WO1998007698A1 - Procede pour la preparation de dihydropiridines - Google Patents

Procede pour la preparation de dihydropiridines Download PDF

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Publication number
WO1998007698A1
WO1998007698A1 PCT/EP1997/004172 EP9704172W WO9807698A1 WO 1998007698 A1 WO1998007698 A1 WO 1998007698A1 EP 9704172 W EP9704172 W EP 9704172W WO 9807698 A1 WO9807698 A1 WO 9807698A1
Authority
WO
WIPO (PCT)
Prior art keywords
solvent
alanine
catalyst
water
different
Prior art date
Application number
PCT/EP1997/004172
Other languages
English (en)
Inventor
Eugenio Castelli
Giuseppe Cascio
Elso Manghisi
Original Assignee
Lusochimica S.P.A.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Lusochimica S.P.A. filed Critical Lusochimica S.P.A.
Priority to EP97935558A priority Critical patent/EP0922031A1/fr
Priority to CA002263601A priority patent/CA2263601A1/fr
Priority to AU38505/97A priority patent/AU3850597A/en
Priority to JP10505637A priority patent/JP2000515855A/ja
Publication of WO1998007698A1 publication Critical patent/WO1998007698A1/fr

Links

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 present invention relates to a novel process for the preparation of dihydropyridines .
  • a number of 4-aryl-l , 4-dihydro-2 , 6-dimethyl-3 , 5- pyridinedicarboxylic acid (V) asymmetric diesters are well known active principles used in the treatment of cardiovascular conditions (see US 3932645, DE 2117573, US 4154839, DE 3222367, EP 7293).
  • EP 124743 discloses the synthesis of benzylidene intermediates of high purity, in order to avoid the formation of by-products in the second step, starting from ordinary raw materials (appropriate benzaldehyde and acetoacetic esters), in a low molecular alcohol as the solvent, and with piperidine acetate as the catalyst.
  • the main drawback of this synthesis resides actually in the use of a catalyst prepared starting from acetic acid and piperidine, which products obviously involve handling problems due to their characteristics of toxicity, corrosivity and inflammability.
  • JP 78 53638 ( CA 89:179714) also discloses, although not in connection with dihydropyridines synthesis, similar reaction conditions in the synthesis of benzylidene acetoacetic esters.
  • EP 534520 describes the inhibition of the formation of by-products during the cyclocondensation (second step, scheme 2), by means of a short thermal reaction between a benzylidene acetoacetic ester and an amino crotonic ester in a water-miscible solvent (preferably a low molecular alcohol), combined with, or followed by, the addition of a strong acid to the reaction mixture.
  • a water-miscible solvent preferably a low molecular alcohol
  • the present invention avoids the formation of byproducts in the Hantzsch synthesis of dihydropyridines (in two steps), thanks to a process which makes use of: a) less expensive and less environmentally risky conditions in the Knoevenagel condensation (first step, scheme 2), which allow to obtain extremely pure intermediate benzylidene acetoacetic esters in a good yield; b) mild reaction conditions (anyhow inhibiting any side-reactions) in the second step (scheme 2), which allow to obtain an extremely pure final product in a high yield, by means of a very simple work up.
  • the process of the invention is carried out in an alcohol medium, at temperatures from 20 * C to 60*C, in the presence of ⁇ -alanine ( 3-aminopropanoic acid) as the catalyst.
  • ⁇ -alanine exerts its catalytic activity in rather low catalyst/aldehyde molar ratios (3%), thus permitting, for example in the preparation of Felodipine intermediate, a ⁇ -alanine/2, 3-dichlorobenzaldehyde 1.5% weight ratio, compared with a piperidine acetate/2, 3-dichlorobenzaldehyde 5.2% weight ratio stated in example 3 of EP 124743.
  • ⁇ -Alanine is also preferable to piperidine acetate for environmental reasons, and it also involves the remarkable advantage of replacing two toxic potential impurities (acetic acid and piperidine) of the final dihydropyridine product with only one ordinary potential impurity ( ⁇ -alanine), as it turns out from the comparison between the data inferable from the Registry of Toxic Effects of Chemical Substances (for the definitions of toxic and ordinary impurities see USP XIII, page 1922) .
  • the process of the present invention being free from risks of formation of by-products, advantageously yields a final dihydropyridine product of high purity, moreover allowing very simple, versatile reaction conditions, which are also advantageous from the environment and costs point of views.
  • the following example further illustrates the process of the invention.
  • the mixture is then slowly cooled to room temperature (20 * -25 * C), again with stirring and under nitrogen atmosphere, keeping these conditions for 12 hours.
  • the reaction product precipitates (optionally by seeding with some methyl 2 , 3-dichlorobenzylidene acetoacetate crystals), the mixture is cooled at 0 * C and left at this temperature for at least 3 hours.
  • the solvent is refluxed for 8-12 hours, then the mixture is slowly cooled to room temperature (20°-25 ⁇ C), with stirring. After about 12 hours, the mixture contains the solid reaction product (as in the above example, in case of a supersaturated solution, seed crystals can be made use of).
  • Lichrosorb Merck mobile phase: acetonitrile/water 1/1): felodipine: 99.8% (area); dimethyl ester: 0.07% (area); diethyl ester: 0.02% (area).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

