CA1111442A - Substituted phenyl acetic acid esters - Google Patents
Substituted phenyl acetic acid estersInfo
- Publication number
- CA1111442A CA1111442A CA282,327A CA282327A CA1111442A CA 1111442 A CA1111442 A CA 1111442A CA 282327 A CA282327 A CA 282327A CA 1111442 A CA1111442 A CA 1111442A
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- CA
- Canada
- Prior art keywords
- methoxy
- process according
- phenoxyacetamide
- preparation
- diethyl
- Prior art date
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-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/53—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and hydroxy groups bound to the carbon skeleton
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention is concerned with a novel process for the preparation of certain known substituted phenylactic acid esters of the general formula:
.....I
wherein each of R1 and R2 represents lower alkyl and may be the same or different, which comprises hydrolyzing novel suitably substituted phenylacetimidate salts, which are themselves obtained from a further class of novel compounds.
Compounds of general formula I have useful pharmacolo-gical properties and have been shown to be valuable agents for inducing narcosis. Illustrative, and probably the most widely recognized, of these compounds at present is 3-methoxy-4-N,N-diethylcarbamoylmethoxy-phenylacetic acid n-ppropyl ester, commonly termed "propanidid".
The present invention is concerned with a novel process for the preparation of certain known substituted phenylactic acid esters of the general formula:
.....I
wherein each of R1 and R2 represents lower alkyl and may be the same or different, which comprises hydrolyzing novel suitably substituted phenylacetimidate salts, which are themselves obtained from a further class of novel compounds.
Compounds of general formula I have useful pharmacolo-gical properties and have been shown to be valuable agents for inducing narcosis. Illustrative, and probably the most widely recognized, of these compounds at present is 3-methoxy-4-N,N-diethylcarbamoylmethoxy-phenylacetic acid n-ppropyl ester, commonly termed "propanidid".
Description
1~114~Z
Field of Invention The present invention relates generally to a process for producing certain known pharmacologically active substituted phenylacetic acid esters in which process two novel classes of intermediate compounds are utilized. More particularly, this invention is concerned with a novel advantageous process for producing substituted phenylacetic acids of the general formula I:
o ~N-C-CHz-O ~ cH2~OcoR3 ............... I
wherein each of Rl and R2 represents lower alkyl and may be the same or different; and R3 represents lower alkyl.
The present process is novel and advantageous in that it utilizes as starting materials a novel class of suitably substituted phenylacetimidate salts of formula II:
R~N C C ~ CH2C-O-R3 ................... II
wherein Rl, R2 and R3 are as defined above and X is an acid anion such as Cl , Br or the like.
Moreover, the novel compounds of formula II are themselves obtained via a further novel class of compounds of formula III:
` 1~1144Z
",'~
,.,~
~,N-c-c.~2-O ~ C~2CN .... III
.~ OCH3 . wherein Rl and R2 are as defined above.
~:. Description of Prior Art ., ~ . !
.- Substituted phenylacetic acids of the formula I
above are described in U.K. Patent No. 906,250 and - Canadian Patent No. 668,696. In the aforementioned .. specifications such compounds are described as :being pharmacologically active and are indicated as being valuable agents for inducing narcosis. In particular, the compounds are capable of inducing a significant but relatively brief narcotizing effect which enables a treated subject to :~ .
make a rapid recovery. This effect is significant in minor operations where it is very advantageous if the patient is incapacitated for only a short period.
Probably the best known of such compounds at the present time is 3-methoxy-4-N,N-dlethylcarbamoylme-thoxy-phenyl-acetic acid n-propyl ester, commonly referred to as "propanidid".
The aforementioned pa-tent specifications teach processes for the preparation of the compounds of formula I
generally involving -the reaction of a homo~anillic acid alkyl ester with N-mono- or N,N-dialkylated haloacetamide or a reactive ester of an N- alkylated glycolic acid amide in the presence of an alkaline condensati.on agent. The conaensation agent used th~ougho~t the specification is a :,.
sodiulr. alcoholate, which is p~oduced in all cases using me~allic sodium. This proc2ss may be i~.. lustrated generally :: 30 ~s follo~,vs:
.
., - 2 -"
OH
~N-CO-CH2 Cl ~: ; CH2COOR3 ., I .
,~; . ~, Na+
OCH2CON~
'~10 ' '~ ' Two modifications of this process are taught, namely, transesterification of an already formed N-alkyl-substituted-3-methoxy-4-carbamoylmethoxy-phenylacetic acid ester or esterification of the corresponding free acid:
in both instances the starting ester and free acid are obtained via the process illustrated above. In these processes, it is necessary to fractionate the crude iiquid product obtained under vacuum in order to separate the desired product in a pure state from the reaction impurities. Such a step requires expensive equipment, i.e. high initial -.
capital investment and is more expensive to operate, due to the repeated heating/condensing steps involved, than other simple separation techniques such as solvent extraction which may involve merely solvent removal by simpie evaporation. ~oreover, the starting homovanlllic acid ester is nct readily available and not easily, and economically, produced (refer for example to the processes noted in the article in Tetrahedron, Vol. 29, pp 1931 to 1939 at p 1933).
'' . .
1~ 4Z
. -; Description of Invention -- It has now been found that the desired N-alkyl-substituted-3-me-thoxy-4-carbamoylmethoxy-phenylacetic acid - esters of formula I can be prepared in a simple step from a : novel intermediate which allows the desired compounds of . formllla I to be obtain~d in a pure state without the need of a vacuum fractionation step.
In one aspect Lherefore, the present invention - provides a process for the production of N-alkyl-substituted ~ 10 3-methoxy-4-carbamoylnethoxy-phenylacetic acid esters of , :` the general formula I:
N-C-CH2-O ~ CH2COR3 ...... I
' comprising hydxolyzing a novel compo~md of the general formula II:
~,N-C-CH~-O ~ NH HX ..... II
.
wherein R1, R2, R3 and X are as defined above.
