A preparation process of sacubitril intermediate

Abstract

The invention discloses a preparation process of a sacubitril intermediate. The process comprises the following steps: using 4-halobiphenyl and (R)-epoxyhalopropane as raw materials, docking them, inserting an ester group, causing an Appel reaction to halogenate a hydroxyl group, and then performing ammonia treatment, inserting a Boc protecting group, and finally synthesizing the sacubitril intermediate. Compared with the existing method, the preparation method of the invention has simpler procedures, easier reactions, and reduced raw material costs.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation process of a sacubitril intermediate. Background Art

[0002] Sacubitril is a NEP inhibitor with an IC50 value of 5nM. It is a component of LCZ696, a drug for treating heart failure, and an antihypertensive drug that can be used in combination with valsartan. The structural formula of an important intermediate in its preparation is as follows:

[0003]

[0004] Patent CN105026361 reports a preparation method, the main steps of which are as follows:

[0005]

[0006] This method has certain defects because succinimide will react and dock with chlorine atoms during the construction of amino groups to form impurities, resulting in a decrease in product yield and purity. Summary of the Invention

[0007] To solve the above problems, the present invention discloses a preparation process of a sacubitril intermediate, which comprises the following steps: using 4-halogenated biphenyl and (R)-epoxyhalopropane as raw materials for docking, inserting an ester group, and performing an Appel reaction to halogenate the hydroxyl group; then undergoing amination, inserting a Boc protecting group, and finally synthesizing the sacubitril intermediate; the present invention adopts an ester group to protect the terminal hydroxyl group, thereby reducing the generation of terminal amino impurities, reducing the discharge of three wastes, and being environmentally friendly; at the same time, utilizing the Appel reaction to construct a specific target chiral center atom, and then replacing the halogen with ammonia, thereby obtaining the target product under simple conditions, with milder reaction conditions and low production cost.

[0008] To achieve the above object, the technical solution of the present invention is as follows:

[0009] A preparation process of a sacubitril intermediate, the synthesis route of which is as follows:

[0010]

[0011] Wherein: X, Y, Z are halogen, and R is H or a C1-C7 alkyl or aryl group.

[0012] The specific preparation steps are as follows:

[0013] (1) Compound 1 was synthesized by Grignard reaction using 4-halobiphenyl and (R)-epoxyhalopropane as raw materials;

[0014] (2) esterifying the compound 1 obtained in step (1) with an alkyl salt to synthesize compound 2;

[0015] (3) subjecting the compound 2 obtained in step (2) to an Appel reaction to halogenate the hydroxyl group to synthesize compound 3;

[0016] (4) Compound 3 obtained in step (3) is further ammonified to synthesize compound 4;

[0017] (5) Compound 4 obtained in step (4) was subjected to Boc anhydride protection to synthesize compound 5.

[0018] As an improvement of the present invention, in step (1), the molar ratio of 4-halobiphenyl to epoxyhalopropane is 1:1-2, and the catalyst for the Grignard reaction is a cuprous halide.

[0019] As an improvement of the present invention, in step (2), the alkyl salt is any one of sodium acetate, potassium acetate, sodium propionate, potassium propionate, sodium butyrate, sodium benzoate, and potassium benzoate.

[0020] As an improvement of the present invention, in step (2), the molar ratio of compound 1 to alkyl salt is 1:1 to 1.5.

[0021] As an improvement of the present invention, in step (3), the molar ratio of compound 2, organic phosphine, and carbon halide is 1:1-3:1-3.

[0022] As an improvement of the present invention, in step (3), the Appel reaction is carried out in the presence of an organic phosphine and a halogenated carbon.

[0023] As an improvement of the present invention, the organic phosphine reagent for the Appel reaction in step (3) is any one of triphenylphosphine, tributylphosphine, and triethylphosphine, and the carbon halide is carbon tetrachloride or carbon tetrabromide.

[0024] As an improvement of the present invention, in step (4), the molar ratio of compound 3 to ammonia is 1:1-3.

[0025] As an improvement of the present invention, in step (5), the molar ratio of compound 4 to Boc anhydride is 1:1-2.

[0026] The beneficial effects of the present invention are:

[0027] (1) The present invention introduces an ester group to protect the terminal hydroxyl group, thereby reducing the generation of terminal amino impurities, reducing the discharge of three wastes, and being environmentally friendly.

