Preparation method of sacubitril valsartan key intermediate

Abstract

The invention provides a preparation method of a sacubitril valsartan key intermediate, which comprises the following steps of: reacting (R)-1-(1-([1, 1 '-biphenyl]-4-yl)-3-chloropropane-2-yl) pyrrolidine-2, 5-diketone and trialkyl phosphite under the action of a catalyst to generate a Witting-Horner reagent, then reacting with ethyl pyruvate under an alkaline condition to generate a double-bond product, and reacting with ethyl pyruvate under an alkaline condition to generate the sacubitril valsartan key intermediate. Hydrolyzing the double bond product to generate (R, E)-5-((1, 1 '-biphenyl)-4-yl)-4-amino-2-methyl-2-ethyl pentenoate; the preparation method comprises the following steps: firstly, taking 4-methyl-2-pentenoic acid as a raw material, then protecting the 4-methyl-2-pentenoic acid through BOC anhydride under the action of an acid-binding agent, and finally hydrolyzing under an alkaline condition to obtain (R, E)-5-([1, 1 '-biphenyl]-4-yl)-4-((t-butyloxycarboryl) amino)-2-methyl-2-pentenoic acid. The preparation method has the advantages of simple process steps, convenient operation, easily available raw materials, and easy industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a method for preparing a key intermediate of sacubitril / valsartan. Background Technology

[0002] (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid is a key intermediate in the preparation of sacubitril / valsartan, and its structural formula is as follows:

[0003] Currently, the synthetic routes for (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid all involve preparing aldehydes through oxidation or reduction, followed by a classic witting reaction with phosphorus ylide or sulfur ylide to generate olefins, as shown in the synthetic route reported in CN114805135A, with the following reaction equation:

[0004] Patent CN114805135A reports this route, which involves oxidation to aldehyde followed by a witting reaction to generate olefins. TEMPO is used as the oxidant in the alcohol-to-aldehyde oxidation, but TEMPO is expensive, increasing costs. CN106946742A uses sodium hypochlorite as the oxidant in the alcohol-to-aldehyde oxidation, which is particularly prone to peroxidation, limiting scale-up.

[0005] Patent CN 108299226 A reports a method for the reduction of (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid to aldehydes in the synthetic route, and the reaction equation is as follows:

[0006] This route uses a reduction to aldehyde method followed by a witting reaction to prepare an alkene. The overall process is lengthy and costly. Patent CN 106795099 A modifies other steps, but still uses a reduction to aldehyde, and suffers from the same problems: lengthy process and high cost. Summary of the Invention

[0007] To overcome the problems existing in the above-mentioned methods for synthesizing key intermediates of sacubitril / valsartan, this invention provides a novel method for preparing key intermediates of sacubitril / valsartan. This invention employs a modified version of the Witting reaction, the Witting-Horner (HWE olefination) reaction, eliminating the oxidation / reduction step to prepare aldehydes, allowing for further scale-up and cost reduction. The trialkyl phosphites and ethyl pyruvate used in this reaction route are inexpensive and readily available, further reducing costs and making it more suitable for industrial production.

[0008] The technical solution of this invention is: a method for preparing a key intermediate of sacubitril / valsartan, wherein the intermediate is (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid, and the preparation method is as follows:

[0009] 1) (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione reacts with trialkyl phosphite under the action of a catalyst to generate Witting-Horner reagent, which then reacts with ethyl pyruvate under alkaline conditions to generate a double bond product. The double bond product is hydrolyzed to generate (R,E)-5-((1,1'-biphenyl)-4-yl)-4-amino-2-methyl-2-pentenoic acid ethyl ester; 2) Ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-amino-2-methyl-2-pentenoate was protected with BOC anhydride under an acid-binding agent to obtain ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoate; 3) Ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid is hydrolyzed under alkaline conditions to give (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid.

[0010] Furthermore, in step 1), the catalyst is at least one of zinc bromide and lithium bromide; the trialkyl phosphite is at least one of trimethyl phosphite, triethyl phosphite, and triphenyl phosphite; the solvent used is at least one of dichloromethane, acetonitrile, and dioxane; and the base is at least one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.

[0011] Furthermore, in step 1), the molar ratio of (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione to trialkyl phosphite, catalyst, and ethyl pyruvate is 1:2-5:1-2:1-3; the reaction temperature for generating the Witting-Horner reagent is 30-120℃, preferably 40-100℃; and the reaction temperature with ethyl pyruvate under alkaline conditions is 20-50℃.

[0012] Furthermore, in step 2), the acid-binding agent is at least one of triethylamine and pyridine; the solvent used is at least one of dichloromethane and dichloroethane; the molar ratio of (R,E)-5-((1,1'-biphenyl)-4-yl)-4-amino-2-methyl-2-pentenoic acid ethyl ester to BOC anhydride is 1:1-2; the reaction temperature is 20-50℃, and the reaction time is 4-8h.

