WO2017081701A1

WO2017081701A1 - An improved process for the preparation of thalidomide

Info

Publication number: WO2017081701A1
Application number: PCT/IN2016/050006
Authority: WO
Inventors: Durga Prasad Konakanchi; Subba Rao Pula; Lakshmana Viswa Venkata Pavan Kumar MADDULA; Sandeep KARNAM; Kali Satya Bhujanga Rao Adibhatla; Venkaiah Chowdary Nannapaneni
Original assignee: Natco Pharma Ltd
Current assignee: Natco Pharma Ltd
Priority date: 2015-11-12
Filing date: 2016-01-09
Publication date: 2017-05-18
Anticipated expiration: 2018-05-12

Abstract

The present invention relates to an improved process for the preparation of thalidomide with high purity and high yield. The present invention also related to preparation thalidomide polymorphic α-form by direct crystallization.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF THALIDOMIDE

Field of the invention:

The present invention relates to a simple and commercially feasible process for the preparation of thalidomide with high purity and high yields. The present invention also relates to preparation of pure a-polymorphic form of thalidomide.

Back ground of the invention:

Alpha-(N-phthalimido) glutarimide or thalidomide is a glutamic acid derivative. The structure of the molecule is

Formula ( 1 )

Thalidomide inhibits TNF-alpha by amplifying the degradation of messenger RNA (mRNA), and decreases the production of interleukin-12, which is involved in immunity responses, the stimulation of inflammation, and suppression of certain cytokines. TNF- alpha is a cytosine produced by immune cells in the blood stream. When these cytokines are chronically overproduced, inflammatory conditions occur as seen in multiple sclerosis, septic shock, leprosy, tuberculosis, and of course-rheumatoid arthritis.

In the study of the effects of thalidomide, researchers have found that if TNF-alpha can be inhibited or blocked, then they would be able to reduce or eliminate the inflammatory conditions. One of the more recent studies for thalidomide is its effects on AIDS. The treatment that Thalidomide offers for HIV patients so far includes cachexia. TNF-alpha also called cachexin, is a cytokine involved in the development of cachexia. Thalidomide inhibits TNF-alpha, which in turn inhibits the development of cachexia. Cachexia, or wasting, is the progressive loss of body and muscle mass which occurs in many people with aids. This becomes a problem because of the lost muscle tissue, which cannot be restored simply by increasing calorie intake. But thalidomide can help rebuild this muscle tissue, by inhibiting TNF-alpha. Thalidomide has become of great interest not only in the treatment of AIDs, leprosy, rheumatoid arthritis and cancer but in the treatment of several other diseases as well. Among these are: Behcet's disease, sarcoidosis, scleroderma, and Crohn's disease (chronic inflammatory bowel disease). Thalidomide has anti-inflammatory and immunosuppressant qualities which make it ideal for the above conditions.

Thalidomide was first disclosed by Chemie Grunenthal in GB768821. This drug was first used therapeutically as a sedative and hypnotic. The process disclosed was that the N-phthalyl-glutamic acid anhydride is converted to thalidomide when heated with at 170- 180°C. In the disclosed processes, yields are less.

US 5,605,914 by Celgene discloses a process wherein N-carboxy thalidomide is reacted with L- glutamine in presence of Na₂C03 and water. The product N-pthalyl L- glutamine is converted to thalidomide when reacted with carbonyldiimidazole and dimethoxyaminopyridine in anhydrous tetrahydrofuran when refluxed for 16 hrs.

CN 1,405,166 by Changchem applied chemistry discloses a process wherein phthalic anhydride is reacted with L-glutamine to obtain N-phthaloyl glutamine which on further reaction with 1, 4 dioxane yields thalidomide. Here high temperatures and vacuum distillations are involved.

EP 1,602,654 by Antibiotics S.P.A (IT) discloses direct preparation of thalidomide in a single reactor. This process involves reacting pthaloylating agent (claims phthalic anhydride and N- carboethoxy phthalimide)with L-glutamine to give N-phthaloyl glutamine and direct conversion of N-phthaloyl glutamine to thalidomide by addition of condensing agent (claims specifically carbonyl-diimidazole and thionyl chloride .

The inventors of the present of invention have developed an alternate improved process for the preparation of thalidomide with high yield and purity. The present process is feasible in large scale production also. Summary of the present invention:

One aspect of the present invention is to provide a process for the preparation of Thalidomide comprising the steps of:

a) reacting phthalic anhydride with 3-amino-piperidine-2, 6-dione hydrochloride in presence of triethyl amine and protic or aprotic solvents at a temperature of about 50 to 130°C to obtain thalidomide,

b) recrystalhzing thalidomide from dimethylsulfoxide and water mixture or dimethylformamide and water mixture, or acetic acid and water and mixtures thereof to give pure thalidomide.

Another aspect of the present invention is to provide purification of thalidomide comprising recrystalhzing thalidomide from dimethylsulfoxide and water mixture or dimethylformamide and water mixture, or acetic acid and water and mixtures thereof.

The present invention is shown in below scheme:

Crude Thalidomide ^Pure Thalidomide In accordance with another aspect of the present invention a process is provides for the preparation of thalidomide having high purity of more than 99.99% and impurity of less than 0.05%.

Detailed description of the invention:

The present invention relates to an improved process for the preparation of Thalidomide, wherein phthalic anhydride is reacted with 3-Aminopiperidine-2, 6-dione HCl in presence of triethyl amine and protic or aprotic solvents to give a-(o-carboxybenzamido) glutarimide which is further subjected to cyclization reaction to give crude thalidomide. Further crude thalidomide is purified using solvent mixture to get pharmaceutical grade thalidomide.

One embodiment of the present invention is to provide a process for the preparation of Thalidomide comprising the steps of:

b) recrystallizing thalidomide from dimethylsulfoxide and water mixture or dimethylformamide and water mixture, or acetic acid and water and mixtures thereof to give pure thalidomide.

According to the present invention phthalic anhydride is reacted with 3-Aminopiperidine-2, 6- dione HCl in presence of trimethylamine and protic or aprotic solvent. The reaction is carried out at a temperature range of about 50 to 130°C for about 1 hours to 6 hours. The above obtained a- (o-carboxybenzamido) glutarimide is subjected to cyclization reaction in acetic acid , dimethylformamide, dimethylsulfoxide ,pyridine and mixtures thereof., aprotic or chlorinated solvents selected from ethyl acetate, acetonitrile, 1 ,4 dioxane, ethylene dichloride , chloroform, acetone etc or mixtures thereof. The reaction is carried out at a temperature range of about 40°C to 130°C, