A kind of synthetic method of promethazine hydrochloride

Abstract

The present invention provides a synthetic method of promethazine hydrochloride. A synthetic method of promethazine hydrochloride, comprising the following steps: (1) thionyl chloride is added to toluene-methanol solvent I, N, N-dimethylisopropanolamine is added dropwise, and alkalization is performed after the reaction to obtain product PMZ-1; (2) phenothiazine and alkali are added to toluene-methanol solvent II, after reflux dehydration, and then reflux water separation reaction with PMZ-1 is performed to obtain product PMZ-2; (3) PMZ-2 is added to methanol-acetone solvent III, and then oxalic acid is added to form a salt, and then the temperature is lowered and crystallized to obtain product PMZ-3; (4) PMZ-3 is added to methanol-acetone solvent IV, dry HCl gas is passed through to react, and vacuum drying is performed to obtain promethazine hydrochloride. The promethazine hydrochloride product prepared by the inventive method not only has a good yield, but also has a high purity of promethazine hydrochloride, effectively reduces the total impurity content, has good quality, can be better applied to the preparation of promethazine hydrochloride pharmaceutical preparations, and improves drug quality.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for synthesizing promethazine hydrochloride. Background Art

[0002] Promethazine hydrochloride, molecular weight: 320.89, this product is (±)-N, N, a-trimethyl-10H-phenothiazine-10-ethylamine hydrochloride. Promethazine hydrochloride, promethazine is a phenothiazine derivative, an antihistamine, can be used for antiemetic, anti-vertigo, motion sickness and sedative hypnotic, with antihistamine, anti-emetic, anti-motion sickness, sedative hypnotic effects.

[0003] The traditional method for preparing promethazine hydrochloride is complicated and has a high impurity content (known impurities: impurity A, impurity B, impurity C, impurity D, impurity E, impurity F), which is not conducive to drug quality control. Therefore, it is urgent to develop a new synthesis method to improve the synthesis process of promethazine hydrochloride and improve product quality. Summary of the invention

[0004] In view of this, the present invention proposes a method for synthesizing promethazine hydrochloride to solve the above problems.

[0005] The technical solution of the present invention is achieved in this way: a method for synthesizing promethazine hydrochloride comprises the following steps:

[0006] (1) Add thionyl chloride to toluene-methanol solvent I, add N,N-dimethylisopropanolamine dropwise, and alkalize after reaction to obtain product PMZ-1;

[0007] (2) Phenothiazine and a base are added to a toluene-methanol solvent II, and after reflux dehydration, the mixture is reacted with PMZ-1 by reflux dehydration to obtain the product PMZ-2;

[0008] (3) PMZ-2 is added with methanol-acetone solvent III, and then oxalic acid is added to form a salt, and then the temperature is lowered for crystallization to obtain the product PMZ-3;

[0009] (4) PMZ-3 is added with methanol-acetone solvent IV, dry HCl gas is introduced into the reaction, and vacuum drying is performed to obtain promethazine hydrochloride.

[0010] Furthermore, in step (1), the toluene-methanol I is prepared by mixing toluene and methanol in a volume ratio of 2 to 3:1; in step (2), the toluene-methanol II is prepared by mixing toluene and methanol in a volume ratio of 1:2 to 3; in step (3), the methanol-acetone III is prepared by mixing methanol and acetone in a volume ratio of 1:0.4 to 0.6; in step (4), the methanol-acetone IV is prepared by mixing methanol and acetone in a volume ratio of 0.4 to 0.6:1.

[0011] Furthermore, in step (1), the reaction temperature is 80-85° C., the reaction time is 0.8-1.2 h; and the alkalization is to adjust the pH value to 10-11.

[0012] Furthermore, in step (1), the molar ratio of N,N-dimethylisopropanolamine to thionyl chloride is 1:1.0-1.2; and the mass ratio of N,N-dimethylisopropanolamine to solvent is 1:1.8-2.2.

[0013] Furthermore, in step (2), the reflux dehydration time is 0.8 to 1.2 hours; and the reaction time is 8 to 9 hours.

[0014] Furthermore, in step (2), the base is at least one of sodium hydroxide or potassium hydroxide, the molar ratio of PMZ-1, phenothiazine and base is 1:1.0-1.2:0.08-0.12; and the mass ratio of phenothiazine to solvent is 1:1.8-2.2.

[0015] Furthermore, in step (3), the reaction temperature is 50-55°C, and the reaction time is 20-40 min; and the cooling and crystallization is performed by cooling to 8-12°C and keeping the temperature for crystallization for 1-1.5 h.

[0016] Furthermore, in step (3), the molar ratio of PMZ-2 to oxalic acid is 1:1.0-1.2; and the mass ratio of oxalic acid to solvent is 1:7-8.

[0017] Furthermore, in step (4), the reaction temperature is 35-38°C, and the vacuum drying temperature is 50-60°C.

[0018] Furthermore, in step (4), the mass ratio of PMZ-3 to solvent is 1:2.5-3.0.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] (1) The promethazine hydrochloride product prepared by the method of the present invention not only has a good yield, but also has high purity of promethazine hydrochloride, effectively reduces the total impurity content, has good quality, and can be better applied to the preparation of promethazine hydrochloride pharmaceutical preparations to improve the quality of drugs.

[0021] (2) The use of toluene-methanol solvent I and toluene-methanol solvent II effectively reduces the amount of toluene used while ensuring the yield and product quality, and improves the reaction rate, reduces the reaction temperature of N,N-dimethylisopropanolamine and dichlorothionyl, and shortens the reaction time of N,N-dimethylamino-2-chloropropane and phenothiazine.

[0022] (3) The present invention adopts methanol-acetone solvent III and methanol-acetone solvent IV, which further improves the reaction rate and reduces the generation of impurities or isomers, thereby effectively shortening the reaction time while ensuring the yield and product quality.

[0023] (4) The preparation method of the present invention is not only relatively simple in process and convenient in operation, but also has a fast reaction rate, a high yield and a high product quality. DETAILED DESCRIPTION

[0024] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0025] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0026] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0027] (1) PMZ-SM1: N,N-dimethylisopropanolamine; (2) PMZ-1: N,N-dimethylamino-2-chloropropane;

[0028] (3) PMZ-2: promethazine; (4) PMZ-3: promethazine oxalate; (5) PMZ: promethazine hydrochloride;

[0029] Synthetic route of the present invention

[0030]

[0031] The sources of impurity standards are as follows: Impurity A: Shandong Daguan; Impurity B, Impurity C, Impurity D: Shenzhen Excellence; Impurity E, Impurity F: Guangzhou Jiatu.

[0032] Promethazine hydrochloride reference substance: Boruikan.

[0033] Example 1

[0034] A method for synthesizing promethazine hydrochloride comprises the following steps:

[0035] (1) Add thionyl chloride to toluene-methanol (2.5:1, v:v) solvent I, and dropwise add N,N-dimethylisopropanolamine, wherein the molar ratio of N,N-dimethylisopropanolamine to thionyl chloride is 1:1.1, and the mass ratio of N,N-dimethylisopropanolamine to the solvent is 1:2.0; after the dropwise addition is completed, react at 82°C±2°C for 1 hour, cool to room temperature after the reaction, add water, alkalize (adjust the pH value to 10.5), separate the water, and obtain the product PMZ-1, i.e., the product N,N-dimethylamino-2-chloropropane.

[0036] (2) Phenothiazine and alkali (potassium hydroxide) are added to toluene-methanol (1:2.5, v:v) solvent II, wherein the molar ratio of PMZ-1, phenothiazine and alkali is 1:1.1:0.1, and the mass ratio of phenothiazine to solvent is 1:2.0. After reflux dehydration for 1 hour, reflux and separate water with PMZ-1, separate water once per hour, and reflux for 8 hours. After the reflux reaction is completed, cool down to obtain the product PMZ-2, i.e., isopromethazine.

[0037] (3) PMZ-2 was added with methanol-acetone (1:0.5, v:v) solvent III, and then oxalic acid was added to form a salt. The molar ratio of PMZ-2 to oxalic acid was 1:1.1, the mass ratio of oxalic acid to solvent was 1:7, the reaction temperature was 53°C ± 2°C, and the reaction time was 30 min. The temperature was then lowered to 10°C and kept warm for 1 h for crystallization to obtain the product PMZ-3, i.e., promethazine oxalate.

[0038] (4) PMZ-3 was added with methanol-acetone (0.5:1, v:v) solvent IV, the mass ratio of PMZ-3 to the solvent was 1:2.8, dry HCl gas was introduced for reaction, the reaction temperature was 37°C ± 1°C, and the end point pH was 4; after the reaction, the reaction was vacuum dried (55°C) to obtain promethazine hydrochloride (PMZ).

