Preparation method of sacubitril intermediate

Abstract

The invention discloses a preparation method of a sacubitril intermediate, which comprises the following steps: taking N-tert-butoxycarbonyl-L-serine ester as an initial raw material, reacting with sulfonyl chloride under the catalysis of an alkaline substance to obtain N-(tert-butoxycarbonyl)-O-sulfonyl-L-serine ester, activating hydroxyl in the compound by sulfonate, and reacting with sodium hydroxide to obtain the sacubitril intermediate. The preparation method comprises the following steps: reacting (R)-3-([1, 1 '-biphenyl]-4-yl)-2-(tert-butoxycarbonyl) amino) propionate with a Grignard reagent under the catalysis of copper to generate (R)-3-([1, 1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl) amino) propionate, and finally reducing ester groups into hydroxyl groups under the action of a catalyst and a reducing agent to generate (R)-tert-butyl (1-([1, 1 '-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate. The preparation method has the advantages of simple preparation process route, cheap and easily available raw materials, short synthesis route, mild reaction conditions, simplicity and convenience in operation and high yield, and has better application value and economic benefit.

Description

Technical Field

[0001] The invention belongs to the field of synthesis of sacubitril intermediates, and specifically relates to a method for preparing (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate, a sacubitril intermediate for treating chronic heart failure. Background Art

[0002] Chronic heart failure (CHF), also known as chronic congestive heart failure, is the terminal stage of various heart diseases. It is very necessary to develop a new therapeutic drug that can significantly improve mortality and morbidity. Sacubitril-valsartan sodium tablets are the world's first dual-acting angiotensin receptor-neprilysin inhibitor (ARNI) developed by Novartis. It is a 1:1 cocrystal complex of angiotensin II receptor antagonist (ARB) valsartan and neprilysin inhibitor sacubitril, a dual inhibitor. Valsartan is an angiotensin II receptor antagonist that can improve vasodilation and stimulate the body to excrete sodium and water. Sacubitril is a neprilysin inhibitor that can block the degradation of two polypeptides responsible for vasodilation to achieve the effect of alleviating heart failure. It has a good application prospect.

[0003] Sacubitril, chemical name 4-(((2S, 4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid, trade name Entresto, has the following structural formula:

[0004]

[0005] There are currently several methods for preparing the sacubitril intermediate (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate:

[0006] Patent CN105330569 uses biphenylaldehyde (1) and N-acylglycine (2) as starting materials, and obtains compound 4 through cyclization and hydrolysis, and then obtains chiral N-acylbiphenylalanine (5) through catalytic hydrogenation with a chiral rhodium catalyst, and obtains compound 6 through hydrochloric acid hydrolysis, and obtains compound 7 through sodium borohydride reduction, and finally protects the amino group with di-tert-butyl dicarbonate to obtain (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate (8). This method requires the use of expensive chiral rhodium metal catalysts, has harsh reaction conditions, high cost, long route, and low yield.

[0007]

[0008] Patent CN105237560 uses D-serine methyl ester hydrochloride (9) and triphenylmethane as starting materials to react to generate N-trityl-D-serine methyl ester (10), which is then further reacted with methanesulfonyl chloride to protect the hydroxyl group to obtain compound 11, which is then subjected to intramolecular cyclization to generate N-trityl-(R)-2-carboxylic acid methyl ester cyclopropylamine (12), followed by trifluoroacetic acid to remove the Tr protecting group and then Boc anhydride protection to form N-tert-butyloxycarbonyl -(R)-2-hydroxymethylcyclopropylamine (13), followed by sodium borohydride reduction and TBS protection to generate (R)-tert-butyl 2-(tert-butyldimethylsilyl(hydroxymethyl))aziridine-1-carboxylate (15), and finally reacting with 4-biphenyl magnesium bromide (16) under the catalysis of cuprous iodide and removing the silyl protecting group to obtain (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate (8). This route is cumbersome and involves multiple functional group protection and deprotection, with low production efficiency and high cost, and is not suitable for industrial production.

[0009]

[0010] Patent CN105884656 uses benzyl magnesium bromide (18) and methyl oxalyl chloride (19) as raw materials, and obtains biphenyl pyruvate (23) through addition, bromination, and Suzuki coupling, and then obtains chiral compound 24 through biocatalytic carbonyl transamination, followed by Boc protection and ester reduction to obtain (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate (8). This biological method has low substrate concentration and low reaction efficiency. In addition, the bromination reaction of the aromatic ring easily produces polybrominated impurities and brominated positional isomers, which are difficult to purify and remove.

[0011]

[0012] Patent CN107382779 reported the use of 4-bromomethylbiphenyl (26) in the presence of a chiral catalyst (R)-(-)-2-amino-2'-hydroxy-1,1'-binaphthyl compound to carry out an asymmetric catalytic alkylation reaction with glycine (27) to obtain compound 29, which was then reduced with lithium aluminum hydride to produce (S)-3-([1,1'-biphenyl]-4-yl)-2-amino-1-propanol (30), and finally Boc protected to obtain (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate (8). The chiral catalyst used in this method is expensive, the production cost is high, and the use of lithium aluminum hydride to reduce the ester group is not only costly, but also has safety risks when the process is scaled up.

[0013]

[0014] The above preparation method of the sacubitril intermediate (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate has the disadvantages of long reaction steps, harsh reaction conditions, low yield, use of noble metal catalysts, high production cost, etc. Therefore, the present invention intends to develop a new method with low production cost to prepare (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate. Summary of the invention

[0015] In order to overcome the deficiencies of the prior art, the present invention provides a method for preparing a sacubitril intermediate (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate.

