CN116969863A - Method for preparing Sha Kuba curved intermediate by utilizing micro-channel method - Google Patents

Abstract

The invention belongs to the field of organic synthesis, in particular to the technical field of organic medicine synthesis, and more particularly relates to a method for preparing a Sha Kuba curved intermediate by utilizing a micro-channel method. The invention obtains the target compound I by reacting the compound II with the compound III in the presence of alkali through a micro-channel reactor. According to the invention, through controlling the temperature and the reaction time of the heat exchanger of the microchannel reactor, the reaction efficiency can be effectively improved, the generation of reaction byproducts is reduced, and the preparation efficiency and the purity of the product are obviously improved, so that the problems of long reaction time, more byproducts, high equipment requirements, low yield and purity and the like in the prior art are effectively solved.

Description

A method for preparing sacubitril intermediate using microchannel method

Technical field

The invention belongs to the field of organic synthesis, in particular to the technical field of organic drug synthesis, and more specifically to a method for preparing sacubitril intermediates using a microchannel method.

Background technique

Heart failure has become a global public health problem that seriously endangers human health. It is the final stage of the development of cardiovascular diseases. Its incidence, rehospitalization rate and mortality rate are increasing year by year, which makes further development of more effective New drugs for the treatment of heart failure are urgent, and the launch of sacubitril/valsartan, which has a dual action mechanism of angiotensin receptor-neprilysin inhibitor, has brought new changes to the treatment of heart failure patients.

Sacubitril/valsartan (Entresto) is a dual-effect angiotensin receptor-neprilysin inhibitor developed by Novartis and can be used clinically for the treatment of hypertension and heart failure. The drug consists of sacubitril, which acts on neprilysin, and valsartan, which acts on the renin-angiotensin-aldosterone system. It can effectively improve symptoms of heart failure, lower blood pressure and actively improve kidney function. It is a drug that An ideal drug for the treatment of heart failure.

Since the synthesis process of valsartan is relatively mature, the research focus of those skilled in the art is on the optimization of the synthesis of the sacubitril part.

Sacubitril, chemical name is 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl- 5-Oxopropan-2-yl)amino)-4-oxobutyric acid, its structure is as follows:

Compound I is an important intermediate for the preparation of sacubitril drugs.

The preparation method of sacubitril is disclosed in the original patent US5217996, and its synthesis route is as follows:

In this synthetic route, compound I is prepared by reacting compound II with a phosphorus ylide reagent, where the structure of the phosphorus ylide reagent is shown in formula a,

This method is currently commonly used in the prior art to prepare compound I through the classic Wittig reaction. However, the yield of compound I under this method is only 78%. The low reaction yield not only causes a waste of chiral alcohol raw materials, but also makes the cost of industrial synthesis of sacubitril high.

Microchannel reactors have high specific surface area and regular laminar flow characteristics. When reactants react in the microchannel reactor, they can continuously participate in subsequent reactions, thereby obtaining high space-time yields. At the same time, compared with traditional preparation processes, microchannel reactors also have the advantages of fast mass transfer rate, short residence time, good repeatability, and easy automatic control.

At present, no technical solution for preparing sacubitril intermediate compound I using a microchannel reactor has been disclosed.

Contents of the invention

The technical problem to be solved by the present invention is to provide a method for preparing sacubitril intermediate using microchannel method, thereby improving the synthesis process of sacubitril intermediate and achieving low cost, high yield, high safety and environmental protection. Environmentally friendly technical effects.

In order to solve the above technical problems, the present invention discloses a method for preparing sacubitril intermediate using microchannel method, which includes the following steps:

(1) Dissolve compound II in a solvent to prepare a solution of material A;

(2) Dissolve compound III in a solvent to prepare a solution of material B;

(3) Dissolve the base in the solvent to prepare a solution of material C;

(4) Pump material A solution, material B solution and material C solution into the microchannel reactor respectively according to the preset flow rate. The heat exchanger temperature of the microchannel reactor is set between -100~-50°C. The residence reaction time in the microchannel reactor is set between 60 and 300 seconds;

The product containing compound I is obtained from the outlet of the microchannel reactor; then compound I is obtained through post-processing; post-processing here refers to the purification, refinement and other processing steps of the compound, including but not limited to quenching, separation, extraction, and washing. , concentration, recrystallization;

The synthesis route of this reaction is as follows:

Among them, R is selected from any of them.

Further, the base is one of sodium hydride, LiHMDS, NaHMDS, sodium methoxide, sodium ethoxide, butyllithium, potassium tert-butoxide, sodium tert-butoxide or LDA.

