CA1273931A - Process for production of the dextrorotatory optical isomer of diastereomer a of ym-09730 - Google Patents
Process for production of the dextrorotatory optical isomer of diastereomer a of ym-09730Info
- Publication number
- CA1273931A CA1273931A CA000492966A CA492966A CA1273931A CA 1273931 A CA1273931 A CA 1273931A CA 000492966 A CA000492966 A CA 000492966A CA 492966 A CA492966 A CA 492966A CA 1273931 A CA1273931 A CA 1273931A
- Authority
- CA
- Canada
- Prior art keywords
- optical isomer
- diastereomer
- dextrorotatory
- mixture
- solution
- 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.)
- Expired
Links
Classifications
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
A B S T R A C T
The present invention relates to the dextrorotatory, optical isomer of diastereomer A of (+)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(1-benzylpyrrolidin-3-yl) ester 5-methyl ester, the pharmaceutically acceptable acid addition salts thereof, and a process for their preparation. The process comprises reacting a levorotatory, optical isomer or a racemate of 5-methoxycarbonyl-2,6-dimethyl-4(m-nitrophenyl)-1,4-dihydro-pyridine-3-carboxylic acid or a reactive derivative thereof, with a levorotatory, optical isomer or a racemate of 1-benzyl-3-hydroxy-pyrrolidine. The compound of this invention is useful as a blood vessel dilator.
The present invention relates to the dextrorotatory, optical isomer of diastereomer A of (+)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(1-benzylpyrrolidin-3-yl) ester 5-methyl ester, the pharmaceutically acceptable acid addition salts thereof, and a process for their preparation. The process comprises reacting a levorotatory, optical isomer or a racemate of 5-methoxycarbonyl-2,6-dimethyl-4(m-nitrophenyl)-1,4-dihydro-pyridine-3-carboxylic acid or a reactive derivative thereof, with a levorotatory, optical isomer or a racemate of 1-benzyl-3-hydroxy-pyrrolidine. The compound of this invention is useful as a blood vessel dilator.
Description
SPECIFICATION
Title of the Invention A NOVEL PROCESS FOR PRODUCTION OF THE DEXTROROTATORY
Detailed Explanation of the Invention:
The present invention relates to a novel process for production of the dextrorotatory, optical isomer of diaste-reomer A of YM-09730 useful as a blood vessel dilator and its pharmaceutically acceptable acid addition sslt.
YM-09730 is given a chemical name of 2,6-dimethyl-4-(m-nitrophenyl)-1,4,-dihydropyridine-3,5-dicarboxylic acid 3-(1-benzylpyrrolidin-3-yl) ester 5-methyl ester which is a dihydropyridine-3,5-dicarboxylic acid ester derivative represented by the following chemical structure:
G~NC)2 3 ~ COO
H CH2 ~9 It is reported that YM-09730 possesses a blood vessel dilating activity and blood pressure reducing activity with long durability (United States Patent No. 4,220,649).
YM 09730 possesses two asymmetric carbon atoms and it is assumed that isomers would be present based on these asymmetric carbon atoms from a viewpoint of stereochemistry.
~.
HoweveT7 the presence Or isome-s is unver~ie~ foT lac~
of the desc~ip~ion about isome~s in ~he above publica;ion.
Previously, some of ~he p~esent invento.s separated diastereomer A of YM-09730 from diastereomeT B thereof foT the fi~st time and found out that isome~ A exhibits much mo~e excellent peculiar pharmacological effects as compared to isome~ B o~ a mixture of both isomers Ca~adia~ Patent Application No. 479,294 They have fur~he~ found that the dextrorotatory, op~ical isome~,-the meltin-g-point of the hydrochlori~e -thereof being 223 to 230~C (decomp.), of diasteTeomer A
can be produced by a method which comprises reac~in~ m-nitroben-aldehyde, l-benzyl~3--acetoacetoxypyrTolidine and methyl 3-aminoclotonate, subjecting the thus obtained ~1-09730 to cloumn chToma~ography using silica gel ~s a carrier znd ethyl acetate-acetic acid as an eluent to separate dizsLeTomeT A and, then effecting op,ical resol~.ion of dizs~ereomer A using L-(-~-malic acid, and that the thus obtained isomer possesses much more excellent peculiar phaTmacologiczl effe'cts zs compared to the levorotatoTy, optical isomer OT a mixture of these both ~somers Car adian Patent Application No. ~79,294 -As i result'of';nvestïgations on a process foT
production of this novel and useful dext~oTotatory, -~ ~ -optical-isomeT of diaste~eomeT-A-of YM-09730, a process for imp~oving the yield of the desired isomer has been found and, the pTesent invention has been accomplished.
~?
~.~i ' 41_", g3~L
Here, diastereomer A ~dl-mixture) the hydro-chloride of which shows the melting point of 200 to 206C (decomp.) is clearly distinguishabie from diaste-reomer B the hydrochloride of which shows the melting point of 180 to 185C ~decomp.).
Also, the hydrochloride of the dextrorotatory, optical isomer of diastereomer A shows the melitng point of 223 to 230C (decomp.) as indicated above.
The present invention provides the new process for production of-the dextrorotatory, optical isomer of diastereomer A of YM-09730 defined by sald melting point of its hydrochloride, or a pharmaceutically acceptab'le-acld,ad'dit.i'on sa,lt-...thereof. The pharmaceuti-.
cally acceptable acid addition salt referred to herein includes an organic acid salt such as an L-(-)-malate~
etc. and a mineral acid salt such as hydrochloride~ etcO
---The dextrorotatory optica-l isomer (I) of diastereo-mer A of the present invention can be produced by reacting a levorotatory, optical isomer or a racemate of 5-methoxycarbonyl-2,6-dimethyl-~-(m-nitrophenyl)-194-dihydropyridine-3-carboxylic acid shown by formula ( f I) o f~a2 ~ (~) ----- - ,, ' .::'~~' ~;c~a ~ C~a~
E~C E ^ C--3 ~`3~
or a reactive derivative thereof with a levorotatory, optical isomer or a racemate of 1-ben~yl-3-hydroxy-pyrrolidine shown by the formula (III):
Ho ~
NJ (III) CH ~
This reaction involves the formation of a carboxylic acid ester and generally applicable methods can appropria-tely be used. No stereochemical inversion occurs in this reaction. Examples of the reactive derivative of compound (II) include an acid halide such as an acid chloride, an acid bromide, etc.; an acid anhydride, a mixed acid anhydride, an active ester and the like. In case that compound ~II) is employed in the form of a free carboxylic acid, the reaction is carried out in the presence of a con~ensing agent such as dicyclohexyl-carbodiimide, etc.
The reaction is advantageously carried out in an organic solvent such as methylene chloride, dimethylform-amide, etc. under cooling or at room temperature.
