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Method for synthesizing Fimasartan

A synthesis method and technology of Fimasartan, applied in the field of drug synthesis, can solve problems such as unfavorable industrial production, low atom economy, difficult and complete reaction of raw materials, avoid the use of silica gel and solvents, facilitate industrial production, reduce The effect of process cost

Active Publication Date: 2018-05-01
珠海市海瑞德生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But, the synthetic yield of compound 1 is lower in this route, only has 57.1%, and the impurity that reaction produces is more, needs chromatographic purification, is unfavorable for industrialized production
Secondly, this synthetic route introduces a larger side chain, that is, N-(trityl)-5-(4'-bromomethylbiphenyl-2-yl)tetrazolium, which is due to triphenyl Influenced by the steric hindrance of the methyl group, the reactivity is not high, the raw materials are difficult to react completely, and the reaction takes a long time, which is not conducive to industrial production
Again, a larger trityl protecting group needs to be removed in the last step, and the atom economy is not high

Method used

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  • Method for synthesizing Fimasartan
  • Method for synthesizing Fimasartan
  • Method for synthesizing Fimasartan

Examples

Experimental program
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Effect test

preparation example 1

[0054] Preparation example 1, prepare 2-(N,N-dimethylaminocarbonylmethyl) methyl acetoacetate (V) with sodium amide as base

[0055]

[0056] Under the protection of nitrogen, 81.92 g (2.10 mol) of sodium amide was added to 2000 ml of toluene, and the stirring was started, and 232.22 g (2.00 mol) of methyl acetoacetate was added dropwise within 1 hour. After completion, the reaction was stirred at 80°C for 1 hours, a white suspension was obtained. Heating was stopped, and 243.14 g (2.00 mol) of 2-chloro-N,N-dimethylacetamide was added dropwise within 1 hour, and then refluxed for 3 hours. The reaction solution was concentrated to remove toluene, then 1300 ml of dichloromethane and 1300 ml of purified water were added thereto, stirred and the organic layer was separated. The organic layer was concentrated, and purified by chromatography with a mixed solvent of ethyl acetate and n-hexane (v / v=1:5) to obtain 370 g of light yellow transparent oil (92% yield, 99.5% purity).

...

preparation example 2

[0058] Preparation example 2, using lithium hydride as base to prepare 2-(N,N-dimethylaminocarbonylmethyl) methyl acetoacetate (V)

[0059]

[0060] Under the protection of nitrogen, 16.70 g (2.10 mol) of lithium hydride was added to 2000 ml of toluene, and the stirring was started, and 232.22 g (2.00 mol) of methyl acetoacetate was added dropwise within 1 hour. After completion, the reaction was stirred at 80°C 1 hours, a white suspension was obtained. Heating was stopped, and 243.14 g (2.00 mol) of 2-chloro-N,N-dimethylacetamide was added dropwise within 1 hour, and then refluxed for 3 hours. The reaction liquid was concentrated to remove toluene, then 1300 ml of chloroform and 1300 ml of purified water were added thereto, stirred and the organic layer was separated. The organic layer was concentrated and purified by chromatography with a mixed solvent of ethyl acetate and n-hexane (v / v=1:5) to obtain 366.22 g of a light yellow transparent oil (91% yield, 99.3% purity). ...

preparation example 3

[0062] Preparation Example 3, Preparation of 2-(N,N-dimethylaminocarbonylmethyl) ethyl acetoacetate (V)

[0063]

[0064] Under the protection of nitrogen, 81.92 grams (2.10 mol) of sodium amide was added to 2000 ml of toluene, and then under stirring, 260.28 grams (2.00 mol) of methyl acetoacetate was added dropwise within 1 hour. After completion, the reaction was stirred at 80°C After 1 hour, a white suspension was obtained. Heating was stopped, and 243.14 g (2.00 mol) of 2-chloro-N,N-dimethylacetamide was added dropwise within 1 hour, and then refluxed for 3 hours. The reaction liquid was concentrated to remove toluene, then 1300 ml of chloroform and 1300 ml of purified water were added thereto, stirred and the organic layer was separated. The organic layer was concentrated and purified by chromatography with a mixed solvent of ethyl acetate and n-hexane (v / v=1:5) to obtain 344.38 g of a colorless transparent oil (80% yield, 99.0% purity).

[0065] 1 H-NMR (600MHz, C...

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Abstract

The invention discloses a method for synthesizing Fimasartan. The method comprises the steps: subjecting a compound VI and a compound VII to a reaction in toluene, so as to obtain a compound V; subjecting the compound V and pentamidine hydrochloride to a reaction in the presence of alkali metal hydroxide, so as to obtain a compound IV; subjecting the compound IV to hydrogen drawing with lithium hydride in a mixed solvent prepared from toluene and DMF, and then, carrying out an N-alkylation reaction with 2-cyano-4'-bromo-methyl biphenyl, so as to obtain a compound III; subjecting the compound III and sodium azide to a reaction in DMF in the presence of zinc chloride, so as to obtain a compound II; and subjecting the compound II to a thio amidation reaction with a Lawesson's reagent, therebyobtaining the target product I. According to the method, the process is simple, the operation is simple and convenient, the raw materials are readily available, and the method is economical and efficient, so that the production cost of the Fimasartan is greatly reduced, and the industrial production is easy to achieve.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, more specifically, the invention relates to a kind of Fimasartan, namely 2-butyl-5-dimethylaminothioformylmethyl-6-methyl-3-[[2 A new synthetic method of '-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one. Background technique [0002] Fimasartan is an angiotensin II receptor blocker (ARB) antihypertensive agent with excellent antihypertensive effect, and has a structural formula shown in Formula 1. [0003] [0004] The synthetic route in the patent WO9608476A1 is to condense pentamidine with diethyl acetylsuccinate into 2-n-butyl-5-ethoxycarbonylmethyl-4-hydroxyl-6-methylpyrimidine (compound 1), compound 1 carries out N-alkylation reaction with 4-[2'-triphenyl-5-tetrazolium] phenyl-benzyl bromide under the action of NaH, obtains 2-n-butyl-5-ethane Oxycarbonylmethyl-6-methyl-3-[[2'-(N-triphenylmethyl-5-tetrazolyl)-4-biphenyl]methyl]-4-pyrimidinone (compound 2), compound 2 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/10
CPCC07D403/10
Inventor 戴新荣
Owner 珠海市海瑞德生物科技有限公司
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