Further, the molar ratio of compound II to compound III and base is 1: (1-1.5): (1-1.5).

Furthermore, the solvents in each step are the same and are selected from any one or more of tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, ethyl acetate, acetone or methyl isopropyl ketone.

Further, the reaction temperature is -90~-60°C, which can be but is not limited to -90°C, -85°C, -80°C, -75°C, -70°C, -65°C or -60°C, in order to obtain For better effect, the reaction temperature is preferably -70°C.

Furthermore, the residence reaction time of materials in the microchannel reactor is preferably set to 80 to 260 s.

Further, the flow rate of the material A, material B, and material C solutions in the microchannel reactor is preferably: the flow rate of the material A solution is 5 ml/min; the flow rate of the material B solution is 7.5 ml/min; the flow rate of the material C solution is 4ml/min.

Further, in the present invention, the synthesis of compound III includes the following steps:

(1) Compound V is reacted with compound VI in the presence of a base and a phase transfer catalyst to obtain compound IV;

(2) In the presence of a catalyst, compound IV is oxidized with an oxidizing agent to obtain compound III,

The specific synthesis route is as follows:

Among them, R is selected from any of them.

Further, in step (1), the phase transfer catalyst is one of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bisulfate, benzyltriethylammonium chloride or 18-crown 6 ether. kind.

Further, in step (1), the base is one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.

Further, the solvent in step (1) is one or more of dimethyl sulfoxide, N,N-dimethylformamide, methanol, isopropyl alcohol or N-methylpyrrolidone.

Further, the reaction temperature in step (1) is 80-140°C, which can be but is not limited to 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C ℃, 130 ℃, 135 ℃ or 140 ℃, in order to obtain better results, the reaction temperature is preferably 125 ℃.

Further, in step (2), the catalyst is one of ammonium heptamolybdate tetrahydrate, phosphomolybdic acid or tungsten trioxide.

Further, the oxidizing agent in step (2) is one of hydrogen peroxide, sodium hypochlorite, potassium permanganate, potassium perborate, sodium dichromate or meta-chloroperoxybenzoic acid.

Further, the solvent in step (2) is one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile or N-methylpyrrolidone.

Further, the reaction temperature in step (2) is -10~40°C, which can be but is not limited to -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C ℃, 35 ℃ or 40 ℃, in order to obtain better results, the reaction temperature is preferably 5 ℃.

In the present invention, the target compound I is obtained by reacting compound II and compound III in the presence of a base through a microchannel reactor. By controlling the temperature and reaction time of the microchannel reactor heat exchanger, the reaction efficiency can be effectively improved, the production of reaction by-products can be reduced, and the preparation efficiency and product purity can be significantly improved, thereby effectively solving the problem of long reaction times in the existing technology. There are many by-products, high equipment requirements, low yield and purity and other problems.

The present invention accurately controls the material reaction procedure through flow rate, temperature and reaction time, greatly shortening the reaction time. The entire reaction has high safety, low cost, simple post-processing, and the yield and purity of the product compound I are high. It is a suitable A new efficient preparation method for industrial large-scale production.

Detailed ways

In order to better understand the present invention, we will further elaborate the present invention with reference to specific embodiments.

Unless otherwise specified, the reagents used in the examples of the present invention are common commercially available products.

Example 1

(1) Synthesis of compound IV-1

Under nitrogen protection, add compound V (10g, 73mmol), compound VI-1 (14.3g, 80.3mmol) and 100ml dimethyl sulfoxide into the reaction vessel, stir and dissolve. Tetrabutylammonium bromide (1.2g, 3.7mmol) and sodium bicarbonate (12.3g, 146mmol) were then added, and the reaction mixture was reacted at 125°C. After the reaction is completed, the reaction mixture is cooled to 20°C, and 200 mL of methyl tert-butyl ether and 200 mL of saturated NaHCO ₃ aqueous solution are added. The organic layer was separated and the aqueous layer was washed with 100 mL of methyl tert-butyl ether. The combined organic phases were washed with 100 mL of saturated NaHCO ₃ aqueous solution, dried over Na ₂ SO ₄ , and concentrated to obtain compound IV-1 with a yield of 96.5% and a purity of 99.4%.

