Process for the preparation of a saperconazole intermediate

Abstract

This invention provides a method for preparing a sacubitril intermediate. Step 1 utilizes inexpensive and readily available biphenylaldehyde and hydantoin as starting materials, undergoing alkali-catalyzed condensation. After the reaction, the product is obtained by cooling and filtration, resulting in high conversion and simple post-processing. Step 2 uses chiral monodentate phosphine as a ligand, and performs asymmetric catalytic hydrogenation to achieve 100% chiral purity with an ee value. The preparation method provided by this invention is concise, exhibits good stereoselectivity, and improves reaction yield. The intermediate obtained during the reaction is easy to separate and purify, significantly reducing the cost of current synthetic methods and possessing practical industrial application prospects.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis, specifically to a method for preparing sacubitril intermediate (R)-tert-butyl(1-((1,1'-biphenyl)-4-yl)-3-hydroxypropane-2-yl)carbamate. Background Technology

[0002] LCZ696, developed by Novartis, is a dual-action angiotensin receptor neprilysin inhibitor. It was approved by the FDA on July 7, 2015, for the treatment of heart failure with reduced ejection fraction. LCZ696 is a complex of sacubitril (AHU-377) and valsartan (Diovan), with a unique mode of action believed to reduce strain on a failing heart. Sacubitril blocks the action of the two peptides responsible for lowering blood pressure, while valsartan improves vasodilation and stimulates the excretion of sodium and water. Cardiovascular drugs have extremely high safety thresholds, and LCZ696 has demonstrated even greater safety than conventional drugs. The industry considers LCZ696's outstanding performance to be one of the most important advances in cardiology over the past decade. Furthermore, in the coming years, no other cardiovascular drug will be able to compete with LCZ696, thus its market prospects are vast.

[0003] Sacubitril's chemical name is 4-((2S,3R)-1-(1,1'-biphenyl-4-yl)-5-ethoxy-4-methyl-5-oxopentane-2-yl)amino)-4-oxobutyric acid, and its structural formula is shown in Formula I. (R)-tert-butyl(1-((1,1'-biphenyl)-4-yl)-3-hydroxypropane-2-yl)carbamate is a key intermediate in the synthesis of sacubitril, and its structure is shown in Formula II.

[0004]

[0005] The literature (J. Med. Chem., 1995, 38, 1689-1700) reports a method for preparing this compound, and the specific preparation method related to this invention is as follows:

[0006]

[0007] The raw material D-tyrosine for this route is a non-natural amino acid and is relatively expensive; the reaction process uses trifluoromethanesulfonic anhydride, which is not only expensive but also highly corrosive and requires high production operation standards; the Suzuki coupling reaction step requires an expensive palladium catalyst.

[0008] Patent WO2014032627 discloses a method for preparing a sacubitril intermediate, the specific synthetic route of which is as follows:

[0009]

[0010] This route introduces a chiral center through a chiral source. Although the route is relatively short, the Grignard reaction initiation is difficult to control, and post-processing is complex. The Mitsunobu reaction uses triphenylphosphine, and its byproduct, triphenylphosphine oxide, is not easily removed completely. Dialkyl azodicarbonate esters are sensitive to light, heat, and vibration, posing certain safety risks.

[0011] Patent WO2010081410 discloses a method for preparing a sacubitril intermediate (2), the specific synthetic route of which is as follows:

[0012]

[0013] This route uses a traditional splitting method, resulting in a lengthy route, low yield, and weak competitiveness.

[0014] Patent WO2013026773 discloses a method for preparing a sacubitril intermediate (2), the specific synthetic route of which is as follows:

[0015]

[0016] This route uses 4-biphenylaldehyde and hippuric acid as starting materials and obtains compound 2 through multiple conversions. The reduction of ester groups and benzamides requires a large amount of lithium aluminum hydride, which is not only expensive but also poses significant safety risks. This results in high synthesis costs for compound 2 and harsh reaction conditions, making it difficult to achieve industrialization.