[0039] Example 2

[0040] A method for synthesizing promethazine hydrochloride comprises the following steps:

[0041] (1) Add thionyl chloride to toluene-methanol (2:1, v:v) solvent I, and dropwise add N,N-dimethylisopropanolamine, wherein the molar ratio of N,N-dimethylisopropanolamine to thionyl chloride is 1:1.1, and the mass ratio of N,N-dimethylisopropanolamine to solvent I is 1:2.0; after the dropwise addition is completed, react at 82°C±2°C for 1.0h, cool to room temperature after the reaction, add water, alkalize (adjust the pH value to 10.5), separate the water, and obtain the product PMZ-1, i.e., the product N,N-dimethylamino-2-chloropropane.

[0042] (2) Phenothiazine and alkali (potassium hydroxide) are added to toluene-methanol (1:2, v:v) solvent II, wherein the molar ratio of PMZ-1, phenothiazine and alkali is 1:1.1 0.1, and the mass ratio of phenothiazine to solvent II is 1:2.0. After reflux dehydration for 1 hour, the mixture is refluxed and dehydrated with PMZ-1, dehydrating the mixture once per hour, and refluxed for 8 hours. After the reflux reaction is completed, the temperature is lowered to obtain the product PMZ-2, i.e., isopromethazine.

[0043] (3) PMZ-2 was added with methanol-acetone (1:0.4, v:v) solvent III, and then oxalic acid was added to form a salt. The molar ratio of PMZ-2 to oxalic acid was 1:1.1, the mass ratio of oxalic acid to solvent III was 1:7, the reaction temperature was 53°C ± 2°C, and the reaction time was 30 min. The temperature was then lowered to 10°C and kept warm for 1 h for crystallization to obtain the product PMZ-3, i.e., promethazine oxalate.

[0044] (4) PMZ-3 was added with methanol-acetone (0.4:1, v:v) solvent IV, the mass ratio of PMZ-3 to solvent IV was 1:2.5, dry HCl gas was introduced to react, the reaction temperature was 37°C ± 1°C, and the end point pH was 4; after the reaction, the reaction was vacuum dried (55°C) to obtain promethazine hydrochloride (PMZ).

[0045] Example 3

[0046] A method for synthesizing promethazine hydrochloride comprises the following steps:

[0047] (1) Add thionyl chloride to toluene-methanol (3:1, v:v) solvent I, and dropwise add N,N-dimethylisopropanolamine, wherein the molar ratio of N,N-dimethylisopropanolamine to thionyl chloride is 1:1:1.1, and the mass ratio of N,N-dimethylisopropanolamine to solvent I is 1:2.0; after the dropwise addition is completed, react at 82°C±2°C for 1.0h, cool to room temperature after the reaction, add water, alkalize (adjust the pH value to 10.5), separate the water, and obtain the product PMZ-1, i.e., the product N,N-dimethylamino-2-chloropropane.

[0048] (2) Phenothiazine and alkali (potassium hydroxide) are added to toluene-methanol (1:3, v:v) solvent II, wherein the molar ratio of PMZ-1, phenothiazine and alkali is 1:1.1:0.1, and the mass ratio of phenothiazine to solvent II is 1:2.0. After reflux dehydration for 1 hour, the mixture is refluxed and dehydrated with PMZ-1, dehydrating the mixture once per hour, and refluxed for 8 hours. After the reflux reaction is completed, the temperature is lowered to obtain the product PMZ-2, i.e., isopromethazine.

[0049] (3) PMZ-2 was added with methanol-acetone (1:0.6, v:v) solvent III, and then oxalic acid was added to form a salt. The molar ratio of PMZ-2 to oxalic acid was 1:1.1, the mass ratio of oxalic acid to solvent III was 1:7, the reaction temperature was 53°C ± 2°C, and the reaction time was 30 min. The temperature was then lowered to 10°C and kept warm for 1 h for crystallization to obtain the product PMZ-3, i.e., promethazine oxalate.

[0050] (4) PMZ-3 was added with methanol-acetone (0.6:1, v:v) solvent IV, the mass ratio of PMZ-3 to solvent IV was 1:2.5, dry HCl gas was introduced to react, the reaction temperature was 37°C ± 1°C, and the end point pH was 4; after the reaction, the reaction was vacuum dried (55°C) to obtain promethazine hydrochloride (PMZ).

