Preparation method of carbamic acid (R)-1-(2-chlorphenyl)-2-(tetrazole-2-yl) ethyl ester

Abstract

The invention provides a preparation method of carbamic acid (R)-1-(2-chlorphenyl)-2-(tetrazole-2-yl) ethyl ester, which comprises the following steps: carrying out substitution reaction by using tetrazole salt, and then carrying out chiral reduction by using a ruthenium catalyst to finally obtain a target product. The preparation method has the advantages of no need of long-time high-temperature reaction, high safety coefficient, no need of chiral resolution in reaction post-treatment, simplicity in operation, high chemical and optical purity of the product, suitability for industrial production and the like.

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and particularly relates to a preparation method of (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate, an antiepileptic drug. Background Art

[0002] Cenobamate, with the chemical name of (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate, is a new generation of antiepileptic drug developed by SK Company in South Korea and is used for the treatment of secondary epilepsy after treatment. Its structural formula is shown in Formula I below:

[0003]

[0004] Currently, the synthesis method of Compound I generally involves preparing a racemic compound and then resolving it. Patent CN101228138B discloses the following Synthetic Route 1. This method uses 2-bromo-1-(2-chlorophenyl)ethan-1-one and tetrazole as raw materials, and through reduction, resolution, and further carbamoylation reaction, the target product is obtained. This method has the following defects: (1) In this synthetic route, tetrazole participates in the reaction, and the reaction is carried out at the reflux temperature of toluene (110 - 120 °C) for a long time, with a relatively high reaction safety risk. Moreover, the stability of tetrazole is not high at this temperature, which is not conducive to large-scale production; (2) This synthetic route first prepares a racemic intermediate, and then further obtains the target product through resolution. The reaction operation is complex and the production cost is high, making it unsuitable for industrial production.

[0005]

[0006] Synthetic Route 1

[0007] Patent CN101228138B also discloses the following Synthetic Route 2. This method uses (R)-2-chlorostyrene oxide and tetrazole as raw materials to obtain an (R)-configured alcohol compound, and then through carbamoylation reaction to obtain Compound I. This method has the following defects: (1) This synthetic process route has a high content of positional isomer impurities and requires further column chromatography for separation and purification, with complex operations and being not conducive to industrial production; (2) The starting material (R)-2-chlorostyrene oxide has no stable source, which limits further batch scale-up production.

[0008]

[0009] Synthetic Route 2

[0010] Patent CN102574821B discloses a method for enantioselective enzymatic reduction of protected aryl ketones to obtain the R-configured compound I. This method has high requirements for production equipment and has a greater impact on the environment, which is not conducive to industrial production. Summary of the Invention

[0011] In view of the deficiencies of the prior art, the present invention provides a method for preparing (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate. This preparation method has the advantages of high safety factor, simple reaction operation, no need for chiral resolution after the reaction, high chemical purity and optical purity of the product, and being suitable for industrial production. Specifically, the present invention adopts the following technical solutions:

[0012] A method for preparing an intermediate of formula 1, which comprises preparing the intermediate 2-bromo-2-chloroacetophenone of formula 1 by bromination of compound o-chloroacetophenone;

[0013]

[0014] A method for preparing (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate, which comprises:

[0015] (a) Reacting the intermediate of formula 1 with a tetrazolium salt by a substitution reaction to obtain the intermediate of formula 2, 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one;

[0016] (b) Catalytic reduction of the intermediate of formula 2 to obtain the intermediate of formula 3, (R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethan-1-ol;

[0017]

[0018] A method for preparing (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate, which comprises: obtaining the crude product of (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate by carbamoylation of the intermediate of formula 3;

[0019]

[0020] In some specific embodiments, the bromination reaction is carried out under the action of a catalyst;

[0021] In some specific embodiments, the catalyst in the bromination reaction is one or two of p-toluenesulfonic acid and p-toluenesulfonic acid monohydrate;

[0022] In some specific embodiments, the bromination reaction is carried out under the action of an organic solvent;

[0023] In some specific embodiments, the organic solvent in the bromination reaction is one or more of acetonitrile, ethyl acetate, isopropyl acetate, and tetrahydrofuran;

[0024] In some specific embodiments, the reaction temperature of the bromination reaction is 60-80°C, preferably 60-70°C;

