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CN-121990984-A - Docetaxel succinate preparation method of lamellarin

CN121990984ACN 121990984 ACN121990984 ACN 121990984ACN-121990984-A

Abstract

The invention belongs to the field of pharmaceutical chemistry synthesis, and discloses a preparation method of doxylamine succinate, which comprises the steps of firstly taking 1-phenyl-1- (pyridine-2-yl) 1-ethanol and a compound 3 as raw materials, carrying out substitution reaction on the 1-phenyl-1- (pyridine-2-yl) 1-ethanol and the compound 3 under the action of an alkali reagent to obtain N, N-dimethyl-2- [ 1-phenyl-1- (2-pyridine) ethoxy ] ethylamine, and carrying out salification reaction on the N, N-dimethyl-2- [ 1-phenyl-1- (2-pyridine) ethoxy ] ethylamine and succinic acid to obtain the doxylamine succinate. The invention uses the sulfonic acid 2- (dimethylamino) ethyl ester with higher boiling point and high conversion efficiency, greatly improves the yield of the product, and can stably reproduce and obtain the target crystal form in a low-temperature salification and crystallization mode. The method has the total yield reaching more than 93.5 percent and the purity reaching more than 99.7 percent.

Inventors

  • WU YUNDENG
  • HU PING
  • CAI YING
  • XIA YUN
  • TIAN LIJUAN
  • TANG QIAN
  • WANG MINGHAO
  • LI JIAN
  • XU XIANGYANG
  • YANG JIAJU
  • Fang Songjie

Assignees

  • 金陵药业股份有限公司

Dates

Publication Date
20260508
Application Date
20241107

Claims (10)

  1. 1. A preparation method of doxylamine succinate is characterized by comprising the following synthetic route: Wherein R 1 is selected from p-toluenesulfonic acid group or methylsulfonic acid group, R 2 is selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl and H; The method comprises the following steps: Step one, taking 1-phenyl-1- (pyridine-2-yl) 1-ethanol and a compound 3 as raw materials, and carrying out substitution reaction on the 1-phenyl-1- (pyridine-2-yl) 1-ethanol and the compound 3 under the action of an alkali reagent to obtain N, N-dimethyl-2- [ 1-phenyl-1- (2-pyridine) ethoxy ] ethylamine; And step two, carrying out salt formation reaction on N, N-dimethyl-2- [ 1-phenyl-1- (2-pyridine) ethoxy ] ethylamine and succinic acid to obtain doxylamine succinate.
  2. 2. The method for preparing doxylamine succinate according to claim 1, wherein in the first step, the molar ratio of 1-phenyl-1- (pyridin-2-yl) 1-ethanol to compound 3 is 1:1.0-1:2.0, preferably 1:1.0-1:1.2.
  3. 3. The method for preparing doxylamine succinate according to claim 1, wherein in the first step, the molar ratio of 1-phenyl-1- (pyridin-2-yl) 1-ethanol to alkaline agent is 1:1.0-1:2.0, preferably 1:1.0-1:1.2.
  4. 4. A process for preparing doxylamine succinate as defined in claim 1 or 3, wherein in step one, said alkaline reagent is selected from one or more of sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, sodium n-propoxide, potassium n-propoxide, sodium isopropoxide, potassium isopropoxide, sodium hydroxide and potassium hydroxide.
  5. 5. The method for preparing doxylamine succinate according to claim 1, wherein in the first step, the reaction solvent is one or two selected from toluene, xylene, tetrahydrofuran, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, and N, N-dimethylacetamide.
  6. 6. The method for preparing doxylamine succinate according to claim 1, wherein in the first step, the temperature of the substitution reaction is 40 ℃ to the reflux temperature corresponding to the reaction solvent, preferably 60 to 100 ℃, and the time of the substitution reaction is 1 to 12 hours, preferably 3 to 5 hours.
  7. 7. The preparation method of doxylamine succinate according to claim 1, wherein in the first step, after the substitution reaction, water is added into the reaction solution according to the volume ratio of the reaction solvent to water of 1:0.5-1:2.5, the pH value is adjusted to 3-4 by 6% -10% hydrochloric acid, the organic phase is discarded, the pH value of the aqueous phase is adjusted to 8-9 by saturated sodium carbonate or potassium carbonate solution, ethyl acetate or isopropyl acetate is added for extraction, the organic phase is reserved, the organic phase is dried by anhydrous sodium sulfate and concentrated, and N, N-dimethyl-2- [ 1-phenyl-1- (2-pyridine) ethoxy ] ethylamine is obtained; preferably, when the reaction solvent is tetrahydrofuran, acetonitrile, N-dimethylformamide, dimethyl sulfoxide or N, N-dimethylacetamide, adding water into the reaction solution according to the volume ratio of the reaction solvent to water of 0.75:1-1:2.5 after the substitution reaction is finished, adding ethyl acetate or isopropyl acetate as an extraction solvent according to the volume ratio of the reaction solvent to the extraction solvent of 0.6:1-1:1, adjusting the pH value to 3-4 by using 6% -10% hydrochloric acid, discarding an organic phase, adjusting the pH value of an aqueous phase to 8-9 by using a saturated sodium carbonate or potassium carbonate solution, adding ethyl acetate or isopropyl acetate for extraction, reserving the organic phase, drying the organic phase by using anhydrous sodium sulfate, concentrating to obtain N, N-dimethyl-2- [ 1-phenyl-1- (2-pyridine) ethoxy ] ethylamine, when the reaction solvent is toluene or xylene, adding water into the reaction solution according to the volume ratio of the reaction solvent to water of 1:0.5-1:0.8 after the substitution reaction is finished, adjusting the pH value to 3-4 by using 6% -10% hydrochloric acid, and regulating the pH value of the water phase to 8-9 by using saturated sodium carbonate or potassium carbonate solution, adding ethyl acetate or isopropyl acetate for extraction, retaining an organic phase, drying the organic phase by using anhydrous sodium sulfate, and concentrating to obtain the N, N-dimethyl-2- [ 1-phenyl-1- (2-pyridine) ethoxy ] ethylamine.
  8. 8. The method for preparing doxylamine succinate according to claim 1, wherein in the second step, the molar ratio of N, N-dimethyl-2- [ 1-phenyl-1- (2-pyridine) ethoxy ] ethylamine to succinic acid is 1:0.9-1:1.1, preferably 1:0.95-1:1.05, more preferably 1:1.
  9. 9. The method for preparing doxylamine succinate according to claim 1, wherein in the second step, the reaction solvent is one or two selected from acetone, ethyl acetate and isopropyl acetate, preferably a mixed solvent of acetone and one selected from ethyl acetate and isopropyl acetate in a volume ratio of 4:1-1:4.
  10. 10. The method for preparing doxylamine succinate according to claim 1, wherein in the second step, the salt forming reaction is performed at a temperature of-10-30 ℃, preferably-5 ℃, and the salt forming reaction is performed for 0.5-12 hours, preferably 5-6 hours.

