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A kind of synthetic method of Fimasartan

A synthetic method, fimasartan technology, applied in the field of pharmaceutical synthesis, can solve the problems of unfavorable industrial production, difficulty in complete reaction of raw materials, and low atom economy, so as to avoid the use of silica gel and solvents, reduce process costs, and facilitate industrialization The effect of production

Active Publication Date: 2021-08-24
珠海市海瑞德生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the synthesis yield of compound 1 in this route is low, only 57.1%, and the impurities produced by the reaction are many, which require chromatographic purification, which is not conducive to industrial 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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  • A kind of synthetic method of Fimasartan
  • A kind of synthetic method of Fimasartan
  • A kind of synthetic method of Fimasartan

Examples

Experimental program
Comparison scheme
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, 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).

[0057...

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, 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 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 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 solution 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 (yield 80%, purity 99.0%).

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

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Abstract

The invention discloses a synthetic method of Fimasartan, comprising reacting compound VI and compound VII in toluene to obtain compound V; reacting compound V and pentamidine hydrochloride in the presence of alkali metal hydroxide to obtain compound IV; compound IV uses lithium hydride to extract hydrogen in the mixed solvent that toluene and DMF form, then with 2-cyano-4'-bromomethyl biphenyl generation N-alkylation reaction obtains compound III; Compound III and sodium azide in Compound II was obtained by reaction in DMF under the catalysis of zinc chloride; compound II was thioamidated with Lawson's reagent to obtain the target product I. The invention has the advantages of simple process, convenient operation, easy-to-obtain raw materials, high economy and high efficiency, greatly reduces the production cost of fimasartan, and is easy to realize industrialized production.

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 antagonist (ARB) antihypertensive agent with excellent antihypertensive effect, and has the 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), compou...

Claims

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Application Information

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Patent Type & Authority Patents(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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