(2) Synthesis of compound III-1

Add compound IV-1 (10 g, 36 mmol) and 100 mL dimethyl sulfoxide to the reaction vessel, and stir to dissolve. The reaction solution was cooled to 5°C, then ammonium heptamolybdate tetrahydrate (0.9g, 0.72mmol) and 30% hydrogen peroxide (16.3g, 144mmol) were added, and the reaction mixture was reacted at 5°C. After the reaction is completed, the reaction mixture is heated to 20°C, and 50 mL of dimethyl sulfoxide and 100 mL of saturated NaHCO ₃ aqueous solution are added. Separate the organic phase, wash with 50 mL saturated NaHCO ₃ aqueous solution, dry with Na ₂ SO ₄ , concentrate the organic phase, and then recrystallize with isopropyl alcohol to obtain compound III-1 with a yield of 92.7% and a purity of 99.1%.

Example 2

(1) Synthesis of compound IV-2

Under nitrogen protection, add compound V (10g, 73mmol), compound VI-2 (13.4g, 80.3mmol) and 100ml N,N-dimethylformamide into the reaction vessel, stir and dissolve. Tetrabutylammonium chloride (1g, 3.7mmol) and sodium carbonate (15.5g, 146mmol) were then added, and the reaction mixture was reacted at 140°C. After the reaction is completed, the reaction mixture is cooled to 20°C, and 200 mL of methyl tert-butyl ether and 200 mL of saturated NaHCO ₃ aqueous solution are added. The organic layer was separated and the aqueous layer was washed with 100 mL of methyl tert-butyl ether. The combined organic phases were washed with 100 mL of saturated NaHCO ₃ aqueous solution, dried over Na ₂ SO ₄ , and concentrated to obtain compound IV-2 with a yield of 94.1% and a purity of 99.2%.

(2) Synthesis of compound III-2

Add compound IV-2 (9.6 g, 36 mmol) and 100 mL acetonitrile to the reaction vessel, and stir to dissolve. The reaction solution was cooled to -10°C, then phosphomolybdic acid (1.3g, 0.72mmol) and 30% hydrogen peroxide (16.3g, 144mmol) were added, and the reaction mixture was reacted at -10°C. After the reaction is completed, the reaction mixture is heated to 20°C, and 50 mL of acetonitrile and 100 mL of saturated NaHCO ₃ aqueous solution are added. Separate the organic phase, wash with 50 mL saturated NaHCO ₃ aqueous solution, dry with Na ₂ SO ₄ , concentrate the organic phase, and then recrystallize with isopropyl alcohol to obtain compound III-2 with a yield of 89.6% and a purity of 99.2%.

Example 3

(1) Synthesis of compound IV-3

Under nitrogen protection, add compound V (10g, 73mmol), compound VI-3 (10.6g, 80.3mmol) and 100ml methanol into the reaction vessel, stir and dissolve. Benzyltriethylammonium chloride (0.84g, 3.7mmol) and sodium hydroxide (5.8g, 146mmol) were then added, and the reaction mixture was reacted at 80°C. After the reaction is completed, the reaction mixture is cooled to 20°C, and 200 mL of methyl tert-butyl ether and 200 mL of saturated NaHCO ₃ aqueous solution are added. The organic layer was separated and the aqueous layer was washed with 100 mL of methyl tert-butyl ether. The combined organic phases were then washed with 100 mL of saturated NaHCO ₃ aqueous solution, dried over Na ₂ SO ₄ , and the organic phase was concentrated to obtain compound IV-3 with a yield of 91.8% and a purity of 99.3%.

(2) Synthesis of compound III-3

Add compound IV-3 (8.4g, 36mmol) and 100mL N,N-dimethylformamide to the reaction vessel, stir and dissolve. The reaction solution was cooled to 40°C, then ammonium heptamolybdate tetrahydrate (0.9g, 0.72mmol) and m-chloroperoxybenzoic acid (24.8g, 144mmol) were added, and the reaction mixture was reacted at 40°C. After the reaction is completed, the reaction mixture is heated to 20°C, and 50 mL of N,N-dimethylformamide and 100 mL of saturated NaHCO ₃ aqueous solution are added. Separate the organic phase, wash with 50 mL saturated NaHCO ₃ aqueous solution, dry with Na ₂ SO ₄ , concentrate the organic phase, and recrystallize with isopropyl alcohol to obtain compound III-3 with a yield of 87.9% and a purity of 99.1%.

Example 4

(1) Prepare material A solution: Add compound II (30g, 92mmol) to tetrahydrofuran, dilute to 100mL, stir evenly, and place it in raw material tank A (the bottom of the raw material tank is connected to the feed pipe corresponding to the microchannel reactor through a valve connected), protected by nitrogen for later use.

