A method for preparing a sacubitril intermediate

Abstract

The present invention belongs to the field of organic synthesis, and in particular to the field of organic drug synthesis technology, and more specifically to a method for preparing a sacubitril intermediate, wherein compound II and compound III are reacted in the presence of zinc powder to obtain compound IV; and compound IV is then subjected to a dehydration reaction to obtain the target product compound I. This synthesis idea breaks away from the conventional synthesis idea in the existing technology, and does not directly prepare compound I from compound II through a witting reaction. In this way, the present invention obtains a preparation process with mild reaction conditions, no need for low-temperature reaction, and low equipment requirements. The preparation process has simple synthesis conditions, high yield of the target compound, high purity, and low production cost, and is suitable for the needs of industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, in particular to the field of organic drug synthesis, and more specifically to a method for preparing a sacubitril intermediate. Background Art

[0002] Heart failure is an extremely important global public health issue that endangers human health. It is the terminal stage of the development of cardiovascular disease. Its incidence, re-hospitalization rate and mortality rate are increasing year by year, which makes it urgent to further develop more effective new heart failure treatment drugs. 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) is a dual-acting angiotensin receptor-neprilysin inhibitor developed by Novartis, which can be used clinically to treat hypertension and heart failure. The drug is composed of sacubitril, which acts on neprilysin, and valsartan, which acts on the renin-angiotensin-aldosterone system. It can effectively improve the symptoms of heart failure, lower blood pressure and actively improve renal function. It is an ideal drug for the treatment of heart failure.

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

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

[0006]

[0007] Compound I is an important intermediate for the preparation of sacubitril drugs.

[0008]

[0009] The original patent US5217996 discloses a method for preparing sacubitril, and its synthesis route is as follows:

[0010]

[0011] In this synthetic route, compound I is prepared by reacting compound II with a phosphorus ylide reagent, wherein the structure of the phosphorus ylide reagent is shown in formula a.

[0012]

[0013] Currently, this method is commonly used in the prior art to prepare compound I through the classic Wittig reaction. However, the yield of compound I under this method is only 78%. The low reaction yield not only causes waste of chiral alcohol raw materials, but also makes the industrial synthesis cost of sacubitril high.

[0014] At the same time, low temperature conditions are required in this reaction, which further increases the synthesis cost in industrial preparation.

[0015] Therefore, developing a method for preparing a sacubitril intermediate (Compound I) with high yield, relatively loose synthesis conditions, low synthesis cost, and more suitable for industrial production has become a hot issue studied by those skilled in the art. Summary of the invention

[0016] The technical problem to be solved by the present invention is to provide a method for preparing a sacubitril intermediate (Compound I), thereby improving the yield and purity of the product and reducing the synthesis cost.

[0017] In order to solve the above technical problems, the present invention discloses a method for preparing a sacubitril intermediate, comprising the following steps:

[0018] (a) reacting compound II with compound III in the presence of zinc powder to obtain compound IV;

[0019] (b) Compound IV undergoes a dehydration reaction in the presence of a dehydrating agent to obtain Compound I;

[0020] The specific synthetic route is as follows:

[0021]

[0022] Wherein, X is any one of Cl, Br, and I.

[0023] Preferably, in step (a), the molar ratio of compound II to compound III is 1:1 to 1.5.

[0024] Preferably, in step (a), the molar ratio of compound II to zinc powder is 1:1 to 1.5.

[0025] Preferably, in step (a), the molar ratio of compound II to zinc powder is 1:1.1.

[0026] Preferably, in step (a), the solvent is one or more of benzene, toluene, tetrahydrofuran, dichloromethane or dimethylformamide.

[0027] Preferably, in step (a), the reaction temperature is 15-50°C, including but not limited to 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C or 50°C. In order to obtain better effects, the reaction temperature is preferably 25°C.

[0028] Preferably, in step (b), the dehydrating agent is phosphorus pentoxide.

[0029] Preferably, in step (b), the molar ratio of compound IV to the dehydrating agent is 1:1 to 1.5.

[0030] Preferably, in step (b), the solvent is one or more of benzene, toluene, tetrahydrofuran, dichloromethane or dimethylformamide.

[0031] The present invention discloses a method for preparing a sacubitril intermediate, wherein compound II and compound III are reacted in the presence of zinc powder to obtain compound IV; and compound IV is then subjected to a dehydration reaction to obtain a target product compound I. This synthesis idea breaks away from the conventional synthesis idea in the existing technology, and compound I is not directly prepared from compound II through a witting reaction. In this way, the present invention obtains a preparation process with mild reaction conditions, no need for low-temperature reaction, and low equipment requirements. The preparation process has simple synthesis conditions, high yield of the target compound, high purity, and low production cost, and is suitable for the needs of industrial large-scale production. DETAILED DESCRIPTION

[0032] In order to better understand the present invention, the present invention is further described below in conjunction with specific embodiments.

[0033] Unless otherwise specified, the reagents used in the examples of the present invention are common commercially available products.

