CA1273932A - Process for production of dihydropyridine compound or salts thereof - Google Patents
Process for production of dihydropyridine compound or salts thereofInfo
- Publication number
- CA1273932A CA1273932A CA000520664A CA520664A CA1273932A CA 1273932 A CA1273932 A CA 1273932A CA 000520664 A CA000520664 A CA 000520664A CA 520664 A CA520664 A CA 520664A CA 1273932 A CA1273932 A CA 1273932A
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- CA
- Canada
- Prior art keywords
- ester
- dihydropyridine
- benzyl
- dimethyl
- pyrrolidinyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
PROCESS FOR PRODUCTION OF DIHYDROPYRIDINE COMPOUND
OR SALTS THEREOF
ABSTRACT OF THE DISCLOSURE
A process is provided for the production of (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester [III] of formula:
or pharmaceutically acceptable acid addition salts thereof which comprises:
(a) reacting (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester [II] of formula:
or salts thereof with a methyl esterifying agent:
(b) directly reacting (4S)-2,6-dimethyl-4-(m-nitro-phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester derivatives [I] of general formula:
wherein R' represents an ester residue capable of being readily split off upon hydrolysis with an alkali without affecting the other groups, with a methyl esterifying agent, or, (c) hydrolyzing the ester derivatives under an alkaline condition to give (4S)-2,6-dimethyl-4-(m-nitro-phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (35)-3-(1-benzyl-3-pyrrolidinyl) ester [II] of formula:
OR SALTS THEREOF
ABSTRACT OF THE DISCLOSURE
A process is provided for the production of (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester [III] of formula:
or pharmaceutically acceptable acid addition salts thereof which comprises:
(a) reacting (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester [II] of formula:
or salts thereof with a methyl esterifying agent:
(b) directly reacting (4S)-2,6-dimethyl-4-(m-nitro-phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester derivatives [I] of general formula:
wherein R' represents an ester residue capable of being readily split off upon hydrolysis with an alkali without affecting the other groups, with a methyl esterifying agent, or, (c) hydrolyzing the ester derivatives under an alkaline condition to give (4S)-2,6-dimethyl-4-(m-nitro-phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (35)-3-(1-benzyl-3-pyrrolidinyl) ester [II] of formula:
Description
393~
PROCESS FOR PRODUCTION OF DIHYDROPYRIDINE
COMPOUND OR SALTS T~EREOF
This invention relates to a process for production of optically active dihydropyridine compound or salts thereof which are useful as medicines.
It is reported that 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3~ benzyl-pyrrolidln-3-yl) ester 5-methyl ester having a chemical structure described below possesses a vasodilating and hypotensive effect and the effect is durative (U.S. Patent 4,220,649 or British Patent 2,014,134).
~, ~rO..
CH3~CC ~ COO
C'dt-~
This compound has 2 asymmetric carbon atoms. From a stereochemical viewpoint, it is assumed that isomers based on these asymmetric carbon atoms would be present. However, the patents supra are silent on these isomers and the existence of the isomers are yet unconfirmed.
/r~
~3~32 The present inventors previously separated diastereomer A and diastereomer B of this compound for the first time and found that diastereomer A showed specific pharmacological effects much superior to those of diastereomer B and a mi~ture of both diastereomers (Canadian Patent Application No. 479,294.
The present inventors further found that a degtro-rotatory optical isomer of diastereomer A having a melting point of 223 to 230DC as the hydrochloride could be produced by subjecting this compound obtained by, e.g., reacting m-nitrobenzaldehyde, l-benzyl-3-acetoaceto~ypyrrolidine and methyl 3-aminocrotonate, etc. to column chromatography using silica gel as a carrier and ethyl acetate-acetic acid as an eluent to separate diastereomer A therefrom and then performing optical resolution of diastereomer A using L~ malic acid, etc. and that his isomer had specific pharmacological effects much more excellent than those of its levo-rotatory optical isomer and a mixture of both isomers (Canadian Patent Application No. 479,29~).