[0016] A method for preparing a sacubitril intermediate (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate as shown in Formula 8,

[0017]

[0018] In the formula 32 and formula 33, R 1 is methyl, ethyl, isopropyl, n-butyl or tert-butyl; in the formula 32, R 2 is p-toluenesulfonyl chloride, methanesulfonyl chloride or p-nitrobenzenesulfonyl chloride;

[0019] The preparation method is carried out according to the following steps:

[0020] (1) N-tert-butoxycarbonyl-L-serine ester represented by Formula 31 is dissolved in an organic solvent A to obtain a solution A, an alkaline substance is added to the solution A under ice bath conditions and stirred evenly, then a sulfonyl chloride solution is slowly added dropwise thereto, and stirred at a temperature of -0 to 50°C for 2 to 15 hours (preferably at 10 to 25°C for 5 to 10 hours), followed by post-treatment: treatment with hydrochloric acid, separation of the liquids, washing the organic phase with water, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a crude product, which is then treated with 20% ethyl acetate to obtain a crude product. The target product is purified by column chromatography using a petroleum ether solution of the ester as an eluent, and concentrated to obtain the N-(tert-butoxycarbonyl)-O-sulfonyl-L-serine ester shown in Formula 32. The molar ratio of the N-tert-butoxycarbonyl-L-serine ester shown in Formula 31 to the alkaline substance and the sulfonyl chloride is 1:1-3:1-2; preferably, the molar ratio of the N-tert-butoxycarbonyl-L-serine ester to the alkali and the sulfonyl chloride in the sulfonyl chloride solution is 1:2:1.6; R 1 Preferably ethyl;

[0021] (2) dissolving the N-(tert-butoxycarbonyl)-O-sulfonyl-L-serine ester of formula 32 prepared in step (1) together with cuprous halide and a nitrogen-containing compound in an organic solvent B to obtain a solution B, adding a Grignard reagent to the solution B, and reacting at a temperature of -30 to 20° C. for 10 to 24 h (preferably -5 to 0° C. for 15 to 20 h), followed by purification: adding a saturated ammonium chloride solution to quench, extracting the reaction solution with ethyl acetate, and then separating the liquids, washing the organic phase with water, washing with saturated brine, and drying over anhydrous sodium sulfate in sequence, Filter, concentrate the filtrate under reduced pressure to obtain a crude product, perform silica gel column chromatography on the crude product with a 20% ethyl acetate petroleum ether solution to collect the target product, and concentrate to obtain (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoic acid ester shown in formula 33, wherein the molar ratio of N-(tert-butoxycarbonyl)-O-sulfonyl-L-serine ester shown in formula 32 to cuprous halide, nitrogen-containing compound, and Grignard reagent is 1:0.05-0.5:0.025-1:1-2; preferably 1:0.2:0.4:1.5;

[0022] (3) dissolving the (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate of formula 33 obtained in step (2) in an organic solvent C to obtain a solution C, adding a reducing agent and a catalyst to the solution C, reacting at a temperature of 25 to 80° C. for 10 to 24 h (preferably 60 to 70° C. for 12 to 18 h), and then purifying the solution by adding water to the reaction solution, stirring evenly, adding ethyl acetate, separating the liquids, washing the organic phase (ethyl acetate layer) with water, washing with saturated brine, drying with anhydrous sodium sulfate, and filtering, and concentrating the filtrate under reduced pressure to obtain a crude product, and silicating the crude product with a 35% ethyl acetate petroleum ether solution. The target product is collected by gel column chromatography purification treatment, and concentrated to obtain (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate shown in Formula 8, wherein the molar ratio of the (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino) propanoate shown in Formula 33 to the reducing agent and the catalyst is 1:1-4:1-2 (preferably: 1:2:1.5); the reducing agent is potassium borohydride or sodium borohydride (preferably sodium borohydride); and the catalyst is one or more of lithium chloride, calcium chloride, zinc chloride, magnesium chloride or boron trifluoride ether complex (preferably lithium chloride).

[0023] It is recommended that the alkaline substance is one or more of triethylamine, diisopropylethylamine, diethylaniline, N-methylmorpholine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, lithium hydroxide or potassium hydroxide.

[0024] It is also recommended that the sulfonyl chloride is one or more of p-toluenesulfonyl chloride, methanesulfonyl chloride or p-nitrobenzenesulfonyl chloride.

[0025] Furthermore, the organic solvent A in step (1) is one or more of dichloromethane, 1,2-dichloroethane, chloroform, toluene, xylene, 1,4-dioxane, tetrahydrofuran, ethyl acetate, methyl acetate, and butyl acetate; the total volume amount of the organic solvent A is 3 to 10 mL / g based on the mass of N-tert-butoxycarbonyl-L-serine ester.

[0026] Furthermore, the cuprous halide in step (2) is one or more of cuprous chloride, cuprous bromide or cuprous iodide.

[0027] Furthermore, the nitrogen-containing compound described in step (2) is one or more of N,N,N',N'-tetramethylethylenediamine, N,N,N',N",N"-pentamethyldiethylenetriamine, 1,1,4,7,10,10-hexamethyltriethylenetetramine, 2,2'-bipyridine, 2,2',6',2"-tripyridine, o-phenanthroline or diisopropylethylamine.

