A method for synthesizing a sacubitril drug intermediate

Abstract

The present invention relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a method for synthesizing a sacubitril pharmaceutical intermediate. The synthetic route comprises reacting Compound II with Compound III in the presence of a catalyst to obtain a sacubitril intermediate, N-tert-butyloxycarbonyl-amino-4,4-biphenyl-R-alanine methyl ester, i.e., Compound I. This synthetic method eliminates the need for expensive and highly toxic trifluoromethanesulfonic anhydride and allows the synthesis of the target compound I in a single step. The experimental protocol employed in the present invention is simple to operate, employs mild reaction conditions, provides high yield and purity, and offers low cost, making it suitable for industrial scale-up production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediate synthesis, and specifically relates to a method for synthesizing sacubitril pharmaceutical intermediate, N-tert-butyloxycarbonyl-amino-4,4-biphenyl-R-alanine methyl ester. Background Art

[0002] Heart failure has become a global public health issue that seriously endangers human health. It is the terminal stage of the development of cardiovascular disease. Its incidence, rehospitalization rate and mortality rate are increasing year by year, which makes the further development of more effective new heart failure treatment drugs urgent. The launch of sacubitril / valsartan, which has a dual mechanism of action of angiotensin receptor neprilysin inhibitor, has brought new changes to the treatment of heart failure patients.

[0003] Sacubitril / valsartan (Entresto), a dual-acting angiotensin receptor-neprilysin inhibitor developed by Novartis, is clinically used to treat hypertension and heart failure. Composed of sacubitril, which acts on neprilysin, and valsartan, which acts on the renin-angiotensin-aldosterone system, Entresto effectively improves heart failure symptoms, lowers blood pressure, and positively improves renal function, making it an ideal treatment for heart failure.

[0004] Since the synthesis process of valsartan is relatively mature, the research focus of those skilled in the art is mainly on the synthesis optimization of the sacubitril part.

[0005] Sacubitril, chemically known as 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopropan-2-yl)amino)-4-oxobutanoic acid, has the following structure:

[0006]

[0007] N-tert-Butyloxycarbonyl-amino-4,4-biphenyl-R-alanine methyl ester is an important intermediate in the preparation of sacubitril. The original patent US5217996 uses the following method for the synthesis of N-tert-Butyloxycarbonyl-amino-4,4-biphenyl-R-alanine methyl ester (Compound I):

[0008]

[0009] The above route uses BOC-D-tyrosine methyl ester as the starting material and undergoes a two-step reaction to produce the target compound I. This process requires the use of expensive and highly toxic trifluoromethanesulfonic anhydride, phenylboronic acid, and a large equivalent of the catalyst tetrakis(triphenylphosphine)palladium. These reagents are relatively expensive and unsuitable for scale-up production.

[0010] In addition, CN112661671B discloses a method for preparing a sacubitril intermediate, comprising the following steps: 1) reacting the raw material compound III with phosphorus trihalide to obtain compound II; 2) reacting compound II with phenylhydrazine in the presence of a catalyst and an additive to obtain a sacubitril intermediate, namely compound I; wherein the catalyst is PdCl2; and the additive is any one of CuI, KI or NaI.

[0011]

[0012] The above-mentioned route uses expensive and highly toxic phenylhydrazine as a reaction raw material, which is also not suitable for industrial production.

[0013] Given the importance of sacubitril in the treatment of heart failure, it is very necessary to develop a method for preparing a sacubitril intermediate (Compound I) that is more economical and more conducive to industrial production. Summary of the Invention

[0014] The present invention aims to provide a method for synthesizing a sacubitril pharmaceutical intermediate, in order to solve the problems of complicated operation, multiple reaction steps, highly toxic reagents and high cost in the preparation process of sacubitril intermediate in the prior art.

[0015] Specifically, the technical solutions adopted by the present invention are as follows:

[0016] A method for synthesizing a sacubitril pharmaceutical intermediate comprises reacting compound II with compound III in the presence of a catalyst to obtain a sacubitril intermediate, N-tert-butyloxycarbonyl-amino-4,4-biphenyl-R-alanine methyl ester, namely compound I. The synthesis route is as follows:

[0017]

[0018] Furthermore, the catalyst is any one of sulfuric acid, phosphoric acid or hydrohalic acid.

[0019] Furthermore, the catalyst is concentrated sulfuric acid with a purity greater than 95%.

[0020] Furthermore, the molar ratio of compound II to compound III is 1:1 to 8, including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8. In order to obtain better effects, the molar ratio of compound II to compound III is preferably 1:2 to 6.

[0021] Furthermore, the molar ratio of compound II to catalyst is 1:0.2 to 1, including but not limited to 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9 or 1:1. In order to obtain better effects, the molar ratio of compound II to catalyst is preferably 1:0.3 to 0.8.