[0034] Example 1 Synthesis of Compound IV

[0035] Under nitrogen protection, compound II (15 g, 46 mmol), compound III (X is Br, 10 g, 55.2 mmol), zinc powder (3.3 g, 50.6 mmol) and 100 ml of benzene were added to the reaction vessel, and the mixture was stirred at 25 ° C for reaction. TLC monitored the complete reaction of the raw materials. After the reaction was completed, the reaction mixture was quenched with cold hydrochloric acid. Ethyl acetate was added for extraction, and the organic layer was washed with water, and then washed with Na2CO3 aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether-ethyl acetate, V: V = 20: 1) to obtain compound IV with a yield of 93.7% and a purity of 99.5%.

[0036] Example 2 Synthesis of Compound IV

[0037] Under nitrogen protection, compound II (15 g, 46 mmol), compound III (X is Cl, 9.4 g, 69 mmol), zinc powder (3 g, 46 mmol) and 100 ml of tetrahydrofuran were added to the reaction vessel, and the mixture was stirred at 50°C for reaction. TLC monitored the complete reaction of the raw materials. After the reaction was completed, the reaction mixture was quenched with cold hydrochloric acid. Ethyl acetate was added for extraction, and the organic layer was washed with water, and then with an aqueous Na2CO3 solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether-ethyl acetate, V:V=20:1) to obtain compound IV with a yield of 89.4% and a purity of 99.3%.

[0038] Example 3 Synthesis of Compound IV

[0039] Under nitrogen protection, compound II (15 g, 46 mmol), compound III (X is I, 10.5 g, 46 mmol), zinc powder (4.5 g, 69 mmol) and 100 ml of dimethylformamide were added to the reaction vessel, and the mixture was stirred at 15 ° C for reaction. TLC monitored the complete reaction of the raw materials. After the reaction was completed, the reaction mixture was quenched with cold hydrochloric acid. Ethyl acetate was added for extraction, and the organic layer was washed with water, and then washed with Na2CO3 aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether-ethyl acetate, V: V = 20: 1) to obtain compound IV with a yield of 87.6% and a purity of 99.2%.

[0040] Example 4 Synthesis of Compound I

[0041] Compound IV (15 g, 35 mmol), phosphorus pentoxide (6.1 g, 43 mmol) and 100 ml of benzene were added to the reaction vessel, and the mixture was refluxed for reaction. After the reaction was completed, the mixture was cooled, the organic layer was washed with water, and then with a saturated aqueous solution of NaHCO3, filtered, and evaporated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether-ethyl acetate, V:V=20:1) to obtain compound I with a yield of 96.8% and a purity of 99.4%.

[0042] Example 5 Synthesis of Compound I

[0043] Compound IV (15 g, 35 mmol), phosphorus pentoxide (7.4 g, 52 mmol) and 100 ml of tetrahydrofuran were added to the reaction vessel, and the mixture was refluxed for reaction. After the reaction was completed, the mixture was cooled, the organic layer was washed with water, and then with a saturated aqueous solution of NaHCO3, filtered, and evaporated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether-ethyl acetate, V:V=20:1) to obtain compound I with a yield of 94.4% and a purity of 99.1%.

[0044] Example 6 Synthesis of Compound I

[0045] Compound IV (15 g, 35 mmol), phosphorus pentoxide (5 g, 35 mmol) and 100 ml of dimethylformamide were added to the reaction vessel, and the mixture was refluxed for reaction. After the reaction was completed, the mixture was cooled, the organic layer was washed with water, and then with a saturated aqueous solution of NaHCO3, filtered, and evaporated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether-ethyl acetate, V:V=20:1) to obtain compound I with a yield of 90.5% and a purity of 99.2%.

[0046] The above is a specific implementation of the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications are also considered to be within the protection scope of the present invention.

Claims

1. A method for preparing a sacubitril intermediate, characterized in that: It includes the following steps: (a) reacting compound II with compound III in the presence of zinc powder to obtain compound IV; (b) Compound IV undergoes a dehydration reaction under the action of a dehydrating agent to obtain Compound I; The specific synthetic route is as follows: Wherein, X is any one of Cl, Br, and I; In step (a), the reaction temperature is 15-50°C; In step (a), the molar ratio of compound II to zinc powder is 1:1-1.5; The dehydrating agent is phosphorus pentoxide; The molar ratio of the compound IV to the dehydrating agent is 1:1-1.

5.

2. The method for preparing a sacubitril intermediate according to claim 1, characterized in that: In step (a), the molar ratio of compound II to compound III is 1:1-1.

5.

3. The method for preparing a sacubitril intermediate according to claim 1, characterized in that: In step (a), the molar ratio of the compound II to the zinc powder is 1:1.

1.

4. The method for preparing a sacubitril intermediate according to claim 1, characterized in that: In step (a), the reaction solvent is one or more of benzene, toluene, tetrahydrofuran, dichloromethane or dimethylformamide.

5. The method for preparing a sacubitril intermediate according to claim 1, characterized in that: In step (a), the reaction temperature was 25°C.

6. The method for preparing a sacubitril intermediate according to claim 1, characterized in that: In step (b), the reaction solvent is one or more of benzene, toluene, tetrahydrofuran, dichloromethane or dimethylformamide.

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