Preparation method for cardiovascular disease treatment drug

A technology of compounds and inert solvents, which is applied in the field of preparation of drugs for treating cardiovascular diseases, can solve problems such as unfavorable industrial operation and economical industrial production, difficulty in obtaining starting materials, and increased production costs

Active Publication Date: 2016-02-10
SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Patents WO2007 / 026971, FR2867187, JP2009107972 and Bioorg.Med.Chem., 1999, 7: 17432-1754 reported a synthetic route of tolvaptan with a total of 11 steps. This reaction has the following disadvantages: 1) the The single-line route synthesis of the reaction greatly reduces the overall yield; 2) the reduction reaction uses high price and heavy metal platinum oxide as a catalyst, which is not suitable for economical production and environmental protection; 3) each part of the reaction has adopted a column layer 4) in the process, some organic solvents that are unfavorable for safe production have also been used in a large number, such as chloroform as extraction reagent etc.
This route has the disadvantages that the starting material is difficult to obtain, the first step reaction adopts a class of solvent 1,2-dichloroethane, which is not conducive to environmental protection, and the yield of rearrangement reaction and the latter two steps of reduction is low, so this route is not suitable. Conducive to industrialized operation and economical industrialized production
[0012] In summary, there is still a lack of N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxyl-1H- 1-Benzazepine -1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide preparation method

Method used

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  • Preparation method for cardiovascular disease treatment drug
  • Preparation method for cardiovascular disease treatment drug
  • Preparation method for cardiovascular disease treatment drug

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Experimental program
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preparation example Construction

[0104] The preparation of formula (VI) compound

[0105] The present invention also provides a method for preparing the compound of formula (VI), the method comprising the steps of:

[0106] (2) In an inert solvent, react the compound of formula (IV) with the compound of formula (V) to obtain the compound of formula (VI);

[0107]

[0108] In a preferred embodiment of the present invention, the reaction is carried out in the presence of a base catalyst; preferably, the base catalyst is selected from the group consisting of triethylamine, pyridine, diisopropylethylamine, N- Methylmorpholine, DBU, or combinations thereof; preferably triethylamine, diisopropylethylamine, or combinations thereof.

[0109] In another preferred embodiment, in the step (2), the base catalyst is slowly added to the compound of formula (V) at a suitable temperature.

[0110] In another preferred example, in the step (2), the inert solvent is selected from the group consisting of dichloromethane, a...

Embodiment 1

[0197] (1) Synthesis of Compound (Ⅳ)

[0198] Methyl 2-amino-5-chlorobenzoate (30.0 g, 161.63 mmol) and methyl 4-bromobutyrate (Ⅲ) (29.26 g, 161.63 mmol) were dissolved in acetonitrile (600 mL), and sodium carbonate ( 34.26g, 323.26mmol), then stirred and heated to 80°C, reacted for 5h, and detected by TLC, the reaction was complete. Cool to room temperature, pour the reaction solution into water (300mL), take the organic phase, extract the aqueous phase with ethyl acetate twice (200mLx2), combine the organic phases, wash with water twice (200mLx2), and dry over anhydrous sodium sulfate. The solvent was spun off to obtain 43.41 g of compound (IV), with a yield of 94.0%.

[0199] 1 H-NMR(400MHz,DMSO):δ7.69(s,1H),7.50(s,1H),6.75(s,1H),6.61(s,1H),3.85(s,3H),3.65(s, 3H), 3.33(m,2H), 2.50(m,2H), 2.03(m,2H). C 13 h 16 ClNO 4 (M+H) + Calcd: 285.0768, found: 285.0771.

[0200] (2) Synthesis of compound (Ⅵ)

[0201] Compound (Ⅳ) (40.0g, 140.00mmol) was dissolved in dichlorome...

Embodiment 2

[0214] (1) Synthesis of Compound (Ⅳ)

[0215]Methyl 2-amino-5-chlorobenzoate (30.0 g, 161.63 mmol) and methyl 4-bromobutyrate (Ⅲ) (29.26 g, 161.63 mmol) were dissolved in acetonitrile (600 mL), and potassium carbonate ( 44.68g, 323.26mmol), then stirred and heated to 80°C, reacted for 5h, and detected by TLC, the reaction was complete. Cool to room temperature, pour the reaction solution into water (300mL), take the organic phase, extract the aqueous phase with ethyl acetate twice (200mLx2), combine the organic phases, wash with water twice (200mLx2), and dry over anhydrous sodium sulfate. The solvent was spun off to obtain 42.49 g of compound (Ⅳ), with a yield of 92.0%.

[0216] (2) Synthesis of compound (Ⅵ)

[0217] Compound (Ⅳ) (40.0g, 140.00mmol) was dissolved in dichloromethane (600mL), diisopropylethylamine (36.19g, 280.00mmol) was added under stirring, and 2-methyl- 4-Nitrobenzoyl chloride (Ⅴ) (33.53g, 168.00mmol), reacted for 4h, and TLC detected that the reaction w...

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Abstract

The invention provides a preparation method for a cardiovascular disease treatment drug. Specifically, the invention provides a compound represented by a formula (IV) shown in the description and a method for preparing Tolvaptan from the compound represented by the formula (IV). The method provided by the invention has the advantages of being environment-friendly, being easy in raw material obtaining and high in total yield, and the like, thereby being applicable to the industrialized preparation of Tolvaptan.

Description

technical field [0001] The invention relates to the field of drug synthesis, and specifically, the invention provides a method for preparing a drug for treating cardiovascular diseases. Background technique [0002] Tolvaptan English name Tolvaptan, trade name: Samsca, chemical name N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepine -1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide. In 2009, tolvaptan was approved by the US FDA as an oral selective vasopressin antagonist for the treatment of hyponatremia. In 2011, tolvaptan was officially approved by the State Food and Drug Administration and began to be produced and sold in China. This drug is a selective vasopressin V 2 Receptor antagonists that prevent AVP from interacting with V in distal nephrons 2 Receptor binding increases water excretion in urine, but does not change urinary sodium and potassium secretion and blood potassium value, reduces urine osmotic pressure, and increases blood sodium value, so i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/02C07C233/87C07C227/18C07C229/56C07D223/16
Inventor 李新涓子李健之马西来池王胄刘海胡旭华郑肖利翟志军李建勋
Owner SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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