A process for the preparation of a key intermediate of sacubitril

Abstract

The application belongs to the technical field of medicine and relates to a preparation method of a key intermediate of sacubitril, in particular to a preparation method of (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl) carbamate. The method takes D-phenylalanine as a starting material, realizes C(sp 2 )-C(sp 2 ) coupling through Boc anhydride protection, sodium borohydride reduction and palladium-catalyzed remote C(sp 2 )-H bond activation to obtain the target compound. The raw material of the application is cheap and easy to obtain, the steps are short, the operation is simple, the pollution is small, the product yield is high, reaches more than 78%, and the application is beneficial to continuous large-scale industrial production. The synthetic route is as follows:

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a method for preparing a key intermediate of sacubitril, particularly a method for preparing (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate. Background Technology

[0002] Sacubitril / Valsartan Sodium (LCZ696), trade name Entresto, launched by Novartis in July 2015, is a blockbuster anti-heart failure drug and the world's first angiotensin receptor-neprilysin inhibitor. Sacubitril is an essential intermediate for LCZ696. Its industrial synthesis typically involves the oxidation of (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate to an aldehyde via TEMPO, followed by Witting reaction, alkaline hydrolysis, chiral catalytic hydrogenation, esterification and deBoc removal, anhydride condensation, and finally alkaline hydrolysis to obtain the final product. Therefore, (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate has become a key intermediate in the synthesis of sacubitril, with huge market demand. Currently, the main methods for synthesizing this compound are as follows:

[0003] (1) Using 4-bromobiphenyl as the starting material, the target product is obtained by preparing Grignard reagent and reacting it with (S)-ethylene oxide and its derivatives, then constructing CN bond through photoelongation reaction and completing configuration inversion, deprotection, hydrolysis, and finally adding Boc protecting group.

[0004]

[0005] This synthetic route requires a Grignard reaction, which has harsh reaction conditions, including strict anhydrous and oxygen-free environments. It also places strict requirements on the workshop environment and poses certain safety hazards, making it unsuitable for scale-up. The second step, photoelongation reaction, requires high purity of materials. If the product from the previous step is not thoroughly purified, the yield of the photoelongation reaction will be low. In addition, the synthesis process requires the use of large amounts of concentrated hydrochloric acid and sodium hydroxide, involving acid-base neutralization, which generates a large amount of inorganic salt waste and pollutes the environment.

[0006] (2) The target product was prepared by using D-serine methyl ester hydrochloride as the starting material through triphenylmethyl protection, esterification, cyclization, deprotection and Boc addition, reduction, tert-butyldimethylchlorosilane protection, Grignard reaction and deprotection.

[0007]

[0008] This synthetic route frequently employs protecting and deprotecting methods, resulting in lengthy steps, low atom utilization, and increased costs; furthermore, the process also utilizes Grignard reactions, making it unsuitable for scale-up.

[0009] (3) Starting with expensive D-tyrosine, a Boc protecting group is first added, then the phenolic hydroxyl group is activated with trifluoromethanesulfonic anhydride, and finally the target product is obtained by coupling with tetrakis(triphenylphosphine)palladium.

[0010]

[0011] The material used in this synthetic route, trifluoromethanesulfonic anhydride, is extremely irritating and poses a significant risk to human health. The metal catalyst, tetra-triphenylphosphine palladium, is expensive, and the coupling process requires strict control of anhydrous and oxygen-free conditions, resulting in high costs.

[0012] (4) Using glycine methyl ester hydrochloride as the starting material, the target product was obtained through condensation, N-alkylation, hydrolysis, hydrolytic enzyme resolution, Boc anhydride protection, and reduction.

[0013]

[0014] The raw materials used in this route are glycine methyl ester hydrochloride and furfural, which are inexpensive and readily available. However, 4-bromomethylbiphenyl is expensive, and the use of protease for resolution results in significant losses and a low overall yield.

