Preparation method of sacubitril intermediate

Abstract

The invention belongs to the field of synthesis of drug intermediates, and particularly relates to a preparation method of a sacubitril intermediate. The method comprises the following steps: by taking N-[(1R)-2-[1, 1 '-biphenyl]-4-yl-1-(hydroxymethyl) ethyl] tert-butyl carbamate, namely a compound 1, as an initial raw material, firstly protecting hydroxyl with TsCl, and then performing cyclization under strong base to obtain a compound 2; meanwhile, performing acetyl protection on amide of the compound 3 to obtain a compound 4, and then performing LDA and TMSCl to obtain a compound 5; the compound 2 and a compound 5 are subjected to ring opening under the action of a Lewis acid catalyst to obtain a compound 6, and finally, a target compound 7 is obtained through hydrogen extraction and methyl on NaHMDS. The preparation method has the advantages that the raw materials are easy to obtain, expensive catalysts or ligands are not needed, the operation is simple, and the preparation method is more suitable for industrialization.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a method for preparing an intermediate for treating heart failure (sacubitril-valsartan sodium). Background Art

[0002] Sacubitril is a prodrug of the enkephalinase inhibitor AHU377. Its English name is Sacubitril, and its full Chinese name is 4-(((2R,4S)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid. Sacubitril is an important intermediate of sacubitril-valsartan sodium (LCZ 696). LCZ696 is a compound preparation LCZ696 (Entresto) obtained by mixing the prodrug of the enkephalinase inhibitor AHU377 and the angiotensin II (ANGⅡ) receptor antagonist valsartan in sodium hydroxide and co-crystallizing them. LCZ696 was developed by Novartis and approved by the FDA in July 2015. LCZ696 is used for patients with heart failure with reduced ejection fraction to reduce the risk of death due to cardiovascular disease or heart failure. Its high safety and significant clinical performance have made it one of the most important drugs for cardiac treatment in the past decade. Sacubitril accounts for the main cost of LCZ696 and is also a key intermediate, so the synthesis method of sacubitril is particularly important.

[0003] There are many methods for preparing Shakubiqu and its intermediates. The first patent WO2015 / 154673 discloses and documents [Journal of Medicinal Chemistry, 1995, vol.38, #10, p.1689-1700] report the total synthesis of Shakubiqu, using Boc-D-tyrosine methyl ester as a raw material, first with Tf2O to protect the phenolic hydroxyl group, with boric acid Suzuki coupling, then with N, O-dimethylhydroxylamine to form Weinreb amide, reduced to aldehyde group by lithium aluminum tetrahydride, then with ethoxyformyl ethylidene triphenylphosphine to react with Wittig, then Pd / C catalytic hydrogenation addition, then hydrochloric acid deprotection of Boc, and finally with succinic anhydride under the action of triethylamine to obtain Shakubiqu. In this method, another enantiomer appears during Pd / C catalytic hydrogenation addition, and SFC is required for separation, and the yield is low. When Pd catalyst is used, the product Pd has more or less residue, which has an impact on the drug. In addition, the reaction route uses lithium aluminum tetrahydride, which is easily explosive, which is very dangerous and not suitable for large-scale production. The reaction route is shown as follows:

[0004]

[0005] The second method: The literature [Organic Letters, 2015, vol. 17, # 21, p. 5436-5439] reported a synthetic route for the key intermediate (2R, 4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride, with a total yield of up to 52.7%. This route uses 4-iodobiphenyl as a raw material, firstly, it is ligated twice to obtain (4-biphenyl) acetaldehyde, then reacts with S-tert-butylsulfenamide to form a Schiff base, then reacts with tert-butyl 2-(bromomethyl)prop-2-enoate to form (4R)-5-(4-biphenyl)-4-[(S)-tert-butylsulfenylamino]-2-methylenepentanoic acid ethyl ester, then asymmetric hydrogenation, and finally thionyl chloride and ethanol to form an ester. This route uses a variety of Pd catalysts, which greatly increases the cost, and the most critical asymmetric hydrogenation uses (-)-2,3-bis[(2R,5R)-2,5-dimethylphosphino]maleic anhydride (1,5-cyclooctadiene) tetrafluoroborate rhodium (I) catalyst, which is not easy to purchase and is expensive. The reaction route is shown as follows:

