A 4-amino-5-alkylsulfinyl-2-methoxybenzoic acid compound, a preparation method and use thereof

Abstract

The application reports a preparation method and purposes of impurities in 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide. The method is simple and easy to operate, has mild conditions, high yield, low energy consumption and low pollution, and is suitable for laboratory level standard preparation.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to a 4-amino-5-alkylsulfinyl-2-methoxybenzoic acid compound and a preparation method and use thereof. BACKGROUND

[0002] 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide is a new broad-spectrum atypical antipsychotic drug developed by the French Sanofi-Saint-Denis Company, which was approved by the US Food and Drug Administration for marketing in the United States in January 1997. 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide was marketed in China in 2011 and applied in clinical practice. The drug has a unique mechanism of action, can selectively bind to presynaptic and postsynaptic dopamine 2 (dopamine-2, D2) receptors and dopamine 3 (dopamine-2, D3) receptors, and plays a dual dopamine receptor antagonistic role. It is mainly used for the treatment of acute progressive or chronic schizophrenia in clinical practice. At the same time, the drug also has good antidepressant effect and causes less extra-pyramidal symptoms (EPS), and has almost no effect on body mass, blood sugar and blood lipids. It is a safe and effective new broad-spectrum atypical antipsychotic drug.

[0003] In the process of new drug research and development, drug quality is an important standard for measuring drug quality. The related substances (or impurity content) of the drug directly affect the efficacy of the drug and may cause toxic side effects. In order to use drugs safely and effectively, it is necessary to strictly control the purity of the active ingredients of the drug, the limit of impurities, and provide high-quality standard drugs. Therefore, during the production, storage and transportation of the drug, the production of drug impurities must be strictly controlled.

[0004] After searching, patent CN113024433A provides a preparation method of 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide sulfoxide impurities:

[0005]

[0006] The synthetic route uses a toxic and environmentally unfriendly hydrogen peroxide reagent. Hydrogen peroxide is suitable for medical wound disinfection, environmental disinfection and food disinfection, but hydrogen peroxide is also a carcinogen published by the World Health Organization.

[0007] The inventors found, in the research of 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide raw material, that other impurity compounds in 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide raw material also affect the use, storage and transportation of the drug, and the synthesis process and detection method thereof are determined, so that the stability of 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide raw material in the use, storage and transportation process is improved.

[0008] The stability of m-chloroperbenzoic acid used in the synthesis process of the application is better than that of hydrogen peroxide, the higher the concentration of hydrogen peroxide, the worse the stability, and the stability is greatly affected by the acid and alkali, m-chloroperbenzoic acid can form a homogeneous system, so that the reaction can proceed more stably, hydrogen peroxide belongs to a heterogeneous system, and the stability is not good,

[0009] It is easy to lose control and the reaction control is difficult. SUMMARY

[0010] The application discloses a 4-amino-5-alkylsulfinyl-2-methoxybenzoic acid compound, a preparation method and application thereof.

[0011]

[0012] R1 is C1-6 alkyl;

[0013] Step one: compound 1 is dissolved in a solvent, then M-CPBA is added, stirring, after the reaction is completed, separation, extraction, drying, rotary drying to obtain compound 2;

[0014] Step two: compound 2 is dissolved in a solvent, NaOH is added, and stirring is carried out under heating, after the reaction is completed, the temperature is lowered to adjust the pH, extraction, separation, drying, rotary drying to obtain compound 3.

[0015] Further, the solvent used in step 1 is one or several of dichloromethane, chloroform, ethyl acetate, 1,2-dichloroethane, benzene and diethyl ether, preferably dichloromethane.

[0016] Further, the molar ratio of compound 1 to M-CPBA in step 1 is 1:1-1.5, preferably 1:1.4.

[0017] Further, the reaction temperature in step 1 is 0-15℃, preferably 0-10℃.

[0018] Further, the solvent used in step 2 is aqueous solution, and the molar ratio of compound 2 to sodium hydroxide is 1:1.5-3, preferably 1:2.

[0019] Further, the reaction temperature in step 2 is 50-70°C, preferably 60°C, and the pH of the reaction solution is adjusted to 3.5-4.5, preferably pH 4.

