Synthetic method for Sacubitril

A synthetic method, the technology of Sacubitril, applied in the field of Kubitril, can solve the difficulties in the source of chiral auxiliary reagents Bety base and 2R-methyl-4-oxobutanoic acid, the high price of chiral raw materials Eliminate the problems of expensive reagents, etc., and achieve the effect of cheap and easy to obtain, convenient and easy to obtain raw materials, and low price

Inactive Publication Date: 2017-02-08
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the chiral auxiliary reagents Bety base and 2R-methyl-4-oxobutanoic acid used in this method are difficult to obtain.
[0006] The common problem of the synthetic route reported above is that the price of chiral raw materials is high and rare, and chiral methyl groups need to be constructed in the synthesis, the chiral reagents used in the reaction are expensive, and the operating conditions are relatively harsh, which is not suitable for mass production.

Method used

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  • Synthetic method for Sacubitril
  • Synthetic method for Sacubitril
  • Synthetic method for Sacubitril

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Synthesis of Example 1 Compound 3

[0029]

[0030] Dissolve 10g of compound 2 (40mmol) in 100mL of dichloromethane, add 14mL of DBU (2.4eq) and 6mL of RfSO at 0°C 2 F (1.2eq), stirred at 0°C for 3h, quenched with water, extracted the aqueous phase with dichloromethane three times, combined the organic phases and washed with saturated brine once, dried over anhydrous sodium sulfate and filtered, evaporated the solvent under reduced pressure , and separated by column chromatography to obtain compound 3 (8.2 g, yield 88%).

[0031] [α] D 23 +5.3 (c 0.82, CHCl 3 );

[0032] IR (cm -1 ):3410(OH);

[0033] 1H NMR (400MHz, CDCl 3 )3.42-3.52(m,2H),2.94-2.99(m,1H),2.77(t,J=4.4Hz,1H),2.46(dd,J=5.1,2.7Hz,1H),1.82-1.90(m ,1H),1.64-1.70(m,1H),1.27-1.33(m,1H),0.97(d,J=6.7Hz,3H),0.89(s,9H),0.04(s,6H);

[0034] 13 C NMR (100MHz, CDCl 3 )δ68.3,51.2,47.7,36.5,34.1,26.1,18.5,16.8,-5.2,-5.3; HRMS-EI(m / z):[M-C(CH 3 ) 3 ] + calcd for C 8 h 17 o 2 Si:173.0998,found:173.09...

Embodiment 2

[0035] Synthesis of Example 2 Compound 3

[0036]

[0037]Dissolve 10g of compound 2 (40mmol) in 100mL of dichloromethane, add 13mL of pyridine (4eq) and 15g of p-toluenesulfonyl chloride (2eq) at room temperature, stir at room temperature for 3h, add water to quench, dichloromethane to extract the aqueous phase The organic phases were combined three times and washed once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure and separated by column chromatography to obtain compound 3 (8.4 g, yield 90%).

Embodiment 3

[0038] Synthesis of Example 3 Compound 3

[0039]

[0040] Dissolve 10 g of compound 2 (40 mmol) in 100 mL of chloroform, add 33 mL of triethylamine (6 eq) and 9 mL of methanesulfonyl chloride (3 eq) at room temperature, stir at room temperature for 4 h, add water to quench, dichloromethane extracts water After three phases, the organic phases were combined and washed once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure and separated by column chromatography to obtain compound 3 (8.1 g, yield 87%).

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Abstract

The invention provides a preparation method for Sacubitril as one component of a novel hypotensive drug Entresto. According to the method, chiral synthons, obtained in the oxydative degradation wastes of steroid sapogenin, are adopted as raw materials. The raw materials are subjected to five steps of reactions, and then the high-yield synthesis of Sacubitril is realized. The raw materials of the method are simple, easily available and low in cost. Meanwhile, the synthetic method is characterized by being mild in condition, simple in operation, high in yield and few in by-product. The method can be applied to the industrial production.

Description

technical field [0001] The invention provides a method for synthesizing Sacubitril, one of the components of the drug Entresto (LCZ696) for treating hypertension and heart failure. This method uses the (2R,4R)-4-methyl-1,2,5-triol chiral synthon obtained from the oxidative degradation waste of steroidal sapogenin as a raw material, and synthesizes sand with high yield through 5 steps of reaction. Kubiqu. The synthesis method is characterized in that the chiral synthesis raw materials are convenient and easy to obtain, the price is low, the reaction conditions are mild, the operation is simple, no expensive metal reagents are used, the reaction yield is high, the by-products are few, and it is suitable for industrial production. [0002] technical background [0003] Entresto is a new type of drug for the treatment of hypertension and heart failure researched and developed by Novartis. It was approved by the US FDA in 2015. It consists of the neprilysin inhibitor sacubitril ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C235/78C07C231/10
CPCC07B2200/07C07C29/106C07C231/10C07C247/10C07D301/26C07D303/04C07C235/78C07C33/18
Inventor 田伟生汪昀史勇
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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