(2) Prepare material B solution: Add compound III-1 (32.6g, 105mmol) to tetrahydrofuran, dilute to 150mL, stir evenly, and place it in raw material tank B (the bottom of the raw material tank is connected to the microchannel reactor through a valve. The feed pipe is connected), and nitrogen protection is set aside for use.

(3) Prepare material C solution: Add LiHMDS (20.2g, 120mmol) to tetrahydrofuran, dilute to 80mL, stir evenly, and place it in raw material tank C (the bottom of the raw material tank is connected to the feed pipe corresponding to the microchannel reactor through a valve connected), protected by nitrogen for later use.

(4) Open the valve at the bottom of the raw material tank, and transport the material A solution in raw material tank A, the material B solution in raw material tank B, and the material C solution in raw material tank C through the feed pump, and set the flow rate of raw material tank A through the counting pump. 5ml/min, the flow rate of raw material tank B is 7.5ml/min, the flow rate of raw material tank C is 4ml/min, then set the temperature of the heat exchanger to -70°C, and maintain the reaction time in the channel to 180s. After the reaction is completed, a sample is taken from the outlet of the microchannel reactor to obtain a mixture containing the target compound I.

The mixture was warmed to -10 °C and the reaction was quenched with 100 mL of 10% aqueous NaHCO _solution . The phases were separated, the aqueous layer was extracted with 100 mL of ethyl acetate, the combined organic phases were washed with 100 mL of 5% aqueous _Na2CO3 solution and concentrated under _vacuum . After the concentration was completed, methanol was added for recrystallization to obtain compound I with a yield of 95.8% and a purity of 99.6%.

Example 5

(1) Prepare material A solution: Add compound II (30g, 92mmol) to toluene, dilute to 100mL, stir evenly, and place it in raw material tank A (the bottom of the raw material tank is connected to the feed pipe corresponding to the microchannel reactor through a valve connected), protected by nitrogen for later use.

(2) Prepare material B solution: Add compound III-2 (41.3g, 138mmol) to toluene, dilute to 150mL, stir evenly, and place it in raw material tank B (the bottom of the raw material tank is connected to the microchannel reactor through a valve. The feed pipe is connected), and nitrogen protection is set aside for use.

(3) Prepare material C solution: Add sodium hydride (2.3g, 95.8mmol) to toluene, dilute to 80mL, stir evenly, and place it in raw material tank C (the bottom of the raw material tank is connected to the microchannel reactor through a valve. (connected to the material pipeline), nitrogen protection is available for use.

(4) Open the valve at the bottom of the raw material tank, and transport the material A solution in raw material tank A, the material B solution in raw material tank B, and the material C solution in raw material tank C through the feed pump, and set the flow rate of raw material tank A through the counting pump. 5ml/min, the flow rate of raw material tank B is 7.5ml/min, the flow rate of raw material tank C is 4ml/min, then set the temperature of the heat exchanger to -90°C, and maintain the reaction time in the channel as 100s. After the reaction is completed, a sample is taken from the outlet of the microchannel reactor to obtain a mixture containing the target compound I.

The mixture was warmed to -10 °C and the reaction was quenched with 100 mL of 10% aqueous NaHCO _solution . The phases were separated, the aqueous layer was extracted with 100 mL of ethyl acetate, the combined organic phases were washed with 100 mL of 5% aqueous _Na2CO3 solution and concentrated under _vacuum . After the concentration was completed, methanol was added for recrystallization to obtain compound I with a yield of 91.4% and a purity of 99.3%.

Example 6

(1) Prepare material A solution: Add compound II (30g, 92mmol) to dioxane, dilute to 100mL, stir evenly, and place it in raw material tank A (the bottom of the raw material tank is connected to the microchannel reactor through a valve. The feed pipe is connected), and nitrogen protection is set aside for use.

(2) Prepare material B solution: Add compound III-3 (24.4g, 92.3mmol) to dioxane, dilute to 150mL, stir evenly, and place it in raw material tank B (the bottom of the raw material tank passes through the valve and microchannel The corresponding feed pipes of the reactor are connected), and nitrogen protection is set aside.

(3) Prepare material C solution: Add NaHMDS (25.3g, 138mmol) to dioxane, dilute to 80mL, stir evenly, and place it in raw material tank C (the bottom of the raw material tank is connected to the microchannel reactor through a valve. The feed pipe is connected), and nitrogen protection is set aside for use.

(4) Open the valve at the bottom of the raw material tank, and transport the material A solution in raw material tank A, the material B solution in raw material tank B, and the material C solution in raw material tank C through the feed pump, and set the flow rate of raw material tank A through the counting pump. 5ml/min, the flow rate of raw material tank B is 7.5ml/min, the flow rate of raw material tank C is 4ml/min, then set the temperature of the heat exchanger to -60°C, and maintain the reaction time in the channel to 260s. After the reaction is completed, a sample is taken from the outlet of the microchannel reactor to obtain a mixture containing the target compound I.

