A method for synthesizing zopiclone impurity pyrazine-2-carboxylic acid (5-chloro-pyridin-2-yl)-amide

Abstract

The invention discloses a method for synthesizing zopiclone impurity pyrazine-2-carboxylic acid (5-chloro-pyridine-2-yl)-amide, the method comprising the following steps: 1) reacting pyrazine-2-carboxylic acid and 2-amino-5-chloropyridine in a solvent; 2) separating the reaction product; and 3) purifying the product; wherein, in step 1), the solvent is selected from alkyl halides and thionyl chloride. The alkyl halides are selected from any one of dichloromethane, chloroform, 1,1-dichloroethane, and 1,2-dichloroethane, or a combination thereof.

Description

Technical Field

[0001] The invention relates to the field of medicine, and in particular to a method for synthesizing zopiclone impurity pyrazine-2-carboxylic acid (5-chloro-pyridin-2-yl)-amide. Background Art

[0002] Zopiclone is a third-generation sedative hypnotic developed by Rhono-Poulene Rorer, France, for the treatment of sleep disorders. Eszopiclone is a fast-acting, short-acting non-benzodiazepine sedative hypnotic developed by Seprator, USA, and was launched in the United States in April 2005. Its racemic zopiclone has been launched in nearly 100 countries and regions. Eszopiclone is the first drug that can be used for long-term treatment of difficulty in falling asleep and maintaining quality of sleep. Compared with its racemic form, eszopiclone has the advantages of fast efficacy, fewer side effects, and low toxicity.

[0003] The structure of zopiclone is as follows:

[0004]

[0005] The synthesis method generally uses 6-(5-chloro-2-pyridyl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine as a raw material and condenses it with 4-methylpiperazine-1-carbonyl chloride hydrochloride to obtain zopiclone.

[0006] Among them, pyrazine-2-carboxylic acid (I) is a potential impurity in 2,3-pyrazine dianhydride, a key raw material for the synthesis of zopiclone. In the production process, it reacts with 2-amino-5-chloropyridine (II) to form the impurity pyrazine-2-carboxylic acid (5-chloro-pyridin-2-yl)-amide (compound J).

[0007]

[0008] Therefore, there is an urgent need to provide a simple and low-cost method for preparing zopiclone impurity compound J to provide a high-purity impurity reference substance for the quality control of zopiclone.

[0009] Currently, there are few manufacturers of zopiclone impurity compound J in China, the production cost is high, the price is relatively high, and the purity of the product is only 95%. Therefore, there is an urgent need to synthesize zopiclone impurity compound J with higher purity (more than 99%), simple operation, short reaction time and low cost, to provide impurity reference materials for zopiclone consistency evaluation and daily production, and successfully complete research and development and production tasks. Summary of the invention

[0010] The object of the present invention is to provide a method for preparing a high-purity compound J. Another object of the present invention is to provide the use of the compound J prepared according to the preparation method as a standard or reference substance.

[0011] The preparation method of compound J of the present invention is to react pyrazine-2-carboxylic acid and 2-amino-5-chloropyridine as raw materials, and the chemical reaction formula is as follows:

[0012]

[0013] The specific operation steps are as follows:

[0014] 1) pyrazine-2-carboxylic acid and 2-amino-5-chloropyridine react in a solvent;

[0015] 2) separation of reaction products;

[0016] 3) Purification to obtain compound J;

[0017] Wherein, the solvent in step 1) is selected from alkyl halides and thionyl chloride. The alkyl halides are selected from any one of dichloromethane, chloroform, 1,1-dichloroethane, 1,2-dichloroethane or a combination thereof.

[0018] Wherein, the separation in step 2) includes extraction and filtration steps.

[0019] Wherein, the purification method in step 3) is selected from recrystallization, and the solvent for recrystallization is one or a combination of n-hexane, ethyl acetate.

[0020] Preferably, the method of the present invention comprises the following steps:

[0021] 1) Pyrazine-2-carboxylic acid is dissolved in dichloromethane, cooled, thionyl chloride is added, and then 2-amino-5-chloropyridine is added after the addition is completed. The system is cooled to room temperature and stirred at the same temperature.

[0022] 2) After adding water to the system, the liquid is separated, the aqueous phase is extracted with a haloalkane, the organic phases are combined and dried, and the organic phase is vacuum-dried.

[0023] 3) The residue was recrystallized to obtain compound J as an off-white powder.

[0024] Wherein, the cooling method described in step 1) adopts cooling in an ice water bath.

[0025] More preferably, the method of the present invention comprises the following steps:

[0026] 1) Pyrazine-2-carboxylic acid (I) was dissolved in dichloromethane, cooled to 5-10°C in an ice-water bath, and thionyl chloride was slowly added. After the addition, 2-amino-5-chloropyridine (II) was added. The system was returned to room temperature and stirred for 2 hours.

[0027] 2) After adding water to the system, the liquid was separated, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined and dried, and the organic phase was vacuum-dried.

[0028] 3) The residue was recrystallized to obtain compound J as an off-white powder.