[0028] Furthermore, the Grignard reagent in step (2) is one or more of 4-biphenyl magnesium chloride, 4-biphenyl magnesium bromide or 4-biphenyl magnesium iodide.

[0029] Furthermore, the organic solvent B in step (2) is one or more of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane or toluene, and the total volume amount of the organic solvent B is 1.5 to 10 mL / g based on the mass of N-(tert-butoxycarbonyl)-O-sulfonyl-L-serine ester.

[0030] Furthermore, the organic solvent C in step (3) is one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, and 2-methyltetrahydrofuran, and the total volume usage of the organic solvent C is 3 to 10 mL / g based on the mass of (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate.

[0031] The reaction temperature in step (1) is preferably 10 to 25°C; the reaction temperature in step (2) is preferably -5 to 0°C; and the reaction temperature in step (3) is preferably 60 to 70°C.

[0032] The specific recommended refining methods for each step are:

[0033] The post-treatment in step (1) is as follows: adjusting the pH of the reaction solution to 5 with dilute hydrochloric acid, naturally stratifying, separating the organic phase, washing with water, then washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a crude product, subjecting the crude product to column chromatography using a 20% ethyl acetate solution in petroleum ether as an eluent, collecting the target product, and concentrating to obtain a colorless oily substance, which is N-(tert-butoxycarbonyl)-O-sulfonyl-L-serine ester as shown in Formula 32;

[0034] The purification treatment described in step (2) is as follows: the reaction solution after quenching with a saturated ammonium chloride solution is extracted with ethyl acetate, the organic phase is sequentially washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a crude product, the crude product is subjected to silica gel column chromatography using a 20% ethyl acetate petroleum ether solution, the target product is collected, and concentrated to obtain a colorless oil, which is (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate shown in Formula 33;

[0035] The purification treatment described in step (3) is as follows: adding water to the reaction solution, stirring evenly, adding ethyl acetate, separating the liquids, washing the organic phase with water, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a crude product. The crude product is subjected to silica gel column chromatography using a 35% ethyl acetate petroleum ether solution to collect the target product, and concentrating to obtain a white solid, which is (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate shown in Formula 8.

[0036] The present invention uses N-tert-butoxycarbonyl-L-serine ester shown in Formula 31 as a starting material, and reacts with sulfonyl chloride under the catalysis of an alkaline substance to obtain N-(tert-butoxycarbonyl)-O-sulfonyl-L-serine ester shown in Formula 32. After the hydroxyl group in the compound is activated by the sulfonic acid ester, it reacts with a Grignard reagent under the catalysis of copper to generate (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate shown in Formula 33. Finally, under the action of a catalyst and a reducing agent, the ester group is reduced to a hydroxyl group to generate (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate shown in Formula 8. The preparation method has the advantages of a simple preparation process route, cheap and readily available raw materials, a short synthesis path, mild reaction conditions, simple operation, and high yield, and has good application value and economic benefits.

[0037] Compared with the prior art, the present invention has the following beneficial effects:

[0038] The process route of the present invention is simple, and cheap and readily available N-tert-butyloxycarbonyl-L-serine ester is used as a raw material, and the key chiral intermediate of sacubitril (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate is prepared through three-step reactions, and the total yield of the three-step reactions is 52-70%. Patent CN105237560 also uses L-serine as a raw material, and obtains the target product synthesized by the present invention through eight steps of reaction, and requires relatively cumbersome steps such as protection and deprotection. The present invention designs a new route for synthesizing the key chiral intermediate of sacubitril (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate, which avoids the use of protecting groups and precious metal catalysts, greatly shortens the reaction steps, improves atom economy, and has good application prospects. DETAILED DESCRIPTION

[0039] The present invention is further described below by means of specific embodiments, but the protection scope of the present invention is not limited thereto.

[0040] Embodiment 1:

[0041] (a) Preparation of N-(tert-butoxycarbonyl)-O-p-toluenesulfonyl-L-serine ethyl ester

[0042] N-tert-Butoxycarbonyl-L-serine ethyl ester (22.85 g, 98.0 mmol) was dissolved in 70 mL of dichloromethane, and triethylamine (20.00 g, 198.0 mmol) was added thereto at 0°C and stirred evenly. p-Toluenesulfonyl chloride (29.93 g, 157.0 mmol) was dissolved in 40 mL of dichloromethane to obtain a toluenesulfonyl chloride solution, which was slowly added dropwise to the above reaction system, and then stirred at 25°C for 8 h to obtain a product solution. The product solution was detected by TLC to find that the raw material reaction was complete. The pH value of the product solution was adjusted to 5 with 3 mol / L hydrochloric acid, and the organic phase was separated. The organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain a colorless oil (identified as: N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine ethyl ester) 33.01 g (85.3 mmol) with a yield of 87%.

[0043] 1 H NMR(400MHz, CDCl3-d)δ7.76–7.69(m,2H),7.42–7.35(m,2H),4.47(m,1H) ,4.29–4.09(m,4H),2.45(s,3H),1.41(s,9H),1.26(t,J=8.0Hz,3H).[M+H] +388.14.

[0044] (b) Preparation of ethyl (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate

[0045] N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine ethyl ester (15.09 g, 39.0 mmol) was dissolved in tetrahydrofuran (50 mL), and then cuprous iodide (1.49 g, 7.8 mmol) and 2,2'-bipyridine (2.44 g, 15.6 mmol) were added thereto, and a tetrahydrofuran solution of 4-biphenyl magnesium bromide (58 mL, 1.0 mol / L) was slowly added thereto at 0°C. After the addition, the reaction was continued at 0°C for 20 h to obtain a product solution. The product solution was then quenched with a saturated ammonium chloride solution, extracted with ethyl acetate, separated, and the organic phase (ethyl acetate layer) was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain a colorless oil (identified as: (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propionic acid ethyl ester) 13.25 g, (35.9 mmol), yield 92%.

