WO1992011239A1 - Verfahren zur herstellung von dihydropyridincarbonsäuren - Google Patents
Verfahren zur herstellung von dihydropyridincarbonsäuren Download PDFInfo
- Publication number
- WO1992011239A1 WO1992011239A1 PCT/EP1991/002476 EP9102476W WO9211239A1 WO 1992011239 A1 WO1992011239 A1 WO 1992011239A1 EP 9102476 W EP9102476 W EP 9102476W WO 9211239 A1 WO9211239 A1 WO 9211239A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- nitrophenyl
- chlorophenyl
- formula
- compound
- Prior art date
Links
- 0 *C([C@]1[Al])=C(*)NC(*)=C1C(O)=O Chemical compound *C([C@]1[Al])=C(*)NC(*)=C1C(O)=O 0.000 description 3
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Definitions
- the invention relates to a new process for the preparation of dihydropyridine carboxylic acids.
- the compounds produced according to the invention are used as intermediate products in the pharmaceutical industry.
- 1,4-dihydropyridine monocarboxylic acids which are considered to be key intermediates.
- the invention thus relates to a process for the preparation of optically pure 1,4-dihydropyridine monocarboxylic acids of the formula I.
- Rl is 1-4C-alkyl
- R2 is 1-4C-alkyl
- R3 is 1-4C-alkyl or benzyl, and either
- B a 2-chlorophenyl -, 3-chlorophenyl -, 2,3-dichlorophenyl -, 2-nitrophenyl, 3-nitrophenyl, benzoxidazolyl - (4-benzofurazanyl) -, 2-T ⁇ 'fl uormethylphenyl -, 2,3 -Methylenedioxyphenyl - or 2-difluoromethoxyphenylrest means, or
- A a 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-nitrophenyl, 3-nitrophenyl, benzoxidazolyl- (4-benzofurazanyl) -, 2-trifluoromethylphenyl, 2,3-methylenedioxyphenyl or 2-difluoromethoxyphenyl radical and
- the process is characterized in that a compound of the formula II
- the process is characterized in that the undesired enantiomer after ester formation with the compound Rl-X, in which Rl has the meaning given above and X represents a leaving group or a halogenocarbonyloxy group, is used again as the starting compound II.
- 1-4C-Alkyl stands for methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl and tert-butyl. Isobutyl, isopropyl and in particular ethyl and methyl are preferred as 1-4C-alkyl radicals R1. As 1-4C-alkyl radicals R2, ethyl and methyl are preferred. As 1-4C-Al ylrest R3 ethyl is preferred.
- the saponification in the alcohol R1-0H is advantageously carried out at a dilution ratio (compound II: alcohol) of 1: 3 to 1:40, preferably 1: 5 to 1:10.
- Suitable aqueous alkali metal hydroxides are in particular 0.3 to 10 molar, preferably 0.5 to 2 molar sodium hydroxide solution or potassium hydroxide solution, with 0.9 to 1.5 equivalents, preferably based on compound II, preferably 0.95 to 1.20 equivalents, in particular 1.0 equivalent of alkali metal hydroxide are used.
- the saponification is preferably carried out at temperatures between 50 and 120 C, in particular at the boiling point of the alcohol R1-0H used.
- the acid III resulting from the saponification which is present as Race at, can be separated into the enantiomers in a customary manner via the diastereomeric salts using enantiomerically pure, optically active bases [see e.g. Chem. Pharm. Bull. 28: 2809 (1980)].
- the esterification of the optically pure acid III which is not desired or not required with the compound R1-X is carried out in a manner which is familiar to the person skilled in the art.
- the leaving group X of the compound Rl-X is a group which is easily split off during the ester formation, for example a halogen atom, such as chlorine, bromine or iodine, or preferably the alkyl sulfate group.
- X is likewise preferably a halogenocarbonyloxy group, in particular the chlorocarbonyloxy group, so that the compound Rl-X is an alkyl chloroformate.