Now a process -for production of the dextro-rotatory optical isomer (d-form of diastereomer A) of this novel and useful 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester or salts thereof has been investigated and as a result, it has been found that the yield of the isomer increases and this invention has thus been attained. Namely, this invention is directed to a process for production of (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester [III] of formula:
. ~ H
H3COOC ~ CGO
C.~ ~
or pharmaceutically acceptable acid addition salts thereof which comprises reacting (4S)-2,6-dimethyl-4-tm-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester CII] of formula:
~07 E E
~OOC~¢CCO
H, C N C~
c-~ ~
~2~39~;~
or salts thereof with a methyl esterifying agent; and, a process for production of (4S)--2,6-dimethyl-4-(m-nitrophenyl)-1,4-dlhydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester [III] or pharmaceutically a~ceptable salts thereof.which comprises:
(a) directly reacting (4S)-2,6 dimethyl-4-(m-nitro-phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)~3-(1-benzyl-3-pyrrolidinyl) ester derivatives [I] of general formula:
~ NO7 R OOC ~ COO
ca~ ~
wherein R' represents an ester residue capable of being readily split off upon hydrolysis with an alkali without affecting the other groups, with a methyl esterifying agent, or, (b) hydrolyzing the ester derivatives under an alkaline condition to give (4S)-2,6-dimethyl-4-(m-nitro-phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-73'9~
benzyl-3-pyrrolidlnyl) ester [II] of formula:
~a~ :
, ~ H
c~coa ~, C~N l C~3 ~N~
C~ ~3 or salts thereof and then reacting the compound [II] or salts thereof with a methyl esterifying agent.
As the pharmaceutically acceptable salts there are malonates, oxala-tes, p-nitrobenzoates, 2-ketoglutarates, maleates, dl-malates, phosphates, hydrochlorides, sulfates and p-toluenesulfonates.
The raw compounds [I] and [II] used in the process of this invention are novel compounds, planar structures of which have not been described in any publication. Further these raw compounds and the product ~III] are novel compounds in which asymmetric carbon atoms present on the dihydro-pyridine ring and the pyrrolidine ring both take an S-configuration.
That is, the process of this invention comprises using compounds having a specific configuration as raw compounds and subjecting the raw compounds to methyl esterification ~?;j93~
directly or after hydrolysis, without affecting the configuration, to give the corresponding products.
Hereafter the process of this invention is illustrated below.
Hydrolysis Step:
The hydrolysis step in the process of this invention is carried out according to the reaction shown by the following reaction equation:
~o~ ~ NO~
E E base F
R'OOC ~ CCO ~ ~ EC~C ~ COO
E3C N C~.3 ~ ~ E3C
CX~ ~3 C~
[Il [~:~
wherein R' is as defined above.
The term "ester resiue capable of being readily split off upon hydrolysis with an alkali without affecting the other groups" for R' means, e.g~, a cyanoethyl group, a phenyl group, a p-methoxyphenyl group, a p-nitrophenyl group, a 2,4-dinitrophenyl group, a pentachlorophenyl group, etc.
To perform the reaction, a base is reacted with the ester compound of general formula ~I].
As the base, there can be used an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.
~ he base is added to the compound [I] in equimolar or excess amounts. The hydrolysis is performed generally at room temperature or under cooling in an organic solvent.
As the solvent, there can be used a ketone SUC-I as acetone, methyl ethyl ketone, etc.; an alcohol such as methanol, ethanol, etc.i an ether such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.
The reaction time varies depending upon reaction temperature, kind of base and its addition amount but is approximately 10 minutes to an hour. The reaction product can be used as a raw compound at the subsequent step as it is or after it is isolated.
For isolation and purification of the product from the reaction mixture, precipitation by adjusting pH values, extraction, recrystallization, etc, are adopted.
Methyl Esterification Step:
This step is shown by the following reaction equation:
~3~3~
methyl :H esterification HOOC ~ CCO ~ ~COOC ~ COO
E3:3C N C~ ~N H3C ~r ~-I3 C~ 3 c'~3 [II] [m~
This methyl esterification can be conducted by reacting the carboxylic acid of formula [II], salts thereof or reactive derivatives of the carboxylic acid with the methyl esterifying agent. As the salts of the carboxylic acid, there may be appropriately used alkali metal salts, e.g., sodium salts, potassium salts, etc. Further, examples of the reactive derivatives of the carboxylic acid include acid halides (e.g., acid chlorides, acid bromides, etc.), acid anhydrides, acid amides, etc. As the methyl esterifying agents there are used diazomethane, methyl halides (e.g., methyl iodide, methyl bromide, etc.), methanol-hydrochloric acid, etc. The methyl esterification is generally carried out in a solvent. As the solvent, ethers, dichloromethane, chloroform, etc. can be exemplified. When methanol is used as the methyl esterifying agent, it can also be a solvent.
The solvent may be appropriately chosen depending upon kind of the methyl esterifying agent. Further in case that, for ,, ~2~3~;æ
example, methanol is used as the solvent, the addi-tion of mineral acids such as hydrogen chloride, sulfuric acid, etc., Lewis acids such as boron trifluoride, etc. provides good results.
The product ~III] can also be obtained by another process different from the foregoing one, which comprises directing reacting the compound [I] with the methyl esterifying agent to effect ester exchange. This process is advantageous in case that the ester residue for R' in the raw compound [I] is a substituted or unsubstituted phenyl ester.
According to the processes of this invention described above, the optically pure product can be obtained in a high yield, without affecting the configuration of the compound.