When both the starting materials, compounds (II) and (III), are levorotatory, optical isomers, the reaction product comprises essentially only the dextrorotatory, optical isomer of diastereomer A and the isomer can be isolated from the reaction mixture in a conventional manner ~33~3~
J~ , such as extraction, concentration, etc., or by column chromatography, if necessary. When at least one of compounds (II) and (~II) is a racemate, the resultant reaction mixture includes the desired dextrorotatory optical isomer of diastereomer A as well as the levorotatory optical isomer thereof, the levo- or dextrorotatory isomers of diastereomer B, etc. and the desired isomer can be isolated from the reaction mixture by column chromatography or fractional crystallization.
For example, the obtained mixture of the dextrorotatory, optical isomer of diastereomer A and the levorotatory, optical isomer B of YM-09730 is subjected to column chromatography using silica gel as a carrier and ethyl acetate-acetic acid as an eluent, whereby the dextrorotatory, optical isomer of diastereomer A of YM-09730 is separated from the mixture. Alternatively, the mixture is reacted with L-(-)-malic acid and, the thus obtained L-(-)-malates of the dextrorotatory, optical isomer of diastereomer A and the levorotatory, optical isomer of diastereomer B are fractionally recrystallized to obtain L-(-)-malate of the dextrorotatory, optical isomer of diastereomer A.
In the separation by means of column chromatography, the dextrorotatory, optical isomer of diastereomer A can be obtained from the first eluate and from the later eluate, the levorotatory, optical isomer of diastereomer B can be obtained. There is no particular limitation to silica gel used as a carrier as long as it is generally employed in ; !
column chromatography. A mixing ratio of ethyl acetate and acetic acid which is an eluent is not particularly limited but, it is generally preferred that ethyl acetate can be used as a major component and a small quantity of acetic acid can be mixed therewith. It is advantageous that the mixing ratio is approximately 1 to 10 v/v of acetic acid to 30 to 50 v/v of ethyl acetate. When the ratio of acetic acid to be mixed decreases, a time period of eluting the desired compound out is prolonged.
A rate of elution and temperature for treatment may be appropriately adopted.
On the other hand, the method using L-(-)-malic acid is also applicable to separation of the dextrorotatory, optical isomer of diastereomer A through fractional recrystalli-zation since L-(-~-malate of the dextrorotatory optical isomer of diastereomer A is crystalline. As the solvents which can be employed for the fractional recrystallization, methanol, ethanol, ace-tone, aceonitrile, etc. may be mentioned.
The thus obtained L-(-)-malate of the dextrorotatory, optical isomer of diastereomer A can be provided as drugs as they are, but acetate of this isomer and the like may optionally be treated with a base to form a free form, which is then treated with an appropriate acid to lead to suitable other salts.
~3~
The dextrorotatory, optical isomer of diastereomer A of YM-09730 and pharmaceutically acceptable acid addition salts thereof which are the aimed compounds of the present invention are novel compounds that have not been described in any publication and, show an area ratio increased by approximately 40 times over that of the levorotatory, optical isomer (l-form) and an area ratio increased by 2.5 times over that of an equivalent mixture of both isomers (dl-form), in a ra-te of increasing coronary blood flow through direct administration to the coronary arteries and, in addition, have high affinity to the coronary artery.
Accordlng to the process of the present invention, the dextrorotatory, op-tical isomer of diastereomer A of YM-09730 which is novel and useful can be selectively produced in a good yield and, is of extremely high utility value from an industrial viewpoint.
Hereafter, the present invention will be described in more detail with reference to the Examples. The raw compounds (II) and (III) used in the present invention are recognized to be known compounds; however, in application to the present invention, the raw compounds could be produced by novel, useful processes, which are shown as Reference Examples.
Reference Example 1 (1) A solution of 6.04 g of m-nitrobenzaldehyde, 6.32 g of tert-butyl acetoacetate, 0.17 g of piperidine and 0.6 ml of acetic acid in 20 ml of benzene was heated under reflux for 6 hours using an apparatus for azeotropic dehydration.
.~
After cooling the system, 10 ml of water were added thereto and the benzene layer was fractioned. After washing the benzene layer successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, the benzene layer was dried over anhydrous magnesium sulfate. After the solvent was removed by distillatior- under reduced pressure, the resulting residue was subjected to silica gel column chromatography. The crystals obtained from a portion eluted with n-hexane:ethyl acetate (5:1 volume ratio) were washed with n-hexane to obtain 5.82 g of a mixture of geometric isomers of tert-butyl 2-(m-nitrobenzylidene)acetoacetate as colorless crystals.
Melting point: 33 - 36C
Title of the Invention A NOVEL PROCESS FOR PRODUCTION OF THE DEXTROROTATORY
Detailed Explanation of the Invention:
The present invention relates to a novel process for production of the dextrorotatory, optical isomer of diaste-reomer A of YM-09730 useful as a blood vessel dilator and its pharmaceutically acceptable acid addition sslt.
YM-09730 is given a chemical name of 2,6-dimethyl-4-(m-nitrophenyl)-1,4,-dihydropyridine-3,5-dicarboxylic acid 3-(1-benzylpyrrolidin-3-yl) ester 5-methyl ester which is a dihydropyridine-3,5-dicarboxylic acid ester derivative represented by the following chemical structure:
G~NC)2 3 ~ COO
H CH2 ~9 It is reported that YM-09730 possesses a blood vessel dilating activity and blood pressure reducing activity with long durability (United States Patent No. 4,220,649).
YM 09730 possesses two asymmetric carbon atoms and it is assumed that isomers would be present based on these asymmetric carbon atoms from a viewpoint of stereochemistry.
~.
HoweveT7 the presence Or isome-s is unver~ie~ foT lac~
of the desc~ip~ion about isome~s in ~he above publica;ion.
Previously, some of ~he p~esent invento.s separated diastereomer A of YM-09730 from diastereomeT B thereof foT the fi~st time and found out that isome~ A exhibits much mo~e excellent peculiar pharmacological effects as compared to isome~ B o~ a mixture of both isomers Ca~adia~ Patent Application No. 479,294 They have fur~he~ found that the dextrorotatory, op~ical isome~,-the meltin-g-point of the hydrochlori~e -thereof being 223 to 230~C (decomp.), of diasteTeomer A
can be produced by a method which comprises reac~in~ m-nitroben-aldehyde, l-benzyl~3--acetoacetoxypyrTolidine and methyl 3-aminoclotonate, subjecting the thus obtained ~1-09730 to cloumn chToma~ography using silica gel ~s a carrier znd ethyl acetate-acetic acid as an eluent to separate dizsLeTomeT A and, then effecting op,ical resol~.ion of dizs~ereomer A using L-(-~-malic acid, and that the thus obtained isomer possesses much more excellent peculiar phaTmacologiczl effe'cts zs compared to the levorotatoTy, optical isomer OT a mixture of these both ~somers Car adian Patent Application No. ~79,294 -As i result'of';nvestïgations on a process foT
production of this novel and useful dext~oTotatory, -~ ~ -optical-isomeT of diaste~eomeT-A-of YM-09730, a process for imp~oving the yield of the desired isomer has been found and, the pTesent invention has been accomplished.
