CN107365295B

CN107365295B - Improved method of pomalidomide synthesis process

Info

Publication number: CN107365295B
Application number: CN201610307145.5A
Authority: CN
Inventors: 周付潮; 董书茂; 金晓峰
Original assignee: Changzhou Pharmaceutical Factory
Current assignee: Changzhou Pharmaceutical Factory
Priority date: 2016-05-11
Filing date: 2016-05-11
Publication date: 2020-07-07
Anticipated expiration: 2036-05-11
Also published as: CN107365295A

Abstract

The invention relates to a preparation method of high-purity pomalidomide, which is suitable for industrial production.A 3-nitrophthalic anhydride reacts with glutamic acid to obtain an intermediate, the intermediate is obtained by reaction under the condition of acetic anhydride, 3-nitro-N- (2, 6-dioxo-3-piperidyl) phthalimide is obtained by ammoniation reaction under the condition of DMSO, and pomalidomide is obtained by palladium carbon hydrogenation.

Description

Improved method of pomalidomide synthesis process

Technical Field

The invention relates to a preparation method of pomalidomide (shown as a formula I) with optimized synthesis conditions.

Background

Pomalidomide (pomalidomide) is a thalidomide analogue, 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 strains, can cooperate with dexamethasone to induce tumor cell apoptosis, enhance T cell and natural killer cell mediated immune reaction, and inhibit monocytes from generating proinflammatory cytokines. Pomalidomide was developed by american seille gene (Celgene) and approved by the FDA in 2013 for marketing in the treatment of Multiple Myeloma (Multiple myelomas) that are ineffective with other drugs (e.g., lenalidomide, bortezomib).

Pomalidomide (pomalidomide) is the third-degree amine drug after Thalidomide (Thalidomide) and Lenalidomide (Lenalidomide), is mainly used for patients resistant to Lenalidomide and bortezomib, and is expected to sell for $ 10 billion in 2017.

Route 1: in patent CN101253163 (EP 1907373), 3-nitrophthalic anhydride and L-glutamic acid are reacted in DMF, and then are subjected to reduction and cyclization to prepare pomalidomide.

Route 2: WO2012149299A2 (family CN103688176A) has short route, but 3-amino-2, 6-piperidedione hydrochloride has smaller market yield and higher price at present.

Route 3: patent US2007004920, 3-nitro phthalimide reacts with ethyl chloroformate, is condensed with glutamine butyl ester, and finally, the product is obtained through hydrolysis, reduction and intramolecular condensation cyclization. This route is long and the manufacturing cost of 3-nitrophthalimide is higher than that of 3-nitrophthalic anhydride.

Route 4: in patent CN101253163 (EP 1907373), 3-aminophthalic acid hydrochloride and 3-aminoglutarimide hydrochloride are reported to be condensed, the yield is 84%, the market supply of the 3-aminophthalic acid hydrochloride is less, two raw material active groups are more, and the probability of side reaction is higher.

In the route, 5 (3-nitrophthalimide) -ethyl formate and 5-carbamoyl-4-amino-butyl valerate are condensed, hydrolyzed, reduced and subjected to intramolecular condensation to obtain pomalidomide.

The methods have the characteristics of difficult obtainment of intermediates, high cost, poor quality and the like.

Disclosure of Invention

The invention aims to provide a novel synthesis process of pomalidomide, which is more suitable for industrial production. The inventor provides a simple and effective method for improving the synthesis process of pomalidomide by deeply researching the synthesis process of pomalidomide. The improved process overcomes the defects of low yield, long process route and great environmental pollution in the prior art, and simultaneously solves the problem of solvent residue in the refining process.

The invention is realized by the following technical scheme:

1. the method comprises the steps of synthesizing a pomalidomide crude product by using 3-nitrophthalic anhydride and glutamic acid as raw materials through condensation, cyclization, ammoniation and hydrogenation, and then refining to obtain a pomalidomide finished product.

2. An improved method for a pomalidomide synthesis process comprises the following aspects:

3-nitro-N- (2, 6-dioxo-3-piperidyl) phthalimide is directly synthesized by taking 3-nitrophthalic anhydride and glutamic acid as raw materials through condensation, cyclization and ammoniation;

the condensation is characterized in that the solvent adopted in the condensation is alkaline solvents such as pyridine, 4-methylpyridine, N-dimethylformamide, N-methylpyrrolidone and the like, wherein the effect of the N, N-dimethylformamide is optimal;

the ammoniation is characterized in that ammonia gas is introduced at the temperature of 150 ℃ and 250 ℃ and 0.2Mp is added for ammoniation for 3-5 h;

the crystallization solvent of the 3-nitro-N- (2, 6-dioxo-3-piperidyl) phthalimide in the DMSO is methanol, ethanol, acetonitrile, acetone or isopropyl ether.

3. Hydrogenating and refining the 3-nitro-N- (2, 6-dioxo-3-piperidyl) phthalimide in a 1, 4-dioxane/methanol mixed solvent to obtain pomalidomide;

hydrogenation is carried out under the conditions that the volume ratio of the hydrogenation characteristic solvent is 1:0.5-1:10, the temperature is 15-50 ℃, the hydrogen pressure is 0.2-0.4Mp and 10 percent of palladium carbon is used;

DMSO, acetonitrile, ethyl acetate, DMF, ethanol, methanol, isopropyl ether, acetone and their mixed solvent.