Further the thus obtained product in which the asymmetric carbon atoms on the dihydropyridine ring and the pyrrolidine ring have both the S-configuration exhibits much more excellent and specific pharmacological effects than those of the corresponding racemi compound, etc.
The product (diastereomer A (d-form)) and pharmaceutically acceptable acid addition salts of this invention are novel compounds that have not been described in any publication, show an area of about 40 times that of the other corresponding stereoisomer (diastereomer A
1~39~;~
(1-form)) and about 2.5 times that of an equimolar mixture of the respective isomers (dl form) in a coronary blood flow increasing rate by direct administration in the coronary artery and, also have a high affinity to the coronary artery.
Chemical names of the respective isomers are shown below:
Diastereomer A (d-form):
(4S)-2,6-Dimethyl-4-(m-nltrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester Diastereomer A (l-form):
(4R)-2,6-Dimethyl-4-(m-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid t3R)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester Diastereomer B (dl-form):
Mixture of (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3R)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester and (4R)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester The process of this invention is illustrated in more detail by the following examples.
The raw compounds used in the example are novel and their processes for production are shown in the reference example.
7~3932 Reference Example 1 (1) (S)-3-Acetoacetoxy-l-benzylpyrrolidine obtained by reacting 5.23 g of (S)-(-)-1-benzyl-3-hydroxypyrrolidine ([~]20= _~.77o, c = 5, methanol) with 2.48 g of di-ketene at 70 to 80C for 3 hours was dissolved in 20 ml of benzene.
To the solution were added 4.46 g of m-nitrobenzaldehyde,`
0.1 ml of piperidine and 0 3 ml of glacial ace~ic acid.
The mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was washed, in sequence, with 10 ml each of saturated sodium hydrogen carbonate aqueous solution and saturated saline aqueous solution. The benzene layer was concentrated under reduced pressure. The resultant oily substance was subjected to silica gel (1.2 kg was used) column chromatography and eluted with toluene-ethyl acetate (3:1 v/v) to give 8.38 g of oily (S)-l-benzyl-3-[2-(m-nitrobenzylidene)acetoacetoxy]pyrrolidine.
The product was a mixture of E- and Z-forms.
Mass spectrum m/z: 394 tM ) Nuclear magnetic resonance spectrum (CDC13, TMS internal standard, ~ppm) 1.6-3.0 (6H, broad m, CH2 at the 2,4,5-positions of the pyrrolidine ring)
PROCESS FOR PRODUCTION OF DIHYDROPYRIDINE
COMPOUND OR SALTS T~EREOF
This invention relates to a process for production of optically active dihydropyridine compound or salts thereof which are useful as medicines.
It is reported that 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3~ benzyl-pyrrolidln-3-yl) ester 5-methyl ester having a chemical structure described below possesses a vasodilating and hypotensive effect and the effect is durative (U.S. Patent 4,220,649 or British Patent 2,014,134).
~, ~rO..
CH3~CC ~ COO
C'dt-~
This compound has 2 asymmetric carbon atoms. From a stereochemical viewpoint, it is assumed that isomers based on these asymmetric carbon atoms would be present. However, the patents supra are silent on these isomers and the existence of the isomers are yet unconfirmed.
/r~
~3~32 The present inventors previously separated diastereomer A and diastereomer B of this compound for the first time and found that diastereomer A showed specific pharmacological effects much superior to those of diastereomer B and a mi~ture of both diastereomers (Canadian Patent Application No. 479,294.
The present inventors further found that a degtro-rotatory optical isomer of diastereomer A having a melting point of 223 to 230DC as the hydrochloride could be produced by subjecting this compound obtained by, e.g., reacting m-nitrobenzaldehyde, l-benzyl-3-acetoaceto~ypyrrolidine and methyl 3-aminocrotonate, etc. to column chromatography using silica gel as a carrier and ethyl acetate-acetic acid as an eluent to separate diastereomer A therefrom and then performing optical resolution of diastereomer A using L~ malic acid, etc. and that his isomer had specific pharmacological effects much more excellent than those of its levo-rotatory optical isomer and a mixture of both isomers (Canadian Patent Application No. 479,29~).
Now a process -for production of the dextro-rotatory optical isomer (d-form of diastereomer A) of this novel and useful 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester or salts thereof has been investigated and as a result, it has been found that the yield of the isomer increases and this invention has thus been attained. Namely, this invention is directed to a process for production of (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester [III] of formula:
. ~ H
H3COOC ~ CGO
C.~ ~
or pharmaceutically acceptable acid addition salts thereof which comprises reacting (4S)-2,6-dimethyl-4-tm-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester CII] of formula:
~07 E E
~OOC~¢CCO
H, C N C~
c-~ ~
~2~39~;~
or salts thereof with a methyl esterifying agent; and, a process for production of (4S)--2,6-dimethyl-4-(m-nitrophenyl)-1,4-dlhydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester [III] or pharmaceutically a~ceptable salts thereof.which comprises:
(a) directly reacting (4S)-2,6 dimethyl-4-(m-nitro-phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)~3-(1-benzyl-3-pyrrolidinyl) ester derivatives [I] of general formula:
~ NO7 R OOC ~ COO
ca~ ~
wherein R' represents an ester residue capable of being readily split off upon hydrolysis with an alkali without affecting the other groups, with a methyl esterifying agent, or, (b) hydrolyzing the ester derivatives under an alkaline condition to give (4S)-2,6-dimethyl-4-(m-nitro-phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-73'9~
benzyl-3-pyrrolidlnyl) ester [II] of formula:
~a~ :
, ~ H
c~coa ~, C~N l C~3 ~N~
C~ ~3 or salts thereof and then reacting the compound [II] or salts thereof with a methyl esterifying agent.
As the pharmaceutically acceptable salts there are malonates, oxala-tes, p-nitrobenzoates, 2-ketoglutarates, maleates, dl-malates, phosphates, hydrochlorides, sulfates and p-toluenesulfonates.
The raw compounds [I] and [II] used in the process of this invention are novel compounds, planar structures of which have not been described in any publication. Further these raw compounds and the product ~III] are novel compounds in which asymmetric carbon atoms present on the dihydro-pyridine ring and the pyrrolidine ring both take an S-configuration.
That is, the process of this invention comprises using compounds having a specific configuration as raw compounds and subjecting the raw compounds to methyl esterification ~?;j93~
directly or after hydrolysis, without affecting the configuration, to give the corresponding products.
Hereafter the process of this invention is illustrated below.
Hydrolysis Step:
The hydrolysis step in the process of this invention is carried out according to the reaction shown by the following reaction equation:
~o~ ~ NO~
E E base F
R'OOC ~ CCO ~ ~ EC~C ~ COO
E3C N C~.3 ~ ~ E3C
CX~ ~3 C~
[Il [~:~
wherein R' is as defined above.
The term "ester resiue capable of being readily split off upon hydrolysis with an alkali without affecting the other groups" for R' means, e.g~, a cyanoethyl group, a phenyl group, a p-methoxyphenyl group, a p-nitrophenyl group, a 2,4-dinitrophenyl group, a pentachlorophenyl group, etc.
To perform the reaction, a base is reacted with the ester compound of general formula ~I].
As the base, there can be used an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.
~ he base is added to the compound [I] in equimolar or excess amounts. The hydrolysis is performed generally at room temperature or under cooling in an organic solvent.
As the solvent, there can be used a ketone SUC-I as acetone, methyl ethyl ketone, etc.; an alcohol such as methanol, ethanol, etc.i an ether such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.
The reaction time varies depending upon reaction temperature, kind of base and its addition amount but is approximately 10 minutes to an hour. The reaction product can be used as a raw compound at the subsequent step as it is or after it is isolated.
For isolation and purification of the product from the reaction mixture, precipitation by adjusting pH values, extraction, recrystallization, etc, are adopted.
Methyl Esterification Step:
This step is shown by the following reaction equation:
~3~3~
methyl :H esterification HOOC ~ CCO ~ ~COOC ~ COO
E3:3C N C~ ~N H3C ~r ~-I3 C~ 3 c'~3 [II] [m~
This methyl esterification can be conducted by reacting the carboxylic acid of formula [II], salts thereof or reactive derivatives of the carboxylic acid with the methyl esterifying agent. As the salts of the carboxylic acid, there may be appropriately used alkali metal salts, e.g., sodium salts, potassium salts, etc. Further, examples of the reactive derivatives of the carboxylic acid include acid halides (e.g., acid chlorides, acid bromides, etc.), acid anhydrides, acid amides, etc. As the methyl esterifying agents there are used diazomethane, methyl halides (e.g., methyl iodide, methyl bromide, etc.), methanol-hydrochloric acid, etc. The methyl esterification is generally carried out in a solvent. As the solvent, ethers, dichloromethane, chloroform, etc. can be exemplified. When methanol is used as the methyl esterifying agent, it can also be a solvent.
The solvent may be appropriately chosen depending upon kind of the methyl esterifying agent. Further in case that, for ,, ~2~3~;æ
example, methanol is used as the solvent, the addi-tion of mineral acids such as hydrogen chloride, sulfuric acid, etc., Lewis acids such as boron trifluoride, etc. provides good results.
The product ~III] can also be obtained by another process different from the foregoing one, which comprises directing reacting the compound [I] with the methyl esterifying agent to effect ester exchange. This process is advantageous in case that the ester residue for R' in the raw compound [I] is a substituted or unsubstituted phenyl ester.
