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Synthetic method of pomalidomide

A technology of polilidomide and phthalimide, which is applied in the field of synthesis of new immunomodulator polilidomide, can solve the problems of high irritation, high price, and high cost, and achieve low toxicity and pollution, The effect of simple operation and stable process

Inactive Publication Date: 2014-09-03
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this method, the raw material N-(tert-butoxycarbonyl)-L-glutamine is relatively expensive, and the first step adopts EDCI, HOBt as a catalyst, and the first and last steps all need to be separated by column chromatography, which is not suitable for industrial production
In the second step, the use of highly irritating and corrosive trifluoroacetic acid to remove Boc group is not ideal from the perspective of environmental protection and safety (China Pharmaceutical Industry Journal 2009, 40 (10) 721-723)
Wu Gang et al. improved this method, but the catalyst CDI used in the first step is relatively expensive, which limits the industrial application (Chinese Journal of Medicinal Chemistry 2013, Vol N0.2108-110)

Method used

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  • Synthetic method of pomalidomide
  • Synthetic method of pomalidomide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1: the preparation of polilidomide

[0030] A: Preparation of 3-nitrophthalic anhydride

[0031] 3-Nitrophthalic acid (15 g, 71.05 mmol), acetic anhydride (8.7 g, 85.26 mmol), and toluene were added to the reactor. The temperature was raised to 50°C for reaction. After 20 hours of reaction, cool to room temperature, concentrate the solvent to obtain a solid and dry it, then recrystallize it with dichloromethane to obtain 13.23 g of 3-nitrophthalic anhydride after drying the obtained yellow crystal, with a yield of 98.5%.

[0032] B: Preparation of 3-nitro-N-(2,6-dioxo-3-piperidinyl)-phthalimide

[0033] 3-nitrophthalic anhydride (12g, 68.14mmol) and L-glutamine (15.14g, 103.57mmol) obtained in step A were added to the reactor, and toluene and triethylamine (5.72g, 56.49mmol) were added , heated up to 110°C and refluxed for 4.5h; after the reaction, after the solution was cooled to 60°C, acetic anhydride (6.98g, 68.35mmol) was added dropwise, the dropwise c...

Embodiment example 2

[0037] Implementation case 2: the preparation of polilidomide

[0038] A: Preparation of 3-nitrophthalic anhydride

[0039]3-Nitrophthalic acid (15 g, 71.05 mmol), acetic anhydride (54.4 g, 532.85 mmol), and toluene were added to the reactor. Raise the temperature to 110°C for reflux reaction for 1 hour; after the reaction, cool to room temperature, concentrate the solvent and dry the obtained solid, recrystallize with dichloromethane, and obtain 12.36 g of 3-nitrophthalic anhydride after drying the obtained yellow crystal, the yield 90.09%.

[0040] B: Preparation of 3-nitro-N-(2,6-dioxo-3-piperidinyl)-phthalimide

[0041] 3-nitrophthalic anhydride (12g, 62.14mmol) and L-glutamine (4.78g, 32.71mmol) obtained in step A were added to the reactor, and toluene and diethylamine (0.649g, 8.88mmol) were added , After reacting at 80°C for 5.5h, after cooling to 50°C, add acetic anhydride (47.58g, 466.05mmol) dropwise, dropwise closed and continue to heat up at 80°C for 6h; after t...

Embodiment example 3

[0045] Implementation case 3: the preparation of polilidomide

[0046] A: Preparation of 3-nitrophthalic anhydride

[0047] 3-Nitrophthalic acid (15 g, 71.05 mmol), acetic anhydride (29.01 g, 284.19 mmol) were added to the reactor. Add N,N-dimethylformamide and raise the temperature to 150°C to react for 0.5h; after the reaction, cool to room temperature, concentrate the solvent and dry the obtained solid, recrystallize with dichloromethane, and obtain 3-nitro Phthalic anhydride 8.65g, yield 63.05%.

[0048] B: Preparation of 3-nitro-N-(2,6-dioxo-3-piperidinyl)-phthalimide

[0049] 3-Nitrophthalic anhydride (12g, 62.14mmol) and L-glutamine (8.17g, 55.93mmol) obtained in step A were added to the reactor, and N,N dimethylformamide and potassium hydroxide were added (24.86mmol), heat up to 150°C for 0.5h, cool to 70°C, add dropwise acetic anhydride (31.72g, 310.7mmol), dropwise close and continue to heat up to 150°C for 1h; after the reaction, cool to room temperature, filter ...

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Abstract

The invention discloses a method for synthesizing pomalidomide. The method is a three-step synthetic method comprising the steps of step 1, performing condensation on 3-nitrophthalic acid under certain conditions to obtain 3-nitrophthalicanhydride; step 2, preparing 3-nitro-N-(2,6-dioxo-3-piperidyl)-phthalimide by virtue of 3-nitrophthalicanhydride and L-glutamine; step 3, performing reduction on 3-nitro-N-(2,6-dioxo-3-piperidyl)-phthalimide to obtain pomalidomide. The method disclosed by the invention is stable in process, simple in operation, high in yield and high in purity, and does not need harsh reaction conditions such as vacuum and the like; the required pressure and temperature are in conventional ranges; adopted reagents are low in toxicity and pollution, and a key intermediate namely 3-nitro-N-(2,6-dioxo-3-piperidyl)-phthalimide is prepared from 3-nitrophthalicanhydride and L-glutamine by virtue of a one-pot method; the method is used for economic and large-scale preparation of pomalidomide.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a synthesis method of a novel immunomodulator polilidomide. Background technique [0002] Pomalidomide is a third-generation immunomodulator developed by Celgene Corporation of the United States. It can regulate T cells and inhibit their proliferation, and play an immunoregulatory role; it can promote the apoptosis of cell tumors by activating natural killer cells. It is widely used in clinical practice. Treats multiple myeloma. Clinical studies have shown that polilidomide is well tolerated and easy to administer. Compared with thalidomide and lenalidomide, the dosage is smaller and the curative effect is better. Patients who do not respond to amine therapy provide a new treatment approach, bringing hope to patients with drug-resistant and refractory multiple myeloma. [0003] Pollidomide, whose chemical name is 3-amino-N-(2,6-dioxo-3-pipe...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 王德才吴飞袁晨欢赵伟苏鹏朱亦龙
Owner NANJING UNIV OF TECH
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