- the reaction of the compound III with the compound R1-X is preferably carried out under basic conditions, advantageously in the presence of a phase transfer catalyst.
- a phase transfer catalyst In addition to onium salts, such as e.g. Tetrabutylammonium bromide or benzyltriethylammonium chloride, especially crown ethers, such as dibenzo- [18] crown-6, dicyclohexyl- [18] crown-6 and in particular [18] crown-6 are mentioned.
- Bases which are used at least in a molar ratio, preferably in excess, are inorganic bases, such as alkali metal hydroxides (for example sodium or potassium hydroxide), or in particular aluminum metal carbonates (for example sodium or preferably potassium carbonate) .
- alkali metal hydroxides for example sodium or potassium hydroxide
- aluminum metal carbonates for example sodium or preferably potassium carbonate
- the hydroxides or carbonates used are preferably used in finely powdered form.
- the reaction takes place (depending on the type of phase transfer catalyst and the base used) in water-containing or anhydrous organic solvents, or in a mixture of water and an organic solvent which is immiscible or hardly miscible with water.
- water / solvent mixtures are the mixtures of water with chloroform, dichloromethane or toluene.
- water-containing or water-free solvents are dichloromethane, acetonitrile or in particular acetone, methyl ethyl ketone or methyl isobutyl ketone.
- the reaction (depending on the nature of the compound Rl-X used) is carried out at temperatures between 20 and 150 ° C., for example in the reaction with dimethyl sulfate temperatures between 20 and 60 ° C. in the reaction with methyl chloroformate Temperatures between 50 and 120 C are preferred.
- One embodiment of the invention (embodiment a) relates to a process for the preparation of optically pure 1,4-dihydropyridinecarboxylic acids of the formula Ia
- Rl is 1-4C-alkyl
- R2 is 1-4C-alkyl
- R3 denotes 1-4C-A1kyl or benzyl
- Ar is a 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-nitrophenyl, 3-nitrophenyl, benzoxidazolyl- (4-benzofurazanyl) -, 2-trifluoromethylphenyl, 2,3-methylenedioxyphenyl or 2-D means fluoromethoxyphenyl radical.
- a further embodiment of the invention (embodiment b) relates to a process for the production of optically pure 1,4-dihydropyridinecarboxylic acids of the formula Ib
- Rl is 1-4C-alkyl
- R2 is 1-4C-alkyl
- R3 denotes 1-4C-A1kyl or benzyl
- Ar is a 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-nitrophenyl, 3-nitrophenyl, benzoxidazolyl- (4-benzofurazanyl) -, 2-trifluoromethylphenyl, 2,3-methylenedioxyphenyl or 2-difluoromethoxyphenyl est means.
- Rl is 1-4C-alkyl
- R2 is 1-4C-alkyl
- R3 denotes 1-4C-alkyl
- Ar means 3-nitrophenyl or 2,3-dichlorophenyl.
- Rl is methyl or ethyl
- R2 means methyl
- R3 means ethyl
- Ar means 3-nitrophenyl.
- F. stands for melting point, h for hour (s) and min for minute (s).
- the invention provides a process by which pure 1,4-dihydropyridine-5-alkoxycarbonyl-3-carboxylic acids are used, which are valuable intermediates for the synthesis of enantiomerically pure, pharmacologically active 1,4-dihydropyridine -3,5-dicarboxylic acid diesters are required, can be prepared easily and in high yield.