[0025] In some specific embodiments, the tetrazolium salt in step (a) is one or more of sodium tetrazolium salt, potassium tetrazolium salt, and lithium tetrazolium salt; preferably, the tetrazolium salt is sodium tetrazolium;

[0026] In some specific embodiments, the preparation of the tetrazolium salt in step (a) is carried out by reacting tetrazole with a base;

[0027] In some specific embodiments, the reaction temperature in the preparation of the tetrazolium salt in step (a) is 20-50°C, preferably 40-50°C;

[0028] In some specific embodiments, the reaction solvent in the preparation of the tetrazolium salt in step (a) is an organic solvent, and the organic solvent is one or more of methanol, ethanol, methyl tert-butyl ether, and n-heptane;

[0029] In some specific embodiments, the base in the preparation of the tetrazolium salt in step (a) is one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, and lithium bicarbonate; preferably, it is one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide; more preferably, it is sodium hydroxide;

[0030] In some specific embodiments, the substitution reaction solvent in step (a) is one or two of an organic solvent or an inorganic solvent. The organic solvent is one or more of isopropyl acetate, ethyl acetate, methyl tert-butyl ether, and isopropanol; the inorganic solvent is water;

[0031] In some specific embodiments, the substitution reaction temperature in step (a) is 50-100°C, preferably 70-90°C;

[0032] In some specific embodiments, the purification of the substitution reaction product in step (a) is carried out by recrystallization. A solvent with low polarity is used for dissolution, and the main impurities are removed by filtration. The solvent with low polarity is one or more of methyl tert-butyl ether, n-heptane, and diethyl ether. The dissolution temperature is 15-40°C, preferably 20-30°C; the recrystallization uses a solvent with high polarity to purify intermediate 2 from the above filtrate. The solvent with high polarity is one or more of isopropanol, methanol, tert-butanol, and water. The recrystallization temperature is 10-30°C, preferably 10-15°C;

[0033] In some specific embodiments, in the step (b), the catalytic reduction reaction system is a triethylamine and formic acid system; the catalyst is (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethane diamine (p-cumylbenzene) ruthenium chloride;

[0034] In some specific embodiments, in the step (b), the solvent for the catalytic reduction reaction is an organic solvent, and the organic solvent is one or more of toluene, dichloromethane, and isopropyl acetate;

[0035] In some specific embodiments, in the step (b), the temperature of the catalytic reduction reaction is 20 - 30 °C;

[0036] In some specific embodiments, the temperature of the carbamylation reaction is 0 - 25 °C, preferably 0 - 15 °C;

[0037] In some specific embodiments, the solvent for the carbamylation reaction is one or both of DMF and water.

[0038] In some specific embodiments, the crude product of (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate is further crystallized and purified to obtain (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate;

[0039] In some specific embodiments, the crude product of (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate is further crystallized and purified to obtain (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate. The crystallization solvent for the crystallization and purification is one or both of ethyl acetate and n-heptane, and the crystallization temperature for the crystallization and purification is 0 - 10 °C;

[0040] For all the reactions of the present invention, the reaction time is generally determined by the complete reaction of the raw materials and monitored by HPLC and TLC methods. The positive effects of the present invention are as follows: The present invention provides a preparation method of (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate. The reaction is carried out using a tetrazolium salt, and chiral reduction is carried out through a ruthenium catalyst to finally obtain the target product. This preparation method has the advantages of not requiring long-time operation at high temperatures, high reaction safety factor, no need for chiral resolution in post-treatment, simple operation, high chemical and optical purity of the product, and being suitable for industrial production. Specific Embodiments

[0041] The following examples are used to illustrate in detail but should not be construed as limiting the present invention. The present invention can be better understood through these examples.

[0042] Example 1

[0043] Preparation of Intermediate of Formula 1

[0044] Add acetonitrile (155 kg), NBS (99 kg), o-chloroacetophenone (66 kg), and p-toluenesulfonic acid monohydrate (8 kg) into the reaction kettle. Then heat to 60 - 70 °C and stir for 3 - 4 hours. Take samples for HPLC detection until the reaction is qualified. After qualification, add aqueous sodium bicarbonate solution (180 kg), aqueous sodium sulfite solution (148 kg), and isopropyl acetate (175 kg) into the reaction kettle. Concentrate the organic phase until no liquid flows out, stop concentration, and discharge to obtain the intermediate of Formula 1 (204.5 kg). The mass yield of the oily substance is 154.9%.