Detailed description of the preferred embodiments

Examples 1

Pumping N, N-dimethylformamide (50 kg) into a reaction kettle, adding glutamic acid (32 kg) and 3-nitrophthalic anhydride (40 kg) under stirring, heating, reacting at 95-100 ℃ for 3 hours, then distilling out N, N-dimethylformamide under reduced pressure, cooling, adding acetic anhydride (50 kg), heating to 100-phase reaction at 110 ℃ for 1 hour, distilling out excessive anhydride under reduced pressure, adding DMSO (400L), heating the reaction to 200 ℃, slowly introducing ammonia gas under stirring, cooling to room temperature after the reaction is finished, adding methanol (800L), crystallizing, centrifuging, and drying to obtain 3-nitroparaffin (62.76 kg) with the yield of 71%. The purity is 99.99%.

Dissolving 3-nitroprusside (30 kg) in 1, 4-dioxane \ methanol =300L \300L, adding 10% palladium carbon, 35 ℃, 0.4M, hydrogenating until the reaction is finished, performing pressure filtration, concentrating under reduced pressure to dryness, adding DMF (300L) for dissolving, crystallizing by isopropyl ether (600L), centrifuging to obtain a yellow product, recrystallizing by using ethanol to obtain high-purity pomalidomide, and performing HPLC: 99.84 percent.

EXAMPLES example 2

Pumping pyridine (50 kg) into a reaction kettle, adding glutamic acid (32 kg) and 3-nitrophthalic anhydride (40 kg) under stirring, heating, reacting at 95-100 ℃ for 5 hours, then distilling out the pyridine under reduced pressure, cooling, adding acetic anhydride (50 kg), heating to 100 ℃ and 110 ℃ for reaction for 2 hours, distilling off excessive anhydride under reduced pressure, adding DMSO (400L), heating the reaction to 180 ℃, slowly introducing ammonia gas under stirring, cooling to room temperature after the reaction is finished, adding ethanol (800L) for crystallization and centrifugation, and drying to obtain the 3-nitroparaffin amine (62.76 kg), wherein the yield is 71%, and the purity is 99.2%.

Dissolving 3-nitro-pomalidomide (30 kg) in 1, 4-dioxane \ methanol =150L \150L, adding 10% palladium carbon, 35 ℃, 0.4Mp, hydrogenating until the reaction is finished, performing pressure filtration, concentrating under reduced pressure to dryness, adding DMF (300L) for dissolving, crystallizing by isopropyl ether (600L), centrifuging to obtain a yellow product, and recrystallizing by using ethanol to obtain high-purity pomalidomide 99.9%.

Claims

1. An improved method for a pomalidomide synthesis process comprises the following aspects:

pumping 50kg of N, N-dimethylformamide into a reaction kettle, adding 32kg of glutamic acid and 40kg of 3-nitrophthalic anhydride under stirring, heating, reacting at 95-100 ℃ for 3 hours, then distilling out the N, N-dimethylformamide under reduced pressure, cooling, adding 50kg of acetic anhydride, heating to 100 ℃ for 110 ℃ to react for 1 hour, distilling out excessive anhydride under reduced pressure, adding 400L of DMSO, heating the reaction to 200 ℃, slowly introducing ammonia gas under stirring, cooling to room temperature after the reaction is finished, adding 800L of methanol, crystallizing, centrifuging, and drying to obtain 62.76kg of 3-nitroparaffin amine, wherein the yield is 71%, and the purity is 99.99%;

dissolving 30kg of 3-nitroprusside in 1, 4-dioxane \ methanol =300L \300L, adding 10% palladium carbon, 35 ℃, 0.4Mp, hydrogenating until the reaction is finished, performing pressure filtration, concentrating under reduced pressure to dryness, adding 300L of DMF for dissolving, crystallizing by 600L of isopropyl ether, centrifuging to obtain a yellow product, recrystallizing by using ethanol to obtain high-purity pomalidomide, and performing HPLC: 99.84 percent.

pumping 50kg of pyridine into a reaction kettle, adding 32kg of glutamic acid and 40kg of 3-nitrophthalic anhydride under stirring, heating, reacting at 95-100 ℃ for 5 hours, then distilling out the pyridine under reduced pressure, cooling, adding 50kg of acetic anhydride, heating to 100 ℃ and 110 ℃ for reaction for 2 hours, distilling out excessive anhydride under reduced pressure, adding 400L of DMSO, heating the reaction to 180 ℃, slowly introducing ammonia gas under stirring, cooling to room temperature after the reaction is finished, adding 800L of ethanol, crystallizing, centrifuging, and drying to obtain 62.76kg of 3-nitroparaffin amine, wherein the yield is 71%, and the purity is 99.2%;

dissolving 3-nitroparaffin in 1, 4-dioxane \ methanol =150L \150L, adding 10% palladium carbon, 35 ℃, 0.4Mp, hydrogenating until the reaction is completed, performing pressure filtration, concentrating under reduced pressure to dryness, adding 300L of DMF to dissolve, crystallizing by 600L of isopropyl ether, centrifuging to obtain a yellow product, and recrystallizing by using ethanol to obtain the high-purity pomalidomide 99.9%.