The term "lower" when used throughout this specification ~.
: to qualify an alkyl group means such a group having at most six, pre~erably at rnost four, carbon atoms. Examples of lower 31kyl groups include methyl, ethyl, propyl, isopropyl, butyl, isob-ltyl, secondary and tertiary butyl and the various per.tyl and hexyl i.somers.
_ ", _ ~ 1~1 14~2 The hydrolysis may be effected by treatment with water conveniently . at a temperature oE from 20-80C, especially 50-60C. The desired product is rapidly produced in th~ form of an oil which separates to float as an oily layer on the aqueous reaction mixture. The oil may be skimmed off but preferably, the reaction mixture is extracted with a suitable solvent, such as ether, which is then removed by simple evaporation;
the residue being the desired product in a commercially acceptable pure form.
The substituted phenylacetimidate salts of formula II are also novel and constitute a composition of matter aspect of the present invention. These compounds are produced by a novel process comprising treating a compound of formula III:
R~ R ~
,N-C-CH2-O ~ CH2CN ....III
OC~3 wherein Rl and R2 are defined above with an acid of formula:
H-X
and an alcohol of formula:
wherein R3 is defined above.
Conveniently, the reactants are merely stirred - at ambient temperatures, say, 20-30C, for, a perio~ of, for e~c~,ple 10-20 hours. ~o isolate the crystalline product, the ~. I
; solvent may be evaporated off and the residue suspended in a non-solvent, i.e. a liquid medium in which it is substantiallv insoluble, such as ethyl acetate The desired product is subsequently obtained in crystalline form which can be filtered off.
4~2 :
~`i . Additionally, the starting cyanomethyl compounds , of formula III are themselves novel and constitute a further product aspect of the present invention.
I They may be prepared according to either of the processes detailed in the following reaction schemes:
Route A Route B
.
.,,~ I .
,''` .
HO ~ CH20H H ~ CH~OH
. ¦ CH30 , .
, ~ .
CH ~ CH2CN R~N-CO-CH2-O ~ CH20H
CHgO IV
''''.'.,' ,., ~20 ¦ ~N-CO-C ~-0 ~ CH~Cl : \ ~ H30 ' ~
~N-CO~CH~-O 4 ~ CH2CN
,". R2 CtI~o ... .
It will he noted thal: the starting material for both routes is vanillyl alcohol which is readii.].y available at ~elatit7~ lo~; cost.
The aryloxy acetic acid amides of formula I~ and a process for their production are given in Canadian Patent No. 772,161.
.- In a further process aspect the p esent invention-provides a two-step process for the production of the compounds of formu~a I defined d~OVe, wherein a suitably . substituted N-alkyl-substituted-(2'-methoxy-4'-cyanomethyl)-phenoxyacetamide compound of formula III defined above is converted .into a phenylacetimidate salt of formula II
which is subse~uently hydrolyzed to obtain the desired product.
~ The present invention will be further described with reference to the following specific examples. These ; examples illustrate the various aspects of the present . invention with reference to the production of the preferred compound of formula I, namely, 3-methoxy-4-N,N-diethylcarba-moylmethoxy-phenyl acetic acid n-propyl ester. However, the present invention is not limited thereto, the remaining : compounds of formula I and novel compounds of formula II
and III being obtainable, with suitable choice of starting ; ~0 materials, using the same procedures.
.....
` Example 1 Preparation of 3-methoxy-4-N,N-diethylcarbamoylmethoxy-: phenylacetic acid n-propyl ester by the preferred route : involving isolation of the phenylacetimidate salt . . ~
. A solution comprising 1.8 g of n-propyl [3-methoxy-4-. ~diethylcarhamoyl)-methoxy]-phenylacetimidate hydrochloride , in 18 ml of water was heated for 30 mlnutes at 50-60C.
:: The reacti.on mixture was cooled, extracted several times with ether and the combi.ned extracts dried. Removal of the solverlt by si.mple distillation gave 1.53 g (94~ theoretical) of the desi.red prod~ct as a colourless oil. The product was ~na.lyzed hy t.l.c. analysi.s and shown to be pure~
Example 2 Preparation of 3-methoxy-4-N,N diethylcarbamoylmethoxy-Phenylacetic acid n-proPYl ester without isolation of the _henylacetimidate salt
Field of Invention The present invention relates generally to a process for producing certain known pharmacologically active substituted phenylacetic acid esters in which process two novel classes of intermediate compounds are utilized. More particularly, this invention is concerned with a novel advantageous process for producing substituted phenylacetic acids of the general formula I:
o ~N-C-CHz-O ~ cH2~OcoR3 ............... I
wherein each of Rl and R2 represents lower alkyl and may be the same or different; and R3 represents lower alkyl.
The present process is novel and advantageous in that it utilizes as starting materials a novel class of suitably substituted phenylacetimidate salts of formula II:
R~N C C ~ CH2C-O-R3 ................... II
wherein Rl, R2 and R3 are as defined above and X is an acid anion such as Cl , Br or the like.
Moreover, the novel compounds of formula II are themselves obtained via a further novel class of compounds of formula III:
` 1~1144Z
",'~
,.,~
~,N-c-c.~2-O ~ C~2CN .... III
.~ OCH3 . wherein Rl and R2 are as defined above.
~:. Description of Prior Art ., ~ . !
.- Substituted phenylacetic acids of the formula I
above are described in U.K. Patent No. 906,250 and - Canadian Patent No. 668,696. In the aforementioned .. specifications such compounds are described as :being pharmacologically active and are indicated as being valuable agents for inducing narcosis. In particular, the compounds are capable of inducing a significant but relatively brief narcotizing effect which enables a treated subject to :~ .
make a rapid recovery. This effect is significant in minor operations where it is very advantageous if the patient is incapacitated for only a short period.