[0015] It can be seen that existing methods generally suffer from problems such as expensive raw materials, harsh reaction conditions, lengthy steps, complicated operation, low yield, and high production costs. Summary of the Invention

[0016] The purpose of this invention is to overcome the shortcomings of existing production processes and provide a method for preparing (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate, which achieves relatively inexpensive and readily available raw materials, short steps, simple operation, low pollution, and high product yield, thus meeting the needs of industrial production.

[0017] To achieve the objectives of this invention, D-phenylalanine is used as the starting material, and the process involves Boc anhydride protection, sodium borohydride reduction, and palladium-catalyzed long-range C(sp) hydrocarbon synthesis. 2 )-H bond activation achieves C(sp 2 )-C(sp 2 The target compound was prepared by coupling.

[0018] Its synthetic route is as follows:

[0019]

[0020] The specific steps are as follows:

[0021] (1) Add D-phenylalanine to the reaction flask and dissolve it in a mixed solvent. Add sodium bicarbonate solid. Then add BOC-acid anhydride dropwise and react at -5-0℃. Then raise the temperature to react. After the reaction is completed, the system separates into layers. Discard the organic phase and adjust the pH of the aqueous phase to weak acidity. The solid precipitates out and is filtered and dried to obtain BOC-D-phenylalanine.

[0022] (2) Dissolve BOC-D-phenylalanine in an organic solvent, then add boron trifluoride solution dropwise. After mixing evenly, slowly add sodium borohydride solution dropwise and heat the reaction. After the reaction is complete, concentrate and crystallize to obtain N-Boc-D-phenylalanine.

[0023] (3) N-Boc-D-phenylpropanol, phenylboronic acid, palladium catalyst, amino acid derivative ligand, and silver salt were added sequentially to the reaction flask. Organic solvent was added to dissolve the substances, and the reaction was carried out under nitrogen protection and heated. After the reaction was completed, the mixture was cooled to room temperature, filtered, concentrated, and crystallized to obtain the final product (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate.

[0024] In step (1), the molar ratio of D-phenylalanine, sodium bicarbonate, and BOC-anhydride is 1:1-2:1-2, preferably 1:1.5:1.2.

[0025] In step (1), the mixed solvent is water and an organic solvent, and the organic solvent is one of tetrahydrofuran, acetonitrile, and acetone, preferably tetrahydrofuran; the volume ratio of water to organic solvent is 1-5:1, preferably 1:1.

[0026] In step (1), the pH of the aqueous phase is adjusted to 4-6 with hydrochloric acid, preferably to 5.

[0027] In step (2), the molar ratio of BOC-D-phenylalanine, boron trifluoride, and sodium borohydride is 1:1-4:1-4, preferably 1:2:2.

[0028] In step (2), the organic solvent is an ether solvent, including one of 1,2-dimethoxypropane, dimethoxymethane, ethylene glycol dimethyl ether, diethyl ether, dimethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran and 2-methyltetrahydrofuran, preferably one of tetrahydrofuran and diethyl ether.

[0029] In step (2), the reaction temperature is 50-70℃, preferably 60℃.

[0030] In step (2), the crystallization solvent is one or more of ethyl acetate, n-heptane, toluene, xylene, diethyl ether, and methyl tert-butyl ether in any proportion.

[0031] In step (3), the molar ratio of N-Boc-D-phenylpropanol, phenylboronic acid, palladium catalyst, amino acid derivative ligand, and silver salt is 1:1-3:0.02-1:0.02-1:0.05-1, preferably 1:2:0.05:0.05:0.1.

[0032] In step (3), the palladium catalyst is one of palladium acetate, palladium chloride, palladium nitrate, and palladium sulfate, preferably palladium acetate; the silver salt is one of silver chloride, silver bromide, silver iodide, silver nitrate, silver sulfate, and silver acetate, preferably silver acetate; the amino acid derivative ligand is an N-acetyl-amino acid derivative, an N-propionyl-amino acid derivative, or an N-sulfonyl-amino acid derivative, preferably an N-acetyl-amino acid derivative.

[0033] In step (3), the organic solvent used is one of toluene, xylene, acetonitrile, 1,2-dichloroethane, and N,N-dimethylformamide, preferably 1,2-dichloroethane.

