CN107365295A

CN107365295A - A kind of improved method of pomalidomide synthesis technique

Info

Publication number: CN107365295A
Application number: CN201610307145.5A
Authority: CN
Inventors: 周付潮; 董书茂; 金晓峰
Original assignee: CHANGZHOU PHARMACEUTICAL FACTORY Co Ltd
Current assignee: CHANGZHOU PHARMACEUTICAL FACTORY Co Ltd
Priority date: 2016-05-11
Filing date: 2016-05-11
Publication date: 2017-11-21
Anticipated expiration: 2036-05-11
Also published as: CN107365295B

Abstract

The present invention relates to a kind of preparation method of high-purity pomalidomide suitable for industrialized production, 3 nitrophthalic acid acid anhydrides react to obtain intermediate with glutamic acid, are reacted under the conditions of aceticanhydride and obtain intermediate, aminating reaction obtains 3 nitro N under the conditions of DMSO（The piperidyl of 2,6 dioxo 3）Phthalimide, then hydrogenate by palladium carbon to obtain pomalidomide, this technique has the characteristics that high income, is simple to operate and friendly to environment, is adapted to large-scale production, is solved using low poison solvent because dissolvent residual causes the underproof problem of product.

Description

A kind of improved method of pomalidomide synthesis technique

Technical field

The present invention relates to a kind of preparation method of the pomalidomide of optimum conditions (Formulas I).

Background technology

Pomalidomide（pomalidomide）It is thalidomide analogs, there is antitumor activity, hematopoiesis can be suppressed and swollen Oncocyte hyperplasia and inducing cell apoptosis.In addition, the multiple myeloma cell line that pomalidomide can suppress resistance to lenalidomide increases It is raw, the immune response of T cell and NK mediation with dexamethasone co-induction apoptosis of tumor cells, can be strengthened, together When suppress monocyte produce pro-inflammatory cytokine.Pomalidomide is by U.S.'s Sai Er genes（Celgene）Company researches and develops, FDA approval listings are obtained within 2 months 2013, for treating other medicines（Such as lenalidomide, bortezomib）Invalid multiple bone Myeloma（Multiple Myeloma）.

Pomalidomide（pomalidomide）It is after Thalidomide（Thalidomide）, lenalidomide （Lenalidomide）3rd degree amine drug afterwards, is mainly used in the patient to lenalidomide, bortezomib drug resistant, it is contemplated that should Medicine is in 2017 annual sales amounts up to 1,000,000,000 dollars.

Route 1：Patent CN101253163（EP1907373）In, 3- nitrophthalic acids acid anhydride is with Pidolidone in DMF Middle reaction, then pomalidomide is prepared through reduction, cyclization.

Route 2：Patent WO2012149299A2（CN103688176A of the same clan), route is short, but 3- amino -2,6- piperidines two Keto hydrochloride existing market yield is smaller, expensive.

Route 3：Patent US2007004920,3- nitrophthalimide reacts with ethyl chloroformate, with glutamine fourth Ester condensation, most afterwards through hydrolyze, reduce and intramolecular condensation cyclization, obtain product.This route is longer, and 3- nitro phthalyls Imines manufacturing cost is higher than 3- nitrophthalic acid acid anhydrides.

Route 4：Patent CN101253163（EP1907373）Middle report 3- aminophthalic acids hydrochloride and 3- amino Glutarimide hydrochloride is condensed, and yield 84%, 3- aminophthalic acid hydrochloride market supplies are less, and two raw materials are lived Property group is more, and the side reaction probability of generation is larger.

Route 5（3- nitrophthalimides）- Ethyl formate contracts with 5- carbamoyl -4- amino-valeric acids butyl ester Close again through hydrolyzing, reducing, intramolecular condensation obtains pomalidomide.

The features such as intermediate is rare, and cost is high, of poor quality all be present in above method.

The content of the invention

It is an object of the present invention to provide a kind of new synthesis process of the pomalidomide more suitable for industrialized production.Hair A person of good sense to pomalidomide synthesis technique by furtheing investigate, there is provided a kind of simply and effectively pomalidomide synthesis technique changes Enter method.This modified technique overcomes in the prior art the shortcomings that yield is low, process route is long, environmental pollution is big, solves simultaneously The problem of dissolvent residual in process for refining.

The present invention is achieved through the following technical solutions：

1. use 3- nitrophthalic acids acid anhydride and glutamic acid as raw material, by being condensed, being cyclized, ammonification, hydrogenation synthesis pool Ma Du Amine crude product, is then refining to obtain pomalidomide finished product, and synthetic route of the invention is as follows.

2. a kind of improved method of pomalidomide synthesis technique, including following aspect content：

3- nitrophthalic acids acid anhydride and glutamic acid are used as raw material, by being condensed, being cyclized, ammonification directly synthesizes 3- nitros-N- （2,6- dioxo -3- piperidyls）Phthalimide；

Condensation uses solvent as pyridine, 4- picolines, N,N-dimethylformamide, N- methylpyrroles when being characterized in that condensation The basic solvents such as alkanone, wherein DMF best results；

Ammonification is characterized in that under high temperature 150-250 DEG C, is passed through ammonia, 0.2Mp, ammonification 3-5h；

3- nitros-N-（2,6- dioxo -3- piperidyls）Phthalimide in DMSO crystallization solvent be methanol, ethanol, Acetonitrile, acetone, isopropyl ether.