[0006]

[0007] The third type: Patent WO2016 / 135751, 2016 discloses the use of D-4-bromophenylalanine as a raw material, firstly Boc protection of the amino group, then reduction of the carboxylic acid, then oxidation to aldehyde with sodium hypobromite under TEMPO catalysis, then Wittig reaction with ethoxyformylethyltriphenylphosphine, then lithium hydroxide hydrolysis of the ester to carboxylic acid, then asymmetric hydrogenation with diiodo(p-cymene)ruthenium(II) dimer and (α,α)2,2'-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1'-bis-[di(3,5-dimethyl-4-methoxyphenyl)-phosphino]ferrocene, followed by coupling with phenylboronic acid, and finally esterification with thionyl chloride and ethanol to prepare the key intermediate (2R,4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride. This method is similar to the first method. Asymmetric hydrogenation gives a higher yield, but the ruthenium catalyst and ligand are expensive and difficult to purchase. The reaction route is shown below:

[0008]

[0009] It can be seen that most existing routes use asymmetric hydrogenation reactions to obtain chiral methyl groups. The catalysts required for this method are not easy to purchase and are expensive, which is not conducive to large-scale production. Summary of the invention

[0010] In order to overcome the above technical defects, the purpose of the present invention is to disclose a method for preparing a sacubitril intermediate with readily available raw materials, improved quality, economical and environmentally friendly, safe and feasible, so as to overcome the defects of the prior art. The present invention adopts different routes to circumvent the above problem of low selectivity for introducing chiral methyl groups, while avoiding the use of heavy metal catalysts, reducing costs, and being more in line with industrial-scale production, thereby meeting the growing demand.

[0011] The method for preparing a sacubitril intermediate of the present invention comprises the following steps:

[0012]

[0013] The first step: Compound 1 reacts with p-toluenesulfonyl chloride in an organic solvent in the presence of an acid-binding agent, followed by the addition of tetrabutylammonium fluoride and a strong base to close the ring to obtain compound 2;

[0014] Step 2: Compound 3, DMAP and acetic anhydride were used to protect the acetyl group to obtain compound 4;

[0015] Step 3: Compound 4 is deprotonated by LDA at ultra-low temperature, and then reacted with trimethylsilyl chloride to obtain compound 5;

[0016] Step 4: Compound 2 and compound 5 undergo a ring-opening reaction under the catalysis of tri(pentafluorophenyl)borane to obtain compound 6;

[0017] Step 5: Compound 6 was deprotonated in the presence of NaHMDS, and then reacted with iodomethane to obtain a crude product, which was recrystallized to obtain compound 7.

[0018] Furthermore, in the first step of the above technical solution, the organic solvent is selected from dichloromethane or 1,2-dichloroethane; and the acid binding agent is selected from triethylamine or N,N-diisopropylethylamine.

[0019] Furthermore, in the first step of the above technical solution, the strong base is selected from NaOH or 60% NaH.

[0020] Furthermore, in the first step of the above technical scheme, the molar ratio of compound 1, p-toluenesulfonyl chloride, acid binding agent and strong base is 1:1.15-1.20:1.8-2.0:1.5-2.0.

[0021] Furthermore, in the second step of the above technical solution, the molar ratio of compound 2, DMAP and acetic anhydride is 1:0.01:1.3-1.5.

[0022] Furthermore, in the third step of the above technical solution, the molar ratio of compound 4, LDA and TMSCl is 1:1.15-1.20:1.20-1.25.

[0023] Furthermore, in the fourth step of the above technical solution, the molar ratio of compound 2, compound 5 and tri(pentafluorophenyl)borane is 1:1.01-1.04:0.01-0.05.

[0024] Furthermore, in the fifth step of the above technical solution, the molar ratio of compound 6, NaHMDS and methyl iodide is 1:1.20-1.25:1.30-1.35.

