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CN-121991058-A - Preparation method of 9, 10-dihydrolysergic acid

CN121991058ACN 121991058 ACN121991058 ACN 121991058ACN-121991058-A

Abstract

The invention provides a preparation method of 9, 10-dihydrolysergic acid, which is characterized by comprising a continuous flow hydrogenation reactor, lysergic acid and a mixed solvent, wherein the mixed solvent is a mixed solution of an organic solvent and alkali, the preparation method comprises the steps of adding the lysergic acid into the mixed solvent under the protection of room temperature and nitrogen, stirring and dissolving to obtain a mixed solution, carrying out hydrogenation reaction on the mixed solution by adopting the continuous flow hydrogenation reactor to obtain a reaction solution, decolorizing the reaction solution by utilizing a reducing agent, concentrating, supplementing water, regulating pH to 5-8 to obtain a crystallization solution, filtering to obtain a filter cake, and carrying out vacuum drying on the filter cake to obtain the 9, 10-dihydrolysergic acid. The yield of the 9, 10-dihydrolysergic acid prepared by the method is improved, and the safety is also greatly improved.

Inventors

  • YE JIAN
  • ZHANG CHENGWEI
  • TIAN WEN
  • WU HUALONG

Assignees

  • 重庆乾泰医药研究院有限公司

Dates

Publication Date
20260508
Application Date
20251229

Claims (9)

  1. 1. The preparation method of the 9, 10-dihydrolysergic acid is characterized by comprising a continuous flow hydrogenation reactor, lysergic acid and a mixed solvent, wherein the mixed solvent is a mixed solution of an organic solvent and alkali, and the preparation method comprises the following steps: Firstly), adding lysergic acid into a mixed solvent under the protection of nitrogen at room temperature, and stirring and dissolving to obtain a mixed solution; secondly, carrying out hydrogenation treatment on the mixed solution by adopting a continuous flow hydrogenation reactor to obtain a reaction solution; Thirdly, decolorizing the reaction solution by using a reducing agent, concentrating, supplementing water, adjusting the pH value to 5-8 by using acid to obtain a crystal solution, and filtering to obtain a filter cake; fourth, the filter cake is dried in vacuum to obtain 9, 10-dihydrolysergic acid.
  2. 2. The method for preparing 9, 10-dihydrolysergic acid according to claim 1, wherein the organic solvent is ethyl acetate, dichloromethane, acetone, methanol, ethanol, ethylene glycol, N-propanol, isopropanol, N-butanol, tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide or N, N-dimethylacetamide, and the base is sodium hydroxide, potassium hydroxide, calcium hydroxide or ammonia water.
  3. 3. The process for preparing 9, 10-dihydrolysergic acid according to claim 1, wherein the stirring time in the first step is 1.+ -. 0.5h.
  4. 4. The process for preparing 9, 10-dihydrolysergic acid as claimed in claim 1, wherein in the second step), the reaction solution is detected by HPLC method until the lysergic acid residue in the reaction solution is less than or equal to 2.0%, and the hydrogenation reaction is completed.
  5. 5. The process for producing 9, 10-dihydrolysergic acid according to claim 1, wherein the pressure of the hydrogenation reaction in the second step is 1-8 MPa.
  6. 6. The process for preparing 9, 10-dihydrolysergic acid according to claim 1, wherein in the third step), the reducing agent is sodium dithionite, sodium sulfite, sodium bisulfite or ammonium sulfite.
  7. 7. The method for preparing 9, 10-dihydrolysergic acid as set forth in claim 1, wherein in the third step, the process of adjusting pH value for crystallization is performed at a temperature of 0-30 ℃.
  8. 8. The process for preparing 9, 10-dihydrolysergic acid according to claim 1, wherein in the third step), the acid used for adjusting the pH value is formic acid, acetic acid, sulfuric acid or hydrochloric acid.
  9. 9. The process for preparing 9, 10-dihydrolysergic acid as claimed in claim 1, wherein in the fourth step, the vacuum degree of vacuum drying is less than or equal to-0.07 Mpa, and the temperature of the baked material is 10-90 ℃.