[0028] (2) The present invention utilizes the Appel reaction to construct a specific target chiral center atom, and then replaces the halogen with ammonia to obtain the target product under simple conditions. Implementation Method

[0029] The present invention will be further explained below in conjunction with specific embodiments. It should be understood that the following specific embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0030] Example 1: Synthesis of Compound 1

[0031]

[0032] Add 11.6g (0.05mol) of 4-bromobiphenyl, 28.8g (1.2mol) of magnesium powder, and 50mL of tetrahydrofuran to a reactor and stir. Add 0.1g of iodine granules for initiation, and then add an additional 200mL of tetrahydrofuran. Control the temperature at 40-45°C and dropwise add a mixed solution of 221.4g (0.95mol) of 4-bromobiphenyl and 300mL of tetrahydrofuran. After complete addition, incubate for 3 hours. After the reaction is complete, cool to 0°C and add 2g of cuprous iodide. Then, cool to -15--10°C and dropwise add a mixed solution of 92.5g (1mol) of (R)-epichlorohydrin and 100mL of tetrahydrofuran. Incubate for 2 hours.

[0033] After the reaction was completed, the temperature was raised to room temperature, 4M hydrochloric acid was added to the reaction solution to adjust the acidity, the system was separated into layers, the solvent was recovered from the organic phase, ethanol and water were added to the residue for recrystallization, and after drying, compound 1 (231 g, 0.936 mol) was obtained with a yield of 93.6%.

[0034] Example 2: Synthesis of Compound 2

[0035]

[0036] 123.4 g (0.5 mol) of compound 1 and 6 g of triethylamine were added to the reactor in sequence, and 300 mL of ethanol was added and stirred to dissolve. 200 mL of an aqueous solution of 45.1 g (0.55 mol) of sodium acetate was added to the system, and the temperature was raised to 65-70° C. and stirred for reaction for 1 h.

[0037] After the reaction, 300 mL of ethyl acetate was added to the system for extraction twice, and the organic layer was washed twice with 300 mL of water. After the organic layer was dried and the solvent was recovered, compound 2 (126 g, 0.466 mol) was obtained with a yield of 93.2%.

[0038] Example 3: Synthesis of Compound 3

[0039]

[0040] 121.65 g (0.45 mol) of compound 2 was added to the reactor, followed by 138.44 g (0.9 mol) of carbon tetrachloride and 236.06 g (0.9 mol) of triphenylphosphine. 250 mL of acetonitrile was then added and stirred. The mixture was maintained at 25-35° C. and reacted for 16 h.

[0041] After the reaction was complete, the dry solvent was recovered under reduced pressure, 300 mL of ethanol was added to the residue, the temperature was raised and stirred to dissolve, and the temperature was slowly lowered to 5-10°C. Crystallization was carried out for 3 hours, and compound 3 (113.77 g, 0.394 mol) was obtained after filtration and drying. The yield was 87.6%.

[0042] Example 4: Synthesis of Compound 4

[0043]

[0044] 153.28 g of 0.45 mol of 5% ammonia methanol solution was added to the reactor, and 250 mL of methanol solution containing 86.63 g of 0.3 mol of compound 3 was added dropwise to the reactor, and the mixture was stirred at 0-5°C for 2 h.

[0045] After the reaction, the solvent was concentrated under reduced pressure, 200 mL of ethyl acetate and 200 mL of water were added, and the liquid was separated. The aqueous layer was extracted with 200 mL of ethyl acetate, and the organic layers were combined. The organic layers were recovered under reduced pressure to obtain compound 4 (62.28 g, 0.274 mol) with a yield of 91.2%.

[0046] Example 5: Synthesis of Compound 5

[0047]

[0048] 58.83 g (0.25 mol) of compound 4, 50 g of triethylamine, and 300 mL of tetrahydrofuran were added to the reactor and stirred to mix. Then, 65.47 g (0.3 mol) of (Boc)2O were added in batches. The temperature was maintained at 40-45°C and the mixture was stirred for 4 hours.

[0049] 200 mL of water was added to the system, and the mixture was stirred and washed three times. The organic layer was recovered under reduced pressure and dried. 150 mL of ethanol was added to the residue, and the mixture was heated until completely dissolved. The temperature was then lowered to 0-5°C, and the mixture was stirred for crystallization for 2 hours. After filtration, the filter cake was dried to obtain compound 5 (78.58 g, 0.24 mol) with a yield of 96%.

[0050] Examples 6-8: Synthesis of Compound 1

[0051] Other conditions were the same as those in Example 1, except that the molar ratio of 4-halobiphenyl to epoxyhalopropane was changed. The reaction conditions and yields of Example 1 and Examples 6-8 are detailed in Table 1.

[0052] Table 1 Different conditions and results of Example 1 and Examples 6-8

[0053] Example 4-Halogenated biphenyl:epoxyhalopropane Total yield / % 1 1:1 93.6 6 1:2 92.5 7 1:2.5 88.3 8 1:0.8 74.6

[0054] Examples 9-12: Synthesis of Compound 2

[0055] Other conditions were the same as those in Example 2, except that the molar ratio of compound 1 to the alkyl salt and the type of the alkyl salt were changed. The reaction conditions and yields of Example 2 and Examples 9-12 are detailed in Table 2.