Probably the best known of such compounds at the present time is 3-methoxy-4-N,N-dlethylcarbamoylme-thoxy-phenyl-acetic acid n-propyl ester, commonly referred to as "propanidid".
The aforementioned pa-tent specifications teach processes for the preparation of the compounds of formula I
generally involving -the reaction of a homo~anillic acid alkyl ester with N-mono- or N,N-dialkylated haloacetamide or a reactive ester of an N- alkylated glycolic acid amide in the presence of an alkaline condensati.on agent. The conaensation agent used th~ougho~t the specification is a :,.
sodiulr. alcoholate, which is p~oduced in all cases using me~allic sodium. This proc2ss may be i~.. lustrated generally :: 30 ~s follo~,vs:
.
., - 2 -"
OH
~N-CO-CH2 Cl ~: ; CH2COOR3 ., I .
,~; . ~, Na+
OCH2CON~
'~10 ' '~ ' Two modifications of this process are taught, namely, transesterification of an already formed N-alkyl-substituted-3-methoxy-4-carbamoylmethoxy-phenylacetic acid ester or esterification of the corresponding free acid:
in both instances the starting ester and free acid are obtained via the process illustrated above. In these processes, it is necessary to fractionate the crude iiquid product obtained under vacuum in order to separate the desired product in a pure state from the reaction impurities. Such a step requires expensive equipment, i.e. high initial -.
capital investment and is more expensive to operate, due to the repeated heating/condensing steps involved, than other simple separation techniques such as solvent extraction which may involve merely solvent removal by simpie evaporation. ~oreover, the starting homovanlllic acid ester is nct readily available and not easily, and economically, produced (refer for example to the processes noted in the article in Tetrahedron, Vol. 29, pp 1931 to 1939 at p 1933).
'' . .
1~ 4Z
. -; Description of Invention -- It has now been found that the desired N-alkyl-substituted-3-me-thoxy-4-carbamoylmethoxy-phenylacetic acid - esters of formula I can be prepared in a simple step from a : novel intermediate which allows the desired compounds of . formllla I to be obtain~d in a pure state without the need of a vacuum fractionation step.
In one aspect Lherefore, the present invention - provides a process for the production of N-alkyl-substituted ~ 10 3-methoxy-4-carbamoylnethoxy-phenylacetic acid esters of , :` the general formula I:
N-C-CH2-O ~ CH2COR3 ...... I
' comprising hydxolyzing a novel compo~md of the general formula II:
~,N-C-CH~-O ~ NH HX ..... II
.
wherein R1, R2, R3 and X are as defined above.
The term "lower" when used throughout this specification ~.
: to qualify an alkyl group means such a group having at most six, pre~erably at rnost four, carbon atoms. Examples of lower 31kyl groups include methyl, ethyl, propyl, isopropyl, butyl, isob-ltyl, secondary and tertiary butyl and the various per.tyl and hexyl i.somers.
_ ", _ ~ 1~1 14~2 The hydrolysis may be effected by treatment with water conveniently . at a temperature oE from 20-80C, especially 50-60C. The desired product is rapidly produced in th~ form of an oil which separates to float as an oily layer on the aqueous reaction mixture. The oil may be skimmed off but preferably, the reaction mixture is extracted with a suitable solvent, such as ether, which is then removed by simple evaporation;
the residue being the desired product in a commercially acceptable pure form.
The substituted phenylacetimidate salts of formula II are also novel and constitute a composition of matter aspect of the present invention. These compounds are produced by a novel process comprising treating a compound of formula III:
R~ R ~
,N-C-CH2-O ~ CH2CN ....III
OC~3 wherein Rl and R2 are defined above with an acid of formula:
H-X
and an alcohol of formula:
wherein R3 is defined above.
Conveniently, the reactants are merely stirred - at ambient temperatures, say, 20-30C, for, a perio~ of, for e~c~,ple 10-20 hours. ~o isolate the crystalline product, the ~. I
; solvent may be evaporated off and the residue suspended in a non-solvent, i.e. a liquid medium in which it is substantiallv insoluble, such as ethyl acetate The desired product is subsequently obtained in crystalline form which can be filtered off.
4~2 :
~`i . Additionally, the starting cyanomethyl compounds , of formula III are themselves novel and constitute a further product aspect of the present invention.
I They may be prepared according to either of the processes detailed in the following reaction schemes:
Route A Route B
.
.,,~ I .
,''` .
HO ~ CH20H H ~ CH~OH
. ¦ CH30 , .
, ~ .
CH ~ CH2CN R~N-CO-CH2-O ~ CH20H
CHgO IV
''''.'.,' ,., ~20 ¦ ~N-CO-C ~-0 ~ CH~Cl : \ ~ H30 ' ~
~N-CO~CH~-O 4 ~ CH2CN
,". R2 CtI~o ... .
It will he noted thal: the starting material for both routes is vanillyl alcohol which is readii.].y available at ~elatit7~ lo~; cost.
The aryloxy acetic acid amides of formula I~ and a process for their production are given in Canadian Patent No. 772,161.
.- In a further process aspect the p esent invention-provides a two-step process for the production of the compounds of formu~a I defined d~OVe, wherein a suitably . substituted N-alkyl-substituted-(2'-methoxy-4'-cyanomethyl)-phenoxyacetamide compound of formula III defined above is converted .into a phenylacetimidate salt of formula II
which is subse~uently hydrolyzed to obtain the desired product.