[0025] Further, in the preferred technical solution, the typical operation steps of each reaction in the present invention are as follows:

[0026] The first step is as follows: under nitrogen protection, compound 1, p-toluenesulfonyl chloride and dichloromethane are mixed, a catalyst is added, the temperature is lowered to 15°C, an acid binding agent is added dropwise, water is added to quench, the organic phase is allowed to stand and the pH is adjusted to 4-5 with dilute hydrochloric acid, concentrated until liquid does not flow, heptane is added to replace, and then THF is added, the temperature is lowered to 5°C, a strong base is added in batches, and then the temperature is raised to 40°C for reaction for 6-13 hours. After cooling, dilute hydrochloric acid is added to quench, ethyl acetate is added to extract, the organic phase is washed with saturated sodium chloride, the organic phase is concentrated under reduced pressure, n-heptane is added to precipitate a white solid, filtered, and dried to obtain compound 2.

[0027] The specific operation steps of the second step are as follows: Compound 3, DMAP, acetic anhydride and DCM are mixed, cooled to 0-5°C, triethylamine is added dropwise, the temperature is slowly raised to room temperature for reaction for 6 hours, water, dilute hydrochloric acid and sodium bicarbonate aqueous solution are added to wash the organic phase, the organic phase is concentrated under reduced pressure, n-heptane is added for pulping, filtered, and dried to obtain compound 4.

[0028] The specific operation steps of the third step are as follows: Compound 4 and THF are mixed, cooled to -80°C, LDA is added dropwise, followed by trimethylsilyl chloride, the temperature is slowly raised to -10°C, ammonium chloride is added dropwise to quench, extracted with ethyl acetate, washed with saturated sodium chloride, the organic phase is dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain compound 5 for use in the next step.

[0029] Specific operation steps of the fourth step: under nitrogen protection, compound 2 and compound 5 are dissolved in dichloromethane, tri(pentafluorophenyl)borane is added as a catalyst, the reaction is carried out at 35-40°C overnight, the reaction is concentrated under reduced pressure, and IPE is added for pulping to obtain compound 6.

[0030] Specific operation steps of the fifth step: under nitrogen protection, compound 6 is mixed with tetrahydrofuran, cooled to -90°C, 1.2eq of 1.9M NaHMDS is added dropwise, followed by 1.3eq of iodomethane, reacted at this temperature for 2 hours, slowly heated to -40°C, saturated aqueous ammonium chloride solution is added to adjust the pH to <9.5 to prevent hydrolysis, allowed to stand and stratify, isopropyl acetate is added to the aqueous phase for extraction, the organic phases are combined, washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, the filtrate is concentrated under reduced pressure, isopropyl acetate and n-heptane are added for recrystallization to obtain compound 7.

[0031] Compared with the existing technology, this technology has the following advantages: the raw materials are easily available, no expensive catalysts or ligands are required, the operation is simple, the steps are relatively short, and it is more suitable for industrialization. DETAILED DESCRIPTION

[0032] Example 1

[0033]

[0034] Under nitrogen protection, compound 1 (98.2 g, 0.3 mol), p-toluenesulfonyl chloride (65.8 g, 0.345 mol), and 1000 L of dichloromethane were added to a four-necked flask. After stirring to dissolve, DMAP (0.4 g) was added, the temperature was lowered to 15°C, and triethylamine (54.6 g, 0.54 mol) was slowly added dropwise. After the addition was completed, the temperature was slowly raised to room temperature for reaction for 3 hours, 1 L of water was added to quench, and the organic phase was allowed to stand for stratification. The pH value of the organic phase was adjusted to 4-5 with 1% dilute hydrochloric acid, and the organic phase was separated. The organic phase was washed with water and saturated brine, and the organic phase was concentrated until it did not flow, and heptane was added for 5 min. 00mL of water was replaced, and then THF (800mL) was added and transferred to a four-necked bottle. After stirring to dissolve, the temperature was lowered to 5°C, and 60% NaH (18 g, 0.45 mol) was added in batches. The temperature was then raised to 40°C for reaction for 6 hours. After cooling, dilute hydrochloric acid was added to quench and the pH was adjusted to 4-5. 1L of ethyl acetate was added for extraction, and the organic phase was washed with saturated sodium chloride. The organic phase was concentrated under reduced pressure, and a mixed solvent of n-heptane and MTBE (5 / 1) was added to slurry to precipitate a white solid, which was filtered and dried to obtain 84.4g of compound 2, HPLC 97.8%, and a yield of 80.9%. 1 H NMR (400MHz, DMSO-d6): 7.64-7.38(m,9H),3.05-3.99(m,1H),2.78-2.68(m,2H),2.35-2.13(m,2H),1.40(s,9H).