According to the processes of this invention described above, the optically pure product can be obtained in a high yield, without affecting the configuration of the compound.
Further the thus obtained product in which the asymmetric carbon atoms on the dihydropyridine ring and the pyrrolidine ring have both the S-configuration exhibits much more excellent and specific pharmacological effects than those of the corresponding racemi compound, etc.
The product (diastereomer A (d-form)) and pharmaceutically acceptable acid addition salts of this invention are novel compounds that have not been described in any publication, show an area of about 40 times that of the other corresponding stereoisomer (diastereomer A
1~39~;~
(1-form)) and about 2.5 times that of an equimolar mixture of the respective isomers (dl form) in a coronary blood flow increasing rate by direct administration in the coronary artery and, also have a high affinity to the coronary artery.
Chemical names of the respective isomers are shown below:
Diastereomer A (d-form):
(4S)-2,6-Dimethyl-4-(m-nltrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester Diastereomer A (l-form):
(4R)-2,6-Dimethyl-4-(m-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid t3R)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester Diastereomer B (dl-form):
Mixture of (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3R)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester and (4R)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester The process of this invention is illustrated in more detail by the following examples.
The raw compounds used in the example are novel and their processes for production are shown in the reference example.
7~3932 Reference Example 1 (1) (S)-3-Acetoacetoxy-l-benzylpyrrolidine obtained by reacting 5.23 g of (S)-(-)-1-benzyl-3-hydroxypyrrolidine ([~]20= _~.77o, c = 5, methanol) with 2.48 g of di-ketene at 70 to 80C for 3 hours was dissolved in 20 ml of benzene.
To the solution were added 4.46 g of m-nitrobenzaldehyde,`
0.1 ml of piperidine and 0 3 ml of glacial ace~ic acid.
The mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was washed, in sequence, with 10 ml each of saturated sodium hydrogen carbonate aqueous solution and saturated saline aqueous solution. The benzene layer was concentrated under reduced pressure. The resultant oily substance was subjected to silica gel (1.2 kg was used) column chromatography and eluted with toluene-ethyl acetate (3:1 v/v) to give 8.38 g of oily (S)-l-benzyl-3-[2-(m-nitrobenzylidene)acetoacetoxy]pyrrolidine.
The product was a mixture of E- and Z-forms.
Mass spectrum m/z: 394 tM ) Nuclear magnetic resonance spectrum (CDC13, TMS internal standard, ~ppm) 1.6-3.0 (6H, broad m, CH2 at the 2,4,5-positions of the pyrrolidine ring)
2.38, 2.40 (3H, double s, COCH3: mixture of E- and Z-forms) ~L2~739~32
3.4-3.8 (2H, m, CH2~: mixture of E- and Z-forms) 5.4 (lH, m, CH at the 3-position of the pyrrolidine ring) 7.0-8.4 (lOH, m, H and -CH= of the benzene ring) (2) In 40 ml o~ isopropanol were dissolved 3.94 g of (S)-l-benzyl-3-~2-(m-nitrobenzylidene)acetoacetoxy]-pyrrolidine and 1.54 g of (2-cyanoethyl) 3-aminocrotonate.
The mixture was heated under reflux for 20 hours. After cooling, the reaction mixture was concentrated under reduced pressure to give crude (4RS)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl)ester 5-(2-cyanoethyl) ester (hereafter referred to as "diester") in a caramel state (5.3 g: mixture of diastereomers A and B).
With respect to a free base of the thus obtained crude diester, a ratio of the diastereomers produced was analyzed under conditions described below, using high speed liquid chromatography; the ratio of diastereomer A (residence time, 20.7 minutes) to diastereomer B (residence time, 23.0 minutes) was 1:1.
Column: Nucleosil~, 5C18, 4.6 mm~ x 300 mm Mobile tetra-n-pentylammonium bromide (3 mmol)-phase: containing 0.05 mol Potassium dihydrogen phosphate (pH 3)-acetonitrile (80:20 v/v) 273~332 .
Flow speed: 0.9 ml/min Wavelength for UV
detection: 254 nm In the nuclear magnetic resonance spectrum, a difference is noted between diastereomers A and B in a signal for methylene in the,N-benzyl group of the diester.
According to the measurement in chloroform-l, diastereomer A and B show singlet signals corresponding to 2 hydrogen atoms at 3.62 ppm and 3.55 ppm, respectively.
(3) The free base of the obtained crude diester was subjected to silica gel (1.5 kg was used) column chromatography and eluted with ethyl acetate-glacial acetic acid (6:1 v/v). Fractions containing only diastereomer A
of the diester which showed the residence time of 20.7 minutes in high speed liquid chromatography were collected and concentrated under reduced pressure to give 1.7 g of the diastereomer A acetate of the diester in an oily state.