[0046] 1 H NMR (400MHz, CDCl3-d) δ7.64–7.51(m,4H),7.49–7.41(m,2H),7.40–7.33(m,1H),7.24(d,J= 7.9Hz,2H),5.07(d,J=8.3Hz,1H),4.63(q,J=6.7Hz,1H),4.21(q,J=7.1Hz,2H),3.23–3.07(m 2H),1.46(s,9H),1.27(t,J=7.2Hz,3H).[M+H] + 370.19.

[0047] Preparation of (c) (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate

[0048] Dissolve (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propionic acid ethyl ester (9.97 g, 27.0 mmol) in 55 mL of tetrahydrofuran, add lithium chloride (1.72 g, 40.5 mmol) and sodium borohydride (2.04 g, 54.0 mmol), and react at 70°C for 15 h to obtain a product solution. The reaction of the raw materials in the product solution was complete by TLC. 20 mL of water was added to the product solution, stirred for 30 minutes, and 60 mL of ethyl acetate was added for extraction. The organic phase was washed with water, saturated brine, and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (35% ethyl acetate in petroleum ether solution) and concentrated to obtain a white solid (identified as: (R)-tert-butyl(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate) 7.69 g (23.5 mmol) with a yield of 87%.

[0049] 1 H NMR (400MHz, DMSO-d) δ7.65-7.54(m,4H),7.46(d,J=7.6Hz,2H),7.35(d,J=7.4Hz,1H),7.29(d,J=7.6Hz,2H),6.63(d,J=7.2Hz 1H),4.75(s,1H),3.64-3.59(m,1H),3.38(dd,J1=6.4Hz,J2=13.6Hz,1H),3.32(dd,J1=6.8Hz,J2=13.4 Hz,1H),2.85(dd,J1=5.6Hz,J2=13.6Hz,1H),2.62(dd,J1=6.0Hz,J2=14.2Hz,1H),1.34(s,9H,).[M+H] + 328.4.Mp:114-116℃。

[0050] Embodiment 2:

[0051] (a) Preparation of N-(tert-butoxycarbonyl)-O-p-toluenesulfonyl-L-serine ethyl ester

[0052] N-tert-Butoxycarbonyl-L-serine ethyl ester (34.27 g, 147.0 mmol) was dissolved in 90 mL 1,2-dichloroethane, and N-methylmorpholine (38.74 g, 383.0 mmol) was added at 0°C. p-Toluenesulfonyl chloride (44.99 g, 236.0 mmol) was dissolved in 90 mL 1,2-dichloroethane, and slowly added dropwise to the above reaction system, and stirred at 25°C for 8 h. TLC detected that the raw material reaction was complete. The pH was adjusted to 5 with 3 mol / L hydrochloric acid, and the liquid was separated. The organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain 47.80 g (123.5 mmol) of colorless oil with a yield of 84%.

[0053] (b) Preparation of ethyl (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate

[0054] N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine ethyl ester (22.65 g, 58.5 mmol) was dissolved in 2-methyltetrahydrofuran (90 mL), and cuprous chloride (1.16 g, 11.7 mmol) and 2,2'-bipyridine (3.65 g, 23.4 mmol) were added. Then, 4-biphenyl magnesium bromide (87 mL, 1.0 mol / L) tetrahydrofuran solution was slowly added dropwise at 0°C. After the addition, the reaction was continued to stir at 0°C for 18 h. Then, the solution was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, separated, and the organic phase (ethyl acetate layer) was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain 17.93 g (48.6 mmol) of colorless oil with a yield of 83%.

[0055] Preparation of (c) (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate

[0056] Ethyl (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate (12.92 g, 35.0 mmol) was dissolved in 50 mL of tetrahydrofuran, and calcium chloride (3.88 g, 35.0 mmol) and sodium borohydride (2.65 g, 70.0 mmol) were added. The temperature was controlled at 65°C and the reaction was carried out for 16 h. TLC detected that the raw material reaction was complete. 24 mL of water was added, stirred for 30 minutes, and 70 mL of ethyl acetate was added for extraction. The organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (35% ethyl acetate in petroleum ether solution) and concentrated to obtain 9.54 g (29.2 mmol) of a white solid with a yield of 83%.

[0057] Embodiment 3:

[0058] (a) Preparation of N-(tert-butoxycarbonyl)-O-p-toluenesulfonyl-L-serine ethyl ester

[0059] N-tert-Butoxycarbonyl-L-serine ethyl ester (22.85 g, 98.0 mmol) was dissolved in 70 mL toluene, pyridine (20.17 g, 255.0 mmol) was added at -5 °C, and stirred evenly. p-Toluenesulfonyl chloride (29.93 g, 157.0 mmol) was dissolved in 60 mL toluene, slowly added dropwise to the above reaction system, and stirred at 20 °C for 7 h. TLC detected that the raw material reaction was complete. The pH was adjusted to 5 with 3 mol / L hydrochloric acid, and the liquid was separated. The organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain 30.35 g (78.4 mmol) of colorless oil with a yield of 80%.