[0020] In another aspect, the present application relates to a compound having the structure as shown below:

[0021]

[0022] In another aspect, the present application relates to the use of the compound as a standard or control.

[0023] In another aspect, the present application relates to a pharmaceutical composition containing 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide or a pharmaceutically acceptable salt thereof and an amount of not more than 0.2%, more preferably not more than 0.1%, further preferably not more than 500 ppm, more further preferably not more than 150 ppm, still further preferably not more than 100 ppm of a compound of formula A, formula B and / or formula C.

[0024] In another aspect, the present application relates to a detection method, using octylsilane-bonded silica gel as the filler (Agilent ZORBAX RX C8, 4.6 x 250 mm, 5 μm or a chromatographic column with equivalent performance), measuring 45 ml of 5% mass concentration dilute sulfuric acid solution, diluting to 1000 ml with ultrapure water, weighing 0.7 g of sodium octanesulfonate, dissolving the above solution, and adjusting the pH to 2.3 with dilute sulfuric acid as a salt solution, respectively preparing mobile phase A (sodium octanesulfonate buffer salt (0.7 g / 1000 ml) pH 2.3: methanol: acetonitrile in a volume ratio of 72:16:12), mobile phase B (sodium octanesulfonate buffer salt (0.7 g / 1000 ml) pH 2.3: methanol: acetonitrile in a volume ratio of 50:38:12), the flow rate is 1.5 ml per minute, the detection wavelength is 225 nm, the column temperature is 40°C, the injection volume is 10 μl, and the elution is carried out according to the following table of running gradient, respectively precisely weighing the compounds of formula A, formula B and formula C, dissolving and diluting with mobile phase A to prepare a solution containing 1 mg of the product per 1 ml as the test solution, precisely measuring the test solution according to the chromatographic conditions in the following table and injecting it into the liquid chromatograph, and recording the chromatogram,

[0025] Time (min) Mobile phase A (% vol) Mobile phase B (% vol) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0. 0 100 0 18 100 0 35 0 100 36 100 0 45 100 0

[0026] The present application uses the compounds of formula A, formula B and / or formula C as a control, and further provides a method for quality control of 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide finished product: using the compounds of formula A, formula B and / or formula C as a control. The preferred quality control method comprises the following steps: weighing an appropriate amount of the compounds of formula A, formula B and / or formula C, dissolving in diluent to prepare an impurity control solution of suitable concentration; then using LC to qualitatively or quantitatively study the impurities contained in the 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide finished product sample, i.e. the impurities of formula A, formula B and / or formula C, to control these impurity compounds during preparation, and finally no compounds of formula A, formula B or formula C are detected in the 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide finished product. DETAILED DESCRIPTION

[0027] The present application is further described below in conjunction with examples, but is not limited to the examples.

[0028] Example 1:

[0029]

[0030] m-Chloroperoxybenzoic acid (15.14 g, 87.74 mmol) was slowly added in batches to a mixture of 4-amino-5-ethylsulfanyl-2-methoxybenzoic acid methyl ester (15.00 g, 62.16 mmol) and dichloromethane (150 ml) at 7°C, and after the addition was completed, the reaction was stirred at room temperature for 10 minutes. After the reaction was completed as monitored by TLC, 10% mass concentration of sodium sulfite aqueous solution was slowly added dropwise to the reaction solution until the starch iodide paper did not turn blue. The aqueous phase was extracted once with dichloromethane, and the organic layers were combined after separation. The organic layer was dried and rotary evaporated, and 4-amino-2-methoxy-5-ethylsulfinylbenzoic acid methyl ester solid was obtained by column chromatography separation, 13.10 g, yield 81.98%.

[0031] The hydrogen spectrum is as follows:

[0032] 1 H NMR (400 MHz, Chloroform-d) δ 7.80 (s, 1H), 6.21 (s, 1H), 5.80 (s, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.31-3.06 (m, 2H), 1.24 (t, J = 7.5 Hz, 3H).

