CN114075129A

CN114075129A - Sacubitril intermediate and synthetic method and application thereof

Info

Publication number: CN114075129A
Application number: CN202010807163.6A
Authority: CN
Inventors: 郑勇鹏; 赵金辉; 肖烨
Original assignee: Shenzhen Catalys Technology Co Ltd
Current assignee: Shenzhen Green Kate Pharmaceutical Technology Co ltd; Shenzhen Catalys Technology Co Ltd
Priority date: 2020-08-12
Filing date: 2020-08-12
Publication date: 2022-02-22

Abstract

The invention belongs to the technical field of medicinal chemical synthesis, and particularly relates to a shakubiqu intermediate, and a synthesis method and application thereof. The invention provides a novel intermediate (R, E) -5- ([ [1,1' -biphenyl ] -4-yl) -4- (2, 5-dioxapyrrolidine-1-yl) -2-methylpent-2-olefine acid in the process of synthesizing a bulk drug shakubitrex and a synthesis method thereof. The intermediate (R, E) -5- ([ [1,1' -biphenyl ] -4-yl) -4- (2, 5-dioxapyrrolidine-1-yl) -2-methylpent-2-olefine acid can be synthesized with high yield in the synthesis of the Sacubitril, and the intermediate has important significance in the preparation and production of the Sacubitril.

Description

Sacubitril intermediate and synthetic method and application thereof

Technical Field

The invention belongs to the technical field of medicinal chemical synthesis, and particularly relates to a shakubiqu intermediate, and a synthesis method and application thereof.

Background

The shakubiqu, the chemical name of which is 4- [ [ (1S,3R) -1- ([1,1' -biphenyl ] -4-ylmethyl) -4-ethoxy-3-methyl-4-oxobutyl ] amino ] -4-oxobutanoic acid, is an enkephalinase inhibitor originated by Novartis company and is a 3 sodium salt 2.5 hydrate formed by an angiotensin receptor blocker valsartan. FDA approval was given on 7/2015 and eu approval was given on 19/11/2015 for treatment of chronic heart failure with decreased ejection fraction.

The patent WO2014/032627 and the patent EP1903027 disclose preparation methods of the Sacubitril intermediate, which are prepared by carrying out Grignard reaction on halogenated biphenyl serving as a raw material. The partial synthetic route is as follows:

namely, 4-bromobiphenyl is reacted with epichlorohydrin with single configuration by Grignard reaction to obtain a chiral compound 3. Carrying out a mitsunobu reaction on the compound 3 and succinimide to obtain a compound 4 with an inverted configuration; then, carrying out hydrolysis reaction in a hydrochloric acid aqueous solution to obtain a compound 5; protecting amino group of the compound 6 by using di-tert-butyl dicarbonate to obtain a compound 6; oxidizing the compound 6 with sodium hypochlorite to obtain a compound 7; and finally, obtaining the final Sacubitril intermediate compound 8 through a group of continuous alcohol hydroxyl oxidation, phosphine ylide reaction and hydrolysis reaction. The intermediate obtained by the method has a complex obtaining process, the yield of the intermediate needs to be improved, and the industrial application of the shakuibiqu is limited to a certain extent.

In addition, CN201510233583.7 discloses a synthetic process route of shakubiqu, which is specifically as follows:

the technical route uses benzyl glycidyl ether to replace epoxy chloropropane in the traditional route as a chiral starting material, the chiral compound 1 in the technical route is expensive relative to the epoxy chloropropane, and the subsequent debenzylation reaction is required to be carried out under the condition of high pressure of hydrogen/palladium carbon, so that the industrial scale-up production is not facilitated.

Disclosure of Invention

In view of the problems in the prior art, the invention prepares a novel unreported Sacubitril intermediate VII by researching a synthetic process route of Sacubitril, and the intermediate can realize the high-efficiency synthesis of Sacubitril medicines.

The reaction equation is as follows:

the synthesis method comprises the following steps:

1. the starting material 4-bromobiphenyl (formula I) is prepared into a Grignard reagent by metal magnesium, and the Grignard reagent reacts with chiral (S) -epoxy halogenated propane to generate (S) -1- ([1,1' -biphenyl ] -4-yl) -3-halogenated-propan-2-ol (formula II).

Wherein X in the formulas II and III is halogen selected from fluorine, chlorine, bromine and the like, and chlorine is preferred.

2. The preparation of (R) -1- (1- ([ (1,1 '-biphenyl ] -4-yl) -3-halopropan-2-yl) pyrrolidine-2, 5-dione (formula III) is realized by the action of a photo-extension reaction of (S) -1- ([ [1,1' -biphenyl ] -4-yl) -3-halopropan-2-ol (formula II).