~?
~.~i ' 41_", g3~L
Here, diastereomer A ~dl-mixture) the hydro-chloride of which shows the melting point of 200 to 206C (decomp.) is clearly distinguishabie from diaste-reomer B the hydrochloride of which shows the melting point of 180 to 185C ~decomp.).
Also, the hydrochloride of the dextrorotatory, optical isomer of diastereomer A shows the melitng point of 223 to 230C (decomp.) as indicated above.
The present invention provides the new process for production of-the dextrorotatory, optical isomer of diastereomer A of YM-09730 defined by sald melting point of its hydrochloride, or a pharmaceutically acceptab'le-acld,ad'dit.i'on sa,lt-...thereof. The pharmaceuti-.
cally acceptable acid addition salt referred to herein includes an organic acid salt such as an L-(-)-malate~
etc. and a mineral acid salt such as hydrochloride~ etcO
---The dextrorotatory optica-l isomer (I) of diastereo-mer A of the present invention can be produced by reacting a levorotatory, optical isomer or a racemate of 5-methoxycarbonyl-2,6-dimethyl-~-(m-nitrophenyl)-194-dihydropyridine-3-carboxylic acid shown by formula ( f I) o f~a2 ~ (~) ----- - ,, ' .::'~~' ~;c~a ~ C~a~
E~C E ^ C--3 ~`3~
or a reactive derivative thereof with a levorotatory, optical isomer or a racemate of 1-ben~yl-3-hydroxy-pyrrolidine shown by the formula (III):
Ho ~
NJ (III) CH ~
This reaction involves the formation of a carboxylic acid ester and generally applicable methods can appropria-tely be used. No stereochemical inversion occurs in this reaction. Examples of the reactive derivative of compound (II) include an acid halide such as an acid chloride, an acid bromide, etc.; an acid anhydride, a mixed acid anhydride, an active ester and the like. In case that compound ~II) is employed in the form of a free carboxylic acid, the reaction is carried out in the presence of a con~ensing agent such as dicyclohexyl-carbodiimide, etc.
The reaction is advantageously carried out in an organic solvent such as methylene chloride, dimethylform-amide, etc. under cooling or at room temperature.
When both the starting materials, compounds (II) and (III), are levorotatory, optical isomers, the reaction product comprises essentially only the dextrorotatory, optical isomer of diastereomer A and the isomer can be isolated from the reaction mixture in a conventional manner ~33~3~
J~ , such as extraction, concentration, etc., or by column chromatography, if necessary. When at least one of compounds (II) and (~II) is a racemate, the resultant reaction mixture includes the desired dextrorotatory optical isomer of diastereomer A as well as the levorotatory optical isomer thereof, the levo- or dextrorotatory isomers of diastereomer B, etc. and the desired isomer can be isolated from the reaction mixture by column chromatography or fractional crystallization.
For example, the obtained mixture of the dextrorotatory, optical isomer of diastereomer A and the levorotatory, optical isomer B of YM-09730 is subjected to column chromatography using silica gel as a carrier and ethyl acetate-acetic acid as an eluent, whereby the dextrorotatory, optical isomer of diastereomer A of YM-09730 is separated from the mixture. Alternatively, the mixture is reacted with L-(-)-malic acid and, the thus obtained L-(-)-malates of the dextrorotatory, optical isomer of diastereomer A and the levorotatory, optical isomer of diastereomer B are fractionally recrystallized to obtain L-(-)-malate of the dextrorotatory, optical isomer of diastereomer A.
In the separation by means of column chromatography, the dextrorotatory, optical isomer of diastereomer A can be obtained from the first eluate and from the later eluate, the levorotatory, optical isomer of diastereomer B can be obtained. There is no particular limitation to silica gel used as a carrier as long as it is generally employed in ; !
column chromatography. A mixing ratio of ethyl acetate and acetic acid which is an eluent is not particularly limited but, it is generally preferred that ethyl acetate can be used as a major component and a small quantity of acetic acid can be mixed therewith. It is advantageous that the mixing ratio is approximately 1 to 10 v/v of acetic acid to 30 to 50 v/v of ethyl acetate. When the ratio of acetic acid to be mixed decreases, a time period of eluting the desired compound out is prolonged.
A rate of elution and temperature for treatment may be appropriately adopted.
On the other hand, the method using L-(-)-malic acid is also applicable to separation of the dextrorotatory, optical isomer of diastereomer A through fractional recrystalli-zation since L-(-~-malate of the dextrorotatory optical isomer of diastereomer A is crystalline. As the solvents which can be employed for the fractional recrystallization, methanol, ethanol, ace-tone, aceonitrile, etc. may be mentioned.
The thus obtained L-(-)-malate of the dextrorotatory, optical isomer of diastereomer A can be provided as drugs as they are, but acetate of this isomer and the like may optionally be treated with a base to form a free form, which is then treated with an appropriate acid to lead to suitable other salts.
~3~
The dextrorotatory, optical isomer of diastereomer A of YM-09730 and pharmaceutically acceptable acid addition salts thereof which are the aimed compounds of the present invention are novel compounds that have not been described in any publication and, show an area ratio increased by approximately 40 times over that of the levorotatory, optical isomer (l-form) and an area ratio increased by 2.5 times over that of an equivalent mixture of both isomers (dl-form), in a ra-te of increasing coronary blood flow through direct administration to the coronary arteries and, in addition, have high affinity to the coronary artery.
Accordlng to the process of the present invention, the dextrorotatory, op-tical isomer of diastereomer A of YM-09730 which is novel and useful can be selectively produced in a good yield and, is of extremely high utility value from an industrial viewpoint.
Hereafter, the present invention will be described in more detail with reference to the Examples. The raw compounds (II) and (III) used in the present invention are recognized to be known compounds; however, in application to the present invention, the raw compounds could be produced by novel, useful processes, which are shown as Reference Examples.
Reference Example 1 (1) A solution of 6.04 g of m-nitrobenzaldehyde, 6.32 g of tert-butyl acetoacetate, 0.17 g of piperidine and 0.6 ml of acetic acid in 20 ml of benzene was heated under reflux for 6 hours using an apparatus for azeotropic dehydration.