[0033] Example 2:

[0034]

[0035] Sodium hydroxide (1.00 g, 25.00 mmol) was added to a mixture of 4-amino-2-methoxy-5-ethylsulfinylbenzoic acid methyl ester (3.21 g, 12.5 mmol) and water (15 mL), and the mixture was stirred at 60 °C for 1 h. After the reaction was completed by TLC monitoring, the mixture was removed from the ice water bath, and diluted hydrochloric acid was added dropwise to adjust the pH to 4. The reaction mixture was extracted with dichloromethane (30 mL) five times, and the organic layers were combined and dried. The organic layer was concentrated under reduced pressure, and recrystallized from ethyl acetate (50 mL) to give 4-amino-5-ethylsulfinyl-2-methoxybenzoic acid (2.78 g, 91.50% yield).

[0036] Example 3:

[0037]

[0038] MCPBA (15.94 g, 92.40 mmol) was added slowly in portions to a mixture of 4-amino-2-methoxy-5-methylsulfenylbenzoic acid methyl ester (15.00 g, 66.00 mmol) and dichloromethane (150 mL) at 7 °C. After the addition was completed, the mixture was stirred at room temperature for 10 min. After the reaction was completed by TLC monitoring, 10% mass concentration of sodium sulfite aqueous solution was slowly added dropwise to the reaction mixture until the starch-iodine paper did not turn blue. The mixture was separated, and the aqueous phase was extracted with dichloromethane once. The organic layers were combined and dried. The organic layer was concentrated under reduced pressure, and purified by column chromatography to give 4-amino-5-methylsulfinyl-2-methoxybenzoic acid methyl ester (13.22 g, 82.41% yield).

[0039] The hydrogen spectrum is assigned as follows:

[0040] 1 H NMR (400 MHz, Chloroform-d) δ 7.85 (s, 1H), 6.23 (s, 1H), 5.77 (s, 2H), 3.93-3.85 (m, 6H), 2.96 (s, 3H).

[0041] Example 4:

[0042]

[0043] Sodium hydroxide (1.00 g, 25.00 mmol) was added to a mixture of 4-amino-5- methylsulfinyl-2-methoxybenzoic acid methyl ester (3.04 g, 12.5 mmol) and water (15 mL) and warmed to 60 °C for 1 h. After monitoring the reaction by TLC, the reaction was removed from the water bath and cooled to room temperature. The reaction was adjusted to pH 4 by the dropwise addition of dilute hydrochloric acid. The reaction was extracted with dichloromethane (30 mL) five times. The organic layers were combined and dried. The organic layer was concentrated under vacuum. The residue was recrystallized from ethyl acetate (50 mL) to give 4-amino-5-methylsulfinyl-2-methoxybenzoic acid (2.60 g, 90.81 % yield).

[0044] The hydrogen spectrum is assigned as follows:

[0045] 1 H NMR (400 MHz, Chloroform-d) δ 10.31 (s, 1H), 8.05 (s, 1H), 6.28 (s, 1H), 6.01 (s, 2H), 4.09 (s, 3H), 2.98 (s, 3H).

[0046] Example 5:

[0047]

[0048] MCPBA (15.14 g, 87.74 mmol) was added slowly in portions to a mixture of 4-amino-5- ethylsulfanyl-2-methoxybenzoic acid methyl ester (10.59 g, 43.89 mmol) and dichloromethane (150 mL) at 20 °C. After the addition was complete, the reaction was stirred at room temperature for 10 min. After monitoring the reaction by TLC, the reaction was quenched by the slow dropwise addition of 10% w / v sodium sulfite solution until the starch-iodine test paper was no longer blue. The reaction was partitioned between water and dichloromethane. The aqueous layer was extracted once with dichloromethane. The organic layers were combined and dried. The organic layer was concentrated under vacuum. The residue was purified by column chromatography to give 4-amino-2-methoxy-5-ethylsulfinylbenzoic acid methyl ester as a solid (8.47 g, 75.07 % yield).

[0049] Example 6:

[0050]

[0051] Sodium hydroxide (1.00 g, 25.00 mmol) was added to a mixture of 4-amino-5- methylsulfinyl-2-methoxybenzoic acid methyl ester (6.08 g, 25.00 mmol) and water (30 mL), and stirred at 80 °C for 1 h. After the reaction was completed by TLC monitoring, it was moved to an ice water bath, and diluted hydrochloric acid was added dropwise to adjust the pH to 5. The reaction mixture was extracted with dichloromethane (30 mL) five times, and the organic layers were combined and dried. After rotary evaporation, 4-amino-5-methylsulfinyl-2-methoxybenzoic acid was recrystallized from ethyl acetate (50 mL) to give a yield of 4.41 g, 77.02%.

