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Preparation method of anti-heart failure medicine sacubitril intermediate
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A technology for Shakubiqu and intermediates, which is applied in the field of preparing Shakubiqu intermediates, can solve the problems of low yield and high cost of chiral raw materials, achieve high yield, simple technical scheme, and mild conditions Effect
Inactive Publication Date: 2018-05-04
临沂齐泽医药技术有限公司
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[0010] The purpose of the present invention is to overcome the high cost of chiral raw materials used in the preparation process of the existing sacubitril intermediate (R)-2-amino-3-biphenylpropionate ethyl ester, the yield is not high or the preparation method No selectivity must rely on resolution to obtain chiral compounds and other issues, and a preparation method for Sacubitril intermediate (R)-2-amino-3-biphenylpropionate ethyl ester is provided. The method uses glycine ethyl esterBenzophenone imine is that raw material is by introducing specific chiral auxiliary agent, and chemical induction high selectivity obtains chiral (R)-2-amino-3-biphenylpropionate ethyl ester, and method provided by the invention is for R Configuration (R)-2-amino-3-biphenylpropionic acid ethyl ester has excellent chemoselectivity and high yield of target product, and is more suitable for industrial production
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Embodiment 1
[0027] Preparation of (R)-2-biphenylmethylglycine ethyl ester benzophenone imine
[0028] 6.5g (10mmol) of compound shown in formula I, 31.8g (300mmol) of sodiumcarbonate, 26.7g (100mmol) of ethyl glycine benzophenone imine and 24.3g (120mmol) of 4-chloromethylbiphenyl were added to the reaction Stir the reaction in acetonitrile at room temperature in a container to obtain (R)-2-biphenylmethylglycine ethyl ester benzophenone imine; react for 4 hours, concentrate under reduced pressure, and column chromatography to obtain (R)-2-biphenyl 38.6 g of ethyl methylglycinate benzophenone imine, the yield is 89.1%, and the ee value is 99.17%. 1 HNMR (400MHz, d 6 -DMSO) δ7.82~7.85(d,2H),7.74~7.68(d,2H),7.61~7.54(m,3H),7.45~7.32(m,12H),4.12(q,2H),3.75( m,1H), 2.72~2.68(d,1H), 2.62~2.58(d,1H), 1.25(t,3H); ESI-MS(m / z):434.20([M+H] + ).
Embodiment 2
[0030] Preparation of (R)-2-biphenylmethylglycine ethyl ester benzophenone imine
[0031] A preparation method of an anti-heart failure drug sacubitril intermediate, characterized in that the preparation method comprises:
[0032] 9.7g (15mmol) of the compound shown in formula I, 8g (200mmol) of sodiumhydroxide, 26.7g (100mmol) of ethyl glycine benzophenone imine and 28.4g (140mmol) of 4-chloromethylbiphenyl were added to the reaction The reaction was stirred at room temperature in dichloromethane in a container to obtain (R)-2-biphenylmethylglycine ethyl ester benzophenone imine; reacted for 4 hours, concentrated under reduced pressure, and column chromatography obtained (R)-2- Biphenylmethylglycine ethyl ester benzophenone imine 39.2g, yield 90.4%, ee value 99.41%.
Embodiment 3
[0034] Preparation of (R)-2-biphenylmethylglycine ethyl ester benzophenone imine
[0035] A preparation method of an anti-heart failure drug sacubitril intermediate, characterized in that the preparation method comprises:
[0036] 3.2g (5mmol) of the compound shown in formula I, 41.5g (300mmol) of potassiumcarbonate, 26.7g (100mmol) of ethyl glycine benzophenone imine and 37.1g (150mmol) of 4-bromomethylbiphenyl were added to the reaction Stir the reaction in acetonitrile at room temperature in a container to obtain (R)-2-biphenylmethylglycine ethyl ester benzophenone imine; react for 4 hours, concentrate under reduced pressure, and column chromatography to obtain (R)-2-biphenyl 38.8 g of ethyl methylglycinate benzophenone imine, the yield is 89.6%, and the ee value is 99.30%.
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technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for preparing an intermediate of sacubitril. Background technique [0002] Sacubitril / Valsartan (Sacubitril / Valsartan), the trade name Entresto (LCZ696) was approved by the FDA in July 2015, which includes two components that combine valsartan and the experimental drugSacubitril (AHU-377) , the drug was developed by Novartis. For the treatment of heart failure, the effect is outstanding. In the drug, the neprilysin inhibitor sacubitril and the angiotensin Ⅱ (ANG Ⅱ) receptorantagonistvalsartan compound are used synergistically for the treatment of related diseases, by simultaneously inhibiting neprilysin and blocking Angiotensin Ⅱ receptors can reduce the risk of cardiovascular death and hospitalization due to heart failure, and the effect is better than other similar drugs at present. [0003] Sacubitril / Valsartan (Sacubitril / Valsartan) has attracted the a...
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