L'invention a pour objet la préparation de dihydropyridines présentant la formule (V). Ce procédé comprend la condensation Knoevenagel d'un benzaldéhyde avec un ester acétoacétique en présence de β-alanine comme catalyseur; suivie de la cyclocondensation de l'ester acétoacétique de benzylidène ainsi obtenu avec un ester amino crotonique.
PCT/EP1997/004172 1996-08-23 1997-07-31 Procede pour la preparation de dihydropiridines WO1998007698A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP97935558A EP0922031A1 (fr) 1996-08-23 1997-07-31 Procede pour la preparation de dihydropiridines
CA002263601A CA2263601A1 (fr) 1996-08-23 1997-07-31 Procede pour la preparation de dihydropiridines
AU38505/97A AU3850597A (en) 1996-08-23 1997-07-31 A process for the preparation of dihydropyridines
JP10505637A JP2000515855A (ja) 1996-08-23 1997-07-31 ジヒドロピリジン類の製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT96MI001780A IT1283793B1 (it) 1996-08-23 1996-08-23 Processo per la preparazione di diidropiridine
ITMI96A001780 1996-08-23

Publications (1)

Publication Number Publication Date
WO1998007698A1 true WO1998007698A1 (fr) 1998-02-26

Family

ID=11374816

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/004172 WO1998007698A1 (fr) 1996-08-23 1997-07-31 Procede pour la preparation de dihydropiridines

Country Status (6)

Country Link
EP (1) EP0922031A1 (fr)
JP (1) JP2000515855A (fr)
AU (1) AU3850597A (fr)
CA (1) CA2263601A1 (fr)
IT (1) IT1283793B1 (fr)
WO (1) WO1998007698A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103467369A (zh) * 2013-09-30 2013-12-25 山东新华制药股份有限公司 尼莫地平杂质ⅰ的制备方法
CN104177286A (zh) * 2014-08-11 2014-12-03 广东东阳光药业有限公司 一种地平类药物的制备方法