[0052] Example 7:

[0053]

[0054] MCPBA (15.94 g, 92.40 mmol) was slowly added to a mixture of 4-amino-5- methylsulfenyl-2-methoxybenzoic acid methyl ester (8.39 g, 36.96 mmol) and dichloromethane (150 mL) at 25 °C. After the addition was completed, the reaction mixture was stirred at room temperature for 10 min. After the reaction was completed by TLC monitoring, 10% sodium sulfite aqueous solution was slowly added to the reaction mixture until the starch-iodine paper did not turn blue. The mixture was separated, and the aqueous phase was extracted with dichloromethane once. The organic layers were combined and dried. After rotary evaporation, 4-amino-5-methylsulfinyl-2-methoxybenzoic acid methyl ester was separated by column chromatography to give a yield of 6.81 g, 75.80%.

[0055] Example 8:

[0056]

[0057] Sodium hydroxide (1.00 g, 25.00 mmol) was added to a mixture of 4-amino-5- methylsulfinyl-2-methoxybenzoic acid methyl ester (6.08 g, 25.00 mmol) and water (30 mL), and stirred at 80 °C for 1 h. After the reaction was completed by TLC monitoring, it was moved to an ice water bath, and diluted hydrochloric acid was added dropwise to adjust the pH to 5. The reaction mixture was extracted with dichloromethane (30 mL) five times, and the organic layers were combined and dried. After rotary evaporation, 4-amino-5-methylsulfinyl-2-methoxybenzoic acid was recrystallized from ethyl acetate (50 mL) to give a yield of 4.41 g, 77.02%.

[0058] Example 9:

[0059] LC detection method of compounds A, B, and C:

[0060]

[0061] Results: In the preparation of 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide, each compound was precisely weighed, dissolved and diluted with mobile phase A to prepare a solution containing 1 mg of the product per 1 ml as a test sample solution, and the test sample solution was precisely measured and injected into the liquid chromatograph according to the chromatographic conditions in the above table, and the chromatogram was recorded. The peak times were about: 5.187 min, 7.867 min, 2.770 min, respectively.

[0062] Although the present application has been described in detail, those skilled in the art understand that various modifications and changes can be made to the present application without departing from the spirit and scope of the present application. The scope of the right of the present application is not limited to the detailed description made above, but should belong to the claims.

Claims

1. A method for preparing a 4-amino-5-alkylsulfinyl-2-methoxybenzoic acid compound, comprising: Step 1: reacting a compound 1 with M-CPBA to obtain a compound 2, wherein R 1 is C 1-6 alkyl; the molar ratio of compound 1 to M-CPBA is 1:1-1.5; the reaction temperature is 0-10 ℃; and the solvent is one or more of dichloromethane, trichloromethane and 1,2-dichloroethane; Step 2: dissolving compound 2 in a solvent, adding NaOH, stirring at a temperature, after the reaction is completed, adjusting the pH to 3.5-4.5, extracting, separating, drying and rotary evaporation to obtain compound 3; wherein the molar ratio of compound 2 to NaOH is 1:1.5-3; the reaction temperature is 50-70 ℃; and the solvent is water. 2.The method according to claim 1, wherein the solvent used in step 1 is dichloromethane. Step 1 : Compound 1 is dissolved in a solvent, then M-CPBA is added, stirred, after the reaction is completed, separated, extracted, dried, and rotary evaporated to obtain compound 2; wherein, 3.The method according to claim 1, wherein the molar ratio of compound 1 to M-CPBA in step 1 is 1:1.

4. 4.The method according to claim 1, wherein the solvent used in step 2 is an aqueous solution, and the molar ratio of compound 2 to NaOH is 1:

2. 5.The method according to any one of claims 1-3, wherein the reaction temperature in step 2 is 60 ℃, and the pH of the reaction solution is adjusted to 4. ​ ​ ​

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