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CN-121990977-A - Synthesis method of 1,2,3, 9-tetrahydro-4H-2-carbazole-4-one

CN121990977ACN 121990977 ACN121990977 ACN 121990977ACN-121990977-A

Abstract

The invention discloses a preparation method of a compound of a formula II, wherein the compound of the formula I reacts at a reaction temperature of more than or equal to 120 ℃ under the action of zinc chloride to obtain the compound of the formula II, and the reaction formula is shown as follows: The synthesis method of the 1,2,3, 9-tetrahydro-4H-2-carbazole-4-ketone shown in the compound II provided by the invention has the advantages of simple operation, short reaction time, low-cost and easily obtained raw materials, high product purity and high yield, and is very suitable for industrial production.

Inventors

  • YU WENLONG
  • ZHANG HAO
  • WANG ANYU
  • HU JIAXING
  • JIN YONGJUN
  • ZHU WEI
  • MENG YANHUA

Assignees

  • 浙江华海药业股份有限公司
  • 浙江华海立诚药业有限公司

Dates

Publication Date
20260508
Application Date
20251107
Priority Date
20241107

Claims (13)

  1. 1. A process for the preparation of a compound of formula II comprising the steps of: under the action of zinc chloride, the compound of the formula I reacts at the reaction temperature of more than or equal to 120 ℃ to obtain the compound of the formula II, wherein the reaction formula is shown as follows:
  2. 2. The method according to claim 1, wherein the reaction temperature is 120-170 ℃, preferably 120-150 ℃, further preferably 125-135 ℃.
  3. 3. The method of any one of claims 1-2, wherein the reaction is free of acetic acid.
  4. 4. A process according to any one of claims 1 to 3, wherein the reaction is carried out in the absence of a solvent.
  5. 5. A process according to any one of claims 1 to 3, wherein the reaction is carried out in the presence of an organic solvent a in which a non-polar solvent is present, preferably selected from any one or more of an aromatic hydrocarbon solvent and a halogenated aromatic hydrocarbon solvent, further preferably selected from any one or more of cumene, xylene, chlorobenzene, mesitylene.
  6. 6. The method according to claim 5, wherein a polar solvent is further present in the organic solvent A, wherein the polar solvent is selected from any one or more of ethyl acetate, acetonitrile, DMF, DMSO, methanol, ethanol, isopropanol, n-butanol, acetone, methyl isobutyl ketone and tetrahydrofuran, preferably selected from any one or more of DMSO, methanol, ethanol, n-butanol, methanone, methyl isobutyl ketone and tetrahydrofuran, more preferably n-butanol, and the weight of the polar solvent is 1/15-1/99, preferably 1/19-1/99 of the weight of the nonpolar solvent.
  7. 7. The method according to any one of claims 1 to 6, wherein the molar ratio of the compound of formula I to zinc chloride is 1:2 to 1:10, preferably 1:2.5 to 1:7, further preferably 1:3 to 1:5.
  8. 8. The method according to any one of claims 1 to 7, wherein the preparation method further comprises the steps of: (2-1) directly adding an organic solvent B or removing the organic solvent A after the reaction is finished, adding the organic solvent B, controlling the temperature to be the temperature A, and stirring to dissolve system residues to obtain a residual liquid; (2-2) adding an aqueous solution of an inorganic salt or an aqueous solution of an inorganic acid to the residual solution obtained in the step (2-1), stirring at a temperature B, filtering while the mixture is hot, washing the filter residue with an organic solvent B, mixing the obtained filtrates, layering the filtrates, evaporating part of the organic solvent B from the obtained organic phase, and crystallizing to obtain the compound of formula II.
  9. 9. The method according to claim 8, wherein in step (2-1) and step (2-2), the organic solvent A is as described above, the organic solvent B is selected from any one or more of ethyl acetate, dichloromethane, acetonitrile, DMF, DMSO, methanol, ethanol, isopropanol, n-butanol, acetone, methyl isobutyl ketone, tetrahydrofuran, preferably selected from any one or more of DMSO, methanol, ethanol, n-butanol, methanone, methyl isobutyl ketone, tetrahydrofuran, further preferably n-butanol, the temperature A is 60-120 ℃, preferably 80-110 ℃, further preferably 100-110 ℃, the temperature B is 60-100 ℃, preferably 80-100 ℃, the stirring time is not less than 0.5h, preferably not less than 1h, the ratio of the volume of the organic solvent B in step (2-1) to the mass of the compound of formula I added at the beginning of the reaction is not less than 5:1mL/g, preferably not less than 7.1 mL/g.
  10. 10. The method according to any one of claims 8-9, wherein the inorganic salt in step (2-2) is a carbonate, bicarbonate, phosphate, dibasic phosphate, preferably potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, ammonium carbonate, sodium phosphate, dibasic sodium phosphate, ammonium phosphate, dibasic ammonium phosphate, potassium phosphate, dibasic potassium phosphate, further preferably sodium carbonate.
  11. 11. The method according to any one of claims 8 to 9, wherein the mineral acid in step (2-2) is phosphoric acid.
  12. 12. The method according to any one of claims 8 to 11, wherein the ratio of the volume of the solution at the time of crystallization in step (2-2) to the mass of the compound of formula I added at the beginning of the reaction is 1:1 to 5:1ml/g, preferably 2:1 to 4:1ml/g, more preferably 3:1ml/g, and the solvent at the time of crystallization in step (2-2) is n-butanol, and the temperature of the crystallization is-10 to 20 ℃, preferably-5 to 10 ℃, more preferably-5~0 ℃.
  13. 13. A process for the preparation of carvedilol or a salt thereof, comprising a process according to any one of claims 1-12.

Description

Synthesis method of 1,2,3, 9-tetrahydro-4H-2-carbazole-4-one Technical Field The invention relates to the field of synthesis of pharmaceutical and chemical intermediates, in particular to a synthesis method for preparing a carvedilol intermediate. Background Carvedilol is a3 rd generation beta-receptor blocker, has the effects of blocking alpha and beta receptors, antagonizing calcium, resisting oxidation, resisting cell proliferation, protecting cells and the like, can be used for treating hypertension, angina and congestive heart failure, and can remarkably reduce the mortality of congestive heart failure patients, and the structural formula is shown as follows: wherein 4-hydroxy carbazole is a key intermediate of carvedilol, and the structural formula is shown as follows: CN102190613B discloses a main route for preparing 4-hydroxy carbazole as follows: The synthesis route is short, and the raw materials are cheap and easy to obtain. The second step of synthesizing 1,2,3, 9-tetrahydro-4H-2-carbazole-4-ketone has two main catalytic systems, namely a strong acid catalytic system or a zinc chloride and acetic acid catalytic system. FR1566173 discloses a method for synthesizing 1,2,3, 9-tetrahydro-4H-2-carbazole-4-one in a strong acid catalytic system, wherein a reaction solution of the method generally contains a large amount of trifluoroacetic acid, sulfuric acid or phosphoric acid, a large amount of acid wastewater is generated in the post-treatment process, so that a large wastewater treatment pressure is caused, JP2005200344 and DE2928483 disclose a method for synthesizing 1,2,3, 9-tetrahydro-4H-2-carbazole-4-one in a zinc chloride plus acetic acid system, and the method has the advantages of high impurity content and low yield in a reaction solution. In view of the above-described problems, it is necessary to develop a low-cost, high-yield, more environmentally friendly synthetic route for synthesizing 1,2,3, 9-tetrahydro-4H-2-carbazol-4-one. Disclosure of Invention The invention provides a preparation method of a compound of a formula II, which comprises the following steps: under the action of zinc chloride, the compound of the formula I reacts at the reaction temperature of more than or equal to 120 ℃ to obtain the compound of the formula II, wherein the reaction formula is shown as follows: In some embodiments, the reaction temperature is 120 to 170 ℃, preferably 120 to 150 ℃, and more preferably 125 to 135 ℃. In some embodiments, the reaction is free of acetic acid. In some embodiments, the reaction is performed in the absence of a solvent. In some embodiments, the reaction is carried out in the presence of an organic solvent A, wherein the organic solvent A comprises a nonpolar solvent, and the nonpolar solvent is preferably any one or any several of aromatic hydrocarbon solvents and halogenated aromatic hydrocarbon solvents, and further preferably any one or any several of cumene, xylene, chlorobenzene and mesitylene. In some embodiments, the volume of organic solvent A required per gram of compound of formula I in the reaction is less than or equal to 20mL, preferably 5 to 15mL, more preferably 10mL. In some embodiments, the organic solvent a further comprises a polar solvent, wherein the polar solvent is selected from any one or any several of ethyl acetate, acetonitrile, DMF, DMSO, methanol, ethanol, isopropanol, n-butanol, acetone, methyl isobutyl ketone and tetrahydrofuran, preferably selected from any one or any several of DMSO, methanol, ethanol, n-butanol, ketone, methyl isobutyl ketone and tetrahydrofuran, more preferably n-butanol, and the weight of the polar solvent is 1/15-1/99, preferably 1/19-1/99 of the weight of the nonpolar solvent. In some embodiments, the molar ratio of the compound of formula I to zinc chloride is 1:2 to 1:10, preferably 1:2.5 to 1:7, and more preferably 1:3 to 1:5. In some embodiments, the reaction time is 3 to 10 hours, more preferably 3 to 5 hours. In some embodiments, the method of preparation further comprises the steps of, (2-1) Directly adding an organic solvent B or removing the organic solvent A after the reaction is finished, adding the organic solvent B, controlling the temperature to be the temperature A, and stirring to dissolve system residues to obtain a residual liquid; (2-2) adding an aqueous solution of an inorganic salt or an aqueous solution of an inorganic acid to the residual solution obtained in the step (2-1), stirring at a temperature B, filtering while the mixture is hot, washing the filter residue with an organic solvent B, mixing the obtained filtrates, evaporating part of the organic solvent B, and crystallizing to obtain the compound of formula II. In some embodiments, in the step (2-1) and the step (2-2), the organic solvent A is as described above, the organic solvent B is selected from any one or any several of ethyl acetate, dichloromethane, acetonitrile, DMF, DMSO, methanol, ethanol, isopropanol, n-butanol, acetone, methyl is