JS1-1-01 impurity reference substance and preparation method thereof

Abstract

The invention relates to the technical field of drug impurity preparation, and discloses a JS1-1-01 impurity reference substance and a preparation method thereof, and the JS1-1-01 impurity reference substance is (E)-N-isobutyl-5-(3-isobutyl acrylamide)-7-trifluoromethyl-9-(7-trifluoromethylbenzo [d] [1, 3] dioxol-5-yl)-3a, 7a-dimethylene benzo [d] [1, 3] dioxol-8-formamide. The JS1-1-01 impurity provided by the invention is not reported in literatures at present, the preparation method of the JS1-1-01 impurity is simple in process and easy to operate, the prepared JS1-1-01 impurity reference substance is high in purity, and a qualified impurity reference substance can be provided for JS1-1-01 quality control. By controlling the content of the impurity, the quality of the JS1-1-01 can be obviously improved, and a guarantee is provided for safe medication.

Description

Technical Field

[0001] The present invention relates to the technical field of drug impurity preparation, and in particular to a JS1-1-01 impurity reference substance and a preparation method thereof. Background Art

[0002] In today's society, with the accelerated pace of people's lives and increased work pressure, social competition is becoming increasingly fierce, and the prevalence of anxiety disorders is increasing year by year.

[0003] Anxiety disorders are usually treated with psychotherapy and medication, including: psychotherapy, identifying stressors in life, avoiding stress, learning relaxation techniques, and reducing stress; medication, using anti-anxiety drugs to calm overactive parts of the brain. Typical drugs are benzodiazepines (BDZ), which have strong anti-anxiety effects and rapid onset, but long-term use has side effects such as addiction, drug tolerance, and withdrawal reactions; tricyclic antidepressants (TCAs) have good effects on generalized anxiety, but have strong anticholinergic side effects and cardiotoxic effects, which limit their application; other anti-anxiety drugs also have more or less problems such as slow onset, drug interactions, and adverse reactions. The above side effects often make patients very worried, and this worry aggravates anxiety or forces them to give up treatment. Discontinuation reactions are even more difficult for doctors.

[0004] JS1-1-01 is an innovative drug independently developed by Jiangsu Tasly Company for the treatment of major depression. After a single oral administration, it can quickly cross the blood-brain barrier to exert its antianxiety effect. The structural formula is as follows: .

[0005] During the stability study of the JS1-1-01 raw material drug, the applicant discovered that an unknown impurity would be produced under light conditions during the influencing factor test.

[0006] Before a drug is put on the market, it must undergo scientific evaluation of its quality, safety and efficacy. Drug impurities are closely related to drug quality and safety. Impurity reference substances can help determine the reasonable limits of impurities, which will greatly promote the establishment of drug inspection methods and quality standards. Summary of the invention

[0007] Purpose of the invention: In view of the problems existing in the prior art, the present invention provides a JS1-1-01 impurity reference substance and a preparation method thereof, which further guarantees the drug quality and drug safety of the JS1-1-01 raw material drug.

[0008] Technical solution: The present invention provides a JS1-1-01 impurity reference substance, wherein the JS1-1-01 impurity reference substance is (E)-N-isobutyl-5-(3-isobutylacrylamide)-7-trifluoromethyl-9-(7-trifluoromethylbenzo[d][1,3]dioxolane-5-yl)-3a, 7a-dimethylenebenzo[d][1,3]dioxolane-8-carboxamide; its structural formula is as follows: .

[0009] The present invention also provides a method for preparing the JS1-1-01 impurity reference substance as described above, and the specific steps are as follows: S1. Degradation: Dissolve the JS1-1-01 API in a solvent and photodegrade it for 36 to 48 hours. Take a sample and analyze it by high performance liquid chromatography. When the content of the JS1-1-01 impurity reference substance in the reaction solution is greater than or equal to 5%, concentrate the reaction solution under reduced pressure to obtain a crude product. S2. Preparative liquid phase separation: The crude product was dissolved in ethyl acetate, subjected to preparative liquid separation, and the JS1-1-01 impurity reference substance component eluate was collected, concentrated under reduced pressure at room temperature, and freeze-dried to obtain the JS1-1-01 impurity reference substance.