Wherein the phosphine reagent used in the mitsunobu reaction is selected from triphenylphosphine or tri-n-butylphosphine; and carrying out a coupling reaction using a coupling reagent selected from diethyl azodicarboxylate (DEAD) or isopropyl azodicarboxylate (DIAD).

3. (R) -1- (1- ([ (1,1 '-biphenyl ] -4-yl) -3-halopropane-2-yl) pyrrolidine-2, 5-dione (formula III) is hydrolyzed to obtain (R) -1- (1- ([ [, 1' -biphenyl ] -4-yl) -3-hydroxypropane-2-yl) pyrrolidine-2, 5-dione (formula IV).

Wherein all the hydrolytic agents in the hydrolysis reaction are sodium formate, sodium acetate, potassium formate and potassium acetate containing crystal water; the solvent used was N, N-dimethylformamide.

4. (R) -1- (1- ([ [, 1 '-biphenyl ] -4-yl) -3-hydroxypropan-2-yl) pyrrolidine-2, 5-dione (formula IV) is prepared by oxidizing a primary alcohol to an aldehyde with sodium hypochlorite to give (R) -3- ([ [1,1' -biphenyl ] -4-yl) -2- (2, 5-dioxapyrrolidin-1-yl) propanal (formula V).

5. (R) -3- ([ [1,1 '-biphenyl ] -4-yl) -2- (2, 5-dioxapyrrolidin-1-yl) propanal (formula V) was prepared to give (R, E) -5- ([ [1,1' -biphenyl ] -4-yl) -4- (2, 5-dioxapyrrolidin-1-yl) -2-methylpent-2-enoate (formula VI).

6. (R, E) -5- ([ [1,1 '-biphenyl ] -4-yl) -4- (2, 5-dioxapyrrolidin-1-yl) -2-methylpent-2-enoic acid ester (formula VI) was subjected to a two-step hydrolysis reaction using sodium hydroxide and triethylamine as bases to give (R, E) -5- ([ [1,1' -biphenyl ] -4-yl) -4- (2, 5-dioxapyrrolidin-1-yl) -2-methylpent-2-enoic acid (formula VII).

Wherein the alkali used in the first hydrolysis step is selected from sodium hydroxide and potassium hydroxide. The base used in the second reaction step is preferably triethylamine, and the solvent used is toluene.

As a preferred embodiment of the present invention, the method includes:

the beneficial effects of the invention compared with the prior art comprise:

the invention provides a new shakubiqu intermediate, a synthesis method and application thereof, the synthesized compound VII is a new compound and is not reported, and compared with the synthesis method in the CN201510233583.7 patent, the yield of the shakubiqu intermediate in the process of preparing the shakubiqu bulk drug is higher, the reaction condition of the whole route is mild, and the reaction condition of high temperature and high pressure does not exist. Meanwhile, the used raw materials are low in price, have extremely high industrial value and meet the market demand.

Drawings

FIG. 1 is a nuclear magnetic spectrum of H spectrum of (R, E) -5- ([ [1,1' -biphenyl ] -4-yl) -4- (2, 5-dioxapyrrolidin-1-yl) -2-methylpent-2-enoic acid (formula VII) as a novel compound;

FIG. 2 shows the C-spectrum nuclear magnetic spectrum of (R, E) -5- ([ [1,1' -biphenyl ] -4-yl) -4- (2, 5-dioxapyrrolidin-1-yl) -2-methylpent-2-enoic acid (formula VII) as the novel compound.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

In the embodiment of the invention, the shakubiqu intermediate, the synthesis method and the application thereof (taking epoxy chloropropane with S configuration as an example):

example 1: preparation of Compound II

2.15g of magnesium chips were added to a 1000mL dry three-necked flask, 40mL of anhydrous tetrahydrofuran was added thereto under argon protection, and the mixture was stirred at room temperature. Another 20g of tetrabromobiphenyl were dissolved in 40mL of anhydrous tetrahydrofuran, and 5mL of the solution was added to the reaction system. Two iodine pellets were added and the reaction was heated to 40 ℃ and stirred until the color of the solution faded. Heating is removed, tetrahydrofuran solution of tetrabromobiphenyl is slowly dripped into a reaction system substance, the reaction of the system is violent, 1.68g of cuprous iodide is added into the reaction system after the dripping is finished and the reaction is carried out for 1h at room temperature, the temperature is reduced to minus 20 ℃, the stirring is carried out for 20min, 7.92g of (R) -2- (methoxymethyl) epoxy ethane is dissolved by 40mL of anhydrous tetrahydrofuran, and the solution is slowly dripped into the reaction system. After the dropwise addition, the room temperature is recovered and the stirring is carried out for 2 h. After stirring at-10 ℃ for 10min, 30mL of 10% aqueous hydrochloric acid was taken to quench the reaction. Adding 200mL of dichloromethane into the reaction system, filtering to remove insoluble substances, extracting the filtrate, washing an organic phase twice (50mL multiplied by 2) with dilute hydrochloric acid and aqueous sodium chloride solution respectively, drying the organic phase with anhydrous sodium sulfate, removing the solvent under reduced pressure to obtain a white solid, pulping the white solid with n-hexane, and filtering to obtain 20g of a compound II white solid, wherein the yield is as follows: 92 percent.