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2117573A1 (de) * 1971-04-10 1972-10-19 Farbenfabriken Bayer Ag, 5090 Leverkusen Verfahren zur Herstellung von neuen unsymmetrischen 1,4-Dihydropyridindicarbonsäureestern, sowie ihre Verwendung als Arzneimittel
GB1409865A (en) * 1973-02-13 1975-10-15 Science Union & Cie Dihydropyridines derivatives their preparation and pharmaceu tical compositions containing them
US3932645A (en) * 1971-04-10 1976-01-13 Farbenfabriken Bayer Ag Pharmaceutical compositions containing unsymmetrical esters of 1,4-dihydropyridine 3,5-dicarboxylic acid
EP0007293A1 (fr) * 1978-06-30 1980-01-23 Aktiebolaget Hässle 2,6-Diméthyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylique acide, 3-méthyl ester 5-ethylester à activité hypotensive, son procédé de préparation et compositions pharmaceutiques le contenant
EP0088276A1 (fr) * 1982-03-10 1983-09-14 Bayer Ag Composés, leurs procédés de préparation et leur application comme médicaments
EP0100189A2 (fr) * 1982-07-22 1984-02-08 Pfizer Limited Agents anti-ischémiques et antihypertensifs dihydropyridines
EP0124743A2 (fr) * 1983-04-05 1984-11-14 Bayer Ag Procédé de préparation d'esters d'acides 1,4-dihydropyridine carboxyliques asymétriques
EP0319814A2 (fr) * 1987-12-08 1989-06-14 Bayer Ag Procédé de préparation de dihydropyridines asymétriques
EP0534520A2 (fr) * 1991-09-13 1993-03-31 Merck & Co. Inc. Procédé pour la préparation des 1,4-dihydro-pyridines 4-substituées

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2117573A1 (de) * 1971-04-10 1972-10-19 Farbenfabriken Bayer Ag, 5090 Leverkusen Verfahren zur Herstellung von neuen unsymmetrischen 1,4-Dihydropyridindicarbonsäureestern, sowie ihre Verwendung als Arzneimittel
US3932645A (en) * 1971-04-10 1976-01-13 Farbenfabriken Bayer Ag Pharmaceutical compositions containing unsymmetrical esters of 1,4-dihydropyridine 3,5-dicarboxylic acid
GB1409865A (en) * 1973-02-13 1975-10-15 Science Union & Cie Dihydropyridines derivatives their preparation and pharmaceu tical compositions containing them
EP0007293A1 (fr) * 1978-06-30 1980-01-23 Aktiebolaget Hässle 2,6-Diméthyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylique acide, 3-méthyl ester 5-ethylester à activité hypotensive, son procédé de préparation et compositions pharmaceutiques le contenant
EP0088276A1 (fr) * 1982-03-10 1983-09-14 Bayer Ag Composés, leurs procédés de préparation et leur application comme médicaments
EP0100189A2 (fr) * 1982-07-22 1984-02-08 Pfizer Limited Agents anti-ischémiques et antihypertensifs dihydropyridines
EP0124743A2 (fr) * 1983-04-05 1984-11-14 Bayer Ag Procédé de préparation d'esters d'acides 1,4-dihydropyridine carboxyliques asymétriques
EP0319814A2 (fr) * 1987-12-08 1989-06-14 Bayer Ag Procédé de préparation de dihydropyridines asymétriques
EP0534520A2 (fr) * 1991-09-13 1993-03-31 Merck & Co. Inc. Procédé pour la préparation des 1,4-dihydro-pyridines 4-substituées

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103467369A (zh) * 2013-09-30 2013-12-25 山东新华制药股份有限公司 尼莫地平杂质ⅰ的制备方法
CN103467369B (zh) * 2013-09-30 2015-11-04 山东新华制药股份有限公司 尼莫地平杂质ⅰ的制备方法
CN104177286A (zh) * 2014-08-11 2014-12-03 广东东阳光药业有限公司 一种地平类药物的制备方法

Also Published As

Publication number Publication date
ITMI961780A0 (fr) 1996-08-23
JP2000515855A (ja) 2000-11-28
ITMI961780A1 (it) 1998-02-23
AU3850597A (en) 1998-03-06
IT1283793B1 (it) 1998-04-30
EP0922031A1 (fr) 1999-06-16
CA2263601A1 (fr) 1998-02-26

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