- Sausin et al. (Khimiya Geterotsiklicheskikh Soedinenii, No. 2, p. 272, February 1978) describes the partial saponification of N-alkylated 1,4-dihydropyridinedicarboxylic acid dialkyl esters with the aid of potassium hydroxide solution, and European patent application 202652 describes in part the Saponification of N-unsubstituted 1,4-dihydropyridinedicarboxylic acid dialkyl esters has been reported.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4501396A JPH06503824A (ja) | 1990-12-24 | 1991-12-20 | ジヒドロピリジンカルボン酸の製法 |
US08/081,332 US5475111A (en) | 1990-12-24 | 1991-12-20 | Process for the preparation of dihydropyridinecarboxylic acids |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4041814A DE4041814A1 (de) | 1990-12-24 | 1990-12-24 | Verfahren zur herstellung von dihydrophyridincarbonsaeuren |
DEP4041814.6 | 1990-12-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992011239A1 true WO1992011239A1 (de) | 1992-07-09 |
Family
ID=6421465
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1991/002476 WO1992011239A1 (de) | 1990-12-24 | 1991-12-20 | Verfahren zur herstellung von dihydropyridincarbonsäuren |
Country Status (6)
Country | Link |
---|---|
US (1) | US5475111A (de) |
EP (1) | EP0564509A1 (de) |
JP (1) | JPH06503824A (de) |
AU (1) | AU9106591A (de) |
DE (1) | DE4041814A1 (de) |
WO (1) | WO1992011239A1 (de) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4769465A (en) * | 1985-05-21 | 1988-09-06 | Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, N.Sol.O. | Process for the preparation of 2-(N-benzyl-N-methylamino)-ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride salt |
WO1988007524A1 (en) * | 1987-03-27 | 1988-10-06 | Byk Gulden Lomberg Chemische Fabrik Gmbh | New intermediate products and process |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2528431B1 (fr) * | 1982-06-15 | 1986-01-10 | Sandoz Sa | Nouveaux derives de la 1,4-dihydropyridine, leur preparation et leur utilisation comme medicaments |
US4761420A (en) * | 1986-06-13 | 1988-08-02 | Laboratoires Syntex S.A. | Antihypertensive dihydropyridine derivatives |
WO1988007531A1 (en) * | 1987-03-27 | 1988-10-06 | Byk Gulden Lomberg Chemische Fabrik Gmbh | New optically active compounds |
JP2625190B2 (ja) * | 1987-03-27 | 1997-07-02 | ビイク グルデン ロンベルク ヒエーミツシエ フアブリーク ゲゼルシヤフト ミツト ベシユレンクテル ハフツング | 1,4―ジヒドロピリジン―エナンチオマーおよびその製法 |
EP0394243A1 (de) * | 1987-05-22 | 1990-10-31 | Byk Gulden Lomberg Chemische Fabrik GmbH | Verfahren zur herstellung von carbonsäuren |
-
1990
- 1990-12-24 DE DE4041814A patent/DE4041814A1/de not_active Ceased
-
1991
- 1991-12-20 WO PCT/EP1991/002476 patent/WO1992011239A1/de not_active Application Discontinuation
- 1991-12-20 EP EP92901540A patent/EP0564509A1/de not_active Withdrawn
- 1991-12-20 JP JP4501396A patent/JPH06503824A/ja active Pending
- 1991-12-20 AU AU91065/91A patent/AU9106591A/en not_active Abandoned
- 1991-12-20 US US08/081,332 patent/US5475111A/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4769465A (en) * | 1985-05-21 | 1988-09-06 | Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, N.Sol.O. | Process for the preparation of 2-(N-benzyl-N-methylamino)-ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride salt |
WO1988007524A1 (en) * | 1987-03-27 | 1988-10-06 | Byk Gulden Lomberg Chemische Fabrik Gmbh | New intermediate products and process |
Non-Patent Citations (2)
Title |
---|
CHEM. PHARM. BULL., Volume 28, No. 9, 1980, TADAO SHIBANUMA et al., "Synthesis of Optically Active 2-(N-Benzyl-N-methylamino)-ethyl Methyl 2,6-Dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (Nicardipinel)", pages 2809-2812. * |