[0056] Table 2 Different conditions and results of Example 2 and Examples 9-12

[0057] Example Compound 1: Alkyl salt Alkyl salt types Total yield / % 2 1:1.1 Sodium acetate 93.2 9 1:1 Sodium acetate 92.9 10 1:1.5 Sodium acetate 92.4 11 1:1.1 Sodium propionate 86.9 12 1:1.1 Sodium benzoate 88.3

[0058] Examples 13-16: Synthesis of Compound 3

[0059] Other conditions were the same as those in Example 3. The molar ratio of compound 2, organophosphine, and carbon halide, as well as the type of organophosphine and carbon halide (R is methyl) were changed. The reaction conditions and yields of Example 3 and Examples 13-16 are detailed in Table 3.

[0060] Table 3 Different conditions and results of Example 3 and Examples 13-16

[0061] Example Compound 1: Organic phosphine: halocarbon Types of organic phosphine Types of halocarbons Yield / % 3 1:2:2 Triphenylphosphine Carbon tetrachloride 87.6 13 1:1:1 Triphenylphosphine Carbon tetrachloride 85.3 14 1:3:3 Triphenylphosphine Carbon tetrachloride 86.9 15 1:2:2 Tributylphosphine Carbon tetrachloride 84.3 16 1:2:2 Triphenylphosphine carbon tetrabromide 85.7

[0062] Examples 17-18: Synthesis of Compound 4

[0063] Other conditions were the same as those in Example 4, except that the molar ratio of compound 3 to ammonia was changed (R was methyl, Z was Cl). The reaction conditions and results of Example 4 and Examples 17-18 are detailed in Table 4.

[0064] Table 4 Different conditions and results of Example 4 and Examples 17-18

[0065] Example Compound 3: Ammonia Yield / % 4 1:1.5 91.2 17 1:1 89.3 18 1:3 88.6

[0066] Examples 19-20: Synthesis of Compound 5

[0067] Other conditions were the same as those in Example 5, except that the molar ratio of compound 4 to Boc anhydride was changed. The reaction conditions and results of Example 5 and Examples 19-29 are detailed in Table 5.

[0068] Table 5 Different conditions and results of Example 5 and Examples 19-20

[0069] Example Compound 4: Boc anhydride Yield / % 5 1:1.2 96 19 1:1 94.4 20 1:2 94.7

[0070] It should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the scope of protection of the present invention. For ordinary technicians in this technical field, without departing from the principles of the present invention, several improvements and modifications can be made on the basis of the above embodiments, and these improvements and modifications all fall within the scope of protection of the claims of the present invention.

Claims

1. A process for preparing a sacubitril intermediate, characterized in that: The following steps are involved: (1) Compound 1 was synthesized by Grignard reaction using 4-halobiphenyl and (R)-epoxyhalopropane as raw materials; (2) esterifying the compound 1 obtained in step (1) with an alkyl salt to synthesize compound 2; (3) subjecting the compound 2 obtained in step (2) to an Appel reaction to halogenate the hydroxyl group to synthesize compound 3; (4) Compound 3 obtained in step (3) is further aminated to synthesize compound 4; (5) Compound 4 obtained in step (4) was protected with Boc anhydride to synthesize compound 5; Wherein: X, Y, Z are halogen, and R is H or a C1-C7 alkyl or aryl group.

2. The process for preparing a sacubitril intermediate according to claim 1, wherein: In the step (1), the molar ratio of 4-halobiphenyl to epoxyhalopropane is 1:1-2, and the catalyst for the Grignard reaction is cuprous halide.

3. The process for preparing a sacubitril intermediate according to claim 1, wherein: In the step (2), the alkyl salt is any one of sodium acetate, potassium acetate, sodium propionate, potassium propionate, sodium butyrate, sodium benzoate, and potassium benzoate.

4. The process for preparing a sacubitril intermediate according to claim 1, wherein: In the step (2), the molar ratio of compound 1 to alkyl acid salt is 1:1 to 1.

5.

5. The process for preparing a sacubitril intermediate according to claim 1, wherein: In the step (3), the molar ratio of compound 2, organic phosphine and carbon halide is 1:1-3:1-3.

6. The process for preparing a sacubitril intermediate according to claim 1, wherein: In the step (3), the Appel reaction is carried out in the presence of an organic phosphine and a halogenated carbon.

7. The process for preparing a sacubitril intermediate according to claim 6, wherein: The organic phosphine reagent is any one of triphenylphosphine, tributylphosphine and triethylphosphine, and the carbon halide is carbon tetrachloride or carbon tetrabromide.

8. The process for preparing a sacubitril intermediate according to claim 1, wherein: In the step (4), the molar ratio of compound 3 to ammonia is 1:1-3.

9. The process for preparing a sacubitril intermediate according to claim 1, wherein: In the step (5), the molar ratio of compound 4 to Boc anhydride is 1:1-2.

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