[0017] Analysis of the synthetic routes for preparing sacubitril intermediates reported in the aforementioned literature reveals three main methods based on their different construction methods of the chiral center. The first method utilizes a chiral source for introduction. The second method employs a traditional resolution method. The third method involves reduction via a chiral catalyst. The intermediates used directly in these preparation processes are often difficult to obtain, require large quantities of auxiliary reagents, or involve cumbersome routes, making it unfavorable for the economical preparation of the sacubitril intermediate (R)-tert-butyl(1-((1,1'-biphenyl)-4-yl)-3-hydroxypropane-2-yl)carbamate. Summary of the Invention

[0018] To address the shortcomings of existing technologies in preparing the sacubitril intermediate (R)-tert-butyl(1-((1,1'-biphenyl)-4-yl)-3-hydroxypropane-2-yl)carbamate, which are characterized by complex processes, high costs, and limited yields and purity, this invention proposes a novel method for preparing this intermediate using 4-biphenylaldehyde as a raw material. This method utilizes inexpensive and readily available raw and auxiliary materials, exhibits good stereoselectivity, high yield, low cost, and is environmentally friendly.

[0019] To achieve the above-mentioned technical objectives, the technical solution adopted by the present invention is as follows:

[0020] A method for preparing a sacubitril intermediate, the synthetic route is as follows:

[0021]

[0022] Furthermore, the method for preparing the sacubitril intermediate includes the following steps:

[0023] (1) 4-Biphenylcarboxaldehyde and hydantoin undergo a condensation reaction under the catalysis of an organic base to obtain compound 4;

[0024] (2) Compound 4 undergoes an asymmetric catalytic hydrogenation reaction under a hydrogen atmosphere in the presence of a catalyst and a chiral ligand to obtain stereospecific compound 5.

[0025] (3) Hydrolysis of compound 5 yields amino acid compound 6;

[0026] (4) Compound 6 undergoes catalytic hydrogenation reduction of the carboxyl group under the action of a catalyst to obtain amino alcohol compound 7;

[0027] (5) Compound 7 was protected with tert-butoxycarbonyl to obtain target compound 2.

[0028] Further, in step (1), the reaction solvent is one or more of methanol, ethanol, isopropanol, and n-butanol, preferably isopropanol; the reaction temperature is the solvent reflux temperature; the organic base is one or more of triethylamine, diisopropylethylamine, pyridine, piperidine, 4-dimethylaminopyridine, tetramethylethylenediamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene, preferably pyridine;

[0029] Further, in step (1), the molar ratio of 4-biphenylaldehyde, hydantoin and organic base is 1:1-2:0.1-0.5, preferably 1:1.2-1.5:0.2-0.3.

[0030] Further, in step (2), the reaction solvent is one or more of dichloromethane, methanol, ethanol, isopropanol, tetrahydrofuran, methyltetrahydrofuran, and dioxane, preferably tetrahydrofuran; the catalyst is a rhodium catalyst, specifically selected from one or more of [Rh(COD)Cl]2, [Rh(NBD)Cl]2, Rh(COD)2BF4, and Rh(NBD)2BF4; the chiral ligand is a monodentate phosphine ligand; the molar ratio of compound 4, catalyst (based on Rh) and ligand is 1:0.00001-0.0001:0.00002-0.0002:, preferably 1:0.00002-0.00005:0.00004-0.0001.

[0031] Furthermore, the monodentate phosphine ligand has the structure shown in formula (III):

[0032]

[0033] Wherein, R1 and R2 are independently alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, aralkyl, or substituted aralkyl. Preferably, R1 and R2 are independently at least one of methyl, ethyl, propyl, or butyl.

[0034] In a preferred embodiment of the present invention, the catalyst is Rh(NBD)₂BF₄, and the monodentate phosphine ligand is a compound of formula (III) in which both R1 and R2 are methyl groups. The inventors unexpectedly discovered that among many Rh-based catalysts, only Rh(COD)₂BF₄, as a catalyst, and the ligand shown in formula (III) can achieve the best stereoselectivity and yield.

[0035] Further, in step (2), the hydrogen pressure is 1-6 MPa, preferably 3-4 MPa; the reaction temperature is 25-100℃, preferably 50-70℃; the ee value of the product compound 5 obtained in step (2) is ≥99.5%, preferably ≥99.8%, preferably ≥99.9%, and preferably 100%.

[0036] Further, in step (3), the hydrolysis is carried out in the presence of an inorganic acid or an inorganic base, and the reaction solvent is one or more of ethanol, isopropanol, glacial acetic acid, and purified water, preferably glacial acetic acid; the reaction temperature is the solvent reflux temperature; the inorganic acid is one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, preferably sulfuric acid; the inorganic base is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, and barium hydroxide, preferably sodium hydroxide.