[0013] Furthermore, in step 3), the base used is at least one of sodium hydroxide, potassium hydroxide, and lithium hydroxide; the solvent used is at least one of water, methanol, and ethanol; the molar ratio of (R,E)-5-((1,1'-biphenyl)-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid ethyl ester to the base is 1:1-2; the reaction temperature is 20-50℃, and the reaction time is 1-3h.

[0014] Furthermore, the specific steps of the present invention are as follows: 1) Preparation of ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-amino-2-methyl-2-pentenoate (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione was dissolved in a solvent, and then a catalyst and trialkyl phosphite were added. The mixture was heated to the reaction temperature. After the reaction was completed, a base and ethyl pyruvate were added. After HPLC detection, water was added dropwise. After the reaction was completed, the mixture was allowed to stand and separated. The lower organic phase was taken out and washed with water. The organic phase was concentrated and dried under reduced pressure to obtain (R,E)-5-((1,1'-biphenyl)-4-yl)-4-amino-2-methyl-2-pentenoic acid ethyl ester. 2) Preparation of ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoate Ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-amino-2-methyl-2-pentenoate was dissolved in a solvent, an acid-binding agent was added, and then BOC anhydride was added. The reaction was carried out at 20-50℃ for 4-8 hours. After the reaction was detected to be complete, water was added, the mixture was allowed to stand and separated, the lower organic phase was taken off, washed twice with water, the organic phase was concentrated under reduced pressure, and crystallized by methanol water to obtain ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoate. 3) Preparation of (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid Ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid was dissolved in an alkaline solution and reacted at 20-50℃ for 1-3 h. After the reaction was completed, an acidic aqueous solution was added dropwise. As the addition proceeded, a solid precipitated out. After the addition was complete, the mixture was filtered and dried to obtain (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid.

[0015] The beneficial effects of this invention are: 1. The preparation of double bond products is carried out by Witting-Horner reaction, which is a one-pot hydrolysis of amino protecting groups; the present invention adopts a modified version of the Witting reaction, the Witting-Horner (HWE olefination) reaction, which eliminates the oxidation / reduction step to prepare aldehydes, and the batch can be further scaled up and the cost reduced. 2. The trialkyl phosphites and ethyl pyruvate used in this reaction route are inexpensive and readily available, further reducing costs and making them more suitable for industrial production. 3. The preparation method has simple process steps, is easy to operate, uses readily available raw materials, and is easy to industrialize. Attached Figure Description

[0016] Figure 1 HPLC chromatogram of ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoate; Figure 2 HPLC chromatogram of (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid; Figure 3 Mass spectrometry of (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid. Detailed Implementation

[0017] The effects are illustrated below with reference to the embodiments and accompanying drawings.

[0018] Example 1: Preparation of ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-amino-2-methyl-2-pentenoate

[0019] 200 g of (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione was dissolved in 1200 g of dichloromethane, then 151 g of zinc bromide and 304 g of triethyl phosphite were added, and the mixture was heated to reflux. After the reaction was completed, the mixture was cooled to room temperature, and 412 g of 28% sodium methoxide methanol solution and 85 g of ethyl pyruvate were added. The mixture was stirred for 24 h, and after HPLC analysis, water was added dropwise. After the reaction was completed, the mixture was allowed to stand and separated. The lower organic phase was taken off, washed with water, concentrated under reduced pressure, and dried to obtain 170 g of (R,E)-5-((1,1'-biphenyl)-4-yl)-4-amino-2-methyl-2-pentenoic acid ethyl ester with a purity of 99.10% and a yield of 90%.

[0020] Example 2: Preparation of ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-amino-2-methyl-2-pentenoate 200 g of (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione was dissolved in 1200 g of dichloromethane, followed by the addition of 151 g of zinc bromide and 379 g of triphenyl phosphite. The mixture was heated to reflux. After the reaction was completed, the mixture was cooled to room temperature, and 294 g of 28% sodium methoxide methanol solution and 85 g of ethyl pyruvate were added. After HPLC analysis, water was added dropwise. After the reaction was completed, the mixture was allowed to stand and separated. The lower organic phase was collected, washed with water, concentrated under reduced pressure, and dried to obtain 168 g of (R,E)-5-((1,1'-biphenyl)-4-yl)-4-amino-2-methyl-2-pentenoate ethyl ester with a purity of 98.9% and a yield of 89%.

