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CN-121991019-A - Preparation method of high-purity landiolol hydrochloride

CN121991019ACN 121991019 ACN121991019 ACN 121991019ACN-121991019-A

Abstract

The invention discloses a preparation method of high-purity landiolol hydrochloride, which comprises the following steps of adding an organic solvent into a landiolol base for dissolution, adding a hydrogen chloride carrier, regulating the pH value of a system, salifying, crystallizing, filtering and drying to obtain the high-purity landiolol hydrochloride, wherein the organic solvent is preferably acetone, the hydrogen chloride carrier is selected from acetone solution of concentrated hydrochloric acid, the pH value of the system is preferably 5.0-6.0, and the salifying and crystallizing temperatures are preferably 0+/-2 ℃. The preparation method has the advantages of mild reaction conditions, short production period, simple operation and lower cost, reduces the risk of exceeding the standard of related substances, ensures that the chromatographic purity of the product can reach more than 99.9 percent and the yield is more than 80 percent, and is more suitable for industrial production.

Inventors

  • DONG XIAOLIANG
  • LIU DING
  • ZHANG YANCHUN
  • SHANG JIANMIN

Assignees

  • 北京天衡药物研究院有限公司

Dates

Publication Date
20260508
Application Date
20241106

Claims (10)

  1. 1. A preparation method of high-purity landiolol hydrochloride is characterized by comprising the following steps of adding an organic solvent into a landiolol base for dissolution, adding a hydrogen chloride carrier, adjusting the pH value of a system, salifying, crystallizing, filtering and drying to obtain the high-purity landiolol hydrochloride.
  2. 2. The preparation method as claimed in claim 1, wherein the organic solvent is one or more selected from the group consisting of acetone, acetonitrile and ethyl acetate, preferably acetone.
  3. 3. The preparation method of claim 1, wherein the volume-weight ratio of the organic solvent to the landiolol base is 8.0-16.0:1, and preferably the volume-weight ratio is 12.0:1.
  4. 4. The process according to claim 1, wherein the hydrogen chloride carrier is one or more selected from the group consisting of concentrated hydrochloric acid, ethyl hydrogen chloride solution, ethanol hydrogen chloride solution and isopropanol hydrogen chloride solution, preferably concentrated hydrochloric acid, more preferably concentrated hydrochloric acid is prepared into a solution by using an organic solvent, and the HCl concentration of the organic solvent solution of the concentrated hydrochloric acid is 1-6mol/L, preferably 2-4mol/L, and most preferably 2mol/L.
  5. 5. The process according to claim 1, wherein the hydrogen chloride carrier is a concentrated acetone hydrochloride solution having an HCl concentration of 1-6mol/L, preferably 2-4mol/L, most preferably 2mol/L.
  6. 6. The preparation method of claim 1, wherein the pH value of the regulating system is 3.0-6.0, preferably 5.0-6.0.
  7. 7. The process according to claim 1, wherein the salt formation temperature is-25 to 25 ℃, preferably-25 to 15 ℃, most preferably 0.+ -. 2 ℃.
  8. 8. The process of claim 1, wherein the crystallization time is 1.0 to 5.0 hours, preferably 3.0 hours.
  9. 9. The method of claim 1, wherein the crystallization temperature is-25 to 25 ℃, preferably-25 to 0 ℃, and most preferably 0.+ -. 2 ℃.
  10. 10. The preparation method of the catalyst of claim 1, wherein the adopted organic solvent is acetone, the hydrogen chloride carrier is concentrated acetone hydrochloride solution, the concentration is 2mol/L, the hydrogen chloride carrier is added at 0+/-2 ℃ to form salt, the pH value of the system is adjusted to 5.0-6.0, and the crystallization is carried out at 0+/-2 ℃ for 3.0 hours.