[0010] Further, in S1, the structural formula of the JS1-1-01 API is as follows: .

[0011] Preferably, in S1, the photodegradation is degradation by irradiation under sunlight or degradation by irradiation under 254nm and 365nm ultraviolet lamps simultaneously.

[0012] Furthermore, in S1, the solvent is any one of acetonitrile, dichloromethane or ethyl acetate.

[0013] Furthermore, in S2, the specific conditions for the preparative liquid separation are as follows: the chromatographic column is a C8 column, the mobile phase A is a 0.01 mol / L ammonium acetate aqueous solution, the mobile phase B is acetonitrile, the column temperature is 25°C, and the flow rate is 1.5 ml / min.

[0014] Beneficial effects: Compared with the prior art, the present invention has the following specific beneficial effects: The JS1-1-01 impurity provided by the present invention has not been reported in the literature. The preparation method of the JS1-1-01 impurity reference substance provided by the present invention is simple and easy to operate. The JS1-1-01 impurity reference substance has high purity and can provide a qualified impurity reference substance for JS1-1-01 quality control. By controlling the content of the impurity, the quality of JS1-1-01 can be significantly improved, providing a guarantee for safe drug use. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 This is the unknown impurity spectrum in the stability study of JS1-1-01 API; Figure 2 This is the impurity hydrogen spectrum of JS1-1-01 prepared in Implementation Example 1; Figure 3 This is the impurity carbon spectrum of JS1-1-01 prepared in Implementation Example 1; Figure 4 This is the impurity mass spectrum of JS1-1-01 prepared in Implementation Example 1. DETAILED DESCRIPTION

[0016] The present invention is described in detail below in conjunction with the embodiments.

[0017] The applicant found in the stability study of JS1-1-01 API that an unknown impurity would be generated under light conditions during the influencing factor test. Figure 1 The impurities were purified and separated, and the structural formula was determined to be .

[0018] Implementation 1: This embodiment provides a JS1-1-01 impurity reference substance, specifically (E)-N-isobutyl-5-(3-isobutylacrylamide)-7-trifluoromethyl-9-(7-trifluoromethylbenzo[d][1,3]dioxolane-5-yl)-3a, 7a-dimethylenebenzo[d][1,3]dioxolane-8-carboxamide; its structural formula is as follows: .

[0019] This embodiment also provides a method for preparing a JS1-1-01 impurity reference substance, which is as follows: 1) Degradation Take 2 g of JS1-1-01 raw material, add 50 ml of acetonitrile to dissolve, irradiate under sunlight for 36 hours, take a sample for HPLC detection, and it is found that the content of JS1-1-01 impurity reference substance is 7%. Concentrate under reduced pressure to obtain a crude product.

[0020] 2) Preparative liquid phase separation The crude product was dissolved in acetonitrile and separated by preparative liquid phase. The chromatographic conditions of the preparative liquid phase were as follows: the chromatographic column was a C8 column, the mobile phase A was a 0.01 mol / L ammonium acetate aqueous solution, the mobile phase B was acetonitrile for elution, the column temperature was 25°C, and the flow rate was 1.5 ml / min; the JS1-1-01 impurity reference substance component eluate was collected, the collected eluate was concentrated under reduced pressure at room temperature to remove acetonitrile, and then freeze-dried to obtain the JS1-1-01 impurity reference substance. The purity of the obtained JS1-1-01 impurity reference substance was 97.2% by HPLC analysis, and the structural formula was determined by hydrogen spectrum, carbon spectrum, and mass spectrum detection. .

[0021] Implementation 2: This embodiment provides a method for preparing a JS1-1-01 impurity reference substance, which is as follows: 1) Degradation Take 2 g of JS1-1-01 raw material, add 100 ml of dichloromethane to dissolve, irradiate under sunlight for 36 hours, take a sample for HPLC detection, and it is found that the content of JS1-1-01 impurity reference substance is 5%. Concentrate under reduced pressure to obtain a crude product.

