic hydrogen
bromide. The semi-solid hydrobromic acid salt which
results is separated andkrecrystallized from a mixture of
absolutetethanol and pether. , "Ihe l-benizyl-q-phenyl-4
'piperi-di‘neiniethyl 3,4,Sétiirndhdxylienzoatejhydr'obromide
ghu'si o‘btained‘f'is‘ awhit‘e powd'er?rrile'lting ‘at 227-230".
ten.
Example 29’
taken up in ether. The ether solution is ?ltered to re
1
M
_‘
.tfririiethoty
benzoatey-Usihg the procedures 1 detailed inithe preced
ing Example .28, 4-ben'zoylpyridine and .octylziodide ,are
reacted together in chloroform solution‘ to 'giveA-benzoyl
'l-octylpyridiniurn iodide,-whiol1 is converted via;low;wpres
.
su're hydrogenation in the presence ,ofplatinum .oXidecat
:alyst to ~1-octyl:a-phenylé4epiperidinemethanol. ‘ ‘ This .ma
terial, initurn,"is .esteri?ed with .3,4,5..'-_trimethoxybenzoyl .
chloride; and there is thus obtained 1-octyl—a~phenyl-4
piperidinemethyl 3,4,‘5—trimethoxybenzo'ate, of the for- ‘
mula
Example 31
a-phenyl-4-py?dinemethyl‘ 0_-carbOxybenz0ate.-Using
essentially thetechnique of Example 14A,but. substituting
for the 3,4,5-trimethoxybenzoic anhydride and rat-phenyl
2-pyridinemethanol therein approximately 8 parts of
.phthalic =a_nhyd_ride and-.9; parts .-,of ,bz-phenyléllepyridine
methanol,>respeetively, ‘thereiis - obtained a-pheny-le4ypyri
‘ dinemethyl.orcarboxybenzoate, .which ,melts ~at approxi
75
matély 201-202". The ‘product has the formula
3,100,775
1%
acid called for therein, one obtains a-phenyl-4-pyr-idine- ‘
methyl p-nitrobenzoate, which is converted to the corre
sponding hydrochloric acid salt by dissolution in absolute
ethanol and acidi?cation with a slight excess of hydrogen
chloride dissolved in absolute 2-propanol. The product
‘ @-@HO—<>-@
v
7
Example
‘is ‘thrown out of solution'as a granular white solid by
32_
I
V
introduction of anhydrous ether. a-Phenyl-4-pyridine
methyl p-nitrobenzoate hydrochloride melts at 224-227°
I
a-Phenyl-4épyridinemethyl o-meth‘oxycarbonylbenzoate
and has the formula
;
.
hydrochloride.--To a solution of 15 parts of hydrogen _ 10
'chloride and 200 parts of methanol is added 12 parts of
u-phenyl-4-pyridinemethyl o-carboxybenzoate.
The ,re
sultant ‘mixture ‘is heated at the boilingpoint under re?ux
'for 2 hours, then concentratedto approximately 14 ‘vol
~ume by vacuum distillation. Addition of ether to the 15
’ warm residue precipitate u-phenyIA-pyridinemetlhyl o
,
‘methoxycarbonylbenzoate hydrochloride as a granular
‘white solid, which melts at 96—99°. The product has the
'formula‘
'
1
.
'
l.
,
7
Example
36
.
t
a-Plz‘enyl . - 4 ' - ' pyridiriemethyl m-vdimethylaminobelnzo
'
20
‘ate.-—A mixture of 36'parts of methyl m-dimethylamino
benzoate, 37 parts of ot-phenyl-4-pyridinemethanol, and
2900 parts of anhydrous xylene in the presenceof excess
sodium is concentrated to 1/5 volume by-distillation under
a nitrogen atmosphere during-approximately 7 hours.