[0037] Further, in step (3), hydrolysis is preferably carried out in the presence of inorganic acid with glacial acetic acid as solvent; the ratio of compound 5, glacial acetic acid and inorganic acid is 1g:5-15mL:10-50mL; preferably 1g:10-12mL:20-40mL.

[0038] Further, in step (4), compound 6 is not purified and is directly subjected to catalytic hydrogenation to reduce the carboxyl group under the action of a catalyst, wherein the catalyst is one or more of ruthenium carbon, palladium carbon, and platinum carbon, preferably ruthenium carbon; the mass ratio of compound 6 to catalyst is 1:0.05-0.2, preferably 1:0.1-0.5; the hydrogen pressure is 6-12 MPa, preferably 8-10 MPa, and the reaction temperature is 80-120℃, preferably 100-110℃.

[0039] The reaction conditions for the tert-butyloxycarbonyl protection in step (5) are well known in the art.

[0040] The beneficial effects of this invention are:

[0041] (1) Step 1 of the method of the present invention uses inexpensive and readily available biphenylaldehyde and hydantoin as starting materials. After alkaline catalytic condensation, the product is obtained by cooling and filtration after the reaction. The conversion rate is high and the post-processing is simple. However, the method of the reference patent JP2007217402, under the conditions of ammonium acetate and glacial acetic acid, has a momentary solidification phenomenon in the reaction process, which makes stirring difficult and uneven, the raw materials are difficult to convert completely, the post-processing is complicated, and the yield is low.

[0042] (2) In step 2 of the method of the present invention, chiral monodentate phosphine is used as a ligand, and asymmetric catalytic hydrogenation is performed to achieve a chiral purity of 100% with an ee value. Chinese patent CN105884692A discloses asymmetric catalytic hydrogenation of a metal complex of chiral bisphosphine ligand as a catalyst to obtain 5-substituted chiral hydantoin. The ee value obtained by this method is only 45-90%, with poor selectivity, and no product purification method is reported, which is difficult to meet the current market demand.

[0043] (3) The method of the present invention utilizes a one-pot catalytic hydrogenation of amino acids with a metal catalyst to obtain chiral amino alcohols, without the need for chemical reducing agents, which greatly reduces the amount of waste emissions and makes the production process green and environmentally friendly.

[0044] (4) The preparation method provided by this invention has a short procedure, good stereoselectivity, and improved reaction yield. The intermediates obtained during the reaction are easy to separate and purify, which significantly reduces the cost of current synthesis methods and has practical industrial application prospects. Attached Figure Description

[0045] Figure 1 The graph shows the ee values ​​of the racemic mixture of compound 5.

[0046] Figure 2 This is a graph showing the ee values ​​of compound 5 in Example 2. Detailed Implementation

[0047] The present invention will be further described below with reference to specific embodiments, but is not limited to the specific embodiments.

[0048] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0049] Example 1: Preparation of Compound 4

[0050]

[0051] 2000 mL of isopropanol, 182.2 g (1.0 mol) of 4-biphenylaldehyde, and hydantoin (151.2 g, 1.5 mol) were added to a 5000 mL three-necked flask, followed by the addition of pyridine (23.7 g, 0.3 mol). The mixture was heated to reflux and stirred while maintaining the temperature. The reaction was monitored by LC-MS until complete. After cooling to room temperature, a large amount of solid precipitated. The mixture was filtered, and the filtrate could be directly reused for the next batch of reaction. The filter cake was washed with a small amount of isopropanol and dried under vacuum at 60 °C to obtain a yellow solid powder of compound 4 (250.3 g, 94.7%). HNMR(600MHz,DMSO-d6)δppm 11.24(br,1H),10.60(br,1H),7.71-7.67(m,6H),7.46-7.44(m,2H),7.37-7.34(m,1H),6.44(s,1H); LC-MS(EI):

[0052] [MH] - =263.06.

[0053] Example 2: Preparation of Compound 5

[0054]

[0055] Add 50 mL of tetrahydrofuran to a 100 mL three-necked flask, then add 0.82 mg of monodentate phosphine ligand (R1 = R2 = Me).

[0056] 0.0023 mmol) was transferred to a glove box and purged with nitrogen three times. Under nitrogen atmosphere, catalyst Rh(COD)2BF4 (0.47 mg, 0.0012 mmol) was added, the three-way valve was closed, and stirring was continued for 30 minutes under nitrogen protection.