[0051] Comparative Example 1

[0052] The main difference from Example 1 is that the solvent in step (1) is toluene.

[0053] (1) thionyl chloride is added to a toluene solvent, and N, N-dimethylisopropanolamine is added dropwise, the molar ratio of N, N-dimethylisopropanolamine to thionyl chloride is 1: 1.1, and the mass ratio of N, N-dimethylisopropanolamine to toluene solvent is 1: 2.0; after the addition is complete, the reaction is carried out at 82°C ± 2°C for 1h, and after the reaction, the reaction is cooled to room temperature and water is added, alkalized (adjusting the pH value to 10.5), and water is separated to obtain the product PMZ-1, that is, the product N, N-dimethylamino-2-chloropropane. Other operations are consistent with Example 1.

[0054] Comparative Example 2

[0055] The main difference from Example 1 is that the solvent in step (2) is toluene.

[0056] (2) Phenothiazine and alkali (potassium hydroxide) are added to a toluene solvent, the molar ratio of PMZ-1, phenothiazine and alkali is 1:1.1:0.1, and the mass ratio of phenothiazine to toluene solvent is 1:2.0. After reflux dehydration for 1 hour, reflux and separate water with PMZ-1, separate water once per hour, reflux for 8 hours, and after the reflux reaction is completed, cool down to obtain the product PMZ-2, that is, isopromethazine. Other operations are consistent with Example 1.

[0057] Comparative Example 3

[0058] The main difference from Example 1 is that the solvent in step (3) is methanol-acetone (1:1, v:v).

[0059] (3) PMZ-2 was added with methanol-acetone (1:1, v:v) solvent III, and then oxalic acid was added to form a salt, the molar ratio of PMZ-2 to oxalic acid was 1:1.1, the mass ratio of oxalic acid to solvent was 1:7, the reaction temperature was 53°C ± 2°C, and the reaction time was 30 min; then the temperature was lowered to 10°C and kept for crystallization for 1 h to obtain the product PMZ-3, that is, promethazine oxalate. The other operations were consistent with Example 1.

[0060] Comparative Example 4

[0061] The main difference from Example 1 is that the solvent in step (3) is acetone.

[0062] (4) PMZ-3 was added with acetone solvent, the mass ratio of PMZ-3 to acetone solvent was 1:2.8, dry HCl gas was introduced for reaction, the reaction temperature was 37°C ± 1°C, and the end point pH value was 4; after the reaction, vacuum drying (55°C) was performed to obtain promethazine hydrochloride (PMZ). Other operations were consistent with Example 1.

[0063] 1. Calculate the yields of intermediates and final products in each step of Examples 1-3 and Comparative Examples 1-4, including the yields of intermediates PMZ-1 (N,N-dimethylamino-2-chloropropane), PMZ-2 (promethazine), PMZ-3 (promethazine oxalate), and PMZ (promethazine hydrochloride). The results are shown in Table 1.

[0064] Table 1 Intermediate and product yields

[0065]

[0066]

[0067] 2. The final product (promethazine hydrochloride) prepared in Examples 1-3 and Comparative Examples 1-4 was tested for related substances by HPLC. The detection method for promethazine hydrochloride related substances (including impurity A, impurity B, impurity C, impurity D, impurity E, impurity F) was recorded in the 2020 edition of the Chinese Pharmacopoeia Standard. Determined by high performance liquid chromatography (General Rule 0512). The limits of each impurity are shown in Table 2.

[0068] Table 2 Impurity Limits

[0069] name limit% Impurity A 0.1 Impurity B 0.8 Impurity C 0.2 Impurity D 0.1 Impurity E 0.1 Impurity F 0.1 Unknown single impurity 0.1 Total Miscellaneous 1.0 (Impurity B is not included in the total impurities)

[0070] The results are shown in Table 3 below.

[0071] Table 3 Detection results of related substances in the final product (%)

[0072] Impurity A Impurity B Impurity C Impurity D Impurity E Impurity F Unknown single impurity Total Miscellaneous Example 1 Not detected Not detected Not detected 0.01 Not detected Not detected Not detected 0.01 Example 2 0.01 Not detected Not detected 0.02 Not detected Not detected Not detected 0.03 Example 3 0.01 Not detected Not detected 0.01 Not detected Not detected Not detected 0.02 Comparative Example 1 0.09 0.04 0.09 0.08 0.09 0.05 0.06 0.46 Comparative Example 2 0.06 0.02 0.05 0.04 0.06 0.07 0.09 0.37 Comparative Example 3 0.02 0.01 0.01 0.03 0.03 0.02 0.04 0.15 Comparative Example 4 0.05 0.08 0.03 0.04 0.09 0.04 0.06 0.31

[0073] Note: Impurity B is not included in the total impurities.