[0035] Example 2

[0036]

[0037] Under nitrogen protection, compound 1 (98.2 g, 0.3 mol), p-toluenesulfonyl chloride (68.6 g, 0.36 mol), and 1000 L of dichloromethane were added to a four-necked bottle, stirred and dissolved, and DABCO (0.4 g) was added. The temperature was lowered to 15°C, and N,N-diisopropylethylamine (77.5 g, 0.6 mol) was slowly added dropwise. After the addition was completed, the temperature was slowly raised to room temperature for 4 hours, and 1 L of water was added to quench. The organic phase was allowed to stand and the pH was adjusted to 4-5 with dilute hydrochloric acid, and concentrated until no liquid flowed. Heptane was added for replacement, THF (800 mL) was added and transferred to a four-necked bottle, and after stirring to dissolve, the temperature was lowered to 5°C, NaOH (24 g, 0.6 mol) was added in batches, and then the temperature was raised to 40°C for reaction for 13 hours. After cooling, dilute hydrochloric acid was added to quench and the pH was adjusted to 4-5, 1 L of ethyl acetate was added for extraction, the organic phase was washed with saturated sodium chloride, the organic phase was concentrated under reduced pressure, and a mixed solvent of n-heptane and MTBE (5 / 1) was added to slurry to precipitate a white solid, which was filtered and dried to obtain 79.4 g of compound 2, HPLC 98.2%, yield 75.6%.

[0038] Example 3

[0039]

[0040] Compound 3 (53.2 g, 0.3 mol), DMAP (1.8 g, 0.015 mol), acetic anhydride (45.9 g, 0.45 mol) and DCM (500 mL) were added into a four-necked bottle, cooled to 0-5°C, triethylamine (45.5 g, 0.45 mol) was added dropwise, and the temperature was slowly raised to room temperature for 6 hours. The organic phase was washed with water, dilute hydrochloric acid and sodium bicarbonate aqueous solution, respectively, and the organic phase was concentrated under reduced pressure, added with n-heptane for pulping, filtered, and dried to obtain 59.7 g of compound 4. HPLC 99.6%, yield 90.8%. 1 H NMR (400MHz, DMSO-d6): 7.37-7.31(m,2H),7.31-7.27(m,1H),7.23-7.19(m,2H) ,4.71-4.63(m,1H),4.23-4.15(m,2H),3.30(dd,1H),2.76(dd,1H),2.56(s,3H).

[0041] Example 4

[0042]

[0043] Compound 4 (57 g, 0.26 mol) and THF (600 mL) were added into a four-necked bottle, cooled to -80°C, 2 mol / LLDA (156 mL) was added dropwise, reacted for half an hour after the addition, then trimethylsilyl chloride (35.3 g, 0.325 mol) was added dropwise, the temperature was slowly raised to -10°C, ammonium chloride was added dropwise to quench, extracted with ethyl acetate, washed with saturated sodium chloride, the organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 70.7 g of compound 5. HPLC 94.3%, yield 93.3%. 1 H NMR (400MHz, DMSO-d6): 7.34-7.29(m,2H),7.28-7.24(m,1H),7.22-7.18(m,2H),4.78- 4.72(m,1H),4.42-4.17(m,2H),3.66(s,2H),3.10(dd,1H),2.89(dd,1H),0.31(s,9H).

[0044] Example 5

[0045]

[0046] Under nitrogen protection, compound 2 (61.9 g, 0.2 mol), compound 5 (58.5 g, 0.2 mol) and 1200 mL of dichloromethane were added into a four-necked flask, tri(pentafluorophenyl)borane (3.0 g, 0.006 mol) was added, the temperature was raised to 35-40 °C and the reaction was carried out overnight, the dichloromethane was concentrated under reduced pressure, and 430 mL of isopropyl ether was added for slurrying to obtain 93.8 g of compound 6, HPLC 98.7%, yield 88.7%. 1 H NMR (400MHz, DMSO-d6): 7.85-7.20(m,15H),4.74-4.70(m,1H),4.40(dd,1H),4.2 0(dd,1H),4.01-3.97(m,1H),2.92-2.56(m,6H),1.89-1.82(m,2H),1.39(s,9H).