Description

Docetaxel succinate preparation method of lamellarin Technical Field The invention belongs to the field of pharmaceutical chemistry synthesis, and particularly relates to a preparation method of doxylamine succinate. Background The doxylamine succinate is an ethanol antihistamine drug, has antihistaminic effect, anticholinergic effect and obvious sedative and hypnotic effect, has strong activity and low gastrointestinal side effect, and is suitable for short-term treatment of various allergic dermatosis, hay fever, allergic rhinitis, asthmatic bronchitis, insomnia and the like. Doxylamine succinate 25mg tablet of CHATTEM company was approved by FDA in 1978 for use in helping sleep difficulty, OTC (over the counter drug) in 1979, and LNK company was approved as an imitation drug in 8 2004. Oral sustained release tablets (trade name Diclegis) of doxylamine succinate and pyridoxine hydrochloride are FDA approved at 4 and 8 2013 for the treatment of pregnant women with nausea and vomiting, which react poorly to conservative treatments. The existing chemical synthesis route of doxylamine succinate uses 2-acetylpyridine as a starting material, the 2-acetylpyridine reacts with Grignard reagent prepared from iodobenzene or bromobenzene to generate important intermediate 2-pyridylphenyl methyl methanol, the 2-pyridylphenyl methyl methanol and 2-dimethylaminochloroethane react with organic base to generate doxylamine (chemical name: N, N-dimethyl-2- [ 1-phenyl-1- (2-pyridine) ethoxy ] ethylamine), and finally the doxylamine succinate is salified with succinic acid to obtain the doxylamine succinate. The preparation method of doxylamine succinate mainly comprises the following steps: The method I takes pyridine and acetophenone as initial raw materials, and the specific route is as follows: The first step of the reaction route is condensation reaction, metallic aluminum or magnesium gold and mercury chloride with high toxicity are used as catalysts, the reaction efficiency and the yield are low, the post-treatment is complex and difficult to industrialize, the second step of the 2-chloroethyl dimethylamine belongs to a pipe product, the price is high, the storage is difficult, in addition, metallic sodium is used as a hydrogen extracting reagent, hydrogen is generated in the reaction process, the application is dangerous, and the large-scale production operation is not suitable. The yield of the prepared free base is only 75%. The second method uses bromobenzene and 2-acetylpyridine as starting materials, and the specific route is as follows: The first step of the reaction route involves dangerous Grignard reaction, the solvent is inflammable and explosive diethyl ether, the 2-pyridylphenyl methyl methanol needs to be purified by using a rectification method, the reaction efficiency is low, the post-treatment is complex, the melting point of the 2-pyridylphenyl methyl methanol is 33-34.5 ℃, the distillation is difficult to ensure the yield and purity of the product, industrialization is difficult, toxic benzene byproducts are generated, the second step of the 2-chloroethyl dimethylamine belongs to a tubular product, the cost is high, the 2-chloroethyl dimethylamine is difficult to store, the boiling point of the 2-chloroethyl dimethylamine is 109-110 ℃, if toluene (the boiling point of the 2-chloroethyl dimethylamine is 110.6 ℃) is used as the reaction solvent, the conversion rate of doxylamine is reduced due to volatilization of the 2-chloroethyl dimethylamine, the cost is increased due to volatilization of the 2-chloroethyl dimethylamine is also caused to reduce the conversion rate of doxylamine, in addition, ammonia is generated in the reaction process, the use of the ammonia is dangerous, the product is difficult to store, the product is difficult to operate, the product is difficult to realize by using the separation of the product is about 25 ℃ and the industrial yield is about 25%, the industrial yield is difficult to realize, the purification is realized by using the separation of the product is about 20%, and the industrial yield is low, and the yield is about 25% of the industrial yield is difficult to be purified, and the total is low. The method III takes 2-acetyl pyridine as a starting material, and the specific route is as follows: The method is similar to the method II, the first step involves dangerous Grignard reaction, the solvent is inflammable and explosive diethyl ether, the post-treatment is complex, industrialization is difficult, toxic benzene byproducts are generated, the second step is that 2-chloroethyl dimethylamine belongs to a pipe product, the cost is high, the 2-chloroethyl dimethylamine is difficult to store, the boiling point of the 2-chloroethyl dimethylamine is 109-110 ℃, xylene is used as the reaction solvent, the conversion rate of doxylamine is reduced due to volatilization, in addition, sodium amide is used as a hydrogen-extracting reagent, ammonia is generated in the reaction p