[0029] Wherein, in step 1), the molar ratio of pyrazine-2-carboxylic acid and 2-amino-5-chloropyridine is 1:(1-1.3), preferably 1:(1.1-1.2); the molar ratio of pyrazine-2-carboxylic acid and thionyl chloride is 1:(1-1.6), preferably 1:(1.2-1.5); the molar ratio of pyrazine-2-carboxylic acid and dichloromethane is 1:(8-15), preferably 1:(10-12).

[0030] The amount of dichloromethane used in step 2) is a molar ratio of pyrazine-2-carboxylic acid to dichloromethane of 1:(8-15);

[0031] Step 3) Recrystallize using n-hexane and ethyl acetate, with the molar ratio of pyrazine-2-carboxylic acid to n-hexane being 1:(4-15), preferably 1:(5-9); and the molar ratio of pyrazine-2-carboxylic acid to ethyl acetate being 1:(1-5), preferably 1:(2-3).

[0032] As a further improvement, the organic phases were combined after extraction, washed with aqueous sodium bicarbonate solution and then dried under vacuum.

[0033] The compound J prepared according to the preparation method of the present invention can be used as a standard or reference substance for the detection of zopiclone raw materials or preparations.

[0034] Another object of the present invention is to provide the use of compound J as a standard or reference substance, as follows:

[0035] Take the zopiclone raw material drug to be tested, and use the mobile phase to make a solution containing about 1 mg per 1 ml as the test solution. According to the high performance liquid chromatography method, use octadecylsilane bond and silica gel as fillers (Waters Symmetry Shield C18 column, 4.6*250mm, 5mm, end-capped or chromatographic column with equivalent performance); use acetonitrile-buffered salt (take 8.1g sodium dodecyl sulfate and 1.6g sodium dihydrogen phosphate, add water to dissolve and dilute to 1000ml) (538:1000), use 10% phosphoric acid solution to adjust pH to 4.0 as the mobile phase, and the detection wavelength is 303nm; the flow rate is 1.5ml / min. Take 20ml of the test solution and inject it into the liquid chromatograph, record the chromatogram to twice the retention time of the main component peak, and calculate the purity by area normalization method.

[0036] Another object of the present invention is to provide a method for detecting compound J, which is as follows:

[0037] Take the compound J to be tested, and use the mobile phase to make a solution containing about 1 mg per 1 ml as the test solution. According to the high performance liquid chromatography method, use octadecylsilane bond and silica gel as fillers (Waters Symmetry Shield C18 column, 4.6*250mm, 5mm, end-capped or chromatographic column with equivalent performance); use acetonitrile-buffered salt (take 8.1g sodium dodecyl sulfate and 1.6g sodium dihydrogen phosphate, add water to dissolve and dilute to 1000ml) (538:1000), use 10% phosphoric acid solution to adjust pH to 4.0 as the mobile phase, the detection wavelength is 303nm; the flow rate is 1.5ml / min. Take 20ml of the test solution and inject it into the liquid chromatograph, record the chromatogram to twice the retention time of the main component peak, and calculate the purity by area normalization method.

[0038] Glossary

[0039] Compound (I): Pyrazine-2-carboxylic acid, CAS No.: 98-97-5, Molecular formula: C5H4N2O2, Molecular weight: 124.1

[0040] Compound (II): 2-amino-5-chloropyridine, CAS No.: 1072-98-6, Molecular formula: C5H5ClN2, Molecular weight: 128.56

[0041] Compound J: Pyrazine-2-carboxylic acid (5-chloro-pyridin-2-yl)-amide, CAS number: 349125-10-6, molecular formula: C10H7ClN4O, molecular weight: 234.64178

[0042] Thionyl chloride: CAS No.: 7719-09-7 Molecular formula: Cl2OS Molecular weight: 118.97

[0043] Dichloromethane: English name: DCM, CAS number: 75-09-2 Molecular formula: CH2Cl2 Molecular weight: 84.93

[0044] n-Hexane: CAS No.: 110-54-3 Molecular formula: C6H14 Molecular weight: 86.18

[0045] Ethyl acetate: CAS number: 141-78-6 Molecular formula C4H8O2 Relative molecular mass 88.11

[0046] The beneficial effects of the present invention are:

[0047] Compared with the prior art, the invention has simple operation, short reaction time and high yield. The obtained product is purified by recrystallization, avoiding column purification, and the purity of the obtained product is above 99%, which provides a solid foundation for the research of zopiclone impurities. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 Pyrazine-2-carboxylic acid (5-chloro-pyridin-2-yl)-amide mass spectrum (ESI(+), m / z=235.04)

[0049] Figure 2 Pyrazine-2-carboxylic acid (5-chloro-pyridin-2-yl)-amide NMR (DMSO-d6, 400 MHz) DETAILED DESCRIPTION

[0050] The present invention is further illustrated by the following examples.