[0022] Furthermore, the reaction temperature is 20-80° C., including but not limited to 20° C., 30° C., 40° C., 50° C., 60° C., 70° C. or 80° C. In order to obtain better effects, the reaction temperature is preferably 40-60° C.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The present invention improves the synthesis route for N-tert-butyloxycarbonyl-amino-4,4-biphenyl-R-alanine methyl ester, a pharmaceutical intermediate for sacubitril. This method eliminates the use of expensive and highly toxic trifluoromethanesulfonic anhydride or phenylhydrazine, and synthesizes the target compound I in a single step. The experimental protocol employed in the present invention features simple operation, mild reaction conditions, high yield and purity, low cost, and suitability for scale-up production. DETAILED DESCRIPTION

[0025] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0026] Example 1

[0027]

[0028] 98.3% concentrated sulfuric acid (1.8 g, 18 mmol) and compound III (23.4 g, 300 mmol) were added to the reaction flask and stirred evenly. Compound II (17.7 g, 60 mmol) was then slowly added under stirring, and the reaction temperature was controlled at 60°C. After the reaction was completed, the sulfuric acid layer was separated and removed, and the mixture was washed with 100 mL × 3 deionized water, 100 mL × 3 10% sodium hydroxide solution, and 100 mL × 3 saturated brine, dried over anhydrous aluminum chloride, and finally distilled under reduced pressure to obtain compound I with a yield of 94.3% and a purity of 99.5%.

[0029] Example 2

[0030] 98.3% concentrated sulfuric acid (3 g, 30 mmol) and compound III (9.4 g, 120 mmol) were added to the reaction flask and stirred evenly. Compound II (17.7 g, 60 mmol) was then slowly added under stirring, and the reaction temperature was controlled at 80°C. After the reaction was completed, the sulfuric acid layer was separated and removed, and the mixture was washed with 100 mL × 3 deionized water, 100 mL × 3 10% sodium hydroxide solution, and 100 mL × 3 saturated brine, dried over anhydrous aluminum chloride, and finally distilled under reduced pressure to obtain compound I with a yield of 90.6% and a purity of 99.2%.

[0031] Example 3

[0032] 85% concentrated phosphoric acid (5.5 g, 48 mmol) and compound III (37.5 g, 480 mmol) were added to the reaction flask and stirred evenly. Compound II (17.7 g, 60 mmol) was then slowly added under stirring. The reaction temperature was controlled at 20°C. After the reaction was completed, the phosphoric acid layer was separated and removed. The mixture was washed with 100 mL × 3 of deionized water, 100 mL × 3 of 10% sodium hydroxide solution, and 100 mL × 3 of saturated brine, dried over anhydrous aluminum chloride, and finally distilled under reduced pressure to obtain compound I with a yield of 91.8% and a purity of 99.1%.

[0033] Comparative Example 1

[0034] 98.3% concentrated sulfuric acid (0.6 g, 6 mmol) and compound III (23.4 g, 300 mmol) were added to the reaction flask and stirred evenly. Compound II (17.7 g, 60 mmol) was then slowly added under stirring, and the reaction temperature was controlled at 60°C. After the reaction was completed, the sulfuric acid layer was separated and removed, and the mixture was washed with 100 mL × 3 deionized water, 100 mL × 3 10% sodium hydroxide solution, and 100 mL × 3 saturated brine, dried over anhydrous aluminum chloride, and finally distilled under reduced pressure to obtain compound I with a yield of 78.6% and a purity of 95.2%.

[0035] Comparative Example 2

[0036] 98.3% concentrated sulfuric acid (1.8 g, 18 mmol) and compound III (23.4 g, 300 mmol) were added to the reaction flask and stirred evenly. Compound II (17.7 g, 60 mmol) was then slowly added under stirring. The reaction temperature was controlled at 10°C. After the reaction was completed, the sulfuric acid layer was separated and removed. The filtrate was washed with 100 mL × 3 of deionized water, 100 mL × 3 of 10% sodium hydroxide solution, and 100 mL × 3 of saturated brine, dried over anhydrous aluminum chloride, and finally distilled under reduced pressure to obtain compound I with a yield of 73.9% and a purity of 96.4%.

[0037] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing a sacubitril pharmaceutical intermediate, characterized in that: In the presence of a catalyst, compound II is reacted with compound III to obtain a sacubitril intermediate, N-tert-butyloxycarbonyl-amino-4,4-biphenyl-R-alanine methyl ester, namely compound I. The synthesis route is as follows: The catalyst is sulfuric acid or phosphoric acid, the molar ratio of the compound II to the catalyst is 1:0.2-1, and the reaction temperature is 20-80°C.

2. The method for synthesizing the sacubitril pharmaceutical intermediate according to claim 1, wherein: The catalyst is concentrated sulfuric acid with a purity greater than 95%.

3. The method for synthesizing the sacubitril pharmaceutical intermediate according to claim 1, wherein: The molar ratio of compound II to compound III is 1:1-8.

4. The method for synthesizing the sacubitril pharmaceutical intermediate according to claim 3, wherein: The molar ratio of compound II to compound III is 1:2-6.

5. The method for synthesizing the sacubitril pharmaceutical intermediate according to claim 1, wherein: The molar ratio of the compound II to the catalyst is 1:0.3-0.

8.

6. The method for synthesizing the sacubitril pharmaceutical intermediate according to claim 1, wherein: The reaction temperature is 40-60°C.

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