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AHU377 crystal form and preparation method and uses thereof

A technology of AHU377, 1.AHU377, applied in organic chemical methods, medical preparations containing active ingredients, pharmaceutical formulations, etc., can solve problems such as unfavorable process quality control, cumbersome operation, etc.

Active Publication Date: 2016-07-13
CRYSTAL PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The existing process is not only cumbersome to operate, but also introduces a large number of impurity ions, which is not conducive to process quality control

Method used

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  • AHU377 crystal form and preparation method and uses thereof
  • AHU377 crystal form and preparation method and uses thereof
  • AHU377 crystal form and preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Example 1: Preparation of AHU377 Form III:

[0082] Weigh 3.39kg of the product solution of synthetic AHU377 (the product solution contains about 726g of AHU377, and the solvent is dichloromethane) in a 20L jacketed reactor. Add 7.5L of toluene, raise to 50°C, distill under reduced pressure to the remaining 5L volume, cool down to room temperature, add 2.5L of toluene, add 1.2L of n-heptane, after solid precipitation, add 4.8L of n-heptane dropwise into the kettle. Stir and mature overnight, filter and rinse with 1 L of n-heptane and dry under vacuum at 40°C. Add the dried solid into a 20L jacketed reactor, add 8.5L of toluene, rise to 50°C to dissolve, and then cool down to 20°C. Add 1.36L of n-heptane and it becomes turbid, add 200mL of toluene and return to 50°C to dissolve the clear, cool down to 20°C for spontaneous crystallization. Add 5 L of n-heptane dropwise into the kettle at a rate of 8 mL / min, stir and mature overnight. Filter and rinse with 1.5 L of n-h...

Embodiment 2

[0088] Example 2: Preparation of Crystal Form IV Seed Crystals

[0089] 100 mg of the crystal form III solid obtained in Example 1 was added to 1 mL of a mixed solution of n-heptane and toluene at a volume ratio of 1:1, stirred overnight at room temperature, and centrifuged to obtain a solid product.

[0090] After testing, the solid product obtained in this example is crystal form IV, and its X-ray powder diffraction data are shown in Table 2, and its XRPD pattern is as follows Figure 9 .

[0091] Table 2

[0092] theta

Embodiment 3

[0093] Example 3: Preparation of AHU377 Form IV

[0094] Weigh 3.39 kg of the product solution of synthetic AHU377 (the product solution contains about 726 g of AHU377, and the solvent is dichloromethane). Add 7.5L of toluene, rise to 50°C and distill under reduced pressure to the remaining 5L volume, cool down to room temperature, and add 2.5L of toluene. Add 1.2L of n-heptane, and after the solid precipitates, add 4.8L of n-heptane dropwise into the kettle. Stir and mature overnight, filter and rinse with 1 L of n-heptane and dry under vacuum at 40°C. Add the dried solid to a 20L jacketed reactor, add 8.5L of toluene, raise the temperature to 50°C to dissolve, then cool down to 20°C. After adding 1.36L of n-heptane, turbidity appeared, add 200mL of toluene and return to 50°C to dissolve the clear, cool down to 20°C to spontaneously crystallize. Add 5 L of n-heptane dropwise into the kettle at a rate of 8 mL / min, and stir and mature overnight. Filter and rinse with 1.5L n...

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PUM

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Abstract

The invention relates to AHU377 crystal form and a preparation method and uses thereof and provides AHU377 crystal forms III and IV, good in stability, low in hygroscopicity, high in cleaning capacity, good in purifying effect and high in economic value.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and in particular relates to the crystal form of AHU377 and its preparation method and application. Background technique [0002] AHU377, the chemical name is (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, its structural formula is as formula (I): [0003] [0004] Patent US5354892A discloses the structure of AHU377 and the preparation method of its sodium salt for the first time; but the patent does not involve the crystal form of AHU377. [0005] Patent CN102702119A discloses a dual-action compound LCZ696, the structural formula of which is shown in formula (II). The complex uses AHU377 and valsartan as active components, and the two active components are connected by hydrogen bonds. The patent also discloses the use of AHU377 or its salts for the preparation of LCZ696. LCZ696 has been clinically proven to be useful in the treatment of vario...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/47C07C231/24A61K31/216A61K31/41A61P9/04A61P9/00A61P13/12
CPCA61K31/216A61K31/41C07C231/24C07C233/47C07B2200/13A61K2300/00
Inventor 陈敏华张炎锋杨朝惠陆飞张良张晓宇
Owner CRYSTAL PHARMATECH CO LTD
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