Description

Preparation method of high-purity landiolol hydrochloride Technical Field The invention relates to a preparation method of high-purity landiolol hydrochloride, belonging to the field of medicine, Background Landiolol hydrochloride, CAS number 144481-98-1, chinese cultural name [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] methyl 3- [4- [ (2S) -2-hydroxy-3- [2- (morpholin-4-carboxamido) ethylamino ] propoxy ] phenyl ] propionate hydrochloride. The structural formula is as follows: Landiolol hydrochloride is a selective beta 1 receptor blocker, mainly antagonizes the beta 1 receptor existing in the heart, and improves tachycardia arrhythmia by inhibiting the increase of heart rate caused by catecholamine. Is an indispensable emergency medicine for treating arrhythmia in emergency in perioperative period and dynamically monitoring arrhythmia after operation. The half-life is extremely short, the effect is quick, and if side effects occur, the side effects can be quickly removed after the medicine is reduced or stopped. However, the landiolol hydrochloride has complex chemical structure, more sensitive groups and difficult impurity control. Therefore, the salifying conditions have a great influence on the quality of landiolol hydrochloride. Japanese patent laid-open No. Hei 5-306281 (publication day: 11/19/1993), and compound patent US5013734A, EP0397031 disclose a method for preparing landiolol hydrochloride, wherein the synthetic route of one step of salifying is as follows: According to the method, the landiolol base is firstly formed into oxalate, then sodium bicarbonate is added to enable the landiolol oxalate to be free, saturated ammonium chloride aqueous solution is added, hydrochloric acid is added to adjust the aqueous phase to 3.0-4.0, sodium chloride is added to be saturated, ethyl acetate extraction and liquid separation are carried out, drying is carried out, concentration is carried out, and crystallization is carried out, so that landiolol hydrochloride is obtained. In addition, chinese patent CN101768148B, CN106608863a also discloses this method. The disadvantages of this method are: (1) Complicated operation and longer reaction period; (2) Concentrating the landiolol hydrochloride ethyl acetate solution under an acidic condition can generate a large amount of degradation impurities, thereby influencing the product quality; (3) The water solubility of the landiolol hydrochloride is excellent, and the landiolol hydrochloride is easy to remain in the water phase, so that the yield is lower and unstable; (4) Landil hydrochloride has poor solubility in ethyl acetate, and a large amount of ethyl acetate is required for extraction, so that a large amount of anhydrous sodium sulfate is required for drying an organic phase, and more industrial waste residues are generated. Chinese patent CN202011162831 discloses a preparation method of landiolol hydrochloride, which has the following synthetic route in one step: the disadvantages of this method are: (1) The operation is complicated, the salification reaction needs 20 hours, and the reaction period is long; (2) Adding sodium hydroxide strong alkali to free the landiolol oxalate, and concentrating the landiolol under alkaline conditions to generate a large amount of degradation impurities, thereby affecting the product quality; (3) When salifying, isopropanol is adopted as a solution, so that transesterification impurities are generated, and isopropyl alcohol ester which is a byproduct difficult to remove is increased. The isopropyl alcohol ester has the following structural formula: EP2687521A1 discloses a preparation method of landiolol hydrochloride, and the synthetic route of salt formation is as follows: the disadvantages of this method are: (1) During post-treatment, the concentration of the landiolol hydrochloride under the acidic condition can generate a large amount of degradation impurities, thereby influencing the product quality; (2) When salt is formed, isopropanol is adopted as a solution, so that transesterification impurities are generated, and byproducts which are difficult to remove are increased. In summary, the salt forming operation of landiolol in the prior art has the defects of complicated operation, huge solvent consumption, more solid wastes, larger impurities, environmental unfriendly and the like, so that the preparation method which has the advantages of simple operation, high product yield, low production cost, high product purity, environmental friendliness and suitability for industrial production needs to be invented. Disclosure of Invention The invention aims to overcome the defects of complicated operation, poor product purity, more byproducts, low yield, inapplicability to industrial production and the like in the process of preparing the landiolol hydrochloride in the prior art. Based on the purposes, the invention provides the preparation method of the high-purity landiolol hydrochloride, the raw materials, the solvent