[0051] Example 1

[0052] Dissolve pyrazine-2-carboxylic acid (12.4 g) in dichloromethane (70 mL) and cool to an internal temperature of 5°C in an ice-water bath. Add thionyl chloride (18 g) dropwise to the mixture, and add 2-amino-5-chloropyridine (14.1 g) after the addition is complete. Stir for 2 hours after returning to room temperature. Pour the reaction solution into water (100 mL), stir, and separate. Extract the aqueous phase with dichloromethane (30 mL*2), combine the organic phases, wash with saturated sodium bicarbonate aqueous solution 3 times (500 mL*3), dry with anhydrous sodium sulfate (10 g), filter to remove the desiccant, spin dry, and obtain 24.2 g of off-white solid. Add n-hexane (100 mL) and ethyl acetate (20 mL) to the solid and stir under reflux for 1 hour. Cool to 0°C and filter to obtain 22.0 g of off-white solid, with a yield of 94.0% and a purity of 99.3%.

[0053] Example 2

[0054] Dissolve pyrazine-2-carboxylic acid (12.4 g) in dichloromethane (65 mL) and cool to an internal temperature of 5°C in an ice-water bath. Add thionyl chloride (14.3 g) dropwise to the mixture, add 2-amino-5-chloropyridine (15.4 g) after the addition is complete, and stir for 2 hours after returning to room temperature. Pour the reaction solution into water (100 mL), stir, and separate. The aqueous phase is extracted with dichloromethane (30 mL*2), the organic phases are combined, washed with saturated sodium bicarbonate aqueous solution 3 times (500 mL*3), dried over anhydrous sodium sulfate (10 g), filtered to remove the desiccant, and spin-dried to obtain 24.9 g of off-white solid. Add n-hexane (100 mL) and ethyl acetate (20 mL) to the solid and stir under reflux for 1 hour. After cooling to 0°C, filter to obtain 21.2 g of off-white solid, with a yield of 90.6% and a purity of 99.1%.

[0055] Example 3

[0056] Dissolve pyrazine-2-carboxylic acid (12.4g) in dichloromethane (70mL) and cool to an internal temperature of 5°C in an ice-water bath. Add thionyl chloride (14.3g) dropwise to the mixture, add 2-amino-5-chloropyridine (14.1g) after the addition is complete, and stir for 2 hours after returning to room temperature. Pour the reaction solution into water (100mL), stir, and separate. The aqueous phase is extracted with dichloromethane (30mL*2), the organic phases are combined, washed with saturated sodium bicarbonate aqueous solution 3 times (500mL*3), dried with anhydrous sodium sulfate (10g), filtered to remove the desiccant, and spin-dried to obtain 24.3g of off-white solid. Add n-hexane (100mL) and ethyl acetate (20mL) to the solid and stir under reflux for 1 hour. Cool to 0°C and filter to obtain 22.3g of off-white solid, with a yield of 95.3% and a purity of 99.5%.

Claims

1. A method for preparing compound J, characterized in that: The chemical reaction formula is as follows: The method comprises the following steps: 1) Pyrazine-2-carboxylic acid (I) was dissolved in dichloromethane, cooled to 5-10°C in an ice-water bath, and thionyl chloride was slowly added. After the addition, 2-amino-5-chloropyridine (II) was added. The system was returned to room temperature and stirred for 2 hours. 2) adding water to the system and separating the liquids, extracting the aqueous phase twice with dichloromethane, combining the organic phases and drying them, and then drying the organic phase in vacuo, 3) recrystallizing the residue to obtain an off-white powder compound J; the solvents used for recrystallization in step 3) are n-hexane and ethyl acetate, and the molar ratio of pyrazine-2-carboxylic acid to n-hexane is 1:(4-15), and the molar ratio of pyrazine-2-carboxylic acid to ethyl acetate is 1:(1-5).

2. The preparation method according to claim 1, characterized in that: Step 1) The molar ratio of pyrazine-2-carboxylic acid and 2-amino-5-chloropyridine is 1:(1-1.3); The molar ratio of pyrazine-2-carboxylic acid and thionyl chloride is 1:(1-1.6); The molar ratio of pyrazine-2-carboxylic acid and dichloromethane is 1:(8-15).

3. The preparation method according to claim 1, characterized in that: Step 1) The molar ratio of pyrazine-2-carboxylic acid and 2-amino-5-chloropyridine is 1:(1.1-1.2); The molar ratio of pyrazine-2-carboxylic acid and thionyl chloride is 1:(1.2-1.5); The molar ratio of pyrazine-2-carboxylic acid and dichloromethane is 1:(10-12).

4. The preparation method according to claim 1, characterized in that: The amount of dichloromethane used in step 2) is such that the molar ratio of pyrazine-2-carboxylic acid to dichloromethane is 1:(8-15).

5. The preparation method according to claim 1, characterized in that: In step 3), the solvent used for recrystallization is n-hexane and ethyl acetate, and the molar ratio of pyrazine-2-carboxylic acid to n-hexane is 1:(5-9). The molar ratio of pyrazine-2-carboxylic acid to ethyl acetate is 1:(2-3).

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