This oily substance was dissolved in 20 ml of chloroform.
The solution was washed with 10 ml of saturated sodium hydrogen carbonate aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 1.1 g of the free base of diastereomer A
of the diester in a caramel state.
Mass spectrum m/z: 531 (M+l) ~2~3~æ
Nuclear magnetic resonance spectrum (CDC13, TMS internal standard, ~ppm) 1.4-3.0 (8H, m, -CH2O and CH2 at the 2,4,5-positions of the pyrrolidine ring) 2.36, 2.4 (6H, s, CH3 at the 2,5-positions of the dihydropyridine ring) 3.62 (2H, s, N-CH2-)
The mixture was heated under reflux for 20 hours. After cooling, the reaction mixture was concentrated under reduced pressure to give crude (4RS)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl)ester 5-(2-cyanoethyl) ester (hereafter referred to as "diester") in a caramel state (5.3 g: mixture of diastereomers A and B).
With respect to a free base of the thus obtained crude diester, a ratio of the diastereomers produced was analyzed under conditions described below, using high speed liquid chromatography; the ratio of diastereomer A (residence time, 20.7 minutes) to diastereomer B (residence time, 23.0 minutes) was 1:1.
Column: Nucleosil~, 5C18, 4.6 mm~ x 300 mm Mobile tetra-n-pentylammonium bromide (3 mmol)-phase: containing 0.05 mol Potassium dihydrogen phosphate (pH 3)-acetonitrile (80:20 v/v) 273~332 .
Flow speed: 0.9 ml/min Wavelength for UV
detection: 254 nm In the nuclear magnetic resonance spectrum, a difference is noted between diastereomers A and B in a signal for methylene in the,N-benzyl group of the diester.
According to the measurement in chloroform-l, diastereomer A and B show singlet signals corresponding to 2 hydrogen atoms at 3.62 ppm and 3.55 ppm, respectively.
(3) The free base of the obtained crude diester was subjected to silica gel (1.5 kg was used) column chromatography and eluted with ethyl acetate-glacial acetic acid (6:1 v/v). Fractions containing only diastereomer A
of the diester which showed the residence time of 20.7 minutes in high speed liquid chromatography were collected and concentrated under reduced pressure to give 1.7 g of the diastereomer A acetate of the diester in an oily state.
This oily substance was dissolved in 20 ml of chloroform.
The solution was washed with 10 ml of saturated sodium hydrogen carbonate aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 1.1 g of the free base of diastereomer A
of the diester in a caramel state.
Mass spectrum m/z: 531 (M+l) ~2~3~æ
Nuclear magnetic resonance spectrum (CDC13, TMS internal standard, ~ppm) 1.4-3.0 (8H, m, -CH2O and CH2 at the 2,4,5-positions of the pyrrolidine ring) 2.36, 2.4 (6H, s, CH3 at the 2,5-positions of the dihydropyridine ring) 3.62 (2H, s, N-CH2-)
4.28 (2H, t, -CHzCN)
5.10 (lH, s, H at the 4-position of the dihydropyridine ring) 5.0-5.3 (lH, m, H at the 3-position of the pyrrolidine ring) 5.86 (lH, m, NH) 7.1-8.2 (9H, m, H of the benzene ring) The signal ( ~3.55) for N-CH2 in diastereomer B of the diester is not detected.
Example 1 (a) In 6 ml of 1,2-dimethoxyethane was dissolved 0.9 g of the free base of diastereomer A of the diester.
While stirring the solution under ice cooling, 5.1 ml of lN-sodium hydroxide aqueous solution was dropwise added thereto followed by stirring at 0 to 5C for 30 minutes.
The reaction mixture was diluted with 30 ml of water. The dilution was washed twice with 15 ml each of chloroform.
-- 1~ --~2~93~ .
After chloroform contained in the aqueous phase was removed under reduced pressure, 5.7 ml of lN-hydrochloric acid was added to the system under ice cooling to render the pH 4 to 5. The obtained precipitates were taken out by filtration (0.68 g). The precipitates were recrsytallized from 3.4 ml of methanol to give 0.6 g of (4S)-2,6-dimethyl-4-(m-~itrophenyl)-1,4-dihydropyridine-3,5-dicar~oxylic acid t3S)-3-(l-benzyl-3-pyrrolidinyl) ester hydrochloride monohydrate.