.~
After cooling the system, 10 ml of water were added thereto and the benzene layer was fractioned. After washing the benzene layer successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, the benzene layer was dried over anhydrous magnesium sulfate. After the solvent was removed by distillatior- under reduced pressure, the resulting residue was subjected to silica gel column chromatography. The crystals obtained from a portion eluted with n-hexane:ethyl acetate (5:1 volume ratio) were washed with n-hexane to obtain 5.82 g of a mixture of geometric isomers of tert-butyl 2-(m-nitrobenzylidene)acetoacetate as colorless crystals.
Melting point: 33 - 36C
(2) A mixture of 3.56 g of t-butyl 2-(m-nitrobenzyli-dene)acetoacetate obtained in (1) and 1.41 g of methyl 3-aminocrotonate in 7 ml of tert-butanol was heated under reflux for 20 hours. The solvent was removed by distillation under reduced pressure. The thus obtained oily residue was treated with n-hexane to obtain 4.6 g of the aimed 2,6-dimethyl-4-(m-nitro phenyl)-1,4-dihydropyridine-
3,5-dicarboxylic acid-3-tert-butyl ester-5-methyl ester.
Melting point: 120 - 122C
(3) To 5 ml of a 25% ice-water cooled solution of hydrogen bromide in acetic acid, a solution of 2.5 g of 2,6-dimethyl 4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-r~7~
39~
dicarboxylic acid-3-tert-butyl ester-5-methyl ester obtained in (2) in 5 ml of toluene was dropwise added. After stirring the mixture for 5 minutes under ice cooling, the mixture was poured into 50 ml of ice water. After the mixture was made alkaline with a 10% aqueous solution of sodium hydroxide, the mixture was extracted with toluene.
The aqueous layer was made acidic with conc. hydrochloric acid and the precipitated crystals were collected by filtration. The crystals were washed with ether to obtain 1.24 g of aimed 5-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (racemate).
Melting point: 203 - 204C (decomposed) Reference Example 2 A solution of 7.55 g of m-nitrobenzaldehyde, 5.75 g of methyl 3-aminocrotonate and 7.90 g of tert-butyl acetoacetate in 25 ml of tert-butanol was heated under reflux for 22 hours. After the solvent was removed by distillation under reduced pressure, the resulting residue was dissolved in 150 ml of toluene. After washing the solution successively with 10% hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, the solution was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 19.62 g of an oily substance. The oily substance was dissolved in 20 ml of toluene and the solution was dropwise added to 20 ml of a 25% hydrogen bromide in acetic acid under ice cooling. After stirring the mixture for 5 minutes at the same temperature, the rnixture was poured in-to 200 ml of ice water. After adding 250 ml of a 10~ sodium hydroxide solution to the mixture to make it alkaline the mixture was washed with 100 ml of toluene. The aqueous layer was acidified with conc.
hydrochloric acid and the precipitated crystals were taken by filtration to obtain 4.51 g of the aimed 5-methoxy-carbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (racemate).
Each optical isomer of said racemate can be obtained according to a process of T. Shibanuma et al, Chem. Pharm.
Bull., 28, 2809 (1980).
Reference Example 3 (1) In 66 ml of acetone, 17.7 g o~ dl-l-benzyl-3-hydroxypyrrolidine and 15.2 g of D-(-)-mandelic acid were dissolved by heating. The solution was allowed to stand at 4C overnight and, 8.5 g of the precipitated crystals were recrystallized from 26 ml of acetone to obtain 5.1 g of (D)-(-)-mandelate of (S)-(-)-1-benzyl-3-hydroxypyrrolidine.
Specific rotation [~] 20 + 45.5 (C=1, methanol).
D
Recrystallization was further repeated but no change was noted in the specific rotation.
Melting point: 101 - 102C
Nuclear magnetic resonance spectrum of N-CH2-Ph was observed at 4.03 ppm (singlet, 2H) but quartet (J=12.5Hz) of `` ~739~
ll AB type of (R)-(-) form at 4.01 ppm was not observed.
(2) In 50 ml of chloroform, 22 g of (D)~ mandelate of (S)-(-)-l-benzyl-3-hydroxypyrrolidine were dissolved.
The chloroform layer was washed with a solution of 14.4 g of anhydrous sodium carbonate in 90 ml of water and dried over anhydrous magnesium sulfate. After chloroform was removed by distillation, the residue was distilled under reduced pressure to obtain 11.5 g of S-(-)-1-benzyl-3-hydroxypyrro-lidine. ~oiling point 109C/0.65 mmHg. [a] 20 -3.77 (C=5, methanol).
Reference Example 4 (S)-(-)-malic acid, 75 g, was reacted with 75 ml of benzyl amine at 170C for 3 hours to obtain 52.7 g of (S)-(-)-1-benzyl-3-hydroxysuccinic imide (melting point, 99-101 C; specific rotation [a] 20 -51.1 (C=1, methanol)). In 340 ml of absolute tetrahydrofuran, 9.73 g of lithium aluminum hydride were suspended and, a solution of 20.5 g of the imide in 200 ml of absolute tetrahydrofuran was dropwise added to the suspension under ice cooling. After heating under reflux for 3 hrs, the mixture was cooled and 100 g of sodium sulfate decahydrate were added thereto. The mixture was stirred overnight under ice cooling. The insoluble matter was removed by filtration and the solvent was removed by distillation under reduced pressure. The residue was ~' distilled under reduced pressure to obtain 13.8 g of (S)-(-)-l-benzyl-3-hydroxypyrrolidine having a boiling point of 109 - 115 C/0.8 mmHg and a specific rotation of [a] 20 -3Ø The thus obtained (S)-(-) form contained 10% of R-(~) form, based on the nuclear magnetic resonance spectrum of the hydrogen of the 3-position using a shift reagent (Eu-TFMC (III) ). The (S)-(-) form was converted into D-(-)-mandelate as in Reference Example 3, which was recrystallized from a 3-fold volume of ethanol and then from a 6-fold volume of ethanol-toluene (1:5). The thus obtained mandelate ([a] 20 -45.2) was treated as mentioned above to obtain 8.6 g of (S)~ l-benzyl-3-hydroxypyrrolidine (boiling point, 115-120C/1.2-1.5 mmHg, [a] 20 -3.77 (C=5, methanol) ).
