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Preparation method of pomalyst pomalidomide

A technology of pomalidomide and glutarimide, applied in the field of pharmaceutical preparation, can solve the problems of long reaction period, difficult industrialization, pressurized hydrogenation and the like

Inactive Publication Date: 2014-04-02
CHONGQING TAIHAO PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method has disadvantages such as long reaction cycle, pressurized hydrogenation, and final product purity of only 85%, which are not easy to realize industrialization.

Method used

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  • Preparation method of pomalyst pomalidomide
  • Preparation method of pomalyst pomalidomide
  • Preparation method of pomalyst pomalidomide

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preparation example Construction

[0051]The invention discloses a preparation method of pomalidomide, and those skilled in the art can learn from the content of this article and appropriately improve the process parameters to realize it. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and the relevant personnel can obviously make changes or appropriate changes and combinations to the method and application described herein without departing from the content, spirit and scope of the present invention to realize and Apply the technology of the present invention.

[0052] The raw materials or reagents used in the preparation method of pomalidomide provided by the present invention can be purchased from the market.

Embodiment 1

[0054] The preparation of compound pomalidomide shown in embodiment 1 formula I

[0055] Add 56g of N-benzyloxycarbonyl-L-glutamine and 1000mL of acetone into the reaction flask, stir for 10 minutes and then add 49g of N,N'-carbonyldiimidazole. 57°C) until HPLC shows that the reaction of N-benzyloxycarbonyl-L-glutamine is complete, it takes 7 hours, after cooling, it is rotated to dryness at a bath temperature of 40°C, and 800 mL of saturated saline is added to the residue and stirred for 2 hours , suction filtration, washed with an appropriate amount of saturated saline, and dried to obtain 47.2g of white or off-white powder. After testing, the white or off-white powder is S-(-)-(2-phenoxycarboxamido) shown in formula II Glutarimide, purity 96.6%, yield 94.2%. The proton nuclear magnetic resonance spectrum data is: (CDCl 3 )δ=8.2 (s broad, 1H), 7.4 (s aromatic, 5H), 5.8 (d, 1H), 5.15 (s, 2H), 4.4 (dd, J=4.5, 3, 1H), 2.95-2.4 ( m, 3H), 1.86 (d, t, J=11.5, 6.5, 1H).

[0056...

Embodiment 2

[0063] The preparation of compound pomalidomide shown in embodiment 2 formula I

[0064] Add 56g of N-benzyloxycarbonyl-L-glutamine and 1000mL of dichloromethane into the reaction flask, stir for 10 minutes and then add 65g of dicyclohexylcarbodiimide. After the addition is complete, install a drying tube to stir and reflux the reaction (reflux temperature 41°C) until HPLC showed that the reaction of the raw material N-benzyloxycarbonyl-L-glutamine was complete, it took 4 hours, and after cooling, it was rotated to dryness at a bath temperature of 40°C, and 800 mL of saturated saline was added to the residue and stirred for 2 hour, suction filtration, appropriate amount of saturated salt water washing, drying, to obtain white or off-white powder 45.8g, after testing, white or off-white powder is S-(-)-(2-phenoxycarboxamide shown in formula II ) glutarimide, purity 96.2%, yield 91.4%. The proton nuclear magnetic resonance spectrum data is close to the result of embodiment 1. ...

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Abstract

The invention relates to the field of medicine preparation, and particularly relates to a preparation method of pomalyst pomalidomide. The method comprises the following steps: carrying out intramolecular cyclization on N-carbobenzoxy-L-glutamine, so as to generate S-(-)-(2-formamido-phenoxy) glutarimide shown in a formula II; removing carbobenzoxy (CBZ) from the S-(-)-(2-formamido-phenoxy) glutarimide, and then carrying out a salt forming reaction on acid, so as to obtain a salt of S-(-)-2-amino glutaric imide shown in a formula III; carrying out an intermolecular condensation reaction on the salt of the S-(-)-2-amino glutaric imide and 3-nitrophthalicanhydride, so as to obtain 4-nitryl-thalidomide shown in a formula IV; and taking the 4-nitryl-thalidomide to prepare the pomalyst pomalidomide by reduction reaction. The preparation method of the pomalyst pomalidomide, which is provided by the invention, is short in cycle, high in product purity, high in yield, free of pressurized reaction, and more applicable to industrial production, and any individual impurity can be smaller than 0.1% in absence of purification.

Description

technical field [0001] The invention relates to the field of medicine preparation, in particular to a preparation method of pomalidomide. Background technique [0002] Multiple myeloma (MM) is a malignant plasma cell disease in which tumor cells originate from plasma cells in the bone marrow, which are cells that develop to the final functional stage of B lymphocytes. Therefore, multiple myeloma can be classified as B lymphocyte lymphoma. Clinical manifestations mainly include anemia, bone pain, renal insufficiency, infection, bleeding, neurological symptoms, hypercalcemia, amyloidosis, etc. The incidence of multiple myeloma is about 2 to 3 / 100,000, the male to female ratio is 1.6:1, and most patients are >40 years old. [0003] Pomalidomide is a thalidomide analogue with the structural formula shown in Formula I, which has anti-tumor activity and can inhibit the proliferation of hematopoietic tumor cells and induce cell apoptosis. In addition, pomalidomide can inhibit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 李靖王信见夏雪峰吴进
Owner CHONGQING TAIHAO PHARM CO LTD
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