[0034] In step (3), the reaction temperature is 80-100℃, preferably 90℃.

[0035] In step (3), the crystallization solvent is one or more of ethyl acetate, n-heptane, toluene, xylene, diethyl ether, and methyl tert-butyl ether in any proportion.

[0036] Compared with existing technologies, this invention has the following advantages: (1) D-phenylalanine is used as the starting material, which is relatively inexpensive and readily available; (2) The NaBH4-BF3 system is used to directly reduce the carboxyl group to the hydroxyl group, which is mild, low in cost, and suitable for industrial production; (3) The palladium-catalyzed aromatic hydrocarbon remote CH activation is used to construct biaryl groups, which has high catalytic activity, low dosage, easy recovery, recyclability, stable properties, and is green and environmentally friendly; (4) The entire synthesis route only requires three steps, which is simple to operate, has a short reaction time, and a high yield of over 78%, which is conducive to continuous large-scale industrial production. Attached Figure Description

[0037] Figure 1 The hydrogen NMR spectrum of the target compound of this invention;

[0038] Figure 2 This is the carbon NMR spectrum of the target material of this invention. Detailed Implementation

[0039] The present invention will be described in more detail below through embodiments, but this does not limit the scope of protection of the present invention.

[0040] Example 1

[0041] (1) Add 30g of D-phenylalanine to the reaction flask, add 100mL of a mixed solvent of acetonitrile and water (volume ratio 1:1), place the reaction flask in an ice-water bath, wait for the system to cool to 0℃ and stir until it becomes a uniform white turbid state, then add 18.31g of sodium bicarbonate solid; after stirring evenly, add 62mL of BOC-anhydride dropwise to the system. After the addition is complete, maintain the low temperature for 0.5 hours, then raise the temperature to 35℃ and continue stirring for 8-10 hours. Monitor the reaction using thin-layer chromatography. After the reaction is complete, turn off the stirring, let the system stand to allow the layers to separate, discard the upper organic phase, adjust the pH of the aqueous phase to weakly acidic with 10% dilute hydrochloric acid, precipitate a white solid, filter, wash the filter cake with a small amount of distilled water, and dry to obtain 43.8g of BOC-D-phenylalanine, a white powder with a melting point of 82.1-83.3℃, ​​and a yield of 90.8%.

[0042] (2) Add 20g of BOC-D-phenylalanine to the reaction flask and dissolve it in 60mL of tetrahydrofuran. While stirring, add 18mL of tetrahydrofuran solution containing boron trifluoride dropwise. Weigh 5.7g of sodium borohydride, dissolve it in 20mL of tetrahydrofuran, and slowly add it dropwise to the aforementioned mixture of BOC-D-phenylalanine and boron trifluoride. After the addition is complete, heat the system to 60℃ and keep it at that temperature for 3-4 hours. Monitor the reaction using thin-layer chromatography. After the reaction is complete, cool to room temperature, filter, discard the solid residue, concentrate the filtrate, and recrystallize methyl tert-butyl ether to obtain 15.8g of N-Boc-D-phenylalanine, a white crystalline powder with a melting point of 95.7-96.8℃ and a yield of 83.4%.