[0021] Example 3: Preparation of ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoate

[0022] 150 g of ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-amino-2-methyl-2-pentenoate prepared in Example 1 was dissolved in 1500 g of dichloromethane. 59 g of triethylamine was added, followed by dropwise addition of 121 g of BOC anhydride. The reaction was carried out at 35 °C for 8 h. After the reaction was complete, water was added, and the mixture was allowed to stand and separate. The lower organic phase was collected, washed twice with water, and concentrated to dryness under reduced pressure. Then, 150 g of methanol and 450 g of water were added, and the mixture was stirred for 2 h. After filtration, washing with water, and drying, 189 g of ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoate was obtained, with a yield of 95.2% and a purity of 99.34% (see [link to example]). Figure 1 ).

[0023] Example 4: Preparation of (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid

[0024] 150 g of ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid was added to 2000 g of water and stirred until homogeneous. 81 g of 20% sodium hydroxide aqueous solution was added dropwise, and the reaction was carried out at 25°C for 3 h. After the reaction was complete, 46 g of concentrated hydrochloric acid was added dropwise. As the addition continued, a solid precipitated. After the addition was complete, the mixture was filtered, washed with water, and dried to obtain 134 g of (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid, with a yield of 95.9% and a purity of 99.82% (see [link to original text]). Figure 2 Mass spectrum as shown Figure 3 As shown.

Claims

1. A method for preparing a key intermediate of sacubitril / valsartan, wherein the intermediate is (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid, characterized in that, Its preparation method is as follows: 1) (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione reacts with trialkyl phosphite under the action of a catalyst to generate Witting-Horner reagent, which then reacts with ethyl pyruvate under alkaline conditions to generate a double bond product. The double bond product is hydrolyzed to generate (R,E)-5-((1,1'-biphenyl)-4-yl)-4-amino-2-methyl-2-pentenoic acid ethyl ester; 2) Ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-amino-2-methyl-2-pentenoate was protected with BOC anhydride under acid-binding conditions to yield ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoate; 3) Ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid is hydrolyzed under alkaline conditions to give (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid.

2. The preparation method according to claim 1, characterized in that, The catalyst in step 1) is at least one of zinc bromide and lithium bromide; the trialkyl phosphite is at least one of trimethyl phosphite, triethyl phosphite, and triphenyl phosphite.

3. The preparation method according to claim 1, characterized in that, The solvent used in step 1) is at least one of dichloromethane, acetonitrile, and dioxane; the base used in the alkaline condition is at least one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.

4. The preparation method according to claim 1, characterized in that, The reaction temperature for generating the Witting-Horner reagent in step 1) is 30-120℃; the reaction temperature for reacting with ethyl pyruvate under alkaline conditions is 20-50℃.

5. The preparation method according to claim 1, characterized in that, In step 2), the acid-binding agent is at least one of triethylamine and pyridine; the solvent used is at least one of dichloromethane and dichloroethane.

6. The preparation method according to claim 1, characterized in that, In step 2), the reaction temperature is 20-50℃ and the reaction time is 4-8h.

7. The preparation method according to claim 1, characterized in that, The alkali used in step 3) is at least one of sodium hydroxide, potassium hydroxide, and lithium hydroxide; the solvent used is at least one of water, methanol, and ethanol.

8. The preparation method according to claim 1, characterized in that, In step 3), the reaction temperature is 20-50℃ and the reaction time is 1-3h.

9. The preparation method according to any one of claims 1-8, characterized in that, The specific steps are as follows: 1) Dissolve (R)-1-(1-([1,1'-biphenyl]-4-yl)-3-chloropropane-2-yl)pyrrolidine-2,5-dione in a solvent, then add a catalyst and trialkyl phosphite, and heat to the reaction temperature; after the reaction is completed, add a base and ethyl pyruvate, and after HPLC detection, add water dropwise, and after the reaction is completed, allow to stand and separate the layers, take the lower organic phase, wash the organic phase with water, concentrate and dry the organic phase under reduced pressure to obtain (R,E)-5-((1,1'-biphenyl)-4-yl)-4-amino-2-methyl-2-pentenoic acid ethyl ester; 2) Dissolve (R,E)-5-((1,1'-biphenyl)-4-yl)-4-amino-2-methyl-2-pentenoic acid ethyl ester in a solvent, add an acid-binding agent, then add BOC anhydride, react at 20-50℃ for 4-8 h, after the reaction is complete, add water, let stand and separate the layers, take the lower organic phase, wash twice with water, concentrate the organic phase under reduced pressure, and crystallize with methanol water to obtain (R,E)-5-((1,1'-biphenyl)-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid ethyl ester; 3) Ethyl (R,E)-5-((1,1'-biphenyl)-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid was dissolved in an alkaline solution and reacted at 20-50℃ for 1-3 h. After the reaction was completed, an acidic aqueous solution was added dropwise. As the addition proceeded, a solid precipitated out. After the addition was complete, the mixture was filtered and dried to obtain (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid.

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