[0057] 250 mL of tetrahydrofuran was added to a 1000 mL hydrogenation reactor, followed by compound 4 (15.0 g, 56.76 mmol). The mixture was stirred until dissolved, and the reactor was sealed. The reactor was then purged three times under nitrogen-vacuum conditions. While maintaining a vacuum in the autoclave, the ligand-catalyst system was evacuated into the reactor. The reactor was purged three times with hydrogen, maintaining a hydrogen pressure of 3.5–4.0 MPa. The temperature was raised to 60 °C, and the reaction was maintained with stirring. LC-MS was used to monitor the reaction until complete. The reactor was cooled to room temperature, purged three times with nitrogen, filtered, and the filtrate was concentrated under reduced pressure to obtain a gray solid, compound 5 (15.0 g, 99.2%). The ee value was 100%. HNMR(600MHz,DMSO-d6)δppm10.45(br,1H),7.94(br,1H),7.64-7.62(m,2H),7.58-7.56(m,2H),7.44-7.4 1(m,2H),7.34-7.31(m,1H),7.27-7.26(m,2H),4.35(t,J=5.04Hz,1H),2.99-2.92(m,2H); LC-MS(EI):[MH] - =265.10.

[0058] Example 3: Preparation of Compound 6

[0059]

[0060] Add 100 mL of glacial acetic acid, compound 5 (10.0 g, 37.55 mmol), and concentrated hydrochloric acid (40 mL) to a 500 mL three-necked flask. Heat to reflux and stir while maintaining the temperature. Monitor the reaction by TLC until the starting material has completely reacted. Stop heating, cool to room temperature, and use directly for the next reaction.

[0061] Example 4: Preparation of Compound 7

[0062]

[0063] The reaction solution of compound 6 was added to a 500 mL tetrafluoroethylene-lined hydrogenation reactor, along with 5% ruthenium-carbon catalyst (1.0 g). The reactor was sealed, and the mixture was purged three times with nitrogen and three times with hydrogen, maintaining a hydrogen pressure of 8.0 MPa. The temperature was raised to 100 °C, and the reaction was stirred while maintaining the temperature. TLC monitoring was performed until the reaction was complete. The reactor was cooled to room temperature, purged three times with nitrogen, filtered, and the filtrate was concentrated under reduced pressure to obtain a gray solid. Recrystallization from ethanol and water yielded a white solid, compound 7 (7.3 g, 85.3%). HNMR(600MHz,DMSO-d6)δppm 7.63-7.58(m,4H),7.44-7.41(m,2H),7.34-7.31(m,2H),3.49(dd,J=11.5,3.6Hz,1H),3.37(dd,J=11.5,6. 0Hz, 1H), 3.25-3.21 (m, 1H), 2.91 (dd, J=13.5, 5.5Hz, 1H), 2.82 (dd, J=13.4, 8.8Hz,, 1H); LC-MS (EI): [M+H] + =228.24.

[0064] Example 5: Preparation of Compound 2

[0065]

[0066] In a 250 mL three-necked flask, add 70 mL of ethanol and 30 mL of water, then add compound 7 (10.0 g, 44.00 g).

[0067] The system was heated to 45–50 °C and stirred for 30 min. Di-tert-butyl dicarbonate (11 g, 46.19 mmol) and 30% sodium hydroxide solution were added dropwise under controlled temperature, maintaining the pH at 9–10. After the addition was complete, the mixture was kept at this temperature and stirred for 3 hours. Ethanol was recovered under reduced pressure, cooled to room temperature, and filtered to obtain a white solid compound of formula 2 (13.17 g, 91.4%). HNMR(600MHz,CDCl3)δppm 7.57(d,J=7.3Hz,2H),7.53(d,J=8.0Hz,2H),7.43(t,J=7.6Hz,2H),7.33(t,J=7.3Hz,1H),7.28(d,J=8.0Hz,2H),4.76(s,1H),3.91(s,1H ),3.70(dd,J=10.7,2.7Hz,,1H),3.60(dd,J=10.7,5.0Hz,,1H),2.88(d,J=6.8Hz,2H),2.30(br,1H),1.42(s,9H); LC-MS(EI):[M-Boc+H] + =228.32.

[0068] Example 6

[0069] Other conditions and procedures were the same as in Example 2, except that the catalyst was replaced with 0.006 mmol of [Rh(COD)Cl]2. Compound 5 had an ee value of 99.3% and a yield of 97.6%.