Description

Preparation method of 9, 10-dihydrolysergic acid Technical Field The invention relates to the technical field of compound preparation, in particular to a preparation method of 9, 10-dihydrolysergic acid. Background The chemical name of 9, 10-dihydroergodic acid is 6-methyl ergoline-8 beta-carboxylic acid, the chemical structural formula contains 3 asymmetric centers, the absolute configuration is (5R, 8R, 10R), and the 9, 10-dihydroergoline acid is the starting material of cabergoline and dihydroergoline base, and the formula is shown as the formula 1. And a mass spectrum of 9, 10-dihydrolysergic acid is shown in figure 2. Cabergoline is a semisynthetic ergoline derivative which is first developed by French company, belongs to a nervous system medicament, has DA receptor agonistic property, is characterized by strong, long-acting and selective property, has high affinity with D2 receptor, and can be used for treating early-stage and late-stage parkinsonism and hyperprolactinemia. The cause of hyperprolactinemia can be physiological, pharmaceutical and pathological, and its common pathological cause is pituitary prolactinadenoma. At present, the treatment modes of the prolactinoma include operation, medicine and radioactive treatment, and simultaneously, temozolomide is adopted for chemotherapy. Prior to 1971, surgical treatment was the main treatment for pituitary prolactinadenoma, and after the study of the cause and pathology of hyperprolactinemia, dopamine receptor agonist drugs began to be introduced into the clinic, so Gao Bi lactating patients entered the stage of comprehensive treatment. The medicine types of dopamine receptor agonists are also continuously improved from the aspects of receptor specificity selection, half-life length and the like, and at present, medicines commonly used in the world are bromocriptine, cabergoline, bergaptt, quinine Gao Lite and the like, and a plurality of clinical researches have shown that the cabergoline has selective dopamine receptor (D2 receptor) excitation and longer half-life, the clinical effect is better than that of bromocriptine which is still commonly used in China, and the research proves that the cabergoline has good curative effect on bromocriptine resistant patients. Dihydroergot base is used as a carrier, also known as dihydroergoline or dihydroergoline mesylate. It is a classical compound drug derived from natural ergot alkaloids and is commonly used for the treatment of senile related cognitive dysfunction and vascular diseases. The existing production process of 9, 10-dihydrolysergic acid has the following steps: Synthesis route one, J Org Chem,1945,10 (1): 76-86. Report. The route is used for fully synthesizing the racemic dihydrolysergic acid through 7-step reaction, the total yield is low, the raw materials are not easy to obtain, and the three-dimensional configuration of 3 chiral centers can not be solved. The second synthesis route, chinese patent CN102775402, reports: the method comprises the steps of activating hydroxyl through sulfonyl chloride, reacting with sodium cyanide to obtain a compound shown in a formula (7), and then oxidizing and saponifying a compound (8) obtained by removing an R protecting group through hydrolysis to obtain optically active dihydrolysergic acid. The process has long route and low overall yield, and is unfavorable for industrial production. Synthetic route three, RSC ADVANCES,2013, 3, 23146-23156. Report: The method takes ergotamine as a raw material, and the dihydroergotoic acid is prepared by hydrogenation, hydrolysis and acidification in sequence, so that the yield is higher, but the purification process of the initial raw material is more complicated, and the yield is not high. Scheme IV, J.biol. Chem. 1936, 113:767-778, report: The process uses lysergic acid as raw material to prepare target product through one-step reaction, and compared with other processes, the operation is simple, the process is easy to control, the reaction does not need to be pressurized, the introduction of impurities is less, but the yield is lower, the literature report yield is only 50%, according to the process reported in the literature, glacial acetic acid is used as reaction solvent to carry out hydrogenation, the reaction yield is low, and the lysergic acid is easy to isomerize under the acidic condition, as shown in the following figure. The isomerization results in the formation of a large amount of 9, 10-dihydrolysergic acid isomer after hydrogenation, which reduces the yield of hydrogenation reaction. In addition, the hydrogenation reaction process adopted in the preparation process has a large safety risk, the traditional hydrogenation reaction process comprises the steps of adding reactants, solvents and catalysts into an autoclave (reactor) at one time, introducing hydrogen, reacting under stirring, releasing pressure after the reaction is finished, separating products and catalysts, wherein the whole process is in