From ‘the reaction mixture, ‘at room temperature, is ?l
C-OCHa
lrrol
tered a brown granular solid containing the excess sodi
’ vum. The ?ltrate, upon distillation, affords a-pheny1-4
”
Example 33,
u-Phenyl-4;pyridinemethyl p-ethoxycarbbnylbenzoate.—
pyridinemethyl m-dimethylaminobenzoate as a golden
A mixturefof 37 parts of a-phenyl-4-pyridinemethanol, 3O
oil'boiling at 200~210° under 0.2 mm. pressure.
product has the formula
V
approximately 43 parts of p-ethoxycarbonylbenzoyl chlo
(Ni
ride, andSOO parts of pyridine islheated at the boiling
point under re?ux for'one hour.’ The pyridine is then
'removed‘by‘ vacuum distillation, whereupon the residue is
washed with aqueous 10% caustic andthen extracted 35
with ether. The ether extract in turn is extracted with
I
-
aqueous 5% muriatic 'acid. The acid extract is made
, \/
tyrant),
"QtHOi-Q *
.
alkaline, and the resultant mixture is extracted with ether.
o
The
Example'37
"a~Phenyl-4-pyridinemethyl p-diethylamin0benz0ate.—~
This ether extract is dried over anhydrous potassium
carbonate and vthen 'stripped‘ofsolvent -by distillation.
The residual golden oil is a-phe'nyl~4-pyridineniethyl p
Using the technique of Example 36, butsubstituting ap
proximately 42 parts of methyl p-diethylaminobenzoate
for the methyl.m-dimethylaminobenzoate ‘therein, one ob
ethoxycarbonylbenzoate, of ‘the formula
tains a-phenyl-4-pyridinemethyl p-diethylaminobenzoate.
The product has the formula
"
‘ '
‘
//N,
,
Example 34
,
.50
" a-Phenyl-4-py'ridinevmethyl o-nitrobenzoata-To asus
pensionrof 334‘ parts“ of _o¢nitrobenzoic acid-in 4900 parts
Example 38
‘of pyridine at 15° is added 706par‘ts of benzenesulfonyl
chloride followed, portionwise over a 15-minute period,
by 370 parts of a-phenyl-4-pyridinemethanol. The re
4-pyridinemethyl 3,4,5t-trimethoxybenzoate hydrochlo
ride.—A solution of 3:1 parts of 4-pyridine methanol and
sultant mixture is maintained at 15° for 3 hours and then ‘7
dumped into 30,000 parts of ice-water. The precipitated '
" solids are ?ltered off and dissolved in chloroform.’ rI‘he
' chloroform solution is washed with aqueous potash and
the with .water until free of pyridine. The solvent ‘is re
60
45 parts of3,4,5-trimeth0xybenzoyl chloride in 900 parts‘
of dry xylene is heated at theboiling point under reflux
'for 14 hours: The solution isthen cooled and-?ltered,
and to the ?ltrateiis added a slight excess of hydrogen
chloride dissolved in 2-propano1, followed‘ by approx
imately 250 parts of anhydrous'ether. Precipitation of
moved by vacuum distillation, leaving as the residue, a- ' '
>4-pyridinemethyl 3,4,5-trimethoxybenzoate hydrochloride
phenyl-4-pyridinemethyl o-nitrobenzoate.~ _ The product
occurs. The product, recrystallized from ethanol, melts
at approximately 210—2}11°.~ Ithas the formula‘ '
has
the‘ formula
'
‘
i -
I
~
’
N
. (N, i
.
79
'
0 CH3
onzo-ii-®_oom
"
_
, a-Phenyl-4-pyridiltemethylt p-nitrobenzoate 'lhydr'ochlok
6
H01
CH3
Example 39
rida-Using the‘technique of Example 34, but substitut
a,a-DiphényM-pyridineméthyl 3,4,5-trimethoxybenzo
ing 334 parts of p-nitrobenzoic acid for the o-nitrobenzoic 75 ate.—-A solution of 26 parts of a,a-diphenyl-4-pynidine
3,100,775
17
'
18
methanol, 40 parts of 3,4,5-trimethoxybenzoic anhydride,
All:n and All:m are each selected from the group con
and 1 part of concentrated sulfuric acid in 800 parts of
dry xylene is heated at the boiling point under re?ux for
9 hours. The solution is then cooled and ?ltered. The
?ltrate is Washed with aqueous 5% caustic, then with
water, and ?nally is dried over anhydrous sodium sul
sisting of radicals of the formulas
fate. The desired a,a-diphenyl-4-pyridinemethyl 3,4,5
trimethoxybenzoate is isolated from this solution by evap
oration of solvent. The product, crystallized from 2-pro
less than 6; n and m are selected from the group consist
separating the radicals attached thereto by fewer than 5
carbon atoms, x being representative of a positive integer
ing of 0 and the positive integer 1; and Ph" is selected
from the group consisting of radicals of the formulas
panol, melts at approximately 1605-1615". It has the 10
formula
‘
C1
‘
OCHa
\
if
C1
‘
‘
horn
C1
C1
What is claimed is:
1. A compound of the formula
in
n
/
7
Cl
25
\
Ph’-—CH-Alkn-0—C-Alkm-Ph"
Cl
wherein Pyr is selected from the group consisting of radi
cals of the formulas
(‘Mower alkyl '
30
O-lower alkyl
35.
4” l
'
@m
lower alkyl
I
:tHeQ
\/ N
\><
40
O-lowevr alkyl
O-lower alkyl
/
O-lower alkyl
\
O-lower alkyl
45.
2. A compound of the formula
50
N
/_\/\
55
3. u-Phenyl-4-pyridinemethyl 3,4,5-trichlorohenzoate.
4. A compound of the formula
Ph' is selected from the group consisting of radicals of
the formulas
O-lower alkyl
I
(if
O-lower alkyl
C HO-—O—
a
lower alkyl
O-lower alkyl
5. A compound of the formula
01
?
75
OCH3
OCHa
0 CH3
3,100,775
19
Z®
'6. u-Pheny1-4-pyridinemethy1 3,4,5-trimethoxybenzoate.
7. A compound of the’forrnula
13. A compound of the formula
'
N
_
/ W
/N
5
7
i
‘ I
CH-l
Q
O 0E3
E‘)
1k 1
Ower a yene
'
'
@—CHO—P1—
I
-0—C-—
.
_ (|)-l0wer alkyl
lower alkyl
@I
~OGH
a
'
—0-lower alkyl
01
'
10
1
- owerzl ‘*y
14. u-m-Tolyl-4-pyridinemethyl 3,4,5-trimethoxybenzo
00113
ate.
15. A compound of the formula
'
V
'
N
wherein the lower alkylene radical contains fewer than 3
carbon atoms.
A‘
8. v-Phenyl-4-pyridinepr0pyl
ate.
'
’
’
l5
3,4,5-trimethoxybenzo-
o-lower alkyl
V
.
9. A compound of the formula
-_
H
-
‘
,
'
@-~CHO—C—
20
1 /N
oxybenzoate.
~
|
(|)~lower alkyl
16. a-m-Chlorophenyl~4-pyridinemethyl 3,4,5-trimeth
‘
'
O-lower alkyl
01
ff
OCH3
‘
References Cited in the ?le of this patent
25
gem-04W“ 31mm‘
‘00133
(I)CH3
UNITED STATES PATENTS
2,899,437
Shapiro et a1 __________ __ Aug. 11', 1959
2,907,764
Voegtli et a1. ___________ __ Oct. 6, 1959
FOREIGN PATENTS
wherein the lower alkylene radical contains fewer than 30
920’491
France """""""""" " J'an‘ 4’ 1947
3 carbon atoms.
OTHER REFERENCES
10- vl-Phellyl-‘l-pyl'idl'nemethyl 3,4,5-trimeth0XyPheI1y1acetate.
11. u-Phenyl-4-pyridinemethyl
mate.
3,4,5-trimethoxycinna- 35
7
12. a-Phenyl-4-pyridinemethyl 3,4,5-trimethoxybenzo4
ate 'N-oxide.
I
‘
Karrer: “Organic Chemistry” (4th Eng. ed.), page 222
(1950).
Kharasch et al.: J. Org. Chem, volume 18, pages
1051-4 (1953).
Boyer et al.: J. Am. Chem. Soc, volume 80, pages
2741-3, June 1958.
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