[0070] Example 7

[0071] Other conditions and procedures were the same as in Example 2, except that the catalyst was replaced with 0.006 mmol of [Rh(BND)Cl]2. Compound 5 had an ee value of 99.5% and a yield of 98.0%.

[0072] Example 8

[0073] Other conditions and procedures were the same as in Example 2, except that the catalyst was replaced with 0.012 mmol of Rh(NBD)₂BF₄. Compound 5 had an ee value of 99.2% and a yield of 98.5%.

Claims

1. A method for preparing a sacubitril intermediate, characterized in that, The synthesis route is as follows: ； The preparation method includes the following steps: (1) 4-Biphenylcarboxaldehyde and hydantoin undergo a condensation reaction under the catalysis of an organic base to obtain compound 4; (2) Compound 4 undergoes an asymmetric catalytic hydrogenation reaction under a hydrogen atmosphere in the presence of a catalyst and a chiral ligand to yield a stereospecific compound 5; the catalyst is Rh(COD)2BF4; the chiral ligand is a monodentate phosphine ligand with the structure shown in formula (III) below: (III) R1 and R2 are both methyl groups; the molar ratio of compound 4, catalyst, and ligand is 1:0.00001-0.0001:0.00002-0.0002; (3) Compound 5 is hydrolyzed to give amino acid compound 6; (4) Compound 6 undergoes catalytic hydrogenation reduction of the carboxyl group under the action of a catalyst to obtain amino alcohol compound 7; (5) Compound 7 was protected with tert-butyloxycarbonyl to obtain target compound 2.

2. The preparation method according to claim 1, characterized in that, In step (1), the reaction solvent is one or more of methanol, ethanol, isopropanol, and n-butanol; the reaction temperature is the solvent reflux temperature; and the organic base is one or more of triethylamine, diisopropylethylamine, pyridine, piperidine, 4-dimethylaminopyridine, tetramethylethylenediamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene.

3. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of 4-biphenylaldehyde, hydantoin and organic base is 1:1-2:0.1-0.

5.

4. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of 4-biphenylaldehyde, hydantoin and organic base is 1:1.2-1.5:0.2-0.

3.

5. The preparation method according to claim 1, characterized in that, In step (2), the reaction solvent is one or more of dichloromethane, methanol, ethanol, isopropanol, tetrahydrofuran, methyltetrahydrofuran, and dioxane; the molar ratio of compound 4, catalyst and ligand is 1:0.00002-0.00005:0.00004-0.0001.

6. The preparation method according to claim 1, characterized in that, In step (2), the hydrogen pressure is 1-6 MPa; the reaction temperature is 25-100℃; and the ee value of the product compound 5 obtained in step (2) is ≥99.5%.

7. The preparation method according to claim 6, characterized in that, In step (2), the hydrogen pressure is 3-4 MPa and the reaction temperature is 50-70℃.

8. The preparation method according to claim 1, characterized in that, In step (3), the hydrolysis is carried out in the presence of an inorganic acid or an inorganic base, and the reaction solvent is one or more of ethanol, isopropanol, glacial acetic acid, and purified water; the reaction temperature is the solvent reflux temperature; the inorganic acid is one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; and the inorganic base is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, and barium hydroxide.

9. The preparation method according to claim 8, characterized in that, In step (3), hydrolysis is carried out in the presence of inorganic acid in glacial acetic acid as solvent; the ratio of compound 5, glacial acetic acid and inorganic acid is 1g:5-15mL:10-50mL.

10. The preparation method according to claim 9, characterized in that, The ratio of compound 5, glacial acetic acid, and inorganic acid is 1g:10-12mL:20-40mL.

11. The preparation method according to claim 1, characterized in that, In step (4), compound 6 is directly subjected to catalytic hydrogenation to reduce the carboxyl group without purification. The catalyst is one or more of ruthenium carbon, palladium carbon, and platinum carbon. The mass ratio of compound 6 to the catalyst is 1:0.05-0.

2. The hydrogen pressure is 6-12 MPa and the reaction temperature is 80-120℃.

12. The preparation method according to claim 11, characterized in that, The mass ratio of compound 6 to catalyst is 1:0.1-0.5, the hydrogen pressure is 8-10 MPa, and the reaction temperature is 100-110℃.

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