[0045] Example 2

[0046] Preparation of Intermediate of Formula 1

[0047] Add isopropyl acetate (150 kg), NBS (99 kg), o-chloroacetophenone (66 kg), and p-toluenesulfonic acid (7.8 kg) into the reaction kettle. Heat to 60 - 70 °C and stir for 3 - 4 hours. Take samples for HPLC detection until the reaction is qualified. After qualification, add aqueous sodium bicarbonate solution (180 kg), aqueous sodium sulfite solution (148 kg), and isopropyl acetate (175 kg) into the reaction kettle. Extract and separate the aqueous layer. Concentrate the organic layer until no liquid flows out, stop concentration, and discharge to obtain the intermediate of Formula 1 (195.0 kg). The mass yield of the oily substance is 147.7%.

[0048] Example 3

[0049] Preparation of Sodium Tetrazole

[0050] Add methanol (86 kg) into the reaction kettle. Add solid sodium hydroxide in portions (total 20 kg), control the temperature at 40 - 50 °C, add tetrazole (35 kg). After feeding, stir for 1 hour. Concentrate under reduced pressure to dryness, add methyl tert-butyl ether (150 kg), stir for crystallization for 1 hour, and filter to obtain the wet product of sodium tetrazole.

[0051] Example 4

[0052] Preparation of Potassium Tetrazole

[0053] Add methanol (86 kg) into the reaction kettle, and then add solid potassium hydroxide in portions (total 29.0 kg), control the temperature at 40 - 50 °C, add tetrazole (35 kg). After feeding, stir for 1 hour. Concentrate under reduced pressure to dryness, add methyl tert-butyl ether (150 kg), stir for crystallization for 1 hour, and filter to obtain the wet product of potassium tetrazole.

[0054] Example 5

[0055] Preparation of Intermediate of Formula 2

[0056] Add isopropyl acetate (960 kg) and Intermediate of Formula 1 (960 kg) to the reaction kettle, stir, add the whole batch of wet sodium tetrazole prepared in Example 3, heat up to 70 - 80 °C, stir for 15 - 20 hours, take the reaction solution for detection until qualified, add drinking water (200 kg), separate the layers, concentrate the organic phase, add methyl tert-butyl ether (600 kg) for crystallization, filter, collect the filtrate, add isopropyl alcohol (340 kg) for crystallization, and obtain Intermediate of Formula 2 (75.6 kg). Molar yield: 39.78% (calculated based on o-chloroacetophenone), HPLC purity: 99.2%.

[0057] Example 6

[0058] Preparation of Intermediate of Formula 3

[0059] Under the protection of nitrogen, add toluene (300 kg) and triethylamine (170 kg) to the reaction kettle, control the temperature at 0 - 20 °C, and dropwise add formic acid (77 kg). After the feeding is completed, add Intermediate of Formula 2 (75 kg) and catalyst (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethane diamine (p-isopropylbenzene) ruthenium chloride (0.23 kg), and stir. Take the reaction solution for detection until qualified. After qualification, quench with water, directly concentrate the organic layer to dryness, and obtain Intermediate of Formula 3 (71.3 kg). Yield: 93.60%, HPLC purity: 99.05%, and no isomers are detected.

[0060] Example 7

[0061] Preparation of Intermediate of Formula 3

[0062] Under the protection of nitrogen, add dichloromethane (350 kg) and triethylamine (170 kg) to the reaction kettle, control the temperature at 0 - 20 °C, and dropwise add formic acid (77 kg). After the feeding is completed, add Intermediate of Formula 2 (75 kg) and catalyst (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethane diamine (p-isopropylbenzene) ruthenium chloride (0.23 kg), and stir. Take the reaction solution for detection until qualified. After qualification, quench with water, concentrate the organic layer to dryness, and crystallize with toluene and n-heptane (toluene: n-heptane = 1:5) to obtain Intermediate of Formula 3 (68.5 kg). Yield: 89.92%, HPLC purity: 99.32%, and no isomers are detected.

[0063] Example 8

[0064] Preparation of crude (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate

[0065] Add DMF (44 kg) and N,N'-carbonyldiimidazole (95 kg) into the reaction kettle, control the temperature at 0 - 15 °C, dropwise add the DMF solution of the intermediate of formula 3 (115 kg) into the kettle, add ammonium acetate (54 kg), after the feeding is completed, stir. Take samples for detection until qualified. After qualification, add water (500 kg) for crystallization, centrifuge, and dry to obtain the crude product of benbanate (69.4 kg), molar yield: 81.65%, HPLC purity: 99.56%, and no isomers are detected.

[0066] Example 9

[0067] Preparation of the fine product of (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate

[0068] Take the crude product of benbanate (65 kg) and ethyl acetate (117 kg) and add them into the decolorization kettle, add activated carbon (3.35 kg), stir for 1 hour, filter under pressure, add n-heptane (380 kg) to the filtrate, control the temperature at 20 - 30 °C, stir until solid precipitates, continue to cool down to 0 - 10 °C, stir for 1 hour to obtain the fine product of benbanate (60.5 kg), molar yield: 87.25%, HPLC purity: 99.98%, and no isomers are detected.

Claims

1. A method for preparing (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate, characterized in that, it comprises the following steps: (a) The intermediate of formula 1, 2-bromo-2-chloroacetophenone, reacts with a tetrazole salt through a substitution reaction to obtain the intermediate of formula 2, 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one; (b) The intermediate of formula 2 is catalytically reduced to obtain the intermediate of formula 3, (R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethan-1-ol; 2. The preparation method according to claim 1, characterized in that, the intermediate of formula 3 is further prepared into (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate through a carbamylation reaction; 3. The preparation method according to claim 1, characterized in that, the intermediate of formula 1, 2-bromo-2-chloroacetophenone, is prepared from the compound o-chloroacetophenone through a bromination reaction; 4. The preparation method according to claim 1, characterized in that, in the step (a), the tetrazole salt is one or more of sodium tetrazolate, potassium tetrazolate, and lithium tetrazolate; preferably, the tetrazole salt is sodium tetrazolate.

5. The preparation method according to claim 1, characterized in that, in the preparation of the tetrazole salt in the step (a), the reaction of tetrazole with a base is adopted; the base is one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, and lithium bicarbonate; preferably, it is one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide; more preferably, it is sodium hydroxide.

6. The preparation method according to claim 1, characterized in that, in the preparation of the tetrazole salt in the step (a), the reaction temperature is 20-50 °C, preferably 40-50 °C; in the preparation of the tetrazole salt in the step (a), the reaction solvent is an organic solvent, and the organic solvent is one or more of methanol, ethanol, methyl tert-butyl ether, and n-heptane.

7. The preparation method according to claim 1, characterized in that, in the step (a), the substitution reaction solvent is one or two of an organic solvent or an inorganic solvent, the organic solvent is one or more of isopropyl acetate, ethyl acetate, methyl tert-butyl ether, and isopropanol; the inorganic solvent is water; in the step (a), the substitution reaction temperature is 50-100 °C, preferably 70-90 °C.

8. The preparation method according to claim 1, characterized in that, in the step (a), the purification of the substitution reaction product adopts a recrystallization operation, including dissolving with a solvent having low polarity, filtering to remove main impurities, the solvent having low polarity is one or more of methyl tert-butyl ether, n-heptane, and ether, the dissolution temperature is 15-40 °C, preferably 20-30 °C; the recrystallization uses a solvent having high polarity to purify the intermediate 2 of the above filtrate, the solvent having high polarity is one or more of isopropanol, methanol, tert-butanol, and water, and the recrystallization temperature is 10-30 °C, preferably 10-15 °C.

9. The preparation method according to claim 1, characterized in that, in the step (b), the catalytic reduction reaction system is a triethylamine and formic acid system; the catalyst is (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethane diamine (p-cumene) ruthenium chloride; the temperature of the catalytic reduction reaction in the step (b) is 20-30 °C; the solvent for the catalytic reduction reaction in the step (b) is an organic solvent, and the organic solvent is one or more of toluene, dichloromethane, and isopropyl acetate.

10. The preparation method according to claim 3, characterized in that, the bromination reaction is carried out under the action of a catalyst; the catalyst is one or both of p-toluenesulfonic acid and p-toluenesulfonic acid monohydrate; the bromination reaction is carried out under the action of an organic solvent; the organic solvent is one or more of acetonitrile, ethyl acetate, isopropyl acetate, and tetrahydrofuran; the reaction temperature of the bromination reaction is 60-80 °C, preferably 60-70 °C.

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