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Method for preparing pomalidomide key intermediate

A technology of pomalidomide and intermediates, applied in the field of preparation of N--DL-glutamine, which can solve the problem of difficult price of DL-glutamine tert-butyl ester, low reaction yield and low total yield etc. to achieve good yield, simple reaction conditions and easy operation

Inactive Publication Date: 2013-08-07
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] (2) The yield of the second step reaction is low, and requires chromatographic separation
[0013] (3) DL-glutamine tert-butyl ester (VII) used in this route is difficult to obtain and expensive
[0014] (4) the route total yield is too low, only 44%

Method used

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  • Method for preparing pomalidomide key intermediate
  • Method for preparing pomalidomide key intermediate
  • Method for preparing pomalidomide key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The preparation of embodiment 1N-(3-nitrophthaloyl)-DL-glutamic acid (IV)

[0041] Add 3-nitrophthalic anhydride (II) (10.05g, 0.052mol), DL-glutamic acid (III) (9.26g, 0.063mol) and dry DMF100mL to the reaction flask, react at 86°C for 6h, TLC Monitor the reaction for completion. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain an oil. Add 80 mL of water to the oily substance, and a large amount of solid precipitates out under stirring. After filtering, the filter cake is washed with water several times, and dried to obtain a crude product. Add 100 mL of ethyl acetate to the crude product, stir for 6 h, filter, wash the filter cake with ethyl acetate, and dry to obtain 13.56 g of light yellow solid (IV), mp 195-197°C, yield: 81%.

[0042] 1 H-NMR (DMSO-d 6 )δ: 8.33 (d, 1H), 8.22 (d, 1H), 8.10 (t, 1H), 4.86-4.82 (dd, 1H), 2.38-2.21 (m, 4H).

[0043] ESI-MS (m / z): 321 [M-H] -

Embodiment 2

[0044] The preparation of embodiment 2N-(3-nitrophthaloyl)-DL-glutamic anhydride (V)

[0045] Add N-(3-nitrophthaloyl)-DL-glutamic acid (IV) (12.14g, 0.031mol) and 60mL acetic anhydride to the reaction flask, heat to reflux temperature, react for 5.5h, and monitor by TLC The reaction is complete. The reaction solution was cooled to room temperature, a large amount of solids precipitated, filtered, the filter cake was washed with ether, and dried to obtain 10.53 g of off-white solid (V), mp 235-237°C, yield: 92%.

[0046] 1 H-NMR (DMSO-d 6 )δ: 8.37(d, 1H), 8.26(d, 1H), 8.13(t, 1H), 5.54-5.48(dd, 1H), 3.18-2.94(m, 2H), 2.65-2.50(m, 1H) , 2.22-2.10 (m, 1H).

Embodiment 3

[0047] The preparation of embodiment 3N-(3-nitrophthaloyl)-DL-glutamine (I)

[0048] Add N-(3-nitrophthaloyl)-DL-glutamic anhydride (V) (9.87g, 0.032mol), ammonium acetate (4.63g, 0.06mol) and 75mL of glacial acetic acid to the reaction flask, heat up To 55°C, the reaction was stirred for 6h, and the reaction was completed as monitored by TLC. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain an oil. Add 60mL of water to the oil, stir for 6h, a large amount of solid precipitates, filter and dry to obtain the crude product. Add 80 mL of ethyl acetate to the crude product, stir for 8 hours, filter, wash the filter cake with ethyl acetate, and dry to obtain 8.76 g of off-white solid (I), mp 194-196°C, yield: 84%.

[0049] 1 H-NMR (DMSO-d 6 )δ: 13.24 (brs, 1H), 8.34 (d, 1H), 8.22 (d, 1H), 8.11 (t, 1H), 7.15 (s, 1H), 6.68 (s, 1H), 4.80-4.77 (dd , 1H), 2.36-2.13 (m, 4H).

[0050] ESI-MS(m / z): 322[M+H] + .

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Abstract

The invention relates to a method for preparing compound N-(3-nitro-ortho-formyl)-DL-glutamine in a formula (I). The compound is a key intermediate for preparing an antitumor drug pomalidomide.

Description

technical field [0001] The invention relates to a preparation method of N-(3-nitrophthaloyl)-DL-glutamine, which is a key intermediate for synthesizing antitumor drug pomalidomide. Background technique [0002] Pomalidomide (Pomalidomide), the chemical name is 3-amino N-(2,6-dioxo-3-piperidinyl)-phthalimide, which is manufactured by Celgene Corp. An oral immunomodulatory antineoplastic drug developed. The drug was approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with advanced multiple myeloma on February 8, 2013. Its racemic mixture is used clinically, and its chemical structure is as follows: [0003] [0004] The compound represented by formula (I) is a key intermediate for the synthesis of pomalidomide. (1) Cyclization after hydrogenation promptly makes pomalidomide. The conventional method for preparing compound (I) is reported in the patent US6380239, and its synthetic route is as follows: [0005] [0006] The method obtai...

Claims

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Application Information

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IPC IPC(8): C07D209/48
Inventor 陈国华郭祥昌孙立超滕海堂
Owner CHINA PHARM UNIV
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