~ The present invention will be further described with reference to the following specific examples. These ; examples illustrate the various aspects of the present . invention with reference to the production of the preferred compound of formula I, namely, 3-methoxy-4-N,N-diethylcarba-moylmethoxy-phenyl acetic acid n-propyl ester. However, the present invention is not limited thereto, the remaining : compounds of formula I and novel compounds of formula II
and III being obtainable, with suitable choice of starting ; ~0 materials, using the same procedures.
.....
` Example 1 Preparation of 3-methoxy-4-N,N-diethylcarbamoylmethoxy-: phenylacetic acid n-propyl ester by the preferred route : involving isolation of the phenylacetimidate salt . . ~
. A solution comprising 1.8 g of n-propyl [3-methoxy-4-. ~diethylcarhamoyl)-methoxy]-phenylacetimidate hydrochloride , in 18 ml of water was heated for 30 mlnutes at 50-60C.
:: The reacti.on mixture was cooled, extracted several times with ether and the combi.ned extracts dried. Removal of the solverlt by si.mple distillation gave 1.53 g (94~ theoretical) of the desi.red prod~ct as a colourless oil. The product was ~na.lyzed hy t.l.c. analysi.s and shown to be pure~
Example 2 Preparation of 3-methoxy-4-N,N diethylcarbamoylmethoxy-Phenylacetic acid n-proPYl ester without isolation of the _henylacetimidate salt
2.06 G of N,N-diethyl 2-(2'-methoxy-4'-cyanomethyl)-phenoxyacetamide were added to a solution comprising 3.8 g of hydrogen chloride in 8.4 ml of n-propanol. The resulting solution was stirred at a temperature of 20-25C for 18 hours. The solvent was removed by simple distillation and 20 ml of water added to the residue. The resulting solution was heated at 50-60C for 30 minutes, the mixture cooled and subsequently extracted several times with ether. The combined ether extracts were dried and the ether removed by simple distillation. The desired product was obtained as a pale yellow oil in a yield of 2.3 g (93% theoretical).
Example 3 Preparation of n-Propyl[3-methoxy-4-_dlethylcarbamoyl)-methoxyl]-phenylacetimidate hydrochlorlde -:, .
2.06 G of N,N-diethyl 2-(2'-methoxy-4'-cyanomethyl)-, ..
phenoxyacetamide were added to a solution comprising 3.8 g of hydrogen chloride in 8.4 ml of n-propanol. A solution ~;, resulted and this was stirred at a temperature of 20=25C
for 18 hours. The solvent was removed by simple distillation and 20 ml of ethyl acetate added to the oil, residue whereby a suspension was formed. After stirring at a temperature of 20-25C for six hours the desired product was obtained as a white precipitated solid and was filtered off. The product, obtained in a yield of 1.85 g (67% theoretical) had a melting~
point of about 86-90C.
'~`
Example 4 Preparation of N,N-diethyl 2-(2'-methoxy-4'-cyanomethyl)-phenoxyacetamide via Route A
Step 1 Preparation of 3-methoxy-4-hydroxybenzyl cyanide A mixture of 10.8 g (0.22 mole) of sodium cyanide and 30.8 g (0.2 mole) of vanillyl alcohol in 200 ml of - dimethyl formamide was heated at 135-140C bath temperaturefor four hours. The dimethyl formamide was distilled off as completely as possible under a reduced pressure, the rsidue cooled and then dissolved in 200 ml of water. The resultant solution was decolourized with activated charcoal and acidified with 40 ml of acetic acid. The product was extracted with ethyl acetate and the solvent removed by distillation leaving the crude product as a brown semi-solid.
Simple distillation under reduced pressure gave the desired - product as an off-white solid in a yield of 21.4 g (65.5~ of theory) having a b.p. of 127C/1 mm and a m.p. of 48-50C
-~ (capilliary tube method).
Step 2 Preparation of N,N-diethyl 2-(2'-met_oxy-4'-cyanomethyl)-phenoxyacetamide A solution of 1.72 g (0.0105 mole) of 3-methoxy-4-hydroxybenzyl cyanide (from Step 1) in 8 ml of ethanol IX
was added to a solution comprising 0.24 g ~0.0105 g. atom) of sodium in 15 ml of ethanol IX. After the addition of 1.57 g (0.0105 mole) of N,N-diethylchloroacetamide, the mix~ure was refluxed for one hour. The etnanoi was distiiled off under reduc~d pressur^ and 25 mi of water added to the residue. A suspension resulted which was stirred at 20-25C
.''. .
for one hour, following which the solid product was filtered off. The solid was dried to give 2.1 g (74% of theory) of the desired product as an off-white solid, m.p. 66-69C.
Example 5 Preparation of N,N-diethyl 2-(2'-methoxy-4'-cyanomethyl)-~henoxyacetamide via Route B
Step 1 .
Preparation of N,N-diethyl 2-(2'-methoxy-4'-chloromethyl)-~henoxyacetamide . .
20.8 G of thionyl chloride were added to a solution comprising 30.0 g of N,N-diethyl 2-(2'-methoxy-4'-hydroxymethyl)-phenoxyacetamide in 200 ml of methylene ~`: chloride and 1.04 g of dimethyl formamide. Throughout . :
the addition the temperature was maintained within the range of 15-20C. The resulting solution was stirred at a temperature of 15-20C for one and one-half hours. The - solution was then poured slowly into a solution of 45.8 g .:
` sodium carbonate in 250 ml water, the temperature being maintained below lQC throughout the addition. The methylene chloride layer was then separated, washed with saturated sodium chloride solution and then dried. The solvent was removed by simple distillation to give 30.8 g (96% theoretical) of the desired product as a pale yellow oil having a boiling point of 194-196C~0.2 mm.
Step 2
Example 3 Preparation of n-Propyl[3-methoxy-4-_dlethylcarbamoyl)-methoxyl]-phenylacetimidate hydrochlorlde -:, .