[0022] 2) Preparative liquid phase separation The crude product was dissolved in dichloromethane and separated by preparative liquid phase. The chromatographic conditions of the preparative liquid phase were as follows: the chromatographic column was a C8 column, the mobile phase A was a 0.01 mol / L aqueous solution of ammonium acetate, the mobile phase B was acetonitrile for elution, the column temperature was 25°C, and the flow rate was 1.5 ml / min; the eluate of the JS1-1-01 impurity reference substance component was collected, and the collected eluate was concentrated under reduced pressure at room temperature to remove acetonitrile, and then freeze-dried to obtain the JS1-1-01 impurity reference substance. The purity of the obtained JS1-1-01 impurity reference substance was 95.8% by HPLC analysis.

[0023] Implementation 3: This embodiment provides a method for preparing a JS1-1-01 impurity reference substance, which is as follows: 1) Degradation Take 2 g of JS1-1-01 raw material, add 70 ml of ethyl acetate to dissolve, irradiate under sunlight for 32 hours, take a sample for HPLC detection, and it is found that the content of JS1-1-01 impurity reference substance is 5%. Concentrate under reduced pressure to obtain a crude product.

[0024] 2) Preparative liquid phase separation The crude product was dissolved in acetonitrile and separated by preparative liquid phase. The chromatographic conditions of the preparative liquid phase were as follows: the chromatographic column was a C8 column, the mobile phase A was a 0.01 mol / L aqueous solution of ammonium acetate, the mobile phase B was acetonitrile for elution, the column temperature was 25°C, and the flow rate was 1.5 ml / min; the eluate of the JS1-1-01 impurity reference substance component was collected, and the collected eluate was concentrated under reduced pressure at room temperature to remove acetonitrile, and then freeze-dried to obtain the JS1-1-01 impurity reference substance. The purity of the obtained JS1-1-01 impurity reference substance was 96.5% by HPLC analysis.

[0025] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A JS1-1-01 impurity reference substance, characterized in that: The JS1-1-01 impurity reference substance is (E)-N-isobutyl-5-(3-isobutylacrylamide)-7-trifluoromethyl-9-(7-trifluoromethylbenzo[d][1,3]dioxolan-5-yl)-3a, 7a-dimethylenebenzo[d][1,3]dioxolan-8-carboxamide; its structural formula is as follows: 。 2. A method for preparing the JS1-1-01 impurity reference substance as claimed in claim 1, characterized in that: The specific steps are as follows: S1. Degradation: Dissolve the JS1-1-01 API in a solvent and photodegrade it for 36 to 48 hours. Take a sample and analyze it by high performance liquid chromatography. When the content of the JS1-1-01 impurity reference substance in the reaction solution is greater than or equal to 5%, concentrate the reaction solution under reduced pressure to obtain a crude product. S2. Preparative liquid phase separation: The crude product was dissolved in ethyl acetate, subjected to preparative liquid separation, and the JS1-1-01 impurity reference substance component eluate was collected, concentrated under reduced pressure at room temperature, and freeze-dried to obtain the JS1-1-01 impurity reference substance.

3. The method for preparing the JS1-1-01 impurity reference substance according to claim 2, characterized in that: In S1, the structural formula of the JS1-1-01 API is as follows: 。 4. The method for preparing the JS1-1-01 impurity reference substance according to claim 2, characterized in that: In S1, the photodegradation is irradiation degradation under sunlight or irradiation degradation under 254nm and 365nm ultraviolet lamps at the same time.

5. The method for preparing the JS1-1-01 impurity reference substance according to claim 2, characterized in that: In S1, the solvent is any one of acetonitrile, dichloromethane or ethyl acetate.

6. The method for preparing the JS1-1-01 impurity reference substance according to claim 2, characterized in that: In S2, the specific conditions for the preparative liquid phase separation are as follows: the chromatographic column is a C8 column, the mobile phase A is a 0.01 mol / L ammonium acetate aqueous solution, the mobile phase B is acetonitrile, the column temperature is 25°C, and the flow rate is 1.5 ml / min.

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