[0043] (3) Add 10g N-Boc-D-phenylpropanol, 9.7g phenylboronic acid, 0.4g palladium acetate, 0.6g (S)-2-acetamido-3-methyl-N-(6-(trifluoromethyl)pyridin-2-yl)butanamide, and 0.57g silver chloride sequentially to the reaction flask. Dissolve the residue in 60mL of 1,2-dichloroethane. Under nitrogen protection, heat the system to 90℃ and maintain the temperature for 6-8 hours. Monitor the reaction using thin-layer chromatography. After the reaction is complete, cool the reaction system to room temperature, filter, and wash the filter cake 2-3 times with a small amount of 1,2-dichloroethane. Collect the filtrate, concentrate it, and recrystallize it from methyl tert-butyl ether to obtain 10.2g of the final product (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate, with a melting point of 147.3-149.6℃ and a yield of 78.3%. Its NMR data are as follows: 1H NMR (400MHz, DMSO-d6) δ7.63 (d, J=7.2Hz, 2H, Ar-H), 7.56 (d, J=8.0Hz, 2H, Ar-H), 7.45 (t, J=7.6Hz, 2 H,Ar-H),7.38–7.29(m,1H,Ar-H),7.29(d,J=7.9Hz,2H,Ar-H),6.63(d,J=8.6Hz,1H,-NH-),4.73(t, J=5.7Hz,1H,-OH),3.62(q,J=7.9Hz,1H,-CH-),3.39(d,J=5.8Hz,1H,-CH2-),3.29(q,J=5.5Hz,1H,- CH2-),2.87(dd,J=13.6,5.2Hz,1H,-CH2-),2.60(dd,J=13.6,8.7Hz,1H,-CH2-),1.32(s,9H,-CH3). 13 C NMR(101MHz,DMSO)δ155.18,140.12,138.69,137.69,129.89,129.51,129.02 ,128.70,127.30,126.42,126.33,126.19,77.41,62.94,54.05,28.36,28.00.

[0044] Example 2

[0045] (1) Add 50g of D-phenylalanine to the reaction flask, add 150mL of a mixed solvent of tetrahydrofuran and water (volume ratio 1:1), place the reaction flask in an ice-water bath, wait for the system to cool to 0℃ and stir until it becomes a uniform white turbid state, add 30.51g of sodium bicarbonate solid; after stirring evenly, add 105mL of BOC-anhydride dropwise to the system. After the addition is complete, maintain the low temperature for 0.5 hours, then raise the temperature to 35℃ and continue stirring for 8-10 hours. Monitor the reaction using thin-layer chromatography. After the reaction is complete, turn off the stirring, let the system stand to allow the layers to separate, discard the upper organic phase, adjust the pH of the aqueous phase to weakly acidic with 15% dilute hydrochloric acid, precipitate a white solid, filter, wash the filter cake with a small amount of distilled water, and dry to obtain 76.8g of BOC-D-phenylalanine, a white powder with a melting point of 82.3-83.6℃, ​​and a yield of 95.6%.

[0046] (2) Add 40g of BOC-D-phenylalanine to the reaction flask, dissolve it in 60mL of tetrahydrofuran, and add 37mL of boron trifluoride diethyl ether solution dropwise while stirring; weigh 11.5g of sodium borohydride, dissolve it in 20mL of tetrahydrofuran, and slowly add it dropwise to the aforementioned mixture of BOC-D-phenylalanine and boron trifluoride. After the addition is complete, heat the system to 60℃ and keep it at that temperature for 3-4 hours; monitor the reaction using thin-layer chromatography. After the reaction is complete, cool to room temperature, filter, discard the solid residue, concentrate the filtrate, recrystallize methyl tert-butyl ether to obtain 32.2g of N-Boc-D-phenylalanine, a white crystalline powder with a melting point of 96.4~98.1℃ and a yield of 85.4%.

[0047] (3) Add 25g N-Boc-D-phenylpropanol, 24.3g phenylboronic acid, 1.12g palladium acetate, 1.55g (S)-2-acetamido-3-methyl-N-p-toluenesulfonylbutyramide, and 1.66g silver acetate sequentially to the reaction flask. Dissolve the residue in 80mL of 1,2-dichloroethane. Under nitrogen protection, heat the system to 90℃ and maintain the temperature for 6-8 hours. Monitor the reaction using thin-layer chromatography. After the reaction is complete, cool the reaction system to room temperature, filter, and wash the filter cake 2-3 times with a small amount of 1,2-dichloroethane. Collect the filtrate, concentrate it, and recrystallize it from ethyl acetate / n-heptane at a ratio of 5:1 to obtain 26.8g of the final product (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate, with a melting point of 147.9-149.2℃ and a yield of 82.7%.

[0048] Example 3

[0049] (1) Add 200g of D-phenylalanine to a reaction flask, add 500mL of a mixed solvent of acetonitrile and water (volume ratio 1:1), place the reaction flask in an ice-water bath, wait for the system to cool to 0℃ and stir until it becomes a uniform white turbid state, add 122g of sodium bicarbonate solid; after stirring evenly, add 420mL of BOC-anhydride dropwise to the system. After the addition is complete, maintain the low temperature for 1 hour, then raise the temperature to 40℃ and continue stirring for 8-10 hours. Monitor the reaction using thin-layer chromatography. After the reaction is complete, turn off the stirring, let the system stand to allow the layers to separate, discard the upper organic phase, adjust the pH of the aqueous phase to weakly acidic with 20% dilute hydrochloric acid, precipitate a white solid, filter, wash the filter cake with a small amount of distilled water, and dry to obtain 310.8g of BOC-D-phenylalanine, a white powder with a melting point of 81.8-83.2℃, and a yield of 96.2%.

[0050] (2) Add 150g of BOC-D-phenylalanine to the reaction flask, dissolve it in 300mL of tetrahydrofuran, and add 140mL of boron trifluoride diethyl ether solution dropwise while stirring; weigh 43g of sodium borohydride, dissolve it in 80mL of tetrahydrofuran, and slowly add it dropwise to the aforementioned mixture of BOC-D-phenylalanine and boron trifluoride. After the addition is complete, heat the system to 60℃ and keep it at that temperature for 3-4 hours; monitor the reaction using thin-layer chromatography. After the reaction is complete, cool to room temperature, filter, discard the solid residue, concentrate the filtrate, recrystallize methyl tert-butyl ether to obtain 122.8g of N-Boc-D-phenylalanine, a white crystalline powder with a melting point of 96.2-97.8℃ and a yield of 86.4%.

[0051] (3) Add 60g N-Boc-D-phenylpropanol, 58g phenylboronic acid, 2.68g palladium acetate, 2.39g (S)-N,N'-(3-methyl-1-oxobutane-1,2-diyl)diacetamide, and 3.98g silver acetate sequentially to the reaction flask. Dissolve the mixture in 280mL of 1,2-dichloroethane. Under nitrogen protection, heat the system to 90℃ and maintain the temperature for 6-8 hours. Monitor the reaction using thin-layer chromatography. After the reaction is complete, cool the reaction system to room temperature, filter, and wash the filter cake 2-3 times with a small amount of 1,2-dichloroethane. Collect the filtrate, concentrate it, and recrystallize it from toluene to obtain 65.2g of the final product (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate, a white solid powder with a melting point of 146.8-148.1℃ and a yield of 83.4%.

Claims

1. A method for preparing (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate, characterized in that, This can be achieved through the following steps: (1) Add D-phenylalanine to the reaction flask, dissolve it in a mixed solvent, add sodium bicarbonate solid; then add BOC-acid anhydride dropwise, react at -5-0℃, then heat up to react; after the reaction is completed, the system separates into layers, discard the organic phase, adjust the pH of the aqueous phase to weak acidity, precipitate the solid, filter and dry to obtain BOC-D-phenylalanine. (2) Dissolve BOC-D-phenylalanine in an organic solvent, then add boron trifluoride solution dropwise, mix well, then slowly add sodium borohydride solution dropwise, heat the reaction, and after the reaction is completed, concentrate and crystallize to obtain N-Boc-D-phenylalanine. (3) N-Boc-D-phenylpropanol, phenylboronic acid, palladium catalyst, amino acid derivative ligand, and silver salt were added to the reaction flask in sequence, dissolved in organic solvent, and heated under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, filtered, concentrated and crystallized to obtain the final product (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate. In step (3), the palladium catalyst is one of palladium acetate, palladium chloride, palladium nitrate, and palladium sulfate; the silver salt is one of silver chloride, silver bromide, silver iodide, silver nitrate, silver sulfate, and silver acetate; and the amino acid derivative ligand is an N-acetyl-amino acid derivative, an N-propionyl-amino acid derivative, or an N-sulfonyl-amino acid derivative.

2. The method for preparing (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate as described in claim 1, characterized in that, The mixed solvent in step (1) is water and an organic solvent, wherein the organic solvent is one of tetrahydrofuran, acetonitrile, and acetone.

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