A method for preparing sacubitril intermediate by microchannel method

Abstract

The present invention belongs to the field of organic synthesis, particularly relates to the technical field of organic drug synthesis, and more specifically relates to a method for preparing the sacubitril intermediate by using a microchannel method. In the present invention, compound II and compound III are reacted in the presence of a base through a microchannel reactor to obtain the target compound I. In the present invention, by controlling the temperature of the heat exchanger of the microchannel reactor and the reaction time, the reaction efficiency can be effectively improved, the generation of reaction by-products can be reduced, the preparation efficiency and the product purity are significantly improved, thereby effectively solving the problems of long reaction time, many by-products, high requirements for equipment, low yield and low purity in the prior art.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, particularly to the field of organic drug synthesis, and more specifically to a method for preparing sacubitril intermediates by a microchannel method. Background Art

[0002] Heart failure has become a global public health problem seriously endangering human health. It is the terminal stage of the occurrence and development of cardiovascular diseases, and its incidence, rehospitalization rate and mortality are all increasing year by year. This makes it urgent to further develop more effective new drugs for the treatment of heart failure. The listing of sacubitril / valsartan with a dual mechanism of action of angiotensin receptor-neprilysin inhibitor has brought new changes to the treatment of heart failure patients.

[0003] Sacubitril / valsartan (Entresto) is a dual-acting angiotensin receptor-neprilysin inhibitor developed by Novartis and can be clinically used for the treatment of hypertension and heart failure. This drug is composed of sacubitril acting on neprilysin and valsartan acting on the renin-angiotensin-aldosterone system. It can effectively improve the symptoms of heart failure, lower blood pressure and actively improve renal function, and is an ideal drug for the treatment of heart failure.

[0004] Since the synthesis process of valsartan is relatively mature, the research focus of those skilled in the art has been concentrated on the synthesis optimization of the sacubitril part.

[0005] Sacubitril, chemically named 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid, has the following structure:

[0006]

[0007] Compound I is an important intermediate for the preparation of sacubitril drugs.

[0008]

[0009] The preparation method of sacubitril was disclosed in the original patent US5217996, and its synthetic route is as follows:

[0010]

[0011] In this synthetic route, Compound I is prepared by reacting Compound II with a phosphonium ylide reagent, and the structure of the phosphonium ylide reagent is shown in Formula a.

[0012]

[0013] Currently, in the existing technologies, this method is generally adopted to prepare compound I through the classical Wittig reaction. However, under this method, the yield of compound I is only 78%, and the low reaction yield not only causes waste of chiral alcohol raw materials, but also makes the cost of industrial synthesis of sacubitril remain high.

[0014] Microchannel reactors have a high specific surface area and regular laminar flow characteristics. When the reactants react in a microchannel reactor, they can continuously participate in subsequent reactions, thereby obtaining a high space-time yield. At the same time, compared with traditional preparation processes, microchannel reactors also have advantages such as fast mass transfer rate, short residence time, good repeatability, and convenience for automatic control.

[0015] Currently, no technical solutions for preparing the sacubitril intermediate compound I using a microchannel reactor have been publicly reported. Summary of the Invention

[0016] The technical problem to be solved by the present invention is to provide a method for preparing a sacubitril intermediate using a microchannel method, so as to improve the synthesis process of the sacubitril intermediate and achieve technical effects of low cost, high yield, high safety, and environmental friendliness.

[0017] To solve the above technical problem, the present invention discloses a method for preparing a sacubitril intermediate using a microchannel method, including the following steps:

[0018] (1) Dissolve compound II in a solvent to prepare a solution of material A;

[0019] (2) Dissolve compound III in a solvent to prepare a solution of material B;

[0020] (3) Dissolve the base in a solvent to prepare a solution of material C;

[0021] (4) Pump the solution of material A, the solution of material B, and the solution of material C into the microchannel reactor at preset flow rates respectively. The temperature of the heat exchanger of the microchannel reactor is set between -100 °C and -50 °C, and the residence reaction time of the materials in the microchannel reactor is set between 60 s and 300 s;

[0022] Obtain a product containing compound I from the outlet of the microchannel reactor; then obtain compound I through post-treatment; here, the post-treatment refers to treatment steps such as purification and refinement of the compound, including but not limited to quenching, separation, extraction, washing, concentration, and recrystallization;

[0023] The synthesis route of this reaction is as follows:

[0024]

[0025] Among them, R is selected from Any one of them.

