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Fimasartan compound

A technology for fimasartan and compounds, applied in the field of fimasartan compounds and their crystal forms, can solve the problems of difficult separation of impurities, low yield, unsatisfactory overall yield, etc.

Inactive Publication Date: 2018-05-29
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] 1) WO / 1996008476 uses pentamidine as the starting material to generate 2-butyl-5-ethoxycarbonylmethyl-4-hydroxy-6-methylpyrimidine through ring closure reaction, and then undergoes N-alkylation, Hydrolysis, amidation, thioamidation, and deprotection group 6-step reaction to synthesize compound 1, this method will produce O-alkylation impurities during the N-alkylation reaction process, and the separation of the impurities is difficult to cause this step Very low yield (1.28%)
[0004] 2) CN01823745.2 uses pentamidine as the starting material, generates 2-butyl-5-ethoxycarbonylmethyl-4-hydroxy-6-methylpyrimidine through ring-closing reaction, and undergoes N-alkylation, amide Compound 1[9] was synthesized by 5-step reaction of thioamidation, thioamidation and detriphenylmentation. In this method, the non-selective reaction of N, O-alkylation was avoided by adding lithium hydride reagent in the N-alkylation reaction. The impurity brought, the method yield (28.2%) is significantly improved compared with method 1, but the reaction steps are still relatively complicated, and the overall yield is not ideal

Method used

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Experimental program
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Effect test

Embodiment 1

[0018] In the reaction flask, add Fimasartan potassium (2.95kg, prepared according to Lu Xiusheng's "Synthesis of Fimasartan" "Chemical Reagent", 2016, 38 (3), 283-286), 80% ethanol (4.5L ), after the addition, stir and heat up to 75°C-80°C. After the solution is clear, naturally cool down to room temperature and stir overnight. The next day, the mother liquor was cooled to -5°C-0°C and stirred for 2 hours, filtered with suction, the filter cake was washed with purified water (0.2L×2), filtered with suction, and the filter cake was air-dried at 30-35°C for 3 hours to obtain Fimasartan Potassium white solid 2.60Kg, HPLC purity 99.14%. Powder X-ray diffraction: using Cu-K radiation, the X-ray powder diffraction pattern of this compound is shown in the attached figure 1 . Differential scanning calorimetry analysis: The differential thermal analysis spectrum of this compound is shown in the attached figure 2 .

Embodiment 2

[0020] In the reaction flask, add Fimasartan potassium raw material (2.85kg is prepared according to Lu Xiusheng's "Synthesis of Fimasartan" "Chemical Reagent", 2016, 38 (3), 283-286), 63% acetone (3.8L ), after the addition, stir and heat up to 65°C-70°C. After the solution is clear, naturally cool down to room temperature and stir overnight. The next day, the mother liquor was cooled to -5°C-0°C and stirred for 2.5 hours, filtered with suction, the filter cake was washed with purified water (0.2L×2), filtered with suction, and the filter cake was air-dried at 30-35°C for 3 hours to obtain Fimarsa Potassium Tan is 2.31Kg white solid, and its HPLC purity is 99.25%. . Powder X-ray diffraction: using Cu-K radiation, the X-ray powder diffraction pattern of this compound is shown in the attached figure 1 . Differential scanning calorimetry analysis: The differential thermal analysis spectrum of this compound is shown in the attached figure 2 .

[0021] Table 1 embodiment ful...

Embodiment 3

[0024] prescription:

[0025]

[0026] Preparation Process:

[0027] (1) Fimasartan is mixed with croscarmellose sodium, sieved, then mixed with microcrystalline cellulose and silicon dioxide, added magnesium stearate, and mixed uniformly;

[0028] (2) direct compression to get the fimasartan tablet of embodiment 3.

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Abstract

The present invention provides a fimasartan compound. The Fimasartan (1) has a chemical name of 2-butyl-5-dimethylaminothiocarbamoylmethyl-6-methyl-3-[[2'-(1H) tetrazole-5-yl)biphenyl-4-yl-]methyl]pyrimidine-4(3H)-one, and is a novel angiotensin II receptor blocker antihypertensive drug. Preclinical studies and clinical trials show that the Fimasartan is safer than other ARB (angiotensin receptorblocker) drugs, and more effective in reducing diastolic blood pressure of hearts, and has good tolerance. The Fimasartan compound has characteristic peaks at 18.74, 21.10, and 24.00 in an X-ray powder diffraction spectrum.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and in particular relates to a fimasartan compound and its crystal form. Background technique [0002] Bibliographical information mainly contains following 3 kinds of methods about the synthetic route of Fimasartan: [0003] 1) WO / 1996008476 uses pentamidine as the starting material to generate 2-butyl-5-ethoxycarbonylmethyl-4-hydroxy-6-methylpyrimidine through ring closure reaction, and then undergoes N-alkylation, Hydrolysis, amidation, thioamidation, and deprotection group 6-step reaction to synthesize compound 1, this method will produce O-alkylation impurities during the N-alkylation reaction process, and the separation of the impurities is difficult to cause this step The yield was very low (1.28%). [0004] 2) CN01823745.2 uses pentamidine as the starting material, generates 2-butyl-5-ethoxycarbonylmethyl-4-hydroxy-6-methylpyrimidine through ring-closing reaction, and undergoes N-alkyl...

Claims

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Application Information

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IPC IPC(8): C07D403/10A61K31/506A61P35/00A61P15/00A61P1/08
CPCC07D403/10C07B2200/13
Inventor 易仕旭刘好罗浩
Owner SICHUAN HAISCO PHARMA CO LTD
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