Reference Example 5 To 50 ml of 9-borobicyclo 3.3.1 nonane (0.5M tetra-hydrofuran solution), 3.4 g of 2-(+)-pinene was added and the mixture was stirred for 5 hours of 60C. The mixture was cooled to room temperature and 1.75 g of 1-benzyl-3-pyrrolidinone was added thereto. After stirring the mixture at room temperat~re for 4 days, 1.3 ml of acetoaldehyde was added to the mixture at 0C. The solvent was removed by distillation under reduced pressure and 20 ml of ether was added to the residue. The mixture was cooled to 0C and 1.5 ml of 2-aminoethanol was added thereto. The mixture was stirred. The formed precipitates were removed by distilla-tion. The ethereal solution was extracted with lN hydro-chloric acid. The hydrochloric acid layer was rendered alkaline with sodium carbonate and ex~racted with dichloro-methane. The extract was dried over anhydrous magnesium sulfate and concentrated to obtain 1.1 g of the crude product. The crude product was distilled under reduced pressure to obtain 0.6 g of the pure product. Boiling point, 106-C/0.9 mmHg. The thus obtained (S)-( )-1-benzyl-3-hydroxypyrrolidine was 30% enantio excess (e.e.), based on the nuclear magnetic resonance spectrum of the hydrogen at the 3-position after adding a shift reagent (Eu-TFMC (III)).
~xample 1 In 3 ml of dichloromethane, 332 mg of 5-methoxycarbonyl-2,6-dimethyl-~-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was dissolved and 250 mg of phosphorus pentachloride was added to the solution while stirring under ice cooling. The mixture was stirred for an additional 1 hour at the same temperature. The reaction mixture was cooled to -30C and 177 mg of (S)-1-benzyl-3-hydroxypyrrolidine was added thereto. After stirring at -30C for two hours, -the reaction mixture was washed with water and then with a saturated aqueous solution of sodium hydrogen carbonate. The solvent was removed by distillation to obtain an oily substance. The oily substance was subjected to silica gel column chromatography eluting with ethyl acetate-acetic acid (5:1 v/v) to obtain the dextroro-tatory optical isomer (I) of diastereomer A of YM-09730 ~ r r ~2~3~3~
1~
showing retention time of 28 minutes in a high speed liquid chromatographic system [column: Nucleosil S C18 4.6 mm ~ x 300 mm, column temperature: 30C, mobile phase: 0.05 mol dihydrogen potassium phosphate (pH 3)-acetonitrile ~80:20 v/v) including tetra-n-pentylammonium bromide, flow rate: 0.9 ml/min., UV
detector (~ 254 nm)]. In chloroform, the thus obtained isomer was treated with a saturated aqueous solution of hydrogen sodium carbonate and then with dilute hydro-chloric acid to obtain 161 mg of the hydrochloride of the dextrorotatory optical isomer of diastereomer A
of YM-09730.
Melt-ing point: 228 - 230C ~decomp.) Specific rotation: ~]20 +116.3 (C=0.5, methanol)O
Example 2 In 3 ml of dichloromethane, 332 mg of (-)-5-methoxy-carbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydro-pyridine-3-carboxylic acid was dissolved and 250 mg of phosphorus pentachloride was added to the solution while stirring under ice cooling. The mixture was further stirred for 1 hour at the same temperature. The reaction mixture was.cooled to -30-C-~and 1-77 mg of (S)-l-benzyl-3-hydr~xypyrrolidine was added thereto. After stlrring at -30C for 2 hours, the Teaction mixture was diluted with 5 ml of dichloromethane and washed successively with water and a saturated aqueous solution of sodlum hydroge~
carbonate twice in a portion of 5 ml. The solvent was was removed by distillation under reduced pressure to obtain an oily substance. The oily substance was subjected to silica gel (15 g) column chromatography eluting with toluene-acetic acid ~4:1 v/v). The fraction containing the desired isomer was concentrated under reduced pressure, and the resultant residue was dissolved in 5 ml of chloroform.
~fter adding 1 ml of a solution of 0.8 N hydrogen chloride in ethanol to said chloroform solution, the solution was again concentrated under reduced pressure. The residue was dissolved in 2 ml of methanol and the solution was allowed to stand overnight under ice cooling. The precipitated crystals were collected by filtration and dried to obtain 350 mg of the hydrochloride of the dextrorotatory optical isomer of diastereomer A of YM-09730.
Melting point: 226 - 228C (decomp.) Specific rotation: ([o~] 20 +116.4(C=1, methanol) NMR (in CD30D, TMS internal standard, ~ppm):
1.80-2.70 (2H, broad m, C4--H2) 2.32, 2.34 (6H, s, C2,6--CH3) 3.0-4.0 (4H, m, C2lsl-H2) 3.64 (3H, s, -COOCH3)
Melting point: 120 - 122C
(3) To 5 ml of a 25% ice-water cooled solution of hydrogen bromide in acetic acid, a solution of 2.5 g of 2,6-dimethyl 4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-r~7~
39~
dicarboxylic acid-3-tert-butyl ester-5-methyl ester obtained in (2) in 5 ml of toluene was dropwise added. After stirring the mixture for 5 minutes under ice cooling, the mixture was poured into 50 ml of ice water. After the mixture was made alkaline with a 10% aqueous solution of sodium hydroxide, the mixture was extracted with toluene.
The aqueous layer was made acidic with conc. hydrochloric acid and the precipitated crystals were collected by filtration. The crystals were washed with ether to obtain 1.24 g of aimed 5-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (racemate).
Melting point: 203 - 204C (decomposed) Reference Example 2 A solution of 7.55 g of m-nitrobenzaldehyde, 5.75 g of methyl 3-aminocrotonate and 7.90 g of tert-butyl acetoacetate in 25 ml of tert-butanol was heated under reflux for 22 hours. After the solvent was removed by distillation under reduced pressure, the resulting residue was dissolved in 150 ml of toluene. After washing the solution successively with 10% hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, the solution was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 19.62 g of an oily substance. The oily substance was dissolved in 20 ml of toluene and the solution was dropwise added to 20 ml of a 25% hydrogen bromide in acetic acid under ice cooling. After stirring the mixture for 5 minutes at the same temperature, the rnixture was poured in-to 200 ml of ice water. After adding 250 ml of a 10~ sodium hydroxide solution to the mixture to make it alkaline the mixture was washed with 100 ml of toluene. The aqueous layer was acidified with conc.
hydrochloric acid and the precipitated crystals were taken by filtration to obtain 4.51 g of the aimed 5-methoxy-carbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (racemate).
Each optical isomer of said racemate can be obtained according to a process of T. Shibanuma et al, Chem. Pharm.
Bull., 28, 2809 (1980).
Reference Example 3 (1) In 66 ml of acetone, 17.7 g o~ dl-l-benzyl-3-hydroxypyrrolidine and 15.2 g of D-(-)-mandelic acid were dissolved by heating. The solution was allowed to stand at 4C overnight and, 8.5 g of the precipitated crystals were recrystallized from 26 ml of acetone to obtain 5.1 g of (D)-(-)-mandelate of (S)-(-)-1-benzyl-3-hydroxypyrrolidine.
Specific rotation [~] 20 + 45.5 (C=1, methanol).