[0026] Further, the base is one of sodium hydride, LiHMDS, NaHMDS, sodium methoxide, sodium ethoxide, butyllithium, potassium tert-butoxide, sodium tert-butoxide or LDA.

[0027] Further, the molar ratio of the compound II to the compound III and the base is 1:(1 - 1.5):(1 - 1.5).

[0028] Further, the solvents in each step are the same and are each selected from any one or several of tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, ethyl acetate, acetone or methyl isopropyl ketone.

[0029] Further, the reaction temperature is -90 to -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. For better results, the reaction temperature is preferably -70 °C.

[0030] Further, the residence reaction time of the materials in the microchannel reactor is preferably set to 80 - 260 s.

[0031] Further, the flow rates of the material A, material B and material C solutions in the microchannel reactor are 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 4 ml / min.

[0032] Further, the synthesis of the compound III in the present invention includes the following steps:

[0033] (1) Reacting the compound V and the compound VI in the presence of a base and a phase transfer catalyst to obtain the compound IV;

[0034] (2) Oxidizing the compound IV with an oxidant in the presence of a catalyst to obtain the compound III.

[0035] The specific synthesis route is as follows:

[0036]

[0037] Among them, R is selected from Any one of them.

[0038] Further, in the step (1), the phase transfer catalyst is one of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogensulfate, benzyltriethylammonium chloride or 18-crown-6 ether.

[0039] Further, in the step (1), the base is one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.

[0040] Furthermore, the solvent in step (1) is one or more of dimethyl sulfoxide, N,N-dimethylformamide, methanol, isopropanol or N-methylpyrrolidone.

[0041] Furthermore, 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 °C, 135 °C or 140 °C. For better results, the reaction temperature is preferably 125 °C.

[0042] Furthermore, in step (2), the catalyst is one of ammonium heptamolybdate tetrahydrate, phosphomolybdic acid or tungsten trioxide.

[0043] Furthermore, the oxidant in step (2) is one of hydrogen peroxide, sodium hypochlorite, potassium permanganate, potassium perborate, sodium dichromate or m-chloroperoxybenzoic acid.

[0044] Furthermore, the solvent in step (2) is one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile or N-methylpyrrolidone.

[0045] Furthermore, 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 °C or 40 °C. For better results, the reaction temperature is preferably 5 °C.

[0046] In the present invention, compound II and compound III are reacted in the presence of a base through a microchannel reactor to obtain the target compound I. By controlling the temperature of the heat exchanger of the microchannel reactor and the reaction time, the reaction efficiency can be effectively improved, the generation of reaction by-products can be reduced, and the preparation efficiency and product purity are significantly improved, thus effectively solving the problems of long reaction time, many by-products, high requirements for equipment, low yield and low purity in the prior art.

[0047] The present invention precisely controls the material reaction process through the flow rate, temperature and reaction time, greatly shortening the reaction time. The whole reaction has high safety, low cost and simple post-treatment, and the product compound I has high yield and purity, which is an efficient preparation new method suitable for industrial large-scale production. Detailed Embodiments

[0048] To better understand the present invention, the following specific embodiments are used to further illustrate the present invention.

[0049] Unless otherwise specified, the reagents used in the embodiments of the present invention are all ordinary commercially available products.