Melting point, 174-176 C (decomposed) Elemental analysis (as C26H27N306.HCl.H20) C(%) H(%) N(%) Cl(%) Calcd. 58.70 5.68 7.90 6.66 Found 58.66 5.64 7.97 6.65 ~]D = + 146.5 (c=l, methanol) Nuclear magnetic resonance spectrum (CD30D, TMS internal standard, ~ppm) 1.9-2.6 (2H, m, CH2 at the 4-position of the pyrrolidine ring) 2.33, 2.35 (6H, s, CH3 at the 2,6-positions of the dihydropyridine ring) 3.3-3.9 (4H, m, CH2 at the 2,5-positions of the pyrrolidine ring) 4.40 (2H, s, N-CH2) 5.08 (lH, s, H at the 4-position of the ~273~32 dihydropyridine ring) 5.1-5.4 (lH, m, H at the 3-position of the pyrrolidine ring) 7.3-8 2 (9H, m, H-of the benzene ring) (b) In 30 ml of methanol was dissolved 230 mg of (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester hydrochloride monohydrate. ~hile stirring the solution at room temperature, 10 ml of a solution of diazomethane in ether was added thereto and the mixture was stirred for further 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 10 ml of chloroform. The solution was treated with saturated sodium hydrogen carbonate aqueous solution, water and then lN
hydrochloric acid. After drying the chloroform layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in 0.5 ml of methanol with heating and then ice-cooled overnight. The precipitated crystals were taken by filtration to give 180 mg of (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester hydrochloride. The thus obtained hydrochloride shows the following physico-chemical properties.
~257~93;;~
Melting point, 228-230 C (decomposed) Elemental analysis (as C27H30N3O6Cl) C(%) H(%) N(%) Cl(%) Calcd. 61.42 5.73 7.96 6.71 Found 61 25 5.67 7.95 6.92 ~]2D0= ~ 116.2 (~c=1, methanol) Nuclear magnetic resonance spectrum (CD30D, TMS internal standard, ~ppm) 1.8-2.7 (2H, m, CH2 at the 4-position of the pyrrolidine ring) 2.32, 2.34 (6H, s, CH3 at the 2,6-positions of the dihydropyridine ring) 3.0-4.0 (4H, m, CH2 at the 2,5-positions of the pyrrolidine ring) 3.64 (3H, s, COOCH3) 4.42 (2H, s, N-CH2) 5.08 (lH, s, H at the 4-position of the dihydropyridine ring) 5.1-5.5 (lH, m, H at the 3-position of the pyrrolidine ring) 7.3-8.2 (9H, m, H of the benzene ring) The thus obtained (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)~3-(1-benzyl-~L273~
3-pyrrolidinyl) ester 5-methyl ester hydrochloride was measured by high speed liquid chromatography as in Reference Example 1 (2); only the peak showing diastereomer A having the residence time of 28 minutes was observed but the peak showing diastereomer B having the residence time of 29 minutes was not.
Example 1 (a) In 6 ml of 1,2-dimethoxyethane was dissolved 0.9 g of the free base of diastereomer A of the diester.
While stirring the solution under ice cooling, 5.1 ml of lN-sodium hydroxide aqueous solution was dropwise added thereto followed by stirring at 0 to 5C for 30 minutes.
The reaction mixture was diluted with 30 ml of water. The dilution was washed twice with 15 ml each of chloroform.
-- 1~ --~2~93~ .
After chloroform contained in the aqueous phase was removed under reduced pressure, 5.7 ml of lN-hydrochloric acid was added to the system under ice cooling to render the pH 4 to 5. The obtained precipitates were taken out by filtration (0.68 g). The precipitates were recrsytallized from 3.4 ml of methanol to give 0.6 g of (4S)-2,6-dimethyl-4-(m-~itrophenyl)-1,4-dihydropyridine-3,5-dicar~oxylic acid t3S)-3-(l-benzyl-3-pyrrolidinyl) ester hydrochloride monohydrate.
Melting point, 174-176 C (decomposed) Elemental analysis (as C26H27N306.HCl.H20) C(%) H(%) N(%) Cl(%) Calcd. 58.70 5.68 7.90 6.66 Found 58.66 5.64 7.97 6.65 ~]D = + 146.5 (c=l, methanol) Nuclear magnetic resonance spectrum (CD30D, TMS internal standard, ~ppm) 1.9-2.6 (2H, m, CH2 at the 4-position of the pyrrolidine ring) 2.33, 2.35 (6H, s, CH3 at the 2,6-positions of the dihydropyridine ring) 3.3-3.9 (4H, m, CH2 at the 2,5-positions of the pyrrolidine ring) 4.40 (2H, s, N-CH2) 5.08 (lH, s, H at the 4-position of the ~273~32 dihydropyridine ring) 5.1-5.4 (lH, m, H at the 3-position of the pyrrolidine ring) 7.3-8 2 (9H, m, H-of the benzene ring) (b) In 30 ml of methanol was dissolved 230 mg of (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester hydrochloride monohydrate. ~hile stirring the solution at room temperature, 10 ml of a solution of diazomethane in ether was added thereto and the mixture was stirred for further 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 10 ml of chloroform. The solution was treated with saturated sodium hydrogen carbonate aqueous solution, water and then lN
hydrochloric acid. After drying the chloroform layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in 0.5 ml of methanol with heating and then ice-cooled overnight. The precipitated crystals were taken by filtration to give 180 mg of (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester hydrochloride. The thus obtained hydrochloride shows the following physico-chemical properties.