[0074] In summary, the promethazine hydrochloride product prepared by the method of Examples 1-3 not only has a good yield, but also effectively reduces the total impurity content, improves the purity of promethazine hydrochloride (promethazine HPLC purity reaches 99.99%), and has good quality.

[0075] 3. Stability inspection

[0076] The stability of the promethazine hydrochloride prepared in Examples 1-3 and Comparative Examples 1-4 was investigated. A long-term test was conducted at a temperature of 25°C ± 2°C and a relative humidity of 60% ± 5%, with samples taken at 0, 6, 12, and 24 months.

[0077] The results showed that the impurity content of the promethazine hydrochloride prepared in Examples 1-3 did not change significantly; the impurity content of some promethazine hydrochloride prepared in Comparative Examples 1-4 increased significantly, but was still within the limit.

[0078] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing promethazine hydrochloride, characterized in that: The following steps are involved: (1) Add thionyl chloride to toluene-methanol solvent I, add N,N-dimethylisopropanolamine dropwise, and alkalize after reaction to obtain the product PMZ-1; (2) adding phenothiazine and a base into a toluene-methanol solvent II, refluxing for dehydration, and then reacting with PMZ-1 for reflux and water separation to obtain a product PMZ-2; the base is at least one of sodium hydroxide and potassium hydroxide; (3) PMZ-2 is added with methanol-acetone solvent III, and then oxalic acid is added to form a salt, and then the temperature is lowered for crystallization to obtain the product PMZ-3; the methanol-acetone III is prepared by mixing methanol and acetone in a volume ratio of 1:0.4 to 0.6; (4) Add methanol-acetone solvent IV to PMZ-3, introduce dry HCl gas to react, and dry under vacuum to obtain promethazine hydrochloride.

2. The method for synthesizing promethazine hydrochloride according to claim 1, characterized in that: In step (1), the toluene-methanol I is prepared by mixing toluene and methanol in a volume ratio of 2 to 3:1; in step (2), the toluene-methanol II is prepared by mixing toluene and methanol in a volume ratio of 1:2 to 3; in step (4), the methanol-acetone IV is prepared by mixing methanol and acetone in a volume ratio of 0.4 to 0.6:

1.

3. The method for synthesizing promethazine hydrochloride according to claim 1, characterized in that: In step (1), the reaction temperature is 80-85° C. and the reaction time is 0.8-1.2 h; and the alkalization is to adjust the pH value to 10-11.

4. The method for synthesizing promethazine hydrochloride according to claim 1, characterized in that: In step (1), the molar ratio of N,N-dimethylisopropanolamine to thionyl chloride is 1:1.0-1.2; the mass ratio of N,N-dimethylisopropanolamine to solvent is 1:1.8-2.

2.

5. The method for synthesizing promethazine hydrochloride according to claim 1, characterized in that: Step (2), the reaction time is 8 to 9 hours.

6. The method for synthesizing promethazine hydrochloride according to claim 1, characterized in that: In step (2), the molar ratio of PMZ-1, phenothiazine and base is 1: 1.0-1.2: 0.08-0.12; the mass ratio of phenothiazine to solvent is 1: 1.8-2.

2.

7. The method for synthesizing promethazine hydrochloride according to claim 1, characterized in that: In step (3), the reaction temperature is 50-55°C and the reaction time is 20-40 min; and the crystallization is carried out by cooling to 8-12°C and keeping the temperature for crystallization for 1-1.5 h.

8. The method for synthesizing promethazine hydrochloride according to claim 1, characterized in that: In step (3), the molar ratio of PMZ-2 to oxalic acid is 1:1.0-1.2; the mass ratio of oxalic acid to solvent is 1:7-8.

9. The method for synthesizing promethazine hydrochloride according to claim 1, characterized in that: In step (4), the reaction temperature is 35-38°C, and the vacuum drying temperature is 50-60°C.

10. The method for synthesizing promethazine hydrochloride according to claim 1, characterized in that: In step (4), the mass ratio of PMZ-3 to solvent is 1:2.5-3.0.

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