[0060] (b) Preparation of ethyl (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate

[0061] N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine ethyl ester (30.20 g, 78.0 mmol) was dissolved in 1,4-dioxane (90 mL), and cuprous bromide (2.70 g, 18.8 mmol) and 2,2'-bipyridine (4.87 g, 31.2 mmol) were added. 4-biphenyl magnesium bromide (116 mL, 1.0 mol / L) was slowly added dropwise at 0°C. After the addition, the reaction was continued at 0°C for 20 h. Then the solution was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, separated, and the organic phase (ethyl acetate layer) was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain 24.48 g (66.3 mmol) of colorless oil with a yield of 85%.

[0062] Preparation of (c) (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate

[0063] (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propionic acid ethyl ester (9.97g, 27.0mmol) was dissolved in 55mL tetrahydrofuran, lithium chloride (1.72g, 40.5mmol) and sodium borohydride (2.04g, 54.0mmol) were added, the temperature was controlled at 60°C, the reaction was carried out for 18h, and the reaction of the raw material was completed by TLC detection. 20mL of water was added, stirred for 30 minutes, 60mL of ethyl acetate was added for extraction, and the organic phase (ethyl acetate layer) was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (35% ethyl acetate in petroleum ether solution) and concentrated to obtain 7.77g (23.7mmol) of a white solid with a yield of 88%.

[0064] Embodiment 4:

[0065] (a) Preparation of N-(tert-butoxycarbonyl)-O-p-toluenesulfonyl-L-serine methyl ester

[0066] N-tert-Butoxycarbonyl-L-serine methyl ester (21.91g, 100.0mmol) was dissolved in 80mL ethyl acetate, ice bath, triethylamine (20.04g, 198.0mmol) was added, and stirred evenly. p-Toluenesulfonyl chloride (29.93g, 157.0mmol) was dissolved in 60mL ethyl acetate, slowly added dropwise to the above reaction system, stirred at 25°C for 10h, and the reaction of the raw materials was complete after TLC detection. The pH was adjusted to 5 with 3mol / L hydrochloric acid, and the liquid was separated. The organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain 30.97g (83.0mmol) of colorless oil, with a yield of 83%.

[0067] (b) Preparation of methyl (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate

[0068] N-(tert-Butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester (24.74 g, 66.3 mmol) was dissolved in methyl tert-butyl ether (102 mL), and cuprous iodide (2.53 g, 13.3 mmol) and 2,2'-bipyridine (4.14 g, 26.5 mmol) were added. Then 4-biphenyl magnesium bromide (99 mL, 1.0 mol / L) was slowly added dropwise at 0°C. After the addition, the reaction was continued to stir at 0°C for 20 h. Then the solution was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, separated, and the organic phase (ethyl acetate layer) was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain 20.02 g (56.4 mmol) of colorless oil with a yield of 85%.

[0069] Preparation of (c) (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate

[0070] Methyl (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate (9.59 g, 27.0 mmol) was dissolved in 55 mL of 2-methyltetrahydrofuran, and zinc chloride (4.09 g, 30.0 mmol) and sodium borohydride (2.04 g, 54.0 mmol) were added. The temperature was controlled at 70°C, and the reaction was stirred for 15 h. TLC detected that the raw material reaction was complete. 20 mL of water was added, and the mixture was stirred for 30 minutes. 60 mL of ethyl acetate was added for extraction, and the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (35% ethyl acetate in petroleum ether solution) and concentrated to obtain 7.16 g (21.9 mmol) of a white solid with a yield of 81%.

[0071] Embodiment 5:

[0072] (a) Preparation of N-(tert-butoxycarbonyl)-O-p-toluenesulfonyl-L-serine methyl ester

[0073] N-tert-Butyloxycarbonyl-L-serine methyl ester (32.21 g, 147.0 mmol) was dissolved in 90 mL of xylene, and N-methylmorpholine (38.74 g, 383.0 mmol) was added at -10 °C and stirred evenly. p-Toluenesulfonyl chloride (44.99 g, 236.0 mmol) was dissolved in 70 mL of xylene, and slowly added dropwise to the above reaction system, and stirred at 15 °C for 8 h. TLC detected that the raw material reaction was complete. The pH was adjusted to 5 with 3 mol / L hydrochloric acid, and the liquid was separated. The organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain 44.43 g (119.1 mmol) of colorless oil, with a yield of 81%.

[0074] (b) Preparation of methyl (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate

[0075] N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester (14.55 g, 39.0 mmol) was dissolved in tetrahydrofuran (60 mL) solution, and then cuprous chloride (0.77 g, 7.8 mmol) and N,N,N',N'-tetramethylethylenediamine (1.81 g, 15.6 mmol) were added, and 4-biphenyl magnesium bromide (58 mL, 1.0 mol / L) was slowly added dropwise at 0°C. After the addition, the reaction was continued to stir at 0°C for 20 h. Then the solution was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, separated, and the organic phase (ethyl acetate layer) was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain 11.50 g (32.4 mmol) of colorless oil, with a yield of 83%.

[0076] Preparation of (c) (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate

[0077] Methyl (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate (12.43 g, 35.0 mmol) was dissolved in 80 mL of tetrahydrofuran, and magnesium chloride (3.33 g, 35.0 mmol) and sodium borohydride (2.65 g, 70.0 mmol) were added. The temperature was controlled at 65°C, and the reaction was stirred for 15 h. TLC detected that the raw material reaction was complete. 24 mL of water was added, and the mixture was stirred for 30 minutes. 70 mL of ethyl acetate was added for extraction, and the organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (35% ethyl acetate in petroleum ether solution) and concentrated to obtain 8.93 g (27.3 mmol) of a white solid with a yield of 78%.

