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Sacubitril dicyclohexylamine salt, crystal form and preparation method of crystal form

A technology of dicyclohexylamine salt and sacubitril, applied in the field of drug synthesis, can solve the problems of low production efficiency, unsatisfactory crystallization effect, unfavorable industrial purification and the like, and achieves reduction of production cost, easy production amplification, storage and circulation, Impurity control ideal effect

Inactive Publication Date: 2016-04-20
ZHEJIANG TIANYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patent WO2007045663 discloses the preparation method of triethanolamine salt and tromethamine salt of sacubitrat, wherein the triethanolamine salt of sacubitrat needs to use highly volatile ether as a solvent for salt formation and crystallization, which is not conducive to industrial purification. And the content of some impurities is greater than 0.5%, (see attached Figure 8 ); the preparation of the tromethamine salt of Shakubiqu needs a long time (more than 20 hours) to reflux, the production efficiency is low, and the crystallization effect is also not ideal, and the content of some impurities is greater than 1.0%, and the control of the content of impurities still exists Insufficient (see attached Figure 9 )
Moreover, the organic amine salts of sacubitril disclosed in these patents are directly used to form a pharmaceutical combination preparation with valsartan, and these organic amine salts are not reacted with valsartan and sodium hydroxide to prepare LCZ696 by co-crystallization

Method used

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  • Sacubitril dicyclohexylamine salt, crystal form and preparation method of crystal form
  • Sacubitril dicyclohexylamine salt, crystal form and preparation method of crystal form
  • Sacubitril dicyclohexylamine salt, crystal form and preparation method of crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] The preparation of the crude product of embodiment 1 sand library than tricyclohexylamine salt

[0040] At room temperature (10-30°C), add 4.5g of Sacubitril to 25mL of ethyl acetate, stir to dissolve, then slowly drop in 1.7g of dicyclohexylamine, continue to stir to form solids, and then cool down naturally to After 2 hours of heat preservation at 3°C, filter, wash the filter cake with ethyl acetate, and dry in vacuo to obtain 6.0 g of white powder, which is the crude product of sacubitril dicyclohexylamine salt.

Embodiment 2

[0041] The preparation of the crystalline form of embodiment 2 Sacubitril dicyclohexylamine salt

[0042] Add 6.0 g of the crude dicyclohexylamine salt of Sacubitril prepared in Example 1 into 50 mL of ethyl acetate, heat to 78°C to dissolve, stir for half an hour and then slowly cool to 2°C to crystallize, filter, and dry in vacuo Finally, 5.6 g of white crystals were obtained with a yield of 93% and a melting point of 122-123°C. The DSC figure of gained crystal (crystalline form I) sees figure 1 , powder X-ray diffraction pattern see figure 2 .

[0043] Sacubitril Dicyclohexylamine Salt 1 HNMR picture as shown image 3 Shown; Shakubi tricyclohexylamine salt after heavy water exchange 1 HNMR picture as shown Figure 4 Shown; Sacubitril dicyclohexylamine salt 13 CNMR picture as Figure 5 shown.

[0044] The NMR data are as follows: 1 HNMR (400MHz, CDCl 3 ):δ8.70(br,2H),7.49(m,2H),7.41(m,2H),7.37(m,1H),7.25-7.10(m,2H),4.05(br,1H),4.01( m,2H),2.86(m,2H),2.70(m,2H),2....

Embodiment 3～8

[0048] According to the operation process of Example 2, different solvents, dosages and temperature conditions were changed to carry out crystallization, the results are shown in the following list of examples, and the DSC figure of the obtained crystal form is shown in figure 1 , powder X-ray diffraction pattern see figure 2 , nuclear magnetic data is the same as embodiment 2, and HPLC collection of illustrative plates is as Figure 6 shown.

[0049]

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Abstract

The invention discloses Sacubitril dicyclohexylamine salt, a crystal form and a preparation method of the crystal form. The structure of the sacubitril dicyclohexylamine salt is shown in the formula III in the description. The invention also discloses the crystal from of the sacubitril dicyclohexylamine salt and the preparation method thereof. The sacubitril dicyclohexylamine salt provided by the invention is ideal on the aspects of refinement of the sacubitril and impurity control of a refined product, is conducive to controlling the quality of subsequent LCZ696, and is high in crystallization yield, can effectively reduce the production cost, and is beneficial to industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to sacubitril dicyclohexylamine salt, crystal form and preparation method thereof. Background technique [0002] LCZ696 is a new antihypertensive drug developed by Novartis, which mainly contains Novartis' Diovan (generic name: valsartan) and experimental drug Sacubitril (AHU-377) Among them, sacubitril can block the mechanism of action of two polypeptides that are responsible for lowering blood pressure. The drug was approved by the US FDA on July 7, 2015 for heart failure with reduced ejection fraction ( heart failure) patients, reduce the risk of cardiovascular death and heart failure hospitalization. LCZ696 is usually obtained by co-crystallization of Diovan and Sacubitril in an equimolar ratio in a mixed solvent of sodium hydroxide aqueous solution and organic solvent. The composition of LCZ696 is Diovan:Sacubitril:Na:H 2 O=1:1:3:2.5 (molar ratio), its chemical formula is shown ...

Claims

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Application Information

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IPC IPC(8): C07C231/24C07C231/12C07C233/47C07C209/00C07C209/86C07C211/35
CPCC07C233/47C07B2200/13C07C209/00C07C209/86C07C211/35C07C231/12C07C231/24
Inventor 王臻谢文龙朱国荣徐少军屠勇军
Owner ZHEJIANG TIANYU PHARMA
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