The mixture was warmed to -10 °C and the reaction was quenched with 100 mL of 10% aqueous NaHCO _solution . The phases were separated, the aqueous layer was extracted with 100 mL of ethyl acetate, the combined organic phases were washed with 100 mL of 5% aqueous _Na2CO3 solution and concentrated under _vacuum . After the concentration was completed, methanol was added for recrystallization to obtain compound I with a yield of 90.7% and a purity of 99.4%.

The above are specific embodiments of the present invention. It should be pointed out that for those of ordinary skill in the art, several improvements and modifications can be made without departing from the principles of the present invention, and these improvements and modifications are also regarded as the protection scope of the present invention.

Claims (10)

1. A method for preparing sacubitril intermediate using microchannel method, which is characterized in that it includes the following steps: (1) Dissolve compound II in a solvent to prepare a solution of material A; (2) Dissolve compound III in a solvent to prepare a solution of material B; (3) Dissolve the base in the solvent to prepare a solution of material C; (4) Pump material A solution, material B solution and material C solution into the microchannel reactor respectively according to the preset flow rate. The heat exchanger temperature of the microchannel reactor is set between -100~-50°C. The residence reaction time in the microchannel reactor is set between 60 and 300 seconds; The product containing compound I is obtained from the outlet of the microchannel reactor; then compound I is obtained through post-processing; The synthesis route of this reaction is as follows: Among them, R is selected from any of them. 2. The method for preparing sacubitril intermediate by microchannel method according to claim 1, wherein the base is sodium hydride, LiHMDS, NaHMDS, sodium methoxide, sodium ethoxide, butyl lithium, tert-butyl Any one of potassium alkoxide, sodium tert-butoxide or LDA. 3. The method for preparing sacubitril intermediate by microchannel method according to claim 1, characterized in that the molar ratio of compound II to compound III and base is 1: (1-1.5): (1 ~1.5). 4. The method for preparing sacubitril intermediate by microchannel method according to claim 1, characterized in that the solvents in each step are the same and selected from the group consisting of tetrahydrofuran, toluene, methyl tert-butyl ether, and dioxygen. Any one or more of six rings, ethyl acetate, acetone or methyl isopropyl ketone. 5. The method for preparing sacubitril intermediate by microchannel method according to claim 1, characterized in that the heat exchanger temperature of the microchannel reactor is preferably set to -90~-60°C. 6. The method for preparing sacubitril intermediate by microchannel method according to claim 1, characterized in that the material residence reaction time in the microchannel reactor is preferably set to 80 to 260 s. 7. The method for preparing sacubitril intermediate by microchannel method according to claim 1 or 3, characterized in that the flow rate of the solutions of material A, material B and material C in the microchannel reactor is preferably: material The flow rate of solution A is 5ml/min; the flow rate of solution B is 7.5ml/min; the flow rate of solution C is 4ml/min. 8. The method for preparing sacubitril intermediate by microchannel method according to claim 1, characterized in that the synthesis of compound III includes the following steps: (1) Compound V is reacted with compound VI in the presence of a base and a phase transfer catalyst to obtain compound IV; (2) In the presence of a catalyst, compound IV is oxidized with an oxidizing agent to obtain compound III, The specific synthesis route is as follows: Among them, R is selected from any of them. 9. The method for preparing sacubitril intermediate by microchannel method according to claim 8, characterized in that any one or more of the following conditions are preferred in step (1): a. The phase transfer catalyst is one of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bisulfate, benzyltriethylammonium chloride or 18-crown 6 ether; b. The alkali is one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide; c. The solvent is one or more of dimethyl sulfoxide, N,N-dimethylformamide, methanol, isopropyl alcohol or N-methylpyrrolidone; d. The reaction temperature is 80~140°C. 10. The method for preparing sacubitril intermediate by microchannel method according to claim 8, characterized in that any one or more of the following conditions are preferred in step (2): a. The catalyst is one of ammonium heptamolybdate tetrahydrate, phosphomolybdic acid or tungsten trioxide; b. The oxidizing agent is one of hydrogen peroxide, sodium hypochlorite, potassium permanganate, potassium perborate, sodium dichromate or meta-chloroperoxybenzoic acid; c. The solvent is one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile or N-methylpyrrolidone; d. The reaction temperature is -10~40°C.