D
Recrystallization was further repeated but no change was noted in the specific rotation.
Melting point: 101 - 102C
Nuclear magnetic resonance spectrum of N-CH2-Ph was observed at 4.03 ppm (singlet, 2H) but quartet (J=12.5Hz) of `` ~739~
ll AB type of (R)-(-) form at 4.01 ppm was not observed.
(2) In 50 ml of chloroform, 22 g of (D)~ mandelate of (S)-(-)-l-benzyl-3-hydroxypyrrolidine were dissolved.
The chloroform layer was washed with a solution of 14.4 g of anhydrous sodium carbonate in 90 ml of water and dried over anhydrous magnesium sulfate. After chloroform was removed by distillation, the residue was distilled under reduced pressure to obtain 11.5 g of S-(-)-1-benzyl-3-hydroxypyrro-lidine. ~oiling point 109C/0.65 mmHg. [a] 20 -3.77 (C=5, methanol).
Reference Example 4 (S)-(-)-malic acid, 75 g, was reacted with 75 ml of benzyl amine at 170C for 3 hours to obtain 52.7 g of (S)-(-)-1-benzyl-3-hydroxysuccinic imide (melting point, 99-101 C; specific rotation [a] 20 -51.1 (C=1, methanol)). In 340 ml of absolute tetrahydrofuran, 9.73 g of lithium aluminum hydride were suspended and, a solution of 20.5 g of the imide in 200 ml of absolute tetrahydrofuran was dropwise added to the suspension under ice cooling. After heating under reflux for 3 hrs, the mixture was cooled and 100 g of sodium sulfate decahydrate were added thereto. The mixture was stirred overnight under ice cooling. The insoluble matter was removed by filtration and the solvent was removed by distillation under reduced pressure. The residue was ~' distilled under reduced pressure to obtain 13.8 g of (S)-(-)-l-benzyl-3-hydroxypyrrolidine having a boiling point of 109 - 115 C/0.8 mmHg and a specific rotation of [a] 20 -3Ø The thus obtained (S)-(-) form contained 10% of R-(~) form, based on the nuclear magnetic resonance spectrum of the hydrogen of the 3-position using a shift reagent (Eu-TFMC (III) ). The (S)-(-) form was converted into D-(-)-mandelate as in Reference Example 3, which was recrystallized from a 3-fold volume of ethanol and then from a 6-fold volume of ethanol-toluene (1:5). The thus obtained mandelate ([a] 20 -45.2) was treated as mentioned above to obtain 8.6 g of (S)~ l-benzyl-3-hydroxypyrrolidine (boiling point, 115-120C/1.2-1.5 mmHg, [a] 20 -3.77 (C=5, methanol) ).
Reference Example 5 To 50 ml of 9-borobicyclo 3.3.1 nonane (0.5M tetra-hydrofuran solution), 3.4 g of 2-(+)-pinene was added and the mixture was stirred for 5 hours of 60C. The mixture was cooled to room temperature and 1.75 g of 1-benzyl-3-pyrrolidinone was added thereto. After stirring the mixture at room temperat~re for 4 days, 1.3 ml of acetoaldehyde was added to the mixture at 0C. The solvent was removed by distillation under reduced pressure and 20 ml of ether was added to the residue. The mixture was cooled to 0C and 1.5 ml of 2-aminoethanol was added thereto. The mixture was stirred. The formed precipitates were removed by distilla-tion. The ethereal solution was extracted with lN hydro-chloric acid. The hydrochloric acid layer was rendered alkaline with sodium carbonate and ex~racted with dichloro-methane. The extract was dried over anhydrous magnesium sulfate and concentrated to obtain 1.1 g of the crude product. The crude product was distilled under reduced pressure to obtain 0.6 g of the pure product. Boiling point, 106-C/0.9 mmHg. The thus obtained (S)-( )-1-benzyl-3-hydroxypyrrolidine was 30% enantio excess (e.e.), based on the nuclear magnetic resonance spectrum of the hydrogen at the 3-position after adding a shift reagent (Eu-TFMC (III)).
~xample 1 In 3 ml of dichloromethane, 332 mg of 5-methoxycarbonyl-2,6-dimethyl-~-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was dissolved and 250 mg of phosphorus pentachloride was added to the solution while stirring under ice cooling. The mixture was stirred for an additional 1 hour at the same temperature. The reaction mixture was cooled to -30C and 177 mg of (S)-1-benzyl-3-hydroxypyrrolidine was added thereto. After stirring at -30C for two hours, -the reaction mixture was washed with water and then with a saturated aqueous solution of sodium hydrogen carbonate. The solvent was removed by distillation to obtain an oily substance. The oily substance was subjected to silica gel column chromatography eluting with ethyl acetate-acetic acid (5:1 v/v) to obtain the dextroro-tatory optical isomer (I) of diastereomer A of YM-09730 ~ r r ~2~3~3~
1~
showing retention time of 28 minutes in a high speed liquid chromatographic system [column: Nucleosil S C18 4.6 mm ~ x 300 mm, column temperature: 30C, mobile phase: 0.05 mol dihydrogen potassium phosphate (pH 3)-acetonitrile ~80:20 v/v) including tetra-n-pentylammonium bromide, flow rate: 0.9 ml/min., UV
detector (~ 254 nm)]. In chloroform, the thus obtained isomer was treated with a saturated aqueous solution of hydrogen sodium carbonate and then with dilute hydro-chloric acid to obtain 161 mg of the hydrochloride of the dextrorotatory optical isomer of diastereomer A
of YM-09730.
Melt-ing point: 228 - 230C ~decomp.) Specific rotation: ~]20 +116.3 (C=0.5, methanol)O
Example 2 In 3 ml of dichloromethane, 332 mg of (-)-5-methoxy-carbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydro-pyridine-3-carboxylic acid was dissolved and 250 mg of phosphorus pentachloride was added to the solution while stirring under ice cooling. The mixture was further stirred for 1 hour at the same temperature. The reaction mixture was.cooled to -30-C-~and 1-77 mg of (S)-l-benzyl-3-hydr~xypyrrolidine was added thereto. After stlrring at -30C for 2 hours, the Teaction mixture was diluted with 5 ml of dichloromethane and washed successively with water and a saturated aqueous solution of sodlum hydroge~
carbonate twice in a portion of 5 ml. The solvent was was removed by distillation under reduced pressure to obtain an oily substance. The oily substance was subjected to silica gel (15 g) column chromatography eluting with toluene-acetic acid ~4:1 v/v). The fraction containing the desired isomer was concentrated under reduced pressure, and the resultant residue was dissolved in 5 ml of chloroform.