2.06 G of N,N-diethyl 2-(2'-methoxy-4'-cyanomethyl)-, ..
phenoxyacetamide were added to a solution comprising 3.8 g of hydrogen chloride in 8.4 ml of n-propanol. A solution ~;, resulted and this was stirred at a temperature of 20=25C
for 18 hours. The solvent was removed by simple distillation and 20 ml of ethyl acetate added to the oil, residue whereby a suspension was formed. After stirring at a temperature of 20-25C for six hours the desired product was obtained as a white precipitated solid and was filtered off. The product, obtained in a yield of 1.85 g (67% theoretical) had a melting~
point of about 86-90C.
'~`
Example 4 Preparation of N,N-diethyl 2-(2'-methoxy-4'-cyanomethyl)-phenoxyacetamide via Route A
Step 1 Preparation of 3-methoxy-4-hydroxybenzyl cyanide A mixture of 10.8 g (0.22 mole) of sodium cyanide and 30.8 g (0.2 mole) of vanillyl alcohol in 200 ml of - dimethyl formamide was heated at 135-140C bath temperaturefor four hours. The dimethyl formamide was distilled off as completely as possible under a reduced pressure, the rsidue cooled and then dissolved in 200 ml of water. The resultant solution was decolourized with activated charcoal and acidified with 40 ml of acetic acid. The product was extracted with ethyl acetate and the solvent removed by distillation leaving the crude product as a brown semi-solid.
Simple distillation under reduced pressure gave the desired - product as an off-white solid in a yield of 21.4 g (65.5~ of theory) having a b.p. of 127C/1 mm and a m.p. of 48-50C
-~ (capilliary tube method).
Step 2 Preparation of N,N-diethyl 2-(2'-met_oxy-4'-cyanomethyl)-phenoxyacetamide A solution of 1.72 g (0.0105 mole) of 3-methoxy-4-hydroxybenzyl cyanide (from Step 1) in 8 ml of ethanol IX
was added to a solution comprising 0.24 g ~0.0105 g. atom) of sodium in 15 ml of ethanol IX. After the addition of 1.57 g (0.0105 mole) of N,N-diethylchloroacetamide, the mix~ure was refluxed for one hour. The etnanoi was distiiled off under reduc~d pressur^ and 25 mi of water added to the residue. A suspension resulted which was stirred at 20-25C
.''. .
for one hour, following which the solid product was filtered off. The solid was dried to give 2.1 g (74% of theory) of the desired product as an off-white solid, m.p. 66-69C.
Example 5 Preparation of N,N-diethyl 2-(2'-methoxy-4'-cyanomethyl)-~henoxyacetamide via Route B
Step 1 .
Preparation of N,N-diethyl 2-(2'-methoxy-4'-chloromethyl)-~henoxyacetamide . .
20.8 G of thionyl chloride were added to a solution comprising 30.0 g of N,N-diethyl 2-(2'-methoxy-4'-hydroxymethyl)-phenoxyacetamide in 200 ml of methylene ~`: chloride and 1.04 g of dimethyl formamide. Throughout . :
the addition the temperature was maintained within the range of 15-20C. The resulting solution was stirred at a temperature of 15-20C for one and one-half hours. The - solution was then poured slowly into a solution of 45.8 g .:
` sodium carbonate in 250 ml water, the temperature being maintained below lQC throughout the addition. The methylene chloride layer was then separated, washed with saturated sodium chloride solution and then dried. The solvent was removed by simple distillation to give 30.8 g (96% theoretical) of the desired product as a pale yellow oil having a boiling point of 194-196C~0.2 mm.
Step 2
3.75 G of sodium cyanide was added to a solution comprising 20.0 g of N,N-diethyl 2-(2'-methoxy-4'-chloro-methyl)-phenoxyacetamide in 40 ml of dimethyl sulfoxide which solution was cooled to 15C. The resulting suspension was stirred at a temperature of 20-25C for three hours and subsequently 100 ml of water added thereto. The reaction mixture, again in the form of a suspension, was stirred at a temperature of 20-25C for one and one-half hours when the desired product, an off-white solid was filtered off. The product which was obtained in a yield of 15.6 g (81%
theoretical) had a melting point of 67-72C. An analysis sample recrystallized from isopropanol had a melting point of 71-73C.
C15H20N2o3 Requires : C, 65.19; H, 7.30; N, 10.14~ -Found : C, 65.36; H, 7.54; N, 10.32%
:
., I
' .. , I
. . .
Example 6 Produc_ion of 3-methoxy-4-~,N-diethylcarbamoylmethoxy-phenylacetic acid ethyl ester A solution of 2.5 g of ethyl 2-t3'-methoxy-4'-diethylcarbamoylmethoxy)-phenylacetimidate hydrochloride in 25 ml of water was heated at a temperature of from 50-60C
., for 30 minutes. The mixture was cooled, extracted several times with ether and the combined extracts dried. The solvent was removed by distillation leaving 2.2 g (94% theory) of the desired product as a pale yellow oil. The identity of the product was confirmed by I.R. and t.l.c. examination.
:
Example 7 Preparation of ethyl 2-(3'-methoxy-4'-diethylcarbamoyl-, .
methoxy)-phenylacetimidate hydrochloride
theoretical) had a melting point of 67-72C. An analysis sample recrystallized from isopropanol had a melting point of 71-73C.
C15H20N2o3 Requires : C, 65.19; H, 7.30; N, 10.14~ -Found : C, 65.36; H, 7.54; N, 10.32%
:
., I
' .. , I
. . .