Example 2: preparation of Compound III

17g of the compound II and 200mL of toluene are taken and added into a 500mL double-mouth bottle, 7.5g of succinimide and 20.4g of triphenylphosphine are taken and added into the bottle, argon is used for protection, the mixture is placed at the temperature of minus 10 ℃ and stirred for 20min, then diisopropyl azodicarboxylate (21.25g) solution diluted by 100mL of toluene is slowly dripped into a reaction system, and the color of the reaction system turns yellow. After the dropwise addition, the mixture is stirred for 2 hours at room temperature, the solvent is removed under reduced pressure to obtain yellow solid, the yellow solid is pulped by 300mL of petroleum ether and filtered, and a filter cake is washed by 200mL of petroleum ether to obtain 48g of white solid which is a mixture of a compound III and triphenylphosphine oxide and is directly used for the next reaction.

Example 3: preparation of Compound IV

And adding 500mL of DMF (dimethyl formamide) serving as a solvent into the compound III obtained in the previous step, stirring at room temperature, adding 45g of sodium acetate trihydrate and 1.2g of potassium iodide, and heating to 120-130 ℃ for reaction for 5 hours. And cooling to room temperature, adding 1000mL of water, separating out a large amount of white solid, filtering, washing a filter cake with water and ethanol, and drying to obtain a white solid (a product and a triphenoxyphosphate mixture) which is directly used for the next reaction. LC-MS: 310.19(M + H)⁺

Example 4: preparation of Compound VI

The compound IV obtained in the previous step was taken and added to a 1L single-neck flask, 100mL of water and 400mL of isopropyl acetate were added, and stirring was started at-5 ℃. 11.5g of sodium bromide, 8.7g of sodium bicarbonate and 202mg of tetramethylpiperidine oxide (TEMPO) were weighed into a flask, and after stirring at-5 ℃ for 10 minutes, 60g of an aqueous sodium hypochlorite solution (10%) was slowly dropped into the reaction system, whereby the color of the system became deep red. After the dropwise addition, 150mL of saturated sodium thiosulfate solution is taken to quench the reaction and extract, 23g of carbethoxyethylidene triphenylphosphine is directly added into the organic phase, the mixture is stirred for 4 hours, and then the solvent is removed under reduced pressure, so that the crude product of the compound VI can be directly used for the next reaction.

Example 5: preparation of Compound VII

Adding 400mL of 95% ethanol serving as a solvent into the crude compound VI obtained in the previous step, adding 20g of sodium hydroxide into a reaction system, heating to 60 ℃ for reaction for 2H, cooling to room temperature, removing part of the solvent under reduced pressure, drying an ethyl acetate/water extraction organic phase, removing the solvent under reduced pressure to obtain a light yellow solid, directly adding 500mL of toluene serving as the solvent, adding 20g of triethylamine, heating for reflux reaction for 8H, cooling to room temperature, removing the solvent under reduced pressure to obtain a yellow solid, recrystallizing with isopropyl acetate to obtain a white solid, namely the target compound VII, wherein H and C spectrum nuclear magnetic spectrograms are respectively shown in fig. 1 and fig. 2.

¹H NMR(400MHz,Chloroform-d)δ7.62-7.57(m,2H),7.54(d,J＝8.2Hz,2H),7.45(t,J＝7.6Hz,2H),7.39-7.30(m,2H),7.25(s,1H),5.33-5.23(m,1H),4.24(t,J＝6.0Hz,1H),3.41(dd,J＝13.7,9.4Hz,1H),3.19(dd,J＝13.7,7.0Hz,1H),2.58(q,J＝2.4Hz,4H),1.85(d,J＝1.5Hz,3H).¹³C NMR(400MHz,Chloroform-d)δ176.65,171.89,139.79,138.39,135.47,130.90,129.51,128.78,127.32,127.21,126.95,77.23,68.18,50.69,36.77,30.37,29.71,28.94,27.92,23.00,12.50,10.98.

Example 6: preparation of Shakubiqu AHU-377

(1) 50g of Compound VII was taken, 300mL of anhydrous methanol was added as a solvent, and 11mg of catalyst [ Ru (OAc)₂]Adding (S) -O-SDP into a reaction system under the anhydrous and oxygen-free conditions, replacing the reaction system with hydrogen, keeping the hydrogen pressure of the system at 40-80 Mpa, heating the system to the internal temperature of the system at 50-70 ℃ for reacting for 48 hours, adding 300mL of n-hexane into the reaction system, filtering, recrystallizing and purifying to obtain 46g of a compound VIII; ee% is greater than 95%.