[0078] Embodiment 6:

[0079] (a) Preparation of N-(tert-butoxycarbonyl)-O-p-toluenesulfonyl-L-serine methyl ester

[0080] N-tert-Butoxycarbonyl-L-serine methyl ester (21.47 g, 98.0 mmol) was dissolved in 40 mL of dichloromethane, ice-bathed, pyridine (20.19 g, 255.3 mmol) was added, and stirred evenly. p-Toluenesulfonyl chloride (29.99 g, 157.3 mmol) was dissolved in 47 mL of dichloromethane, slowly added dropwise to the above reaction system, and stirred at 25 ° C for 10 h. TLC detected that the raw material reacted completely. The pH was adjusted to 5 with 3 mol / L hydrochloric acid, and the liquid was separated. The organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain 31.08 g (83.3 mmol) of colorless oil, with a yield of 85%.

[0081] (b) Preparation of methyl (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate

[0082] N-(tert-Butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester (20.37 g, 54.6 mmol) was dissolved in ether (60 mL) solution, cuprous chloride (1.08 g, 10.9 mmol) and N,N,N',N",N"-pentamethyldiethylenetriamine (4.23 g, 24.4 mmol) were added, and 4-biphenyl magnesium chloride (82 mL, 1.0 mol / L) was slowly added dropwise at 0°C. After the addition, the mixture was kept at 0°C and stirred vigorously for 18 h. Then the solution was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, separated, and the organic phase (ethyl acetate layer) was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain 16.48 g (83.3 mmol) of colorless oil with a yield of 85%.

[0083] Preparation of (c) (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate

[0084] Methyl (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate (19.18 g, 54.0 mmol) was dissolved in 100 mL of tetrahydrofuran, and lithium chloride (3.44 g, 81.0 mmol) and sodium borohydride (4.09 g, 108.0 mmol) were added. The temperature was controlled to 70°C, stirred evenly, and reacted for 15 h. TLC detected that the raw material had reacted completely. 40.0 mL of water was added, stirred for 30 minutes, and the organic solvent was evaporated under reduced pressure. 120 mL of ethyl acetate was added for extraction, and the organic phase was separated. The organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (35% ethyl acetate in petroleum ether solution) and concentrated to obtain 15.90 g (48.6 mmol) of a white solid with a yield of 90%.

[0085] Embodiment 7:

[0086] (a) Preparation of N-(tert-butoxycarbonyl)-O-p-toluenesulfonyl-L-serine ethyl ester

[0087] The raw material N-tert-butoxycarbonyl-L-serine ethyl ester (23.31 g, 100.0 mmol) was dissolved in 60 mL 1,2-dichloroethane, the temperature was controlled at -5 °C, pyridine (20.2 g, 255 mmol) was added, and stirred evenly. p-Toluenesulfonyl chloride (29.93 g, 157.0 mmol) was dissolved in 40 mL 1,2-dichloroethane, slowly added dropwise to the above reaction system, stirred at 25 °C for 10 h, and the raw material reaction was complete when detected by TLC. The pH was adjusted to 5 with 3 mol / L hydrochloric acid, the liquid was separated, the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain 31.75 g (82.0 mmol) of colorless oil, with a yield of 82%.

[0088] (b) Preparation of ethyl (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate

[0089] N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine ethyl ester (22.65 g, 58.5 mmol) was dissolved in 2-methyltetrahydrofuran (90 mL), and cuprous bromide (1.68 g, 11.7 mmol) and 2,2'-bipyridine (3.65 g, 23.4 mmol) were added. Then, 4-biphenyl magnesium chloride (87 mL, 1.0 mol / L) tetrahydrofuran solution was slowly added dropwise at 0°C. After the addition, the reaction was continued to stir at 0°C for 20 h. Then, the solution was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, separated, and the organic phase (ethyl acetate layer) was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain 17.71 g (48.0 mmol) of colorless oil with a yield of 82%.

[0090] Preparation of (c) (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate

[0091] Ethyl (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate (11.81 g, 32.0 mmol) was dissolved in 55 mL of 2-methyltetrahydrofuran, and calcium chloride (3.91 g, 35 mmol) and sodium borohydride (2.45 g, 64.8 mmol) were added. The temperature was controlled at 70°C, and the reaction was stirred for 15 h. TLC detected that the raw material reaction was complete. 20 mL of water was added, and the mixture was stirred for 30 minutes. 60 mL of ethyl acetate was added for extraction, and the organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (35% ethyl acetate in petroleum ether solution) and concentrated to obtain 9.32 g (28.5 mmol) of a white solid with a yield of 89%.

[0092] Embodiment 8:

[0093] (a) Preparation of N-(tert-butoxycarbonyl)-O-p-toluenesulfonyl-L-serine ethyl ester

[0094] N-tert-Butoxycarbonyl-L-serine ethyl ester (34.27g, 147.0mmol) was dissolved in 100mL 1,2-dichloroethane, and N-methylmorpholine (38.74g, 383.0mmol) was added at -10℃ and stirred evenly. p-Toluenesulfonyl chloride (44.99g, 236.0mmol) was dissolved in 80mL 1,2-dichloroethane, and slowly added dropwise to the above reaction system, and stirred at 20℃ for 8h. TLC detected that the raw material reaction was complete. The pH was adjusted to 5 with 3mol / L hydrochloric acid, and the liquid was separated. The organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain 44.39g (114.7mmol) of colorless oil with a yield of 78%.