~fter adding 1 ml of a solution of 0.8 N hydrogen chloride in ethanol to said chloroform solution, the solution was again concentrated under reduced pressure. The residue was dissolved in 2 ml of methanol and the solution was allowed to stand overnight under ice cooling. The precipitated crystals were collected by filtration and dried to obtain 350 mg of the hydrochloride of the dextrorotatory optical isomer of diastereomer A of YM-09730.
Melting point: 226 - 228C (decomp.) Specific rotation: ([o~] 20 +116.4(C=1, methanol) NMR (in CD30D, TMS internal standard, ~ppm):
1.80-2.70 (2H, broad m, C4--H2) 2.32, 2.34 (6H, s, C2,6--CH3) 3.0-4.0 (4H, m, C2lsl-H2) 3.64 (3H, s, -COOCH3)
4.42 (2H, s, --CH2~)
5.08(lH, s, C4-H) 5.30(lH, m, C3--H) 7.30-8.20 (9H, m, benzene ring-H) Example 3 In 6 ml of dichloromethane and N,N-dimethylformamide (4:1 v/v), 840 mg of (-)-5-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was suspended and 0.2 ml of thionyl chloride was added to the solution under ice cooling. The mix~ure was stirred for 1 hour at the same temperature. To the reaction mixture was dropwise added 450 mg of (S)-1-benzyl-3-hydroxy-pyrrolidine in 3 ml of dichloromethane under ice cooling, the resultant mixture was further stirred for 15 hours under ice cooling, and then the reaction mixture was diluted with 10 ml of dichloromethane. After washing the obtained solution successively with 10 ml of water and 10 ml of a saturated aqueous solution of sodium hydrogen carbonate, the solution was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain an oily substance. The oily substance was subjected to silica gel (40 g) column chromatography eluting with toluene-acetic acid (4:1 v/v, followed by 1:1 v/v). The fraction containing the desired isomer was concentrated under reduced pressure to obtain 990 mg of a concentrated oily substance, the oily substance was dissolved in 10 ml of chloroform.
After adding 2.6 ml of a solution of 0.8 N hydrogen chloride in ethanol, the solution was again concentrated under reduced pressure. The obtained residue was dissolved in 5 ml of methanol, the solution was allowed to stand overnight under ice cooling. The precipitated crystals '~
were taken by filtration and dried to obtain 850 mg of the hydrochloride of the dextrorotatory, optical iSOmer of diastereomer A of YM-09730.
Melting point: 226 - 228C (decomp.) Specific rotation: [c~]D +116.4 (c=l, methanol) N~R spectra were consistent with those of the product prepared by Example 2.
Example 4 1) The concentrated oily substance (990 mg) obtained by following the Example 3 procedure was dissolved in 10 ml of ethanol, the solution was again concentrated under reduced pressure. The resulting residue was dissolved in--5- ml--of--ethanol, the solution was allowed to stand overnight undeT ice cooling. The precipitated crystals were collected by filtration and dried to obtain 730 mg of the free base of the dextro-- - - rotatory, -opitical isomer -of diastereomer A of YM-09730D
Melting point: 137 - 139C
Specific rotation: [U]D -~64.8 (c-l, methanol) NMR (in CDC13, TMS internal standard9 ~ppm) 1.4 - 3.0 (6H, m, C2"4,~5, H2 2.34, 2.36 (6H, s, C2 6~CH3) 3.65 (5H, s, -COOCH3 and -CH2~) 5.10 (lH, s, C4-H) -- - - 5.12 (lH, m, C3,-H) 5.78 ~lH, broad s, NH) 7.16 - 8.24 ~9H, m, benzene ring-H) ~3~
2) The free base (700 mg) obtained above was dissolved in 10 ml of chloroform and 1.8 ml of a solution of 0.8 N
hydrogen chloride in ethanol, the solution was concentrated under reduced pressure. The obtained residue was dissolved in 3.5 ml of methanol, the solution was allowed to stand overnight under ice cooling. The precipitated crystals were collected by filtration and dried to obtain 630 mg of the hydrochloride of the dextrorotatory, optical isomer of diastereomer A of YM-09730.
Melting point: 228-230 C (decomp.) Specific rotation: ([~] 20 +116.7 (c=1, methanol) NMR spectrum were consistent with those of the product prepared by Example 2).
'~ '
After adding 2.6 ml of a solution of 0.8 N hydrogen chloride in ethanol, the solution was again concentrated under reduced pressure. The obtained residue was dissolved in 5 ml of methanol, the solution was allowed to stand overnight under ice cooling. The precipitated crystals '~
were taken by filtration and dried to obtain 850 mg of the hydrochloride of the dextrorotatory, optical iSOmer of diastereomer A of YM-09730.
Melting point: 226 - 228C (decomp.) Specific rotation: [c~]D +116.4 (c=l, methanol) N~R spectra were consistent with those of the product prepared by Example 2.
Example 4 1) The concentrated oily substance (990 mg) obtained by following the Example 3 procedure was dissolved in 10 ml of ethanol, the solution was again concentrated under reduced pressure. The resulting residue was dissolved in--5- ml--of--ethanol, the solution was allowed to stand overnight undeT ice cooling. The precipitated crystals were collected by filtration and dried to obtain 730 mg of the free base of the dextro-- - - rotatory, -opitical isomer -of diastereomer A of YM-09730D
Melting point: 137 - 139C
Specific rotation: [U]D -~64.8 (c-l, methanol) NMR (in CDC13, TMS internal standard9 ~ppm) 1.4 - 3.0 (6H, m, C2"4,~5, H2 2.34, 2.36 (6H, s, C2 6~CH3) 3.65 (5H, s, -COOCH3 and -CH2~) 5.10 (lH, s, C4-H) -- - - 5.12 (lH, m, C3,-H) 5.78 ~lH, broad s, NH) 7.16 - 8.24 ~9H, m, benzene ring-H) ~3~
2) The free base (700 mg) obtained above was dissolved in 10 ml of chloroform and 1.8 ml of a solution of 0.8 N
hydrogen chloride in ethanol, the solution was concentrated under reduced pressure. The obtained residue was dissolved in 3.5 ml of methanol, the solution was allowed to stand overnight under ice cooling. The precipitated crystals were collected by filtration and dried to obtain 630 mg of the hydrochloride of the dextrorotatory, optical isomer of diastereomer A of YM-09730.
Melting point: 228-230 C (decomp.) Specific rotation: ([~] 20 +116.7 (c=1, methanol) NMR spectrum were consistent with those of the product prepared by Example 2).