Example 6 Produc_ion of 3-methoxy-4-~,N-diethylcarbamoylmethoxy-phenylacetic acid ethyl ester A solution of 2.5 g of ethyl 2-t3'-methoxy-4'-diethylcarbamoylmethoxy)-phenylacetimidate hydrochloride in 25 ml of water was heated at a temperature of from 50-60C
., for 30 minutes. The mixture was cooled, extracted several times with ether and the combined extracts dried. The solvent was removed by distillation leaving 2.2 g (94% theory) of the desired product as a pale yellow oil. The identity of the product was confirmed by I.R. and t.l.c. examination.
:
Example 7 Preparation of ethyl 2-(3'-methoxy-4'-diethylcarbamoyl-, .
methoxy)-phenylacetimidate hydrochloride
4.12 G of N,N-diethyl 2-(2'-methoxy-4'-cyanomethyl)-phenoxyacetamide were added to a solution of 8 g of hydrogen chloride in 17 ml of ethanol IX and the resulting solution stirred at 20-25C for 18 hours. The solvent was distilled off and 30 ml of acetone added to the oily residue. A
suspension resulted and this was stirred at 20-25C for three hours and the resulting white solid (3.9 g - 72% theory) filtered off and dried. This was the desired product having a melting point of 116-117C.
Example 8 Preparation of N,N-dimethyl 2-~2'-methoxy-~'-cyanomethyl~-phenoxyacetamide via Route A
A solution of 0.66 g of sodium in 41 ml of ethanol lX was added to a solution of 4.7 y of 3-methoxy-4-hydroxy-benzyl cyanide in 21 ml of ethanol IX. After the addition of 3.5 g of N,N-dimethylchloracelamide, the mixture was ref~uxed for one hour. The alcohol was distilled off and water added to the oi1y residue. The mixture was extracted se~eral times with ethyl acetate and the combined extracts .
1~11442 dried. Removal of the solvent gave the product as an off-white solid having a melting point of 95-lOO~C in a yield of 4.9 g, i.e. 69% of theory. A sample was recrystallized from benzene for complete analysis purposes. Melting point 107-108C.
Elemental ~,nalysis ; C H N
. .
- Calculated for :62.88 6.50 11.29 Cl3Hl6N2O3 Found :62.66 6.58 11.31 - Example 9 ...i ` Preparation of propyl 2-(3'-methoxy-4'-dimethylcarbamoyl-, . , methoxy)-phenylacetimidate hydrochloride ,.
The product of Example ~ was sub~ected to the same procedure as laid out in Example 7 above with, of course, the appropriate change in reactants. The desired product was found to have a m~lting point of from 107-110C.
Example 10 Preparation of 3-methoxy-4-N,N-diethylcarbamoylmethoxy-phenylacetic acid methyl ester Methyl 2-(3'-methoxy-4'-dimethylcarbamoylmethoxy)-phenylacetimidate hydrochloride prepared by the process of Example 9 was subjected to the same procedure as detailed in Example 6. The desired product was identified by I.R. and t.l.c. examination.
n .: .
Example 11 Preparation of 3-methGxy-4-N,N-diethylcarbamoylmethoxy-.:
phenylacetic acid methyl ester This compound, and the intermediate phenylacetimidate hydrochloride, were obtained using the procedures detailed in Examples 6 and 7 with, of course, the ethanol reactant being replaced by methanol. The ~ntermediate phenylacetimidate had a melting point of 66-74C and the identity of the desired product was confirmed by I.R. and t.l.c. analysis.
Example 12 .
Preparation of 3-methoxy-4-N,N-dipropylcarbamoylmethoxy-phenylacetic acid propyl ester This compound, and the intermediate phenoxyacetimide, were prepared according to the procedures detailed in Examples 8, 9 and 10, with, of course, the appropriate change in reactants.
The intermediate phenoxyacetamide W2S found to have a melting point of 35-37C and the corresponding phenyl-acetimidate hydrochloride of 73-80C. The identity of the desired product was confirmed by I.R. and t.l.c. analysis~
. .
suspension resulted and this was stirred at 20-25C for three hours and the resulting white solid (3.9 g - 72% theory) filtered off and dried. This was the desired product having a melting point of 116-117C.
Example 8 Preparation of N,N-dimethyl 2-~2'-methoxy-~'-cyanomethyl~-phenoxyacetamide via Route A
A solution of 0.66 g of sodium in 41 ml of ethanol lX was added to a solution of 4.7 y of 3-methoxy-4-hydroxy-benzyl cyanide in 21 ml of ethanol IX. After the addition of 3.5 g of N,N-dimethylchloracelamide, the mixture was ref~uxed for one hour. The alcohol was distilled off and water added to the oi1y residue. The mixture was extracted se~eral times with ethyl acetate and the combined extracts .
1~11442 dried. Removal of the solvent gave the product as an off-white solid having a melting point of 95-lOO~C in a yield of 4.9 g, i.e. 69% of theory. A sample was recrystallized from benzene for complete analysis purposes. Melting point 107-108C.
Elemental ~,nalysis ; C H N
. .
- Calculated for :62.88 6.50 11.29 Cl3Hl6N2O3 Found :62.66 6.58 11.31 - Example 9 ...i ` Preparation of propyl 2-(3'-methoxy-4'-dimethylcarbamoyl-, . , methoxy)-phenylacetimidate hydrochloride ,.
The product of Example ~ was sub~ected to the same procedure as laid out in Example 7 above with, of course, the appropriate change in reactants. The desired product was found to have a m~lting point of from 107-110C.
Example 10 Preparation of 3-methoxy-4-N,N-diethylcarbamoylmethoxy-phenylacetic acid methyl ester Methyl 2-(3'-methoxy-4'-dimethylcarbamoylmethoxy)-phenylacetimidate hydrochloride prepared by the process of Example 9 was subjected to the same procedure as detailed in Example 6. The desired product was identified by I.R. and t.l.c. examination.
n .: .
Example 11 Preparation of 3-methGxy-4-N,N-diethylcarbamoylmethoxy-.:
phenylacetic acid methyl ester This compound, and the intermediate phenylacetimidate hydrochloride, were obtained using the procedures detailed in Examples 6 and 7 with, of course, the ethanol reactant being replaced by methanol. The ~ntermediate phenylacetimidate had a melting point of 66-74C and the identity of the desired product was confirmed by I.R. and t.l.c. analysis.
Example 12 .
Preparation of 3-methoxy-4-N,N-dipropylcarbamoylmethoxy-phenylacetic acid propyl ester This compound, and the intermediate phenoxyacetimide, were prepared according to the procedures detailed in Examples 8, 9 and 10, with, of course, the appropriate change in reactants.
The intermediate phenoxyacetamide W2S found to have a melting point of 35-37C and the corresponding phenyl-acetimidate hydrochloride of 73-80C. The identity of the desired product was confirmed by I.R. and t.l.c. analysis~
. .
Claims (24)
1. A process for the preparation of 3-methoxy-4-carbamoylmethoxy-phenylacetic acid esters of the general formula:
.....I
wherein each of R1 and R2 represent lower alkyl and may be the same or different; and R3 represents lower alkyl, which comprises hydrolyzing by any known procedure, a compound of the general formula:
.....II
wherein R1, R2 and R3 are as defined hereinbefore and X represents halogen.
.....I
wherein each of R1 and R2 represent lower alkyl and may be the same or different; and R3 represents lower alkyl, which comprises hydrolyzing by any known procedure, a compound of the general formula:
.....II
wherein R1, R2 and R3 are as defined hereinbefore and X represents halogen.
2. A process according to claim 1 wherein the phenylaceti-midate salts of general formula II are prepared by reacting a compound of the general formula:
....III
wherein R1 and R2 are as defined in claim 1, with (i) an acid of the general formula:
H -X
wherein X is as defined in claim 1; and (ii) an alcohol of the general formula:
wherein R3 is as defined in claim 1.
....III
wherein R1 and R2 are as defined in claim 1, with (i) an acid of the general formula:
H -X
wherein X is as defined in claim 1; and (ii) an alcohol of the general formula:
wherein R3 is as defined in claim 1.
3. A process according to claim 1 wherein the hydrolysis is effected at a temperature up to and including 80°C.
4. A process according to claim 1 wherein the hydrolysis is effected at a temperature of from 20° - 80°C.
5. A process according to claim 1 wherein the hydrolysis is effected at a temperature of from 50° - 60°C.
6. A process according to claim 2 wherein the reactants are stirred for a period of time up to and including 20 hours at a tmperature up to and including 30°C.
7. A process according to claim 6 wherein the reactants are stirred for a period of time from 10 - 20 hours at a temperature from 20°- 30°C in any known suitable solvent.
8. A process according to claim 7 wherein the solvent is the alcohol of the general formula R2-OH wherein R3 represents lower alkyl.
9. A process according to claim 2 wherein the 3-methoxy-4-carbamoylmethoxy-phenylacetic acid esters of general formula I are prepared without isolation of the phenyl-acetimidate salt of general formula II.
10. A process according to claim 1 for the preparation of 3-methoxy-4-N,N-diethylcarbamoylmethoxy-phenylacetic acid n-propyl ester wherein n-propyl [3-methoxy-4-(diethyl-carbamoly)methoxy]-phenylacetimidate hydrochloride is hydrolyzed.
11. A process according to claim 1 for the preparation of 3-methoxy-4-N,N-diethylcarbamoylmethoxy-phenylacetic acid ethyl, ester, wherein ethyl 2-(3'-methoxy-4-diethylcarba-moylmethoxy)-phenylacetimidate hydrochloride is hydrolyzed.
12. A process according to claim 1 for preparation of 3-methoxy-4-N,N- diethylcarbamoylmethoxy-phenykacetic acid methyl ester wherein methyl 2-(3'-methoxy-4'-diethylcarba-moylmethoxy)-phenylacetimidate hydrochloride is hydrolyzed.
13. A process according to claim 2 for the preparation of 3-methoxy-4-N,N-diethylcarbamoylmethoxy-phenylacetic acid methyl ester wherein N,N-diethyl-2-(3'-methoxy-4'-cyanomethyl) -phenoxyacetamide is reacted with a solution of hydrogen chloride in methanol and the resulting methyl 2-(3'-methoxy-4'-diethylcarbamoylmethoxy)-phenylacetimidate hydrochloride is hydrolyzed.
14. A process according to claim 2 for the preparation of 3-methoxy-4-N,N-dipropylcarbamoylmethoxy-phenylacetic acid propyl ester wherein N,N-dipropyl-2-(3'-methoxy-4'-cyanomethyl) -phenoxyacetamide is reacted with a solution of hydrogen chloride in propanol and the resulting propyl 2-(3'-methoxy-4'-dipropylcarbamoylmethoxy)-phenylacetimidate hydrochloride is hydrolyzed.
15. A process according to claim 9 for the prepartion of 3-methoxy-4-N,N-diethylcarbamoylmethoxy-phenylacetic acid propyl ester wherein N,N-diethyl-2-(2'-methoxy-4'-cyanomethyl) -phenoxyacetamide is reacted with a solution of hydrogen chloride in propanol and the mixture reacted with water to effect the desired hydrolysis.
16. A process according to claim 2 for the preparation of 3-methoxy-4-N,N-diethylcarbamoylmethoxy-phenylacetic acid propyl ester wherein N,N-diethyl-2-(2'-methoxy-4'-cyanomethyl) -phenoxyacetamide is reacted with a solution of hydrogen chloride in n-propanol and the resulting n-propyl(3-methoxy-4-diethylcarbamoymethoxy)-phenylacetimidate hydrochloride id hydrolyzed.
17. A process according to claim 2 for the preparation of 3-methoxy-4-N,N-diethylcarbamoylmethoxy-phenylacetic acid ethyl ester wherein N,N-diethyl-2-(2'-methoxy-4'-cyanomethyl) -phenoxyacetamide is reacted with a solution of hydrogen chloride in ethanoland the resulting ethyl 2-(3'-methoxy-4'-diethylcarbamoylmethoxy)-phenylacetimidate hydrochloride is hydrolyzed.
18. A process according to claim 2 for the preparation of 3-methoxy-4,N,N-dimethylcarbamoylmethoxy-phenylacetic acid propyl ester wherein N,N-dimethyl-2-(3'-methoxy-4'-cyanomethyl) -phenoxyacetamide is reacted with a solution of hydrogen chloride in propanol and the resulting propyl 2-(3'-methoxy-4'-dimethylcarbamoylmethoxy)-phenlacetimidate hydrochloride is hydrolyzed.
19. A process according to claim 2 wherein the N,N-di-(lower alkyl)-2-(2'-methoxy-4'-cyanomethyl)-phenylacetamide of general formula III is prepared by:
(i) reacting vanillyl alcohol in any known suitable solvent with sodium cyanide to produce 3-methoxy-4-hydroxybenzyl cyanide, and reacting the so-obtained 3-methoxy-4-hydroxybenzyl cynaide in any known suitable solvent with N,N-di(lower alkyl) chloracetamide; or (ii) reacting N,N-di(lower alkyl)-2-(2'-methoxy-4'-hydroxymethyl)-phenoxyacetamide in any known suitable solvent with thionyl chloride, and reacting the so-obtained N,N-dl(lower alkyl)-2-(2'-methoxy-4'-chloromethyl)phenoxyacetamide, in any known suitable solvent, with sodium cyanide.
(i) reacting vanillyl alcohol in any known suitable solvent with sodium cyanide to produce 3-methoxy-4-hydroxybenzyl cyanide, and reacting the so-obtained 3-methoxy-4-hydroxybenzyl cynaide in any known suitable solvent with N,N-di(lower alkyl) chloracetamide; or (ii) reacting N,N-di(lower alkyl)-2-(2'-methoxy-4'-hydroxymethyl)-phenoxyacetamide in any known suitable solvent with thionyl chloride, and reacting the so-obtained N,N-dl(lower alkyl)-2-(2'-methoxy-4'-chloromethyl)phenoxyacetamide, in any known suitable solvent, with sodium cyanide.
20. A process according to claim 19(i) wherein the solvents employed for vanillyl alcohol and 3-methoxy-4-hydroxybenzyl cyanide are dimethyl formamide and ethanol, respectively.
21. A process according to claim 19(i) for the preparation of N,N-diethyl-2-(2'-methoxy-4'-cyanomethyl)-phenoxyacetamide wherein vanillyl alcohol in dimethyl formamide is reacted with sodium cyanide and the so-obtained 3-methoxy-4-hydro-benzyl cyanide, in ethanol, is reacted with N,N-diethyl-chloracetamide.
22. A process according to claim 19(i) for the preparation of N,N-dimethyl-2-(2'-methoxy-4'-cyanomethyl)-phenoxyacetamide wherein vanillyl alcohol in dimethyl formamide is reacted with sodium cyanide and so-obtained 3-methoxy-4-hydroxybenzyl cyanide, in ethanol, is reacted with N,N-dimethylchloracetamide.
23. A process according to claim 19(ii) wherein the solvent employed in the reaction of thionyl chloride with N,N-diethyl 2-(2'-methoxy-4'-hydroxymethyl)-phenoxyacetamide is methylene chloride containing dimethyl formamide and in the reaction of sodium cyanide with N,N-diethyl-2-(2'-methoxy-4'-chloromethyl) -phenoxyacetamide is dimethyl sulfoxide.
24. A process according to claim l9(ii) for the preparation of N,N-diethyl-2-(2'-methoxy-4'-cyanomethyl)-phenoxy-acetamide wherein N,N-diethyl-2-(2'-methoxy-4'-hydroxymethyl) -phenoxyacetamide is reacted with thionyl chloride and the so-obtained N,N-diethyl-2-(2'-methoxy-4'-chloromethyl)-phenoxyacetamide is reacted with sodium cyanide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB28833/76 | 1976-07-12 | ||
| GB2883376A GB1571395A (en) | 1976-07-12 | 1976-07-12 | Substituted phenyl acetic acid esters |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1111442A true CA1111442A (en) | 1981-10-27 |
Family
ID=10281896
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA282,327A Expired CA1111442A (en) | 1976-07-12 | 1977-07-08 | Substituted phenyl acetic acid esters |
Country Status (3)
| Country | Link |
|---|---|
| CA (1) | CA1111442A (en) |
| DE (1) | DE2731460A1 (en) |
| GB (1) | GB1571395A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6887866B2 (en) | 2002-01-25 | 2005-05-03 | Theravance, Inc. | Short-acting sedative hypnotic agents for anesthesia and sedation |
| PT1648413E (en) | 2003-07-23 | 2009-12-28 | Theravance Inc | Pharmaceutical compositions of short-acting sedative hypnotic agent |
-
1976
- 1976-07-12 GB GB2883376A patent/GB1571395A/en not_active Expired
-
1977
- 1977-07-08 CA CA282,327A patent/CA1111442A/en not_active Expired
- 1977-07-12 DE DE19772731460 patent/DE2731460A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| DE2731460A1 (en) | 1978-01-19 |
| GB1571395A (en) | 1980-07-16 |
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