[0047] Example 6

[0048]

[0049] Compound 6 (52.9 g, 0.1 mol) and tetrahydrofuran (530 mL) were added into a four-necked bottle, and the temperature was lowered to -90°C under nitrogen protection. 1.9 mol / L NaHMDS (63.2 mL) was added dropwise, followed by iodomethane (18.5 g, 0.13 mol). The reaction was carried out at this temperature for 2 hours, and the temperature was slowly raised to -40°C. A saturated aqueous solution of ammonium chloride was added to adjust the pH to <9 to prevent hydrolysis. The mixture was allowed to stand for stratification. Isopropyl acetate was added to the aqueous phase for extraction. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Isopropyl acetate and n-heptane (1 / 3) were added for recrystallization to obtain 43.7 g of compound 7, HPLC 99.4%, yield 80.5%. 1 HNMR (400MHz, DMSO-d6): 7.83-7.19(m,15H),4.78-4.74(m,1H),4.55-4.51(m,1H),4.20-4.16(m,2H), 3.47(dd,1H),2.97-2.92(m,2H),2.66-2.60(m,2H),1.60-1.54(m,1H),1.38(s,9H),1.14-1.08(m,2H).

[0050] The embodiments described above are only preferred embodiments of the present invention and are not intended to limit the concept and scope of the present invention. Although the present invention describes the embodiments in detail, within the spirit and principles of the present invention, various changes, improvements and equivalent substitutions of the technical solutions recorded in the aforementioned embodiments are all within the protection scope of the present invention.

Claims

1. A method for preparing a sacubitril intermediate, characterized in that: The steps include: The first step: Compound 1 reacts with p-toluenesulfonyl chloride in an organic solvent in the presence of an acid-binding agent, followed by the addition of tetrabutylammonium fluoride and a strong base to close the ring to obtain compound 2; Step 2: Compound 3, DMAP and acetic anhydride were used to protect the acetyl group to obtain compound 4; Step 3: Compound 4 is deprotonated by LDA at ultra-low temperature, and then reacted with trimethylsilyl chloride to obtain compound 5; Step 4: Compound 2 and compound 5 undergo a ring-opening reaction under the catalysis of tri(pentafluorophenyl)borane to obtain compound 6; Step 5: Compound 6 was deprotonated in the presence of NaHMDS, and then reacted with iodomethane to obtain a crude product, which was recrystallized to obtain compound 7.

2. The method for preparing the sacubitril intermediate according to claim 1, characterized in that: In the first step, the organic solvent is selected from dichloromethane or 1,2-dichloroethane; and the acid binding agent is selected from triethylamine or N,N-diisopropylethylamine.

3. The method for preparing the sacubitril intermediate according to claim 1, characterized in that: In the first step, the strong base is selected from 60% NaH or NaOH.

4. The method for preparing the sacubitril intermediate according to claim 1, characterized in that: In the first step, the molar ratio of compound 1, p-toluenesulfonyl chloride, acid-binding agent and strong base is 1:1.15-1.20:1.8-2.0:1.5-2.

0.

5. The method for preparing the sacubitril intermediate according to claim 1, characterized in that: In the second step, the molar ratio of compound 2, DMAP and acetic anhydride is 1:0.01:1.3-1.

5.

6. The method for preparing the sacubitril intermediate according to claim 1, characterized in that: In the third step, the molar ratio of compound 4, LDA and TMSCl is 1:1.15-1.20:1.20-1.

25.

7. The method for preparing the sacubitril intermediate according to claim 1, characterized in that: In the fourth step, the molar ratio of compound 2, compound 5 and tri(pentafluorophenyl)borane is 1:1.01-1.04:0.01-0.

05.

8. The method for preparing the sacubitril intermediate according to claim 1, characterized in that: In the fifth step, the molar ratio of compound 6, NaHMDS and methyl iodide is 1:1.20-1.25:1.30-1.35.

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