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Preparation method of pomalidomide

A technology of pomalidomide and glutamine, which is applied in the field of preparing pomalidomide, can solve the problems of difficult industrialization, low product purity, and long reaction cycle, and achieve low production cost, good product quality, and short reaction steps Effect

Active Publication Date: 2016-03-30
HANGZHOU HEZE PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But this method (Bioorg.Med.Chem.Lett.9,1625(1999)) has the shortcoming that the reaction period is long, the reaction needs pressurized hydrogenation, etc. to be difficult to realize industrialization, and the final product purity is not high, only about 85%

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] (1) Preparation of formula IV compound

[0043] 19.32g of 3-nitrophthalic anhydride, 14.62g of D,L-isoglutamine, 8.92g of sodium acetate, and 100ml of acetic acid were stirred, refluxed, kept stirring for 7 hours, cooled to room temperature, filtered, washed with water, After drying, 29.86 g of gray solid was obtained, with a yield of 93.2%.

[0044] 1HNMR (500MHz, CDCl3) δ14.41(s, 1H), 11.48(s, 1H), 8.12(dd, J=7.5, 2.0Hz, 1H), 7.87(dd, J=7.5, 2.0Hz, 1H), 7.73(t, J=7.5Hz, 1H), 7.45(s, 1H), 4.51(dt, J=5.8, 1.1Hz, 1H), 3.19–3.10(m, 1H), 2.96(ddd, J=12.4, 9.0,7.6Hz,1H),2.08(dtd,J=12.4,8.9,5.8Hz,1H),1.63(ddt,J=12.4,7.7,1.4Hz,1H).

[0045] (2) preparation of formula VI compound

[0046] 10 g of the compound of formula IV and 30 ml of DMF were added to the reaction flask, and 5 g of thionyl chloride was added dropwise with stirring at -20°C. Insulation reaction 2-3 hours. The reaction solution was poured into rapidly stirred ice water, extracted with 2×50ml ethyl acetat...

Embodiment 2

[0052] (1) preparation of formula V compound

[0053] 19.32g of 3-nitrophthalic anhydride, 17.6g of D,L-dimethyl glutamate, 8.92g of sodium acetate, and 100ml of acetic acid were stirred, refluxed, kept stirring for 7 hours, cooled to room temperature and filtered. Washed with water and dried to obtain a gray solid, filtered and dried to obtain 34.16 g of the product with a yield of 97.6%.

[0054] 1 HNMR (500MHz, DMSO-d 6 )δ8.11(dd, J=7.4,1.9Hz,1H),8.03(dd,J=7.4,1.9Hz,1H),7.74(t,J=7.4Hz,1H),4.29(t,J=6.9 Hz,1H),3.64(d,J=10.2Hz,6H),2.77(ddd,J=12.3,5.2,1.8Hz,1H),2.55(td,J=12.1,4.5Hz,1H),2.46(dddd ,J=11.8,6.7,4.7,1.9Hz,1H),2.29(tdd,J=12.2,6.9,5.2Hz,1H).

[0055] (2) preparation of formula VI compound

[0056] Add 30 g of the compound of formula V, 100 ml of DMF, and 0.41 g of sodium amide into the reaction flask. 150°C heat preservation reaction for 5 hours. The reaction solution was concentrated under reduced pressure at 60°C, poured into rapidly stirred ice water, and a ...

Embodiment 3

[0063] (1) Preparation of formula IV compound

[0064] 19.66g of 3-nitrophthalic anhydride, 14.73g of D,L-isoglutamine, 3.68g of triethylamine, stirred in 100ml of DMF, reflux reaction, kept stirring for 9 hours, cooled to room temperature, filtered, washed with water, After drying, 23.89 g of gray solid was obtained, with a yield of 74.56%.

[0065] (2) preparation of formula VI compound

[0066] Add 10 g of the compound of formula IV and 50 ml of tetrahydrofuran into the reaction flask, and add 13.12 g of CDI in batches under stirring at 10°C. After the addition, the reaction was refluxed for 2 to 3 hours. After concentration, pour into rapidly stirred ice water, extract with 2×50ml ethyl acetate, and dry over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the mother liquor was concentrated to dryness under reduced pressure. Stir in acetic acid at room temperature for one hour, filter, wash with water, and dry to obtain 4.17 g of the product with...

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Abstract

A preparation method of pomalidomide represented by formula (VII) comprises the following steps: 1, reacting 3-nitrophthalic anhydride represented by formula (I) with D,L-isoglutamine represented by formula (II) or dimethyl D,L-glutamate represented by formula (III) in the presence of an alkaline reagent to obtain a corresponding compound of formula (IV) or formula (V); 2, carrying out ring closure on the compound of formula (IV) or formula (V) to obtain a compound of formula (VI); and 3, carrying out nitro group reduction on the compound of formula (VI) to obtain pomalidomide represented by formula (VII). The method has the advantages of novel technological route, reasonable technological conditions, short reaction steps, simple operation, low production cost, high reaction yield, good product quality, low three wastes, and large enforcement values and social and economic effects.

Description

technical field [0001] The invention relates to a method for preparing pomalidomide. technical background [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 2-3 / 100,000, the male to female ratio is 1.6:1, and most patients are >40 years old. [0003] Pomalidomide is an analogue of thalidomide, which has antitumor activity and can inhibit the proliferation of hematopoietic tumor cells and induce apoptosis. In addition, pomalidomide can inhibit the proliferation of lenalidomide-resistant multiple myeloma cell lines, and can synergistically induce ...

Claims

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Application Information

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IPC IPC(8): C07D401/04
Inventor 倪晟陈鸿翔姜维斌汤建拓
Owner HANGZHOU HEZE PHARMA TECH
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