~257~93;;~
Melting point, 228-230 C (decomposed) Elemental analysis (as C27H30N3O6Cl) C(%) H(%) N(%) Cl(%) Calcd. 61.42 5.73 7.96 6.71 Found 61 25 5.67 7.95 6.92 ~]2D0= ~ 116.2 (~c=1, methanol) Nuclear magnetic resonance spectrum (CD30D, TMS internal standard, ~ppm) 1.8-2.7 (2H, m, CH2 at the 4-position of the pyrrolidine ring) 2.32, 2.34 (6H, s, CH3 at the 2,6-positions of the dihydropyridine ring) 3.0-4.0 (4H, m, CH2 at the 2,5-positions of the pyrrolidine ring) 3.64 (3H, s, COOCH3) 4.42 (2H, s, N-CH2) 5.08 (lH, s, H at the 4-position of the dihydropyridine ring) 5.1-5.5 (lH, m, H at the 3-position of the pyrrolidine ring) 7.3-8.2 (9H, m, H of the benzene ring) The thus obtained (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)~3-(1-benzyl-~L273~
3-pyrrolidinyl) ester 5-methyl ester hydrochloride was measured by high speed liquid chromatography as in Reference Example 1 (2); only the peak showing diastereomer A having the residence time of 28 minutes was observed but the peak showing diastereomer B having the residence time of 29 minutes was not.
Claims (3)
1. A process for producing (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester or a pharmaceutically acceptable salt thereof which comprises:
a) directly reacting an (4S)-2,6-dimethyl-4-(m-nitro-phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl 3-pyrrolidinyl) ester derivative of general formula:
wherein R' represents an ester residue capable of being readily split off upon hydrolysis with an alkali without affecting the other groups, with a methyl esterifying agent, or, b) hydrolyzing said ester derivative under an alkaline condition to give (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester or a salt thereof and then reacting the ester or a salt thereof with a methyl esterifying agent.
a) directly reacting an (4S)-2,6-dimethyl-4-(m-nitro-phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl 3-pyrrolidinyl) ester derivative of general formula:
wherein R' represents an ester residue capable of being readily split off upon hydrolysis with an alkali without affecting the other groups, with a methyl esterifying agent, or, b) hydrolyzing said ester derivative under an alkaline condition to give (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester or a salt thereof and then reacting the ester or a salt thereof with a methyl esterifying agent.
2. The process according to claim 1 which comprises reacting (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-
3-pyrrolidinyl) ester or a salt thereof with a methyl esterifying agent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP23426885 | 1985-10-19 | ||
| JP234,268/1985 | 1985-10-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1273932A true CA1273932A (en) | 1990-09-11 |
Family
ID=16968304
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000520664A Expired - Fee Related CA1273932A (en) | 1985-10-19 | 1986-10-16 | Process for production of dihydropyridine compound or salts thereof |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS62174071A (en) |
| KR (1) | KR960016525B1 (en) |
| AT (1) | AT395976B (en) |
| CA (1) | CA1273932A (en) |
| ES (1) | ES2002208A6 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU6229099A (en) * | 1998-10-23 | 2000-05-15 | Ajinomoto Co., Inc. | Dihydropyridine derivatives and drug compositions containing the same |
| ITMI20130148A1 (en) * | 2013-02-01 | 2014-08-02 | Chemo Iberica Sa | NEW POLYLORPHONE OF BARNIDIPINE CHLORIDRATE AND METHOD FOR ITS PREPARATION |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55301A (en) * | 1978-02-14 | 1980-01-05 | Yamanouchi Pharmaceut Co Ltd | 1,4-dihydropyridine-3,5-dicarboxylic ester derivative and its preparation |
-
1986
- 1986-10-08 AT AT0267686A patent/AT395976B/en active
- 1986-10-15 KR KR1019860008622A patent/KR960016525B1/en not_active IP Right Cessation
- 1986-10-15 JP JP61246366A patent/JPS62174071A/en active Pending
- 1986-10-16 CA CA000520664A patent/CA1273932A/en not_active Expired - Fee Related
- 1986-10-17 ES ES8602659A patent/ES2002208A6/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| AT395976B (en) | 1993-04-26 |
| KR870004020A (en) | 1987-05-06 |
| ES2002208A6 (en) | 1988-07-16 |
| ATA267686A (en) | 1992-09-15 |
| KR960016525B1 (en) | 1996-12-14 |
| JPS62174071A (en) | 1987-07-30 |
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