WO2014139410A1 - Procédé de préparation d'intermédiaire de l'azelnidipine - Google Patents

Procédé de préparation d'intermédiaire de l'azelnidipine Download PDF

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Publication number
WO2014139410A1
WO2014139410A1 PCT/CN2014/073222 CN2014073222W WO2014139410A1 WO 2014139410 A1 WO2014139410 A1 WO 2014139410A1 CN 2014073222 W CN2014073222 W CN 2014073222W WO 2014139410 A1 WO2014139410 A1 WO 2014139410A1
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Prior art keywords
reaction
diphenylmethyl
add
acid
dichloromethane
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PCT/CN2014/073222
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English (en)
Chinese (zh)
Inventor
徐�明
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沈阳中海药业有限公司
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Publication of WO2014139410A1 publication Critical patent/WO2014139410A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

Definitions

  • the invention belongs to the technical field of medicine and provides an important intermediate of dihydropyridine calcium antagonist adipine, 3-amino-3-iminopropionic acid-1-(diphenylhydrazinyl)-3-azetidine The synthesis process of ester acetate. Background technique
  • Azelnidipine is a new type of dihydropyridine calcium channel blocker developed by Sankyo and Ube Industries of Japan. It was approved for sale in Japan in late May 2003 under the trade name Calblock. Adipine has a selective blockade of calcium channels in arterial smooth muscle cells, it can dilate blood vessels, reduce peripheral vascular resistance and arterial pressure, and is widely used clinically for mild or moderate essential hypertension, renal disorders with hypertension And treatment of severe hypertension. Compared with nicardipine and nifedipine dihydropyridine calcium channel blockers, adipine is superior in selectivity, long-lasting and long-lasting, and has little effect on the heart.
  • references to the preparation of agdipine include: European patents EP0266922; Chinese patent CN201010516967.7; Chinese Journal of Medicinal Chemistry, 2010, 20 (3): 192-194; Chinese Journal of Pharmaceutical Industry, 2008, 39 (3): 163-165; Chemical Industry and Engineering, 2009, 26 ( 1 ): 15-18; Qilu Pharmacy, 2005, 24 (6): 365-366.
  • the preparation method of adipine in these literatures is based on the reaction of epichlorohydrin and diphenylamine with N-alkylation, cyclization, esterification, Pinner synthesis, neutralization, and oxime reaction.
  • 3-amino-3-iminopropionic acid-1- (3) is prepared by a three-step reaction from cyanoacetate-1-diphenylhydrazin-3-azetidinyl ester (3) according to the method specifically reported in the above literature.
  • Diphenylhydrazino)-3-azetidinyl acetate (6) the reaction operation is cumbersome, and it is easy to produce by-products of hydrolysis of ester bonds and hydrolysis of imid bonds (7) and (8), three-step reaction.
  • the total yield is only 20 ⁇ 30%, and the purification of the product is difficult, which seriously affects the quality of the final product and greatly increases the production cost.
  • the adipine intermediate of the present invention 3-amino-3-iminopropionic acid-1-(diphenylhydrazinyl)-3-azetidinyl acetate acetate has the following structural formula:
  • the preparation method of 3-amino-3-iminopropionic acid-1-(diphenylindenyl)-3-azetidinyl acetate of the present invention comprises the following steps: 1) Esterification: 1-diphenylhydrazin-3-azetidinol (2), cyanoacetic acid (1) and N,N-dicyclohexylcarbodiimide (DCC) in organic solvent at 0 ⁇ Reacting at 80 ° C, to obtain 7-diphenylindolyl-3-azetidinyl cyanoacetate (3);
  • the carbodiimide (DCC) is reacted in an organic solvent at 0 to 80 ° C for 0.5-11 hours. After cooling, suction filtration, the filtrate is washed with alkali, washed with water, dried and evaporated to dryness to give cyanoacetate-1-diphenylhydrazino-3-azetidinyl ester (3).
  • organic solvent is selected from the group consisting of acetone, dichlorodecane, diethyl ether, chloroform, ethyl acetate, and acetic acid
  • organic solvents are good solvents for 1,3-dicyclohexylurea (DCU) and a good solvent for the product cyanoacetate-1-diphenylindol-3-azetidine, which is at 0°.
  • DCU 1,3-dicyclohexylurea
  • the solubility of the solute at C is greater than 30 g/100 mL, and the poor solvent is such that the solubility of the solute is less than lg/100 mL at 0 °C.
  • a preferred organic solvent is one selected from the group consisting of dichlorosilane, chloroform, diethyl ether, ethyl acetate, toluene, acetonitrile or a mixed solvent of one or more.
  • the alkaline water is a saturated sodium bicarbonate solution.
  • the base is selected from one of an organic base and an inorganic base.
  • the organic base is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • RR 2 and R 3 are independently selected from the group consisting of hydrogen, dC 4 alkyl, phenyl, phenyl dC 4 alkyl, with the proviso that R 1 R 2 and R 3 are not hydrogen at the same time.
  • Preferred organic bases are selected from the group consisting of decylamine, ethylamine, propylamine, decylamine, diethylamine, decylamine, triethylamine, aniline, N-mercaptoaniline, diisopropylethylamine, hydrazine, hydrazine-di Mercaptoaniline, ethylenediamine.
  • More preferred organic bases are selected from the group consisting of diamine, diethylamine, triethylamine, aniline, ethylenediamine. It refers to an organic base C r C 4 primary amines, aromatic primary amines, symmetric or asymmetric C r C 4 secondary amine, symmetrical or asymmetrical aromatic primary amine, symmetrical or asymmetrical tertiary C r C 4, symmetric or asymmetric Aromatic tertiary amine, aliphatic diamine.
  • the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide and potassium hydroxide.
  • the base is added so that the pH of the solution is from 7 to 10, preferably from 7 to 8.
  • the present invention uses an organic base in the neutralization reaction, which reduces side reactions and improves product purity and yield.
  • Preparation of an important intermediate of adipinepine using the method of the invention 3-amino-3-iminopropionic acid -1- (diphenylhydrazine)
  • Method 1 Add 1-diphenylhydrazin-3-azetidinol (2, 235 g, 0.983 mol) and cyanoacetic acid (1, 100 g, 1.18 mol) to 1.5 mL of dichloromethane, and stir until fully dissolved.
  • ⁇ ⁇ -dicyclohexylcarbodiimide (DCC, 243 g, 1.18 mol) was added at 0-10 ° C and allowed to react at room temperature for 3 h. After the completion of the reaction, the reaction mixture was cooled to 0 to 5 ° C, and filtered, filtered, washed with a small portion of dichloromethane. The organic solvent was evaporated to dryness under reduced pressure and dried to give 275 g of white solid.
  • DCC ⁇ -dicyclohexylcarbodiimide
  • Method 2 chloroform was used as the reaction solvent, and the operation was the same as above, and the reaction was carried out at 55 ° C for 5 hours, the HPLC purity was 98.7%, and the product yield was 95.3%.
  • Method 1 Add 1.4 L of dichloromethane to Intermediate 4, cool to 0-5 ° C, add dry diethylamine (182 mL, 1.76 mol) to the solution, adjust pH 7-8, continue to stir after the dropwise addition. 2h. The mixture was suction filtered, and the filtrate was evaporated to dryness vacuo.
  • Method 5 Add 1.4 L of dichloromethane to Intermediate 4, cool to 0-5 ° C, add potassium carbonate (242.88 g, 1.76 mol) to the solution in portions, adjust pH 7-8, continue stirring for 2 h. . The mixture was suction filtered, and the filtrate was evaporated to dryness vacuo.
  • Method 6 Neutralize with sodium carbonate, and operate as above.
  • Method 7 Neutralize with sodium hydroxide, and operate as above.