[0050] Example 1

[0051]

[0052] (1) Synthesis of Compound IV-1

[0053] Under nitrogen protection, compound V (10 g, 73 mmol), compound VI-1 (14.3 g, 80.3 mmol) and 100 ml of dimethyl sulfoxide were added to a reaction vessel and stirred until dissolved. Then tetrabutylammonium bromide (1.2 g, 3.7 mmol) and sodium bicarbonate (12.3 g, 146 mmol) were added, and the reaction mixture was reacted at 125 °C. After the reaction was completed, the reaction mixture was cooled to 20 °C, and 200 mL of methyl tert-butyl ether and 200 mL of saturated NaHCO3 aqueous solution were added. The organic layer was separated, and the aqueous layer was washed with 100 mL of methyl tert-butyl ether. The combined organic phase was then washed with 100 mL of saturated NaHCO3 aqueous solution, dried over Na2SO4, and the organic phase was concentrated to obtain compound IV-1 with a yield of 96.5% and a purity of 99.4%.

[0054] (2) Synthesis of Compound III-1

[0055] Compound IV-1 (10 g, 36 mmol) and 100 mL of dimethyl sulfoxide were added to a reaction vessel and stirred until dissolved. The reaction solution was cooled to 5 °C, then ammonium heptamolybdate tetrahydrate (0.9 g, 0.72 mmol) and 30% hydrogen peroxide (16.3 g, 144 mmol) were added, and the reaction mixture was reacted at 5 °C. After the reaction was completed, the reaction mixture was warmed to 20 °C, 50 mL of dimethyl sulfoxide and 100 mL of saturated NaHCO3 aqueous solution were added. The organic layer was separated, washed with 50 mL of saturated NaHCO3 aqueous solution, dried over Na2SO4, the organic phase was concentrated, and then recrystallized from isopropanol to obtain compound III-1 with a yield of 92.7% and a purity of 99.1%.

[0056] Example 2

[0057]

[0058] (1) Synthesis of Compound IV-2

[0059] Under nitrogen protection, compound V (10 g, 73 mmol), compound VI-2 (13.4 g, 80.3 mmol) and 100 ml of N,N-dimethylformamide were added to a reaction vessel and stirred until dissolved. Then tetrabutylammonium chloride (1 g, 3.7 mmol) and sodium carbonate (15.5 g, 146 mmol) were added, and the reaction mixture was reacted at 140 °C. After the reaction was completed, the reaction mixture was cooled to 20 °C, and 200 mL of methyl tert-butyl ether and 200 mL of saturated NaHCO3 aqueous solution were added. The organic layer was separated, and the aqueous layer was washed with 100 mL of methyl tert-butyl ether. The combined organic phase was then washed with 100 mL of saturated NaHCO3 aqueous solution, dried over Na2SO4, and the organic phase was concentrated to obtain compound IV-2 with a yield of 94.1% and a purity of 99.2%.

[0060] (2) Synthesis of compound III-2

[0061] Compound IV-2 (9.6 g, 36 mmol) and 100 mL of acetonitrile were added to a reaction vessel and stirred until dissolved. The reaction solution was cooled to -10 °C, then phosphomolybdic acid (1.3 g, 0.72 mmol) and 30% hydrogen peroxide (16.3 g, 144 mmol) were added, and the reaction mixture was reacted at -10 °C. After the reaction was completed, the reaction mixture was warmed to 20 °C, 50 mL of acetonitrile and 100 mL of saturated NaHCO3 aqueous solution were added. The organic layer was separated, washed with 50 mL of saturated NaHCO3 aqueous solution, dried over Na2SO4, the organic phase was concentrated, and then recrystallized from isopropanol to obtain compound III-2 with a yield of 89.6% and a purity of 99.2%.

[0062] Example 3

[0063]

[0064] (1) Synthesis of compound IV-3

[0065] Under nitrogen protection, compound V (10 g, 73 mmol), compound VI-3 (10.6 g, 80.3 mmol) and 100 ml of methanol were added to a reaction vessel and stirred until dissolved. Then benzyltriethylammonium chloride (0.84 g, 3.7 mmol) and sodium hydroxide (5.8 g, 146 mmol) were added, and the reaction mixture was reacted at 80 °C. After the reaction was completed, the reaction mixture was cooled to 20 °C, 200 mL of methyl tert-butyl ether and 200 mL of saturated NaHCO3 aqueous solution were added. The organic layer was separated, and the aqueous layer was washed with 100 mL of methyl tert-butyl ether. The combined organic phase was then washed with 100 mL of saturated NaHCO3 aqueous solution, dried over Na2SO4, and the organic phase was concentrated to obtain compound IV-3 with a yield of 91.8% and a purity of 99.3%.

[0066] (2) Synthesis of Compound III-3

[0067] Compound IV-3 (8.4 g, 36 mmol) and 100 mL of N, N-dimethylformamide were added to the reaction vessel and stirred to dissolve. The reaction solution was cooled to 40 ° C, and then ammonium heptamolybdate tetrahydrate (0.9 g, 0.72 mmol) and m-chloroperbenzoic acid (24.8 g, 144 mmol) were added, and the reaction mixture was reacted at 40 ° C. After the reaction was completed, the reaction mixture was warmed to 20 ° C, and 50 mL of N, N-dimethylformamide and 100 mL of saturated NaHCO3 aqueous solution were added. The organic phase was separated, washed with 50 mL of saturated NaHCO3 aqueous solution, dried with Na2SO4, and the organic phase was concentrated and recrystallized from isopropanol to obtain compound III-3 with a yield of 87.9% and a purity of 99.1%.

[0068] Example 4

[0069]

[0070] (1) Preparation of Material A Solution: Compound II (30 g, 92 mmol) was added to tetrahydrofuran, diluted to 100 mL, stirred evenly, and placed in a raw material tank A (the bottom of the raw material tank was connected to the corresponding feed pipe of the microchannel reactor through a valve) and protected with nitrogen for use.

[0071] (2) Preparation of material B solution: Compound III-1 (32.6 g, 105 mmol) was added to tetrahydrofuran, diluted to 150 mL, stirred evenly, and placed in raw material tank B (the bottom of the raw material tank was connected to the corresponding feed pipe of the microchannel reactor through a valve) and protected with nitrogen for use.

[0072] (3) Preparation of Material C Solution: LiHMDS (20.2 g, 120 mmol) was added to tetrahydrofuran, diluted to 80 mL, stirred evenly, and placed in a raw material tank C (the bottom of the raw material tank was connected to the corresponding feed pipe of the microchannel reactor through a valve) and protected with nitrogen for use.

[0073] (4) Open the valve at the bottom of the raw material tank and use the feed pump to deliver 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, respectively. Set the flow rate of raw material tank A to 5 ml / min, the flow rate of raw material tank B to 7.5 ml / min, and the flow rate of raw material tank C to 4 ml / min using the counter pump. Then, set the temperature of the heat exchanger to -70°C and maintain the reaction time in the channel for 180 s. After the reaction is completed, a sample is collected from the outlet of the microchannel reactor to obtain a mixture containing the target compound I.

[0074] The mixture was warmed to -10°C and quenched with 100 mL of 10% aqueous NaHCO₃. The phases were separated, and the aqueous layer was extracted with 100 mL of ethyl acetate. The combined organic phases were washed with 100 mL of 5% aqueous Na₂CO₃ and concentrated under vacuum. After concentration, methanol was added for recrystallization to afford Compound I in a yield of 95.8% and a purity of 99.6%.

[0075] Example 5

[0076]

[0077] (1) Preparation of Material A Solution: Compound II (30 g, 92 mmol) was added to toluene, diluted to 100 mL, stirred evenly, and placed in a raw material tank A (the bottom of the raw material tank was connected to the corresponding feed pipe of the microchannel reactor through a valve) and protected with nitrogen for use.