[0095] (b) Preparation of ethyl (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate

[0096] Dissolve N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine ethyl ester (15.09 g, 39.0 mmol) in tetrahydrofuran (55 mL), add cuprous iodide (1.49 g, 7.8 mmol) and 2,2'-bipyridine (2.44 g, 15.6 mmol), and slowly drop 4-biphenyl magnesium chloride (58 mL, 1.0 mol / L) tetrahydrofuran solution at 0°C. After the dropwise addition, continue the reaction at 0°C for 18 h. Then add saturated ammonium chloride solution to quench the solution, extract with ethyl acetate, separate the liquids, wash the organic phase (ethyl acetate layer) with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain 11.37 g (30.8 mmol) of colorless oil with a yield of 79%.

[0097] Preparation of (c) (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate

[0098] (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propionic acid ethyl ester (8.01 g, 21.7 mmol) was dissolved in 35 mL of tetrahydrofuran, magnesium chloride (2.48 g, 26 mmol) and sodium borohydride (1.63 g, 43.2 mmol) were added, the temperature was controlled at 70°C, the reaction was stirred for 15 h, and the reaction of the raw material was complete by TLC detection. 13 mL of water was added, the mixture was stirred for 30 minutes, 40 mL of ethyl acetate was added for extraction, the organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (35% ethyl acetate in petroleum ether solution) and concentrated to obtain 5.96 g (18.2 mmol) of a white solid with a yield of 84%.

[0099] Embodiment 9:

[0100] (a) Preparation of N-(tert-butoxycarbonyl)-O-p-toluenesulfonyl-L-serine methyl ester

[0101] N-tert-Butyloxycarbonyl-L-serine methyl ester (10.96 g, 50.0 mmol) was dissolved in 40 mL toluene, ice bath, triethylamine (10.12 g, 100.0 mmol) was added, and stirred evenly. p-Toluenesulfonyl chloride (14.97 g, 78.5 mmol) was dissolved in 30 mL toluene, slowly added dropwise to the above reaction system, stirred at 25°C for 9 h, and the reaction of the raw materials was complete by TLC detection. The pH was adjusted to 5 with 3 mol / L hydrochloric acid, and the liquid was separated. The organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain 15.11 g (40.5 mmol) of colorless oil, with a yield of 81%.

[0102] (b) Preparation of methyl (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate

[0103] N-(tert-Butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester (29.10 g, 78.0 mmol) was dissolved in 1,4-dioxane (95 mL), and cuprous chloride (1.86 g, 18.8 mmol) and 2,2'-bipyridine (4.87 g, 31.2 mmol) were added. 4-Biphenyl magnesium bromide (116 mL, 1.0 mol / L) was slowly added dropwise at 0°C. After the addition, the reaction was continued at 0°C for 20 h. Then the solution was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, separated, and the organic phase (ethyl acetate layer) was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether solution) and concentrated to obtain 23.27 g (65.5 mmol) of colorless oil with a yield of 84%.

[0104] Preparation of (C)(R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate

[0105] Methyl (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate (9.59 g, 27 mmol) was dissolved in 55 mL of 2-methyltetrahydrofuran, and lithium chloride (1.72 g, 40.5 mmol) and sodium borohydride (1.63 g, 43.2 mmol) were added. The temperature was controlled at 65°C, and the reaction was stirred for 16 hours. TLC detected that the raw material reaction was complete. 20 mL of water was added, stirred for 30 minutes, and 60 mL of ethyl acetate was added for extraction. The organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (35% ethyl acetate in petroleum ether solution) and concentrated to obtain 7.42 g (22.7 mmol) of a white solid with a yield of 84%.

