Preparing method for anti-heart-failure medicine LCZ696

A technology of sacubitril and sodium hydroxide, which is applied in the field of drug synthesis, can solve the problems of cumbersome production process, difficult control of calcium ion residues and the like, achieves that the preparation process is simple and feasible, suitable for long-term storage and transportation, and improves production efficiency. Effect

Active Publication Date: 2016-02-24
ZHEJIANG TIANYU PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The whole production process needs repeated ion exchange and ion exchange, which makes the production process more cumbersome and the calcium ion residue is not easy to control
[0008] In addition, Novartis patents WO03059345, WO2006086456, and WO2007045663 disclose triethanolamine salts and tromethamine salts of sacubitril, and the organic amine salts of sacubitril disclosed in these patents are directly used to form valsartan Pharmaceutical combination preparations, did not use these organic amine salts to react with valsartan and sodium hydroxide to prepare LCZ696 by co-crystallization

Method used

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  • Preparing method for anti-heart-failure medicine LCZ696
  • Preparing method for anti-heart-failure medicine LCZ696
  • Preparing method for anti-heart-failure medicine LCZ696

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] The preparation of the crude product of embodiment 1 sand library than tricyclohexylamine salt

[0052] 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

[0053] The preparation of the crystalline form of embodiment 2 Sacubitril dicyclohexylamine salt

[0054] 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 .

[0055] 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.

[0056] 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

[0060] 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.

[0061]

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Abstract

The invention discloses a preparing method for an anti-heart-failure medicine LCZ696. The preparing method comprises the following steps that in an organic solvent, sacubitril dicyclohexyl amine salt and diovan are reacted under the effect of a sodium hydroxide aqueous solution, and the anti-heart-failure medicine LCZ696 is obtained. The preparing method is simple in process, the procedures of ion exchange to calcium salt from sodium salt and hydrochloric acid dissociation in the existing production process are omitted, residues of calcium ions are avoided, and the production efficiency is effectively improved. The formula of sacubitril dicyclohexyl amine salt and the formula of diovan can be seen in the specification.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of an anti-heart failure drug LCZ696. Background technique [0002] LCZ696 is a new type of antihypertensive and anti-heart failure drug developed by Novartis. -377) and other two components, among which sacubitril can block the mechanism of action of two polypeptides that are responsible for lowering blood pressure. Reduced risk of cardiovascular death and hospitalization for heart failure in patients with heart failure. 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 in Formula I below. [0003] [0004] As an important component of LCZ696, Sacubi has received widespread attention. The chemical name of Sacubi is: 4-{[(2S,4...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/04C07C233/47C07C231/02
CPCC07C231/02C07D257/04C07B2200/13C07C233/47A61P9/12B01D9/0054B01D9/0063C07D257/02
Inventor 王臻谢文龙朱国荣徐少军屠勇军
Owner ZHEJIANG TIANYU PHARMA
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