'~ '
Claims
OF PRIVILEGE IS CLAIMED ARE DERINED AS FOLLOWS:
1. A process for production of a dextrorotatory optical isomer (I) of diastereomer A of (?)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(1-benzylpyrrolidin-3-yl) ester 5-methyl ester, the melting point of the hydrochloride of said dextrorotatory optical isomer (I) being 223 to 230°C (decomp.), or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a compound represented by the formula (II) with a compound represented by the formula (III) and, when said compounds (II) and (III) are both levorotatory substances, isolating said dextrorotatory optical isomer (I) from the resulting reaction mixture or, when at least one of said compounds (II) and (III) is a racemate, isolating said dextrorotatory optical isomer (I) from the resulting reaction mixture by column chromatography or fractional crystallization.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12051/1985 | 1985-01-24 | ||
| JP1205185 | 1985-01-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1273931A true CA1273931A (en) | 1990-09-11 |
Family
ID=11794796
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000492966A Expired CA1273931A (en) | 1985-01-24 | 1985-10-15 | Process for production of the dextrorotatory optical isomer of diastereomer a of ym-09730 |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JPS61267577A (en) |
| KR (1) | KR900002342B1 (en) |
| CN (1) | CN1023483C (en) |
| AT (1) | AT390613B (en) |
| CA (1) | CA1273931A (en) |
| DK (1) | DK468385A (en) |
| ES (1) | ES8607284A1 (en) |
| FI (1) | FI83517C (en) |
| GR (1) | GR852497B (en) |
| IT (1) | IT1221762B (en) |
| MX (1) | MX260A (en) |
| NO (1) | NO166643C (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1306438B1 (en) | 2000-08-01 | 2008-06-25 | Kaneka Corporation | Novel carbonyl reductase, gene thereof and method of using the same |
| KR100939347B1 (en) | 2005-07-20 | 2010-01-29 | (주)카이로드 | Synthetic Method of optically pure S-3-hydroxypyrrolidine |
| CN101643469B (en) * | 2008-12-27 | 2012-11-21 | 武汉百科药物开发有限公司 | Synthesis process of barnidipine hydrochloride |
| EP4382529A1 (en) | 2022-12-07 | 2024-06-12 | Bayer Consumer Care AG | A process for preparing pure (3s)-pyrrolidin-3-ol and pure (3s)-pyrrolidin-3-ol hydrochloride |
-
1985
- 1985-09-26 FI FI853697A patent/FI83517C/en not_active IP Right Cessation
- 1985-10-08 ES ES547696A patent/ES8607284A1/en not_active Expired
- 1985-10-11 CN CN85107590A patent/CN1023483C/en not_active Expired - Lifetime
- 1985-10-14 NO NO854062A patent/NO166643C/en not_active IP Right Cessation
- 1985-10-14 AT AT0297085A patent/AT390613B/en not_active IP Right Cessation
- 1985-10-14 DK DK468385A patent/DK468385A/en not_active Application Discontinuation
- 1985-10-14 KR KR1019850007554A patent/KR900002342B1/en not_active IP Right Cessation
- 1985-10-14 MX MX260A patent/MX260A/en unknown
- 1985-10-15 IT IT22489/85A patent/IT1221762B/en active
- 1985-10-15 GR GR852497A patent/GR852497B/el unknown
- 1985-10-15 CA CA000492966A patent/CA1273931A/en not_active Expired
-
1986
- 1986-01-22 JP JP61012358A patent/JPS61267577A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| FI853697A0 (en) | 1985-09-26 |
| NO854062L (en) | 1986-07-25 |
| AT390613B (en) | 1990-06-11 |
| GR852497B (en) | 1986-02-18 |
| ATA297085A (en) | 1989-11-15 |
| CN85107590A (en) | 1986-07-23 |
| DK468385A (en) | 1986-07-25 |
| JPS61267577A (en) | 1986-11-27 |
| ES8607284A1 (en) | 1986-05-16 |
| IT8522489A0 (en) | 1985-10-15 |
| ES547696A0 (en) | 1986-05-16 |
| KR900002342B1 (en) | 1990-04-12 |
| MX260A (en) | 1995-01-31 |
| CN1023483C (en) | 1994-01-12 |
| FI853697L (en) | 1986-07-25 |
| NO166643C (en) | 1991-08-21 |
| KR860005637A (en) | 1986-08-11 |
| FI83517B (en) | 1991-04-15 |
| FI83517C (en) | 1991-07-25 |
| IT1221762B (en) | 1990-07-12 |
| DK468385D0 (en) | 1985-10-14 |
| NO166643B (en) | 1991-05-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPH02348B2 (en) | ||
| AU695479B2 (en) | Racemisation and asymmetric transformation processes used in the manufacture of levobupivacaine and analogues thereof | |
| EP0759904B1 (en) | Process and diastereomeric salts useful for the optical resolution of racemic 4-[4-[-4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzene acetic acid. | |
| CA1273931A (en) | Process for production of the dextrorotatory optical isomer of diastereomer a of ym-09730 | |
| JPH02504393A (en) | Stereoselective synthesis of 3-substituted-4-(phenylanilo)piperidine compounds and their derivatives | |
| US4864037A (en) | Optically pure 1,3-dioxenones, methods for preparing same and use thereof | |
| KR920003626B1 (en) | Process for preparing dihydropyridine-3,5-dicarboxylic acid ester derivatives | |
| US5364872A (en) | Dihydropyridine-3,5-dicarboxylic acid ester derivatives | |
| CA1235706A (en) | (substituted-phenyl)-5-oxo-pyrrolidine-2-propanoic acids and derivatives as cognition activators | |
| CN1056843C (en) | Method for preparation of esters of anhydroecgonine | |
| US4495355A (en) | Optically-active diamide derivatives | |
| JPS6112663A (en) | Manufacture of optically active 1,4-dihydropyridines | |
| US4497954A (en) | Cyclopentanone derivatives | |
| TW310324B (en) | ||
| KR960016525B1 (en) | Preparation process for dihydropyridine compound or its salt | |
| FI94242B (en) | Method for preparing heterocyclic derivatives | |
| JPS63503384A (en) | Effective stereoconservative synthesis of 1-substituted (S)- and (R)-2-aminomethylpyrrolidines and their intermediates | |
| US4482561A (en) | Therapeutically effective piperidyl N-(4-quinolyl)-anthraniloyloxyalkanoates | |
| JP3006904B2 (en) | Method for producing 1,4-dihydropyridine derivative and intermediate thereof | |
| EP1140841B1 (en) | 3-phenyl-2,6-dioxopiperidin-3-yl propionamide derivatives and method for preparing same | |
| KR100365526B1 (en) | Synthesis of the bicyclo[3.3.1]nonane structure | |
| US5633383A (en) | Process for producing optically pure 1,4-dihydropyridines | |
| JPH0768241B2 (en) | Optically active 1,4-dihydropyridine derivative | |
| JPH058700B2 (en) | ||
| MXPA06006038A (en) | A process for resolving, optionally substituted, mandelic acids by salt formation with a chiral base cyclic amide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |