Synthesis method of sinocarbamate

Abstract

The invention discloses a synthesis method of sinocarbamate, which shortens the route steps, reduces the process cost, improves the purity and yield of the final product, and is suitable for large-scale production.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and in particular relates to a method for synthesizing cinovadate. Background Art

[0002] Cinobamate is a new tetrazolidinyl carbamate derivative developed and marketed by SK Life Sciences. It has an inhibitory effect on persistent sodium ion currents and has a broad spectrum of anticonvulsant activity. It effectively inhibits epilepsy in focal epilepsy models. It can also inhibit nerve impulses and reduce neuronal excitability by regulating γ-aminobutyric acid (GABA) receptors, thereby exerting an anti-epileptic effect. The drug was approved by the FDA for marketing in November 2019 and can be used as an innovative treatment for epilepsy.

[0003] The chemical name of cinoxate is [(1R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl]carbamate.

[0004]

[0005] The synthesis process of sinocarbamate was first reported in SK's patent CN101228138B, which uses pure enantiomer (R)-aryl-oxacyclopropane as a starting material, and converts it into an alcohol intermediate by ring-opening reaction with tetrazole in the presence of an appropriate base in a solvent, and then introduces a carbamoyl group into the alcohol intermediate. In order to separate and purify the 1N and 2N positional isomers prepared thereby, column chromatography can be performed after forming an alcohol intermediate or carbamate. However, the ring-opening reaction requires a higher temperature, so there is a very high risk of uncontrolled reaction. With regard to the low selectivity of the reaction, the yield of a single positional isomer is relatively low, and it is difficult to separate and purify. In addition, the overall synthetic route is relatively long, and the intermediate by-products are relatively more difficult to remove, which affects the purity of the final product, the process operation is cumbersome, the product production cost is relatively high, and there are more three wastes, which is not suitable for amplified production.

[0006] Then, SK disclosed a new preparation method in its patents CN102803233B and CN102574821B. 2-halogenated-2'-chloroacetophenone first reacts with tetrazole, then asymmetric reduction is used to prepare chiral alcohol, and further reaction is performed to obtain cinovaline. Because the process reported in the literature requires column chromatography for separation and requires oxidoreductase to catalyze the asymmetric reduction reaction, it is not suitable for industrial production. On this basis, SK further applied for patent CN114901647A in 2020, which indicates that 1H-tetrazole is first reacted with an inorganic base to prepare a 1H-tetrazole metal salt, and then 2-bromo-2'-chloroacetophenone is added, which can increase the yield of 2N ketone. The synthesis methods in these patent documents have proposed new synthesis ideas and preparation methods from different perspectives, but these routes still have certain defects when used for scale-up production, such as many intermediate by-products, low yield of cinovaparin finished product, certain risks in post-treatment and more wastes. It is still necessary to continue to study the low-cost, high-efficiency and high-yield green synthesis route of cinovaparin, which is crucial to the economic and technological development of cinovaparin API. Summary of the invention

[0007] In view of the deficiencies in the prior art, the object of the present invention is to provide a method for synthesizing cinnocarbamide, which has a simple process route, low cost, high yield, less pollution, and is suitable for industrial production.

[0008] One of the objects of the present invention is to provide a method for synthesizing cinnocarbamate, using the following scheme: (1) adding a reaction solvent, an azide reagent and compound 1 into a reaction container to react to obtain compound 2; (2) Compound 2 reacts with glacial acetic acid, ammonium chloride and orthoformate to obtain compound 3; (3) Compound 3 is reduced under the action of a metal catalyst to obtain compound 4; (4) Compound 4 is dissolved in a solvent, and chlorosulfonic acid isocyanate is added to react to obtain cinamide.

[0009] The route looks like this: As a preferred technical solution, the molar ratio of compound 1 to azide reagent in step (1) is 1:1.0 to 1:2.0.

[0010] As a preferred technical solution, the nucleophilic reagent in step (1) is sodium azide, potassium azide, lithium azide, trimethylsilyl azide, tributyltin azide, tetrabutylammonium azide, tetramethylguanidine azide, ethyl azidoacetate, diphenylphosphoryl azide, preferably sodium azide, diphenylphosphoryl azide, and most preferably sodium azide.

[0011] As a preferred technical solution, the substitution reaction solvent in step (1) is toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran or acetone, preferably acetone.

[0012] As a preferred technical solution, in step (2), 1 equivalent of ammonium chloride, 0.9 to 1.2 equivalents of compound 2 and 1.0 to 1.5 equivalents of orthoformate are added to the reaction container.

[0013] As a preferred technical solution, the orthoformate in step (2) is methyl orthoformate, ethyl orthoformate, or propyl orthoformate.

[0014] As a preferred technical solution, the metal catalyst in step (3) is selected from ruthenium, platinum, palladium, rhodium, and iridium-based catalysts, preferably a ruthenium-based catalyst.

[0015] As a preferred technical solution, the ruthenium-based catalyst in step (3) is selected from ruthenium (II) chloride {[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(P-isopropyltoluene) salt (II)), ruthenium acetate, ruthenium chloride, dichlorobis(4-methylisopropylphenyl)ruthenium (II), phenylmethylenebis(tricyclohexylphosphine)dichlororuthenium, tris(triphenylphosphine)dichlororuthenium, preferably ruthenium (II) chloride {[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(P-isopropyltoluene) salt (II)).

[0016] As a preferred technical solution, the solvent in step (4) is a mixed solvent of formic acid and triethylamine, and the weight ratio of formic acid to triethylamine is 1:0.5 to 1:2.0, preferably 1:0.8 to 1:1.5.

[0017] As a preferred technical solution, the molar ratio of compound 4 to chlorosulfonic acid isocyanate in step (4) is 1:1.0~1:3.0, preferably 1:1.0~1:1.5.

[0018] Through the above technical scheme, compared with the prior art, the present invention has the following beneficial effects: the present invention reduces the process cost, and improves the structure of the cinovaparin intermediates to improve their crystallization properties, which is beneficial to improve the purity and yield of the final product and is suitable for large-scale production. DETAILED DESCRIPTION

[0019] The following is a detailed description of an embodiment of the present invention. This embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation method and a specific operation process are given, but the protection scope of the present invention is not limited to the following embodiment.

[0020] Comparative Example 1 (prepared with reference to CN101228138A): Tetrazole (0.165 g) was dissolved in methanol (9 mL) and potassium carbonate (0.538 g) was added thereto at room temperature.

[0021] The reaction product was stirred at room temperature for about 15 minutes. After confirming that carbon dioxide gas was no longer generated, n-butyl acetate (9 mL) was added, methanol was removed by reduced pressure distillation, and n-butyl acetate was added. After 2-bromo-2'-chloroacetophenone (0.50 g) was added to the reaction solution, the reaction product was stirred at 50°C for 12 hours, washed with water, and dried to obtain 0.45 g of product, with a yield of 63.8% and a purity of 60.1%.

[0022] Comparative Example 2 (prepared with reference to CN102574821A): 1-(2-chlorophenyl)-2-(2-tetrazolyl)ethanone (100 mg, 0.449 mmol) and nicotinamide adenine dinucleotide (NAD, 0.5 mg) were cultured in PBS (10 mL, pH 7.0) containing 5% (w / v) glycerol at room temperature for 4 days in the presence of the oxidoreductase-producing microbial strain Rhodotorula KCTC7117 (500 mg). After extraction with ethyl acetate (1 mL), 81 mg of (R)-1-(2-chlorophenyl)-2-(2H-1 tetrazol-2-yl)ethan-1-ol was obtained with a yield of 59.8% and a purity of 78.2%. Example 1

[0023] Preparation of compound 2 Compound 1 (100 g, 0.43 mol) was added to a 1L reaction vessel containing acetone (500 mL), and sodium azide (55.9 g, 0.86 mol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure to a zero flow rate to obtain 84.1 g of compound 2. The yield was 100% and the purity was 98.2%. HRMS (ESI): m / z[M+H] + :196.81.

[0024] Preparation of compound 3 To a 2L reaction vessel, glacial acetic acid (200 g, 3.33 mol), ammonium chloride (34.8 g, 0.65 mol), triethyl orthoformate (103.7 g, 0.70 mol), and compound 2 (114.4 g, 0.59 mol) were added in sequence, stirred evenly, heated to 95°C, maintained at the temperature for 12 h, filtered while hot to remove the salt in the reaction solution, and the filtrate was concentrated under reduced pressure in a 65°C water bath until no liquid was evaporated, methyl tert-butyl ether was added, stirred at 50°C for 2 h, cooled to room temperature, and filtered to obtain 51.2 g of compound 3, with a yield of 39.6% and a purity of 96.7%. HRMS (ESI): m / z[M+H] + :223.04.

[0025] Preparation of compound 4 Triethylamine (358.8 g, 3.6 mol) was added to a 3 L hydrogenation reactor, and anhydrous formic acid (598 g, 13.0 mol) was slowly added. After the addition was completed, compound 3 (300 g, 1.3 mol) was added. Under a nitrogen atmosphere, ruthenium (II) chloride (15 g, 5% w / w) {[(1R,2R)-(-)-2-amino-1,2-diphenylethyl] (4-toluenesulfonyl) amino} (P-isopropyltoluene) salt (II)) was added, and the reaction was stirred for 2-3 hours. Water was added, extracted with ethyl acetate, separated, and the organic phase was dried under reduced pressure to obtain 282.9 g of light yellow oil, i.e., compound 4, with a yield of 94.3% and a purity of 99.1%. HRMS (ESI): m / z [M+H] + :225.05.

[0026] Preparation of compound 5 Compound 4 (900 g, 4.0 mol) and tetrahydrofuran (4.5 L, 5 V) were added to a three-necked flask, and chlorosulfonyl isocyanate (560.7 g, 4.0 mol) was slowly added dropwise. After addition, the reaction was stirred for 2 h. The reaction solution was quenched with water. Ethyl acetate was added, the liquids were separated, and the organic phase was dried under reduced pressure to obtain 1210 g of crude compound 5. The crude product was recrystallized from isopropanol to obtain 997.6 g of pure compound 5. Purity 92.4%, yield 96.1%, HRMS (ESI): m / z [M+H] + :268.06. Example 2

[0027] (1) Preparation of Compound 2 Compound 1 (150 g, 0.65 mol) was added to a 2 L reaction vessel containing dimethyl sulfoxide (750 mL), and sodium azide (83.9 g, 1.29 mol) was added. The reaction mixture was stirred at room temperature for 13 hours. After the reaction, the reaction mixture was quenched with water (1 L), extracted and filtered with DCM (2×200 mL), and the filtrate was concentrated under reduced pressure to no flow to obtain 124.6 g of compound 2, with a yield of 98.7% and a purity of 97.1%. HRMS (ESI): m / z[M+H] + :196.81.

[0028] (2) Preparation of compound 3 To a 2 L reaction vessel, glacial acetic acid (300 g, 4.99 mol), ammonium chloride (57.3 g, 1.07 mol), triethyl orthoformate (157.3 g, 1.07 mol), and compound 2 (167.4 g, 0.86 mol) were added in sequence, stirred evenly, heated to 75°C-95°C, maintained at the temperature for 12 h, filtered while hot to filter out the salt in the reaction solution, and the filtrate was concentrated under reduced pressure in a 65°C water bath until no liquid was evaporated, methyl tert-butyl ether was added, stirred at 50°C for 2 h, cooled to room temperature, and filtered to obtain 69.0 g of compound 3, with a yield of 36.0% and a purity of 96.4%. HRMS (ESI): m / z[M+H] + :223.04.

[0029] (3) Preparation of compound 4 Triethylamine (341.6 g, 3.4 mol) was added to a 3 L hydrogenation reactor, and anhydrous formic acid (427 g, 9.3 mol) was slowly added. After the addition was completed, compound 3 (220 g, 1.67 mol) was added. Under a nitrogen atmosphere, ruthenium (II) chloride (11 g, 5% w / w) {[(1R,2R)-(-)-2-amino-1,2-diphenylethyl] (4-toluenesulfonyl) amino} (P-isopropyltoluene) salt (II)) was added, and the reaction was stirred for 2-3 h. Water was added, extracted with ethyl acetate, separated, and the organic phase was dried under reduced pressure to obtain 205.3 g of light yellow oil, i.e., compound 4, with a yield of 93.3% and a purity of 99.1%. HRMS (ESI): m / z [M+H] + :225.05.

[0030] (4) Preparation of compound 5 Compound 4 (500 g, 2.2 mol) and tetrahydrofuran (2.5 L, 5 V) were added to a three-necked flask, and chlorosulfonyl isocyanate (438.7 g, 3.1 mol) was slowly added dropwise. After addition, the reaction was stirred for 2 h. The reaction solution was quenched with water. Ethyl acetate was added, the liquids were separated, and the organic phase was dried under reduced pressure to obtain 608 g of crude compound 5. The crude product was recrystallized from isopropanol to obtain 559.2 g of pure compound 5. Purity 99.9%, yield 93.2%, HRMS (ESI): m / z [M+H] + :268.06. Example 3

[0031] (1) Preparation of Compound 2 Compound 1 (100 g, 0.43 mol) was added to a 1L reaction vessel containing acetone (500 mL), and sodium azide (28.0 g, 0.43 mol) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure to a zero flow rate to obtain 83.5 g of compound 2, which was used directly in the next step without purification. The yield was 99.3% and the purity was 98.2%. HRMS (ESI): m / z[M+H] + :196.81.

[0032] (2) Preparation of compound 3 To a 2 L reaction vessel, glacial acetic acid (300 g, 4.99 mol), ammonium chloride (40.0 g, 0.75 mol), triethyl orthoformate (170.0 g, 1.13 mol), and compound 2 (176.0 g, 0.90 mol) were added in sequence, stirred evenly, heated to 75°C-95°C, maintained at the temperature for 12 h, filtered while hot to filter out the salt in the reaction solution, and the filtrate was concentrated under reduced pressure in a 65°C water bath until no liquid was evaporated, methyl tert-butyl ether was added, stirred at 50°C for 2 h, cooled to room temperature, and filtered to obtain 75.3 g of compound 3, with a yield of 37.2% and a purity of 96.4%. HRMS (ESI): m / z[M+H] + :223.04.

[0033] (3) Preparation of compound 4 Triethylamine (640.5 g, 6.3 mol) was added to a 3 L hydrogenation reactor, and anhydrous formic acid (427 g, 9.3 mol) was slowly added. After the addition was completed, compound 3 (220 g, 1.67 mol) was added. Under a nitrogen atmosphere, ruthenium (II) chloride (11 g, 5% w / w) {[(1R,2R)-(-)-2-amino-1,2-diphenylethyl] (4-toluenesulfonyl) amino} (P-isopropyltoluene) salt (II)) was added, and the reaction was stirred for 2-3 hours. Water was added, extracted with ethyl acetate, separated, and the organic phase was dried under reduced pressure to obtain 201.2 g of light yellow oil, i.e., compound 4, with a yield of 91.5% and a purity of 99.1%. HRMS (ESI): m / z [M+H] + :225.05.

[0034] (4) Preparation of compound 5 Compound 4 (500 g, 2.2 mol) and tetrahydrofuran (2.5 L, 5 V) were added to a three-necked flask, and chlorosulfonyl isocyanate (934 g, 6.6 mol) was slowly added dropwise. After addition, the reaction was stirred for 2 h. The reaction solution was quenched with water. Ethyl acetate was added, the liquids were separated, and the organic phase was dried under reduced pressure to obtain 608 g of crude compound 5. The crude product was recrystallized from isopropanol to obtain 564.6 g of pure compound 5. Purity 99.9%, yield 94.1%, HRMS (ESI): m / z [M+H] + :268.06. Example 4

[0035] (1) Preparation of Compound 2 Compound 1 (100 g, 0.43 mol) was added to a 1L reaction vessel containing acetone (500 mL), and then diphenylphosphoryl azide (118.2 g, 0.43 mol) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure to no flow to obtain 75.9 g of compound 2, which was used directly in the next step without purification. The yield was 90.2% and the purity was 96.7%. HRMS (ESI): m / z [M+H] + :196.81.

[0036] (2) Preparation of compound 3 To a 2L reaction vessel, glacial acetic acid (300 g, 4.99 mol), ammonium chloride (40.0 g, 0.75 mol), trimethyl orthoformate (112.5 g, 1.06 mol), and compound 2 (176.0 g, 0.9 mol) were added in sequence, stirred evenly, heated to 75°C-95°C, maintained at the temperature for 12 h, filtered while hot to filter out the salt in the reaction solution, and the filtrate was concentrated under reduced pressure in a 65°C water bath until no liquid was evaporated, methyl tert-butyl ether was added, stirred at 50°C for 2 h, cooled to room temperature, and filtered to obtain 72.4 g of compound 3, with a yield of 35.8% and a purity of 96.2%. HRMS (ESI): m / z[M+H] + :223.04.

[0037] (3) Preparation of compound 4 Triethylamine (640.5 g, 6.3 mol) was added to a 3 L hydrogenation reactor, and anhydrous formic acid (427 g, 9.3 mol) was slowly added. After the addition was completed, compound 3 (220 g, 1.67 mol) was added. Dichlorobis(4-methylisopropylphenyl)ruthenium (II) (11 g, 5% w / w) was added under a nitrogen atmosphere, and the reaction was stirred for 2-3 h. Water was added, extracted with ethyl acetate, separated, and the organic phase was dried under reduced pressure to obtain 207.2 g of light yellow oil, i.e., compound 4, with a yield of 94.4% and a purity of 99.2%. HRMS (ESI): m / z [M+H] + :225.05.

[0038] (4) Preparation of compound 5 Compound 4 (500 g, 2.2 mol) and dioxane (2.5 L, 5 V) were added to a three-necked flask, and chlorosulfonyl isocyanate (934 g, 6.6 mol) was slowly added dropwise. After addition, the reaction was stirred for 2 h. The reaction solution was quenched with water. Ethyl acetate was added, the liquids were separated, and the organic phase was dried under reduced pressure to obtain 608 g of crude compound 5. The crude product was recrystallized from isopropanol to obtain 559.8 g of pure compound 5. Purity 99.9%, yield 93.3%, HRMS (ESI): m / z [M+H] + :268.06.

Claims

1. A method for synthesizing cinnocarbamide, characterized in that: It includes the following steps: (1) adding a reaction solvent, an azide reagent and compound 1 into a reaction container to react to obtain compound 2; (2) Compound 2 reacts with glacial acetic acid, ammonium chloride and orthoformate to obtain compound 3; (3) Compound 3 is subjected to a reduction reaction in the presence of a solvent and a metal catalyst to obtain compound 4; (4) Compound 4 is dissolved in a solvent, and chlorosulfonic acid isocyanate is added to react to obtain cinamide; The route looks like this: 。 2. The method for synthesizing cinnocarbamide according to claim 1, wherein: The azide reagent in step (1) is sodium azide, potassium azide, lithium azide, trimethylsilane azide, tributyltin azide, tetrabutylammonium azide, tetramethylguanidine azide, ethyl azidoacetate, diphenylphosphoryl azide, preferably sodium azide, diphenylphosphoryl azide, more preferably sodium azide.

3. The method for synthesizing cinnocarbamide according to claim 1, characterized in that: The molar ratio of compound 1 to azide reagent in step (1) is 1:1.0 to 1:2.

0.

4. The method for synthesizing cinnocarbamide according to claim 1, characterized in that: The substitution reaction solvent in step (1) is toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, preferably acetone.

5. The method for synthesizing cinnocarbamide according to claim 1, characterized in that: In the step (2), 1 equivalent of ammonium chloride, 0.9 to 1.2 equivalents of compound 2 and 1.0 to 1.5 equivalents of orthoformate are added into a reaction container.

6. The method for synthesizing cinuobamate according to claim 1, characterized in that: The orthoformate in step (2) is methyl orthoformate, ethyl orthoformate, or propyl orthoformate.

7. The method for synthesizing cinnocarbamide according to claim 1, characterized in that: In step (3), the metal catalyst is selected from ruthenium, platinum, palladium, rhodium, and iridium-based catalysts, preferably a ruthenium-based catalyst.

8. The method for synthesizing cinnocarbamide according to claim 7, characterized in that: In the step (3), the ruthenium-based catalyst is selected from ruthenium (II) chloride {[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(P-isopropyltoluene) salt (II)), ruthenium acetate, ruthenium chloride, dichlorobis(4-methylisopropylphenyl)ruthenium (II), phenylmethylenebis(tricyclohexylphosphine)dichlororuthenium, tris(triphenylphosphine)dichlororuthenium, preferably ruthenium (II) chloride {[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(P-isopropyltoluene) salt (II).

9. The method for synthesizing cinnocarbamide according to claim 1, characterized in that: The solvent in step (3) is a mixed solvent of formic acid and triethylamine, and the weight ratio of formic acid to triethylamine is 1:0.5 to 1:2.0, preferably 1:0.8 to 1:1.

5.

10. The method for synthesizing cinnocarbamide according to claim 1, characterized in that: The molar ratio of compound 4 to chlorosulfonic acid isocyanate in step (4) is 1:1.0 to 1:3.0, preferably 1:1.0 to 1:1.

5.

11. The method for synthesizing cinnocarbamide according to claim 1, characterized in that: The solvent in step (4) is tetrahydrofuran or dioxane.

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