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Preparation method of fimasartan potassium salt hydrate

A technology of trihydrate and Fimasartan, which is applied in the field of preparation of medicine Fimasartan potassium salt trihydrate, can solve the problems of inability to realize industrialized production, difficult to recover and apply mechanically, consume large silica gel and the like, and achieves reduction of process cost. , Simple operation, easy industrial production effect

Inactive Publication Date: 2015-11-18
合肥创新医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The reaction conditions of this route are mild, the starting materials are easy to get, and the reaction reagents are cheap, but the biggest deficiency in this patent is that the preparation of compound (II) adopts silica gel column chromatography, which needs to consume a large amount of silica gel. The mixed solvent of the two solvents is used as the eluent, and it is not easy to realize recycling
The use of a large amount of solvent and silica gel not only greatly increases the cost, but also causes environmental pollution. Therefore, this process will not be able to realize industrial production in the end.

Method used

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  • Preparation method of fimasartan potassium salt hydrate
  • Preparation method of fimasartan potassium salt hydrate
  • Preparation method of fimasartan potassium salt hydrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] (1) Preparation of Compound IV

[0035] Starting material 1: 2-(2-Butyl-4-hydroxy-6-methylpyrimidin-5-yl)-N,N-dimethylacetamide

[0036] Starting material 2: N-(triphenylmethyl)-5-(4'-bromomethylbiphenyl-2-yl)tetrazolium

[0037] Add 80g of starting material 1, 1000mL of ethyl acetate, and 120mL of DMF into a 2000mL reaction flask, stir and cool down to 5°C, add 3g of lithium hydride, keep stirring for 30min, add 250g of starting material 2, and heat up to 55°C , heat preservation reaction for 90h, after the heat preservation reaction, lower the temperature to 5°C, stir, a large amount of solids precipitate out, filter, wash the filter cake with ethyl acetate, and dry at 50°C to obtain 210g of off-white solid, yield: 90.6%.

[0038] (2) Preparation of compound Ⅲ

[0039] Add 210g of compound IV and 1600mL of tetrahydrofuran into a 3000mL reaction flask, add 650mL of 10% hydrochloric acid dropwise at room temperature under stirring, the solid dissolves slowly, after th...

Embodiment 2

[0047] (1) Preparation of Compound IV

[0048] Starting material 1: 2-(2-Butyl-4-hydroxy-6-methylpyrimidin-5-yl)-N,N-dimethylacetamide

[0049] Starting material 2: N-(triphenylmethyl)-5-(4'-bromomethylbiphenyl-2-yl)tetrazolium

[0050] Add 80g of starting material 1, 1000mL of ethyl acetate, and 120mL of DMF into a 2000mL reaction flask, stir and cool down to 0°C, add 3g of lithium hydride, keep stirring for 45min, add 250g of starting material 2, and heat up to 45°C after adding , heat preservation reaction for 105h, after the heat preservation reaction, lower the temperature to 10°C, stir, a large amount of solids precipitate out, filter, wash the filter cake with ethyl acetate, and dry at 60°C to obtain 208g of off-white solid, yield: 89.7%.

[0051] (2) Preparation of compound Ⅲ

[0052] Add 210g of compound IV, 500mL of methanol, 500mL of ethanol, and 600mL of tetrahydrofuran into a 3000mL reaction flask, and add 100mL of 10% hydrochloric acid dropwise at room temperat...

Embodiment 3

[0060] (1) Preparation of Compound IV

[0061] Starting material 1: 2-(2-Butyl-4-hydroxy-6-methylpyrimidin-5-yl)-N,N-dimethylacetamide

[0062] Starting material 2: N-(triphenylmethyl)-5-(4'-bromomethylbiphenyl-2-yl)tetrazolium

[0063] Add 80g of starting material 1, 1000mL of ethyl acetate, and 120mL of DMF into a 2000mL reaction flask, stir and cool down to 10°C, add 3g of lithium hydride, keep stirring for 15min, add 250g of starting material 2, after the addition, heat up to 65°C , heat preservation reaction for 120h, after the heat preservation reaction, lower the temperature to 0°C, stir, a large amount of solid precipitates, filter, wash the filter cake with ethyl acetate, and dry at 40°C to obtain 214g of off-white solid, yield: 92.3%.

[0064] (2) Preparation of compound Ⅲ

[0065] Add 210g of compound IV, 800mL of methanol, and 800mL of ethanol into a 3000mL reaction flask, and add 1000mL of 10% hydrochloric acid dropwise at room temperature under stirring, and th...

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Abstract

The present invention discloses a preparation method of a fimasartan potassium salt hydrate. The method is as below: reacting a starting material 1(2-(2-butyl-4-hydroxy-6-methylpyrimidine-5-yl)-N,N-dimethylacetamide) with a starting material 2 (N-(triphenylmethyl)-5-(4'-bromomethyl-biphenyl-2-yl) tetrazole) in the presence of an alkali metal hydride in a mixed solvent of ethyl acetate and DMF, so as to obtain a compound IV; hydrolyzing the compound IV under acidic conditions to remove the protective group to obtain a compound III; subjecting the compound II to a thioamidation reaction with a Lawesson's reagent to obtain a compound II; and subjecting the compound II and potassium hydroxide to a salt-forming reaction in a mixture of isopropyl alcohol and water to obtain a desired product. The present invention has the advantages of easily available process feedstock, mild reaction conditions at room temperature, economical performance, environment-friendliness and easiness to operation, reduces the process cost to a large extent, and is easy to realize industrial production.

Description

technical field [0001] The invention relates to the design of an organic synthesis route and a new preparation process of a raw material drug and an intermediate, in particular to the field of a preparation method of a drug fimasartan potassium salt trihydrate. Background technique [0002] Fimasartan (fimasartan) is developed by Boryeong Pharmaceutical Co., Ltd. in Korea. It is a new type of non-peptide angiotensin receptor antagonist antihypertensive drug, which has the effect of selectively blocking AT1 receptors. Launched in South Korea in 2011, the trade name is Kanarcb. [0003] Preclinical studies have shown that fimasartan is well tolerated, has a faster onset of antihypertensive effect and better antihypertensive effect than losartan. Compared with the results of other latest research on ARB drugs reducing siDBP or 24ABP, the reduction in siDBP in the fimasartan group was greater than other drugs, and the reduction in 24ABP was also comparable to that of olmesartan...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/10
CPCY02P20/55C07D403/10
Inventor 曹明成
Owner 合肥创新医药技术有限公司
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