(2) Adding 40g of a compound VIII into 300mL of ethanol, heating for dissolving, adjusting the pH value of a reaction to be less than 2 by using concentrated hydrochloric acid, heating until the reaction is refluxed for 4 hours, stopping the reaction, cooling to 15-20 ℃, slowly adding 1.0M of sodium hydroxide solution into a reaction system, adjusting the pH value of a reaction solution to be 8-9, slowly returning to room temperature, stirring for reacting for 2 hours, adding 200mL of n-hexane into the reaction system, precipitating a large amount of white solid from the system, filtering, drying, recrystallizing isopropyl acetate to obtain 38g of a compound AHU-377, wherein the yield is 85%.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included therein.

Claims

1. A novel process for the synthesis of the shakubitqu intermediate, (R, E) -5- ([ [1,1' -biphenyl ] -4-yl) -4- (2, 5-dioxapyrrolidin-1-yl) -2-methylpent-2-enoic acid having the following chemical formula:

the preparation method comprises the following steps:

wherein X is halogen.

2. The method of synthesis according to claim 1, comprising:

(1) preparing a Grignard reagent from 4-bromobiphenyl (formula I) serving as a starting material through metal magnesium, and reacting the Grignard reagent with chiral (S) -epoxy halopropane to generate (S) -1- ([1,1' -biphenyl ] -4-yl) -3-halo-propan-2-ol (formula II);

(2) (S) -1- ([ [1,1 '-biphenyl ] -4-yl) -3-halopropane-2-ol (formula II) is subjected to a photo-extension reaction to prepare (R) -1- (1- ([ (1,1' -biphenyl ] -4-yl) -3-halopropane-2-yl) pyrrolidine-2, 5-dione (formula III);

(3) (R) -1- (1- ([ (1,1 '-biphenyl ] -4-yl) -3-halopropane-2-yl) pyrrolidine-2, 5-dione (formula III) is hydrolyzed to obtain (R) -1- (1- ([ [, 1' -biphenyl ] -4-yl) -3-hydroxypropane-2-yl) pyrrolidine-2, 5-dione (formula IV);

(4) (R) -1- (1- ([ [, 1 '-biphenyl ] -4-yl) -3-hydroxypropan-2-yl) pyrrolidine-2, 5-dione (formula IV) is prepared by oxidizing a primary alcohol to an aldehyde with sodium hypochlorite to give (R) -3- ([ [1,1' -biphenyl ] -4-yl) -2- (2, 5-dioxapyrrolidin-1-yl) propanal (formula V).

(5) Preparation of (R) -3- ([ [1,1 '-biphenyl ] -4-yl) -2- (2, 5-dioxapyrrolidin-1-yl) propanal (formula V) to give (R, E) -5- ([ [1,1' -biphenyl ] -4-yl) -4- (2, 5-dioxapyrrolidin-1-yl) -2-methylpent-2-enoate (formula VI)

(6) (R, E) -5- ([ [1,1 '-biphenyl ] -4-yl) -4- (2, 5-dioxapyrrolidin-1-yl) -2-methylpent-2-enoic acid ester (formula VI) was subjected to a two-step hydrolysis reaction using sodium hydroxide and triethylamine as bases to give (R, E) -5- ([ [1,1' -biphenyl ] -4-yl) -4- (2, 5-dioxapyrrolidin-1-yl) -2-methylpent-2-enoic acid (formula VII).

3. Synthesis process according to claim 1 or 2, characterized in that the halogen is selected from fluorine, chlorine, bromine, etc., preferably chlorine.

4. A synthesis method according to claim 1 or 2, characterized in that it comprises:

5. the synthesis method according to claim 2, wherein in the step (2), the phosphine reagent used in the mitsunobu reaction is selected from triphenylphosphine or tri-n-butylphosphine; and carrying out a coupling reaction using a coupling reagent selected from diethyl azodicarboxylate (DEAD) or isopropyl azodicarboxylate (DIAD).

6. The synthesis method according to claim 2, wherein in the step (3), all the hydrolytic agents for the hydrolysis reaction are sodium formate, sodium acetate, potassium formate, potassium acetate containing crystal water; the solvent used was N, N-dimethylformamide.

7. The process of claim 2, wherein in step (6), the base used in the first hydrolysis step is selected from the group consisting of sodium hydroxide, potassium hydroxide; the base used in the second reaction step is preferably triethylamine, and the solvent used is toluene.

8. A compound which is (R, E) -5- ([ [1,1' -biphenyl ] -4-yl) -4- (2, 5-dioxapyrrolidin-1-yl) -2-methylpent-2-enoic acid having the following chemical formula:

9. use of a compound according to claim 8 for the preparation of shakubitrex, wherein the compound is used as an intermediate.