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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

La présente invention concerne un procédé de préparation d'acétate d'ester d'acide 3-amino-3-iminopropanoïque-1-(diphénylméthyl)-3-azétidinyle utilisé comme intermédiaire d'azelnidipine. Dans ledit procédé, du 1-diphénylméthyl-3-azétidin-ol et de l'acide cyanoacétique utilisés comme matières premières sont soumis aux quatre étapes d'estérification, de réaction de Pinner, de neutralisation et d'amidation pour produire un acétate d'ester d'acide 3-amino-3-iminopropanoïque-1-(diphénylméthyl)-3-azétidinyle. En sélectionnant des solvants et des conditions réactionnels appropriés, le procédé présente les avantages de conditions réactionnelles légères, de post-traitement simple et de rendement de la réaction élevé.
PCT/CN2014/073222 2013-03-14 2014-03-11 Procédé de préparation d'intermédiaire de l'azelnidipine WO2014139410A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310081090.7A CN103130700B (zh) 2013-03-14 2013-03-14 一种阿折地平中间体的制备方法
CN201310081090.7 2013-03-14

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WO2014139410A1 true WO2014139410A1 (fr) 2014-09-18

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CN (1) CN103130700B (fr)
WO (1) WO2014139410A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103130700B (zh) * 2013-03-14 2015-04-29 沈阳中海药业有限公司 一种阿折地平中间体的制备方法
CN104860855B (zh) * 2014-12-08 2017-06-16 宁夏紫光天化蛋氨酸有限责任公司 一种高纯度的d,l‑2‑羟基‑4‑甲硫基丁酸酯的制备方法
CN105949102A (zh) * 2016-06-20 2016-09-21 许昌豪丰化学科技有限公司 一种阿折地平中间体的生产方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102453023A (zh) * 2010-10-21 2012-05-16 大丰市天生药业有限公司 一种阿折地平生产工艺
CN103130700A (zh) * 2013-03-14 2013-06-05 沈阳中海药业有限公司 一种阿折地平中间体的制备方法
CN103509003A (zh) * 2012-06-27 2014-01-15 威海威太医药技术开发有限公司 一种阿折地平的制备方法

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JP3491506B2 (ja) * 1997-10-14 2004-01-26 宇部興産株式会社 ジヒドロピリジン誘導体の製造法
CN101475521B (zh) * 2008-11-13 2010-11-10 青岛黄海制药有限责任公司 1-二苯甲基-3-氮杂环丁烷基脒基乙酸酯的乙酸盐的合成方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102453023A (zh) * 2010-10-21 2012-05-16 大丰市天生药业有限公司 一种阿折地平生产工艺
CN103509003A (zh) * 2012-06-27 2014-01-15 威海威太医药技术开发有限公司 一种阿折地平的制备方法
CN103130700A (zh) * 2013-03-14 2013-06-05 沈阳中海药业有限公司 一种阿折地平中间体的制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LIU, JIAN-FENG ET AL.: "Improved Synthesis of Azelnidipine", CHINESE JOURNAL OF MEDICINAL CHEMISTRY, vol. 20, no. 3, 30 June 2010 (2010-06-30), pages 192 - 194 *
ZHANG, KAI ET AL.: "Synthesis of Azelnidipine", CHINESE JOURNAL OF PHARMACEUTICALS, vol. 39, no. 3, 31 March 2008 (2008-03-31), pages 163 - 165 *

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CN103130700A (zh) 2013-06-05

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