CHEMISTRY OF HETEROCYCLIC COMPOUNDS, Volume 14, No. 2, February 1978, A.E. SAUSIN et al., "Hydrolysis of 1,4-dihydropyridine-3,5-dicarboxylic Acid Esters", page 225. * |
Also Published As
Publication number | Publication date |
---|---|
JPH06503824A (ja) | 1994-04-28 |
EP0564509A1 (de) | 1993-10-13 |
DE4041814A1 (de) | 1992-07-02 |
US5475111A (en) | 1995-12-12 |
AU9106591A (en) | 1992-07-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0088276B1 (de) | Neue Verbindungen, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Arzneimittel | |
US6046337A (en) | Process for the preparation of a dihydropyridine derivative | |
EP1802576B1 (de) | Verfahren zur herstellung eines enantiomers von amlodipin in hoher optischer reinheit | |
DE2756226A1 (de) | 1,4-dihydropyridin-verbindungen, verfahren zu ihrer herstellung und sie enthaltende pharmazeutische mittel | |
US20030078429A1 (en) | Process and diastereomeric salts useful for the optical resolution of racemic a-[4- (1,1-dimethylethy) phenyl) -4- (hydroxydipenylmethyl) -1-piperidinebutanol and derivative compounds | |
EP0039863B1 (de) | 1,4-Dihydropyridine mit unterschiedlichen Substituenten in 2- und 6-Position, Verfahren zu ihrer Herstellung und ihre Verwendung in Arzneimitteln | |
DE60133288T2 (de) | Verfahren zur Herstellung von Fexofenadin und Derivaten hiervon | |
EP0452712A1 (de) | Neue 4-Chinolyl-dihydropyridine, Verfahren zu ihrer Herstellung und ihre Verwendung in Arzneimitteln | |
EP0110259B1 (de) | 1,4-Dihydropyridinderivate, Verfahren zu ihrer Herstellung sowie ihre Verwendung in Arzneimitteln | |
WO1992011239A1 (de) | Verfahren zur herstellung von dihydropyridincarbonsäuren | |
EP0202625B1 (de) | Verfahren zur Herstellung von 2,6-Dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridin-3,5-dicarbonsäure-3 beta-(N-benzyl-N-methylamino)-ethylester-5-methylester und dessen Hydrochlorid-Salz | |
DE60223003T2 (de) | Verfahren zur herstellung von amlodipin | |
EP0287828A1 (de) | Neue Zwischenprodukte und Verfahren | |
US4839348A (en) | 1,4-dihydropyridines | |
EP0225574B1 (de) | Neue, fluorhaltige 1,4-Dihydropyridine, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Arzneimittel | |
DE4341605C2 (de) | Verfahren zur Herstellung homochiraler Aminoalkohole | |
EP0346852B1 (de) | Verfahren zur Herstellung von 4-chlor-3-alkoxy-but-2E-en-säurealkylester | |
DE3786770T2 (de) | Stereokonvergentverfahren zur Herstellung von optisch aktiven Carbonsäuren. | |
KR900002342B1 (ko) | Ym-09730 부분 입체 이성질체 a의 우선성 광학 이성질체의 신규 제조 방법 | |
EP0538690A1 (de) | Aryl-Chinolyl-substituierte 1,4-Dihydropyridin-dicarbonsäurederivate, Verfahren zu ihrer Herstellung und ihre Verwendung in Arzneimitteln | |
DE3628215C2 (de) | 1,4-Dihydro-2-alkylenamino-3,5-dicarbonester-4-(2-propenyl)-phenyl-pyridine, Verfahren zu ihrer Herstellung und pharmazeutische Zubereitung | |
AT395976B (de) | Verfahren zur herstellung von dihydropyridinverbindungen oder ihren salzen | |
EP0347678B1 (de) | 1,4-Dihydropyridin-threonin-Derivate und Verfahren zu ihrer Herstellung | |
US4254279A (en) | Ester resolution process | |
WO1988009331A1 (en) | Process for manufacturing carboxylic acids |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA CS FI HU JP KR NO PL SU US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 1992901540 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 08081332 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 1992901540 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: CA |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1992901540 Country of ref document: EP |