[0106] It should be pointed out that the above experimental examples are only for illustrating the concept and features of the present invention, and their purpose is to allow people familiar with the present invention to understand the experiment and implement it accordingly, and they cannot limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit and essence of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a sacubitril intermediate as shown in Formula 8: (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate, It is characterized in that In the formula 32 and formula 33, R 1 is methyl, ethyl, isopropyl, n-butyl or tert-butyl; in the formula 32, R 2 is p-toluenesulfonyl chloride, methanesulfonyl chloride or p-nitrobenzenesulfonyl chloride; the preparation method is carried out according to the following steps: (1) dissolving N-tert-butoxycarbonyl-L-serine ester shown in formula 31 in organic solvent A to obtain solution A, adding alkaline substance to solution A under ice bath condition and stirring evenly, then slowly dropping sulfonyl chloride solution therein, stirring at -0 to 50°C for 2 to 15 hours, and then post-processing: sequentially treating with hydrochloric acid, separating the liquids, washing the organic phase with water, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography using 20% ​​ethyl acetate petroleum ether solution as eluent to collect the target product, and concentrating to obtain N-(tert-butoxycarbonyl)-O-sulfonyl-L-serine ester shown in formula 32, wherein the molar ratio of the N-tert-butoxycarbonyl-L-serine ester shown in formula 31 to the alkaline substance and sulfonyl chloride is 1:1 to 3:1 to 2; (2) dissolving the N-(tert-butoxycarbonyl)-O-sulfonyl-L-serine ester of formula 32 prepared in step (1) together with cuprous halide and a nitrogen-containing compound in an organic solvent B to obtain a solution B, adding a Grignard reagent to the solution B, and reacting the solution at a temperature of -30 to 20° C. for 10 to 24 hours, and then purifying the solution by adding a saturated ammonium chloride solution to the solution for quenching, extracting the reaction solution with ethyl acetate, separating the layers, washing the ethyl acetate layer with water, washing with saturated brine, and drying over anhydrous sodium sulfate, filtering the solution, and The filtrate is concentrated under reduced pressure to obtain a crude product, the crude product is purified by silica gel column chromatography with a 20% ethyl acetate petroleum ether solution to collect the target product, and concentrated to obtain (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoic acid ester shown in Formula 33, wherein the molar ratio of N-(tert-butoxycarbonyl)-O-sulfonyl-L-serine ester shown in Formula 32 to cuprous halide, nitrogen-containing compound, and Grignard reagent is 1:0.05-0.5:0.025-1:1-2; (3) dissolving the (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate of formula 33 obtained in step (2) in an organic solvent C to obtain a solution C, adding a reducing agent and a catalyst to the solution C, reacting at a temperature of 25 to 80° C. for 10 to 24 hours, and then purifying the solution by adding water to the reaction solution, stirring evenly, adding ethyl acetate, separating the liquids, washing the organic phase with water, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product with a 35% ethyl acetate petroleum ether solution. The target product is collected by purification treatment using a silica gel column, and concentrated to obtain (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate shown in Formula 8, wherein the molar ratio of the (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate shown in Formula 33 to the reducing agent and the catalyst is 1:1 to 4:1 to 2; the reducing agent is potassium borohydride or sodium borohydride; and the catalyst is one or more of lithium chloride, calcium chloride, zinc chloride, magnesium chloride or boron trifluoride ether complex.

2. The method for preparing the sacubitril intermediate (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 1, characterized in that: The alkaline substance is one or more of triethylamine, diisopropylethylamine, diethylaniline, N-methylmorpholine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, lithium hydroxide or potassium hydroxide.

3. The method for preparing the sacubitril intermediate (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 1, characterized in that: The sulfonyl chloride is one or more of p-toluenesulfonyl chloride, methanesulfonyl chloride or p-nitrobenzenesulfonyl chloride.

4. The method for preparing the sacubitril intermediate (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 1, characterized in that: The organic solvent A described in step (1) is one or more of dichloromethane, 1,2-dichloroethane, chloroform, toluene, xylene, 1,4-dioxane, tetrahydrofuran, ethyl acetate, methyl acetate, and butyl acetate; the total volume usage of the organic solvent A is 3 to 10 mL / g based on the mass of N-tert-butoxycarbonyl-L-serine ester.

5. The method for preparing the sacubitril intermediate (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 1, characterized in that: The cuprous halide in step (2) is one or more of cuprous chloride, cuprous bromide or cuprous iodide.

6. The method for preparing the sacubitril intermediate (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 1, characterized in that: The nitrogen-containing compound described in step (2) is one or more of N,N,N',N'-tetramethylethylenediamine, N,N,N',N",N"-pentamethyldiethylenetriamine, 1,1,4,7,10,10-hexamethyltriethylenetetramine, 2,2'-bipyridine, 2,2',6',2"-tripyridine, o-phenanthroline or diisopropylethylamine.

7. The method for preparing the sacubitril intermediate (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 1, characterized in that: The Grignard reagent in step (2) is one or more of 4-biphenyl magnesium chloride, 4-biphenyl magnesium bromide or 4-biphenyl magnesium iodide.

8. The method for preparing the sacubitril intermediate (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 1, characterized in that: The organic solvent B in step (2) is one or more of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane or toluene, and the total volume usage of the organic solvent B is 1.5 to 10 mL / g based on the mass of N-(tert-butoxycarbonyl)-O-sulfonyl-L-serine ester.

9. The method for preparing the sacubitril intermediate (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 1, characterized in that: The organic solvent C in step (3) is one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran or 2-methyltetrahydrofuran, and the total volume usage of the organic solvent C is 3 to 10 mL / g based on the mass of (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate.

10. The method for preparing the sacubitril intermediate (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate according to claim 1, characterized in that: The post-treatment in step (1) is as follows: adjusting the pH of the reaction solution to 5 with dilute hydrochloric acid, naturally stratifying, separating the organic phase, washing with water, then washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a crude product, subjecting the crude product to column chromatography using a 20% ethyl acetate solution in petroleum ether as an eluent, collecting the target product, and concentrating to obtain a colorless oily substance, which is N-(tert-butoxycarbonyl)-O-sulfonyl-L-serine ester as shown in Formula 32; The purification treatment described in step (2) is as follows: the reaction solution after quenching with a saturated ammonium chloride solution is extracted with ethyl acetate, the organic phase is sequentially washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a crude product, the crude product is subjected to silica gel column chromatography using a 20% ethyl acetate petroleum ether solution, the target product is collected, and concentrated to obtain a colorless oil, which is (R)-3-([1,1'-biphenyl]-4-yl)-2-(tert-butoxycarbonyl)amino)propanoate shown in Formula 33; The purification treatment described in step (3) is as follows: adding water to the reaction solution, stirring evenly, adding ethyl acetate, separating the liquids, washing the organic phase with water, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a crude product. The crude product is subjected to silica gel column chromatography using a 35% ethyl acetate petroleum ether solution to collect the target product, and concentrating to obtain a white solid, which is (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl) carbamate shown in Formula 8.

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