Preparation method of asenapine intermediate

A technology for intermediates and compounds, applied in the field of organic synthesis, can solve the problems of a lot of waste water, low reaction yield, difficult removal of impurities, etc., and achieve the effects of reasonable process conditions, high reaction yield and low production cost.

Active Publication Date: 2013-07-24
SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] When the final product asenapine (compound 7) is synthesized by the above-mentioned route, there are problems that the reaction yield of compound 2 or 5 is low, impurities are difficult to remove, and there is a lot of waste water

Method used

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  • Preparation method of asenapine intermediate
  • Preparation method of asenapine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 15

[0022] Example 15-chloro-2,3-dihydro-2-methyl-1H-dibenzo[2,3:6,7]oxepin[4,5-c]pyrrol-1-one (compound 2) Preparation

[0023] Add 232 g of 3-(2-(4-chlorophenoxy)-phenyl)-4-hydroxy-1-methyl-1H-pyrrol-2(5H)-one (compound 1) into a 5-liter four-necked reaction flask , add 2 liters of trifluoromethanesulfonic acid at one time, and raise the temperature to 110°C for 10-15h.

[0024] After the reaction, most of the trifluoromethanesulfonic acid was distilled off under reduced pressure, the residue was cooled to room temperature, poured into ice water, a large amount of solids precipitated, and filtered. The solid was recrystallized with acetone and water to obtain 135 g of the product with a yield of 71% and a purity of >96%.

[0025] HNMR data (DMSO-d6 solvent)

[0026] 3.10(d, J=2.5Hz), 4.70(d, 2H, J=4.2Hz), 7.2-7.6(m, 6H), 8.1(s, 1H)

Embodiment 211

[0027] Example 211-chloro-2,3-dihydro-2-methyl-1H-dibenzo[2,3:6,7]oxepin[4,5-c]pyrrol-1-one (compound 5) Preparation

[0028] Add 232 g of 3-(5-chloro-2-phenoxyphenyl)-1-methyl-1H-pyrrol-2(4H)-one (compound 4) into a 5-liter four-necked reaction flask, and add 2 liters at a time Trifluoromethanesulfonic acid, heated to 110 ° C for 10-15h. After the reaction, most of the trifluoromethanesulfonic acid was distilled off under reduced pressure, the residue was cooled to room temperature, poured into ice water, a large amount of solids precipitated, and filtered. The solid was recrystallized with acetone and water to obtain 145 g of the product with a yield of 76% and a purity of >95%.

Embodiment 3

[0029] The preparation of embodiment 3 asenapine

[0030] With compound 2 or 5, high-purity asenapine (trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-diphenyl and[2,3:6,7]oxazolo[4,5-c]pyrrole).

[0031] Comparative example 15-chloro-2,3-dihydro-2-methyl-1H-dibenzo[2,3:6,7]oxepin[4,5-c]pyrrol-1-one (compound 2) Preparation (polyphosphoric acid method)

[0032] Add 232 g of 3-(5-chloro-2-phenoxyphenyl)-1-methyl-1H-pyrrol-2(4H)-one (compound 1) into a 5-liter four-necked reaction flask, and add 1 L of polyphosphoric acid , heated to 150 ° C for 15 h. The reaction is still not over, add phosphorus pentoxide, heat up to 160 °C, after the reaction, cool the solution to 50 °C, pour it into ice water, a lot of solids precipitate out, filter it. The solid was recrystallized with acetone and water to obtain 110 g of the product with a yield of 50% and a purity of 75%.

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Abstract

The invention discloses a novel preparation method of an asenapine intermediate, comprising the following steps of: carrying out cyclization in protonic acid including trifloromethanesulfonic acid by taking 3-(2-(4- chlorophenoxyl)-phenyl-4-hydroxyl-1-methyl-1H-pyrrole-2(5H)-ketone (compound 1) or 3-(5-chlorine-2-phenoxyl phenyl)-1-methyl-1H-pyrrole-2(4H)-ketone (compound 4) as a raw material to generate key intermediate compounds 2 and 4 of asenapine; and carrying out reduction reaction to obtain asenapine. The invention has the advantages of novel process route, high reaction yield and low production cost, and has greater application value and social economic effect.

Description

technical field [0001] The invention relates to a chemical synthesis method, in particular to a novel preparation method of an intermediate of Asenapine which can be used as a schizophrenic, and belongs to the field of organic synthesis. technical background [0002] The trade name of Asenapine is Saphris, developed by Organon BioSciences and produced by ScheringPlough. On August 14, 2009, the FDA approved the drug for the emergency treatment of adults with schizophrenia, mania, or mixed episodes with type I bipolar disorder. [0003] English chemical name of asenapine: (3aR, 12bR)-rel-5-chloro-2, 3, 3a, 12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4 ,5-c]pyrrole; Chinese chemical name: trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxa Zhuo[4,5-c]pyrrole; molecular formula: C17H16ClNO; relative molecular mass: 285.77; CAS registration number: 65576-45-6. Preparation. WO2006106136, WO2007046554, US20090209608, and WO2008078482 reported that startin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/044
Inventor 高强薛吉军曾亮彭小波郑保富
Owner SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
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