3. above-mentioned 3- nitros-N-（2,6- dioxo -3- piperidyls）Phthalimide 1,4- dioxane methanol In the mixed solvent, hydrogenate through being refining to obtain pomalidomide；

Hydrogenation characteristics solvent volume is than 1:0.5-1:10,15-50 DEG C of temperature, Hydrogen Vapor Pressure 0.2-0.4Mp, under the conditions of 10% palladium carbon Hydrogenation；

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

Specific embodiment mode

Embodiment 1

By N,N-dimethylformamide（50kg）It is pumped into reactor, puts into glutamic acid under agitation（32kg）, 3- nitro neighbour's benzene Dicarboxylic acid anhydride（40kg）, then heat, reacted at 95-100 DEG C 3 hours, then decompression steams DMF, cools down Add acetic anhydride（50kg）, it is heated to 100-110 DEG C and reacts 1 hour, remove excessive acid anhydrides under reduced pressure, adds DMSO（400L）, will Reaction is heated to 200 DEG C, is slowly passed through ammonia under agitation, after having reacted, is cooled to room temperature and adds methanol（800L）, crystallization from The heart, it is drying to obtain 3- nitro pomalidomides（62.76kg）, yield 71%.Purity 99.99%.

3- nitro pomalidomides（30kg）Be dissolved in Isosorbide-5-Nitrae-dioxane methanol=300L in 300L, add 10% palladium carbon, 35 DEG C, 0.4M, it is hydrogenated to reaction and completes, press filtration, be concentrated under reduced pressure dry, add DMF（300L）Dissolving, isopropyl ether（600L）Crystallization, centrifuge To yellow product, ethyl alcohol recrystallization is reused, obtains the pomalidomide of high-purity, HPLC：99.84%.

Embodiment 2

By pyridine（50kg）It is pumped into reactor, puts into glutamic acid under agitation（32kg）, 3- nitrophthalic acid acid anhydrides （40kg）, then heat, reacted at 95-100 DEG C 5 hours, then decompression steams pyridine, and cooling adds acetic anhydride（50kg）, add Hot to 100-110 DEG C is reacted 2 hours, removes excessive acid anhydrides under reduced pressure, adds DMSO（400L）, reaction is heated to 180 DEG C, stirred Mix down and be slowly passed through ammonia, after having reacted, be cooled to room temperature and add ethanol（800L）Crystallization centrifuges, and is drying to obtain 3- nitros pool horse Spend amine（62.76kg）, yield 71%, purity 99.2%.

3- nitro pomalidomides（30kg）Be dissolved in Isosorbide-5-Nitrae-dioxane methanol=150L in 150L, add 10% palladium carbon, 35 DEG C, 0.4Mp, it is hydrogenated to reaction and completes, press filtration, be concentrated under reduced pressure dry, add DMF（300L）Dissolving, isopropyl ether（600L）Crystallization, centrifugation Yellow product is obtained, reuses ethyl alcohol recrystallization, obtains the pomalidomide 99.9% of high-purity.

Claims

1. a kind of improved method of pomalidomide synthesis technique, including following aspect content：

3- nitrophthalic acids acid anhydride and glutamic acid are used as raw material, is condensed, cyclisation, ammonification directly synthesizes 3- nitros-N-（2,6- Dioxo -3- piperidyls）Phthalimide.

2. in claim 1, it, which is condensed, is characterised by using solvent during condensation as pyridine, 4- picolines, N, N- dimethyl methyls The basic solvents such as acid amides, 1-METHYLPYRROLIDONE, wherein DMF best results.

3. in claim 1, its ammonification is characterised by under 150-250 DEG C of high temperature, ammonia, 0.2Mp, ammonification 3-5h are passed through.

4. in claim 1,3- nitros-N-（2,6- dioxo -3- piperidyls）Phthalimide crystallization in DMSO is molten Agent is methanol, ethanol, acetonitrile, acetone, isopropyl ether.

5.3- nitros-N-（2,6- dioxo -3- piperidyls）Phthalimide 1,4- dioxane methanol mixed solvent In, hydrogenation obtains pomalidomide crude product, then through being refining to obtain pomalidomide finished product.

6. in claim 5, its hydrogenation characteristics be Isosorbide-5-Nitrae-dioxane methanol solvate volume ratio be 1:1, temperature 15-50 DEG C, Hydrogen Vapor Pressure 0.2-0.4Mp, hydrogenate under the conditions of 10% palladium carbon.

7. in claim 5, its refining solvent is DMSO, acetonitrile, ethyl acetate, DMF, ethanol, methanol, isopropyl ether, acetone and Its mixed solvent.