[0078] (2) Preparation of material B solution: Compound III-2 (41.3 g, 138 mmol) was added to toluene, diluted to 150 mL, stirred evenly, and placed in raw material tank B (the bottom of the raw material tank was connected to the corresponding feed pipe of the microchannel reactor through a valve) and protected with nitrogen for use.

[0079] (3) Preparation of Material C Solution: Sodium hydride (2.3 g, 95.8 mmol) was added to toluene, diluted to 80 mL, stirred evenly, and placed in a raw material tank C (the bottom of the raw material tank was connected to the corresponding feed pipe of the microchannel reactor through a valve) and protected with nitrogen for use.

[0080] (4) Open the valve at the bottom of the raw material tank and use the feed pump to deliver 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, respectively. Use the counter pump to set the flow rate of raw material tank A to 5 ml / min, the flow rate of raw material tank B to 7.5 ml / min, and the flow rate of raw material tank C to 4 ml / min. Then, set the temperature of the heat exchanger to -90°C and maintain the reaction time in the channel for 100 s. After the reaction is completed, a sample is collected from the outlet of the microchannel reactor to obtain a mixture containing the target compound I.

[0081] The mixture was warmed to -10°C and quenched with 100 mL of 10% aqueous NaHCO₃. The phases were separated, and the aqueous layer was extracted with 100 mL of ethyl acetate. The combined organic phases were washed with 100 mL of 5% aqueous Na₂CO₃ and concentrated under vacuum. After concentration, methanol was added for recrystallization to afford Compound I in a yield of 91.4% and a purity of 99.3%.

[0082] Example 6

[0083]

[0084] (1) Preparation of Material A Solution: Compound II (30 g, 92 mmol) was added to dioxane, diluted to 100 mL, stirred evenly, and placed in a raw material tank A (the bottom of the raw material tank was connected to the corresponding feed pipe of the microchannel reactor through a valve) and protected with nitrogen for use.

[0085] (2) Preparation of material B solution: Compound III-3 (24.4 g, 92.3 mmol) was added to dioxane, diluted to 150 mL, stirred evenly, and placed in raw material tank B (the bottom of the raw material tank was connected to the corresponding feed pipe of the microchannel reactor through a valve) and protected with nitrogen for use.

[0086] (3) Preparation of Material C Solution: NaHMDS (25.3 g, 138 mmol) was added to dioxane, diluted to 80 mL, stirred evenly, and placed in a raw material tank C (the bottom of the raw material tank was connected to the corresponding feed pipe of the microchannel reactor through a valve) and protected with nitrogen for use.

[0087] (4) Open the valve at the bottom of the raw material tank and use the feed pump to deliver 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, respectively. Set the flow rate of raw material tank A to 5 ml / min, the flow rate of raw material tank B to 7.5 ml / min, and the flow rate of raw material tank C to 4 ml / min using the counter pump. Then, set the temperature of the heat exchanger to -60°C and maintain the reaction time in the channel for 260 s. After the reaction is completed, a sample is collected from the outlet of the microchannel reactor to obtain a mixture containing the target compound I.

[0088] The mixture was warmed to -10°C and quenched with 100 mL of 10% aqueous NaHCO₃. The phases were separated, and the aqueous layer was extracted with 100 mL of ethyl acetate. The combined organic phases were washed with 100 mL of 5% aqueous Na₂CO₃ and concentrated under vacuum. After concentration, methanol was added for recrystallization to afford Compound I in a yield of 90.7% and a purity of 99.4%.

[0089] The above is a specific embodiment of the present invention. It should be noted that those skilled in the art can make several improvements and modifications without departing from the principles of the present invention, and these improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. A method for preparing sacubitril intermediate by microchannel method, characterized in that, It includes the following steps: (1) Dissolve Compound II in a solvent to prepare Solution A of the material; (2) Dissolve Compound III in a solvent to prepare Solution B of the material; (3) Dissolve a base in a solvent to prepare Solution C of the material; (4) Pump Solution A of the material, Solution B of the material and Solution C of the material into a microchannel reactor at preset flow rates respectively. The temperature of the heat exchanger of the microchannel reactor is set between -100 °C and -50 °C, and the residence reaction time of the material in the microchannel reactor is set between 60 s and 300 s; Obtain the product containing Compound I from the outlet of the microchannel reactor; then obtain Compound I through post-treatment; The synthetic route of this reaction is as follows: ； wherein, R is selected from any one of 2. The method for preparing the sacubitril intermediate by the microchannel method according to claim 1, wherein The base is any one of sodium hydride, LiHMDS, NaHMDS, sodium methoxide, sodium ethoxide, butyllithium, potassium tert-butoxide, sodium tert-butoxide or LDA.

3. The method for preparing sacubitril intermediate by using the microchannel method according to claim 1, characterized in that, [[ID=?]]The molar ratio of Compound II to Compound III and the base is 1:(1 - 1.5):(1 - 1.5).

4. The method for preparing the sacubitril intermediate by the microchannel method according to claim 1, wherein, The solvents in each step are the same and are each selected from any one or more of tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, ethyl acetate, acetone or methyl isopropyl ketone.

5. The method for preparing the sacubitril intermediate by the microchannel method according to claim 1, wherein, The temperature of the heat exchanger of the microchannel reactor is selected from -90 °C to -60 °C.

6. The method for preparing the sacubitril intermediate by the microchannel method according to claim 1, wherein The residence reaction time of the material in the microchannel reactor is selected from 80 s to 260 s.

7. The method for preparing the sacubitril intermediate by the microchannel method according to claim 1 or 3, characterized in that, The flow rates of Solution A of the material, Solution B of the material and Solution C of the material in the microchannel reactor are selected as follows: the flow rate of Solution A of the material is 5 ml / min; the flow rate of Solution B of the material is 7.5 ml / min; the flow rate of Solution C of the material is 4 ml / min.

8. The method for preparing the sacubitril intermediate by the microchannel method according to claim 1, wherein, The synthesis of Compound III includes the following steps: (III-1) React Compound V and Compound VI in the presence of a base and a phase transfer catalyst to obtain Compound IV; (III-2) Oxidize Compound IV with an oxidizing agent in the presence of a catalyst to obtain Compound III. The specific synthetic route is as follows: ； wherein, R is selected from any one of 9. The method for preparing the sacubitril intermediate by the microchannel method according to claim 8, wherein, The phase transfer catalyst in step (III-1) is one of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogensulfate, benzyltriethylammonium chloride or 18-crown-6-ether.

10. The method for preparing the sacubitril intermediate by the microchannel method according to claim 8, wherein, The base in step (III-1) is one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.

11. The method for preparing the sacubitril intermediate by the microchannel method according to claim 8, wherein, The solvent in step (III-1) is one or more of dimethyl sulfoxide, N,N-dimethylformamide, methanol, isopropanol or N-methylpyrrolidone.

12. The method for preparing the sacubitril intermediate by the microchannel method according to claim 8, characterized in that, The reaction temperature in step (III-1) is 80 °C to 140 °C.

13. The method for preparing sacubitril intermediate by using the microchannel method according to claim 8, characterized in that, The catalyst in step (III-2) is one of ammonium molybdate tetrahydrate, phosphomolybdic acid or tungsten trioxide.

14. The method for preparing the sacubitril intermediate by the microchannel method according to claim 8, wherein, The oxidizing agent in step (III-2) is one of hydrogen peroxide, sodium hypochlorite, potassium permanganate, potassium perborate, sodium dichromate or m-chloroperbenzoic acid.

15. The method for preparing sacubitril intermediate by using the microchannel method according to claim 8, characterized in that, The solvent in step (III-2) is one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile or N-methylpyrrolidone.

16. The method for preparing sacubitril intermediate by microchannel method according to claim 8, characterized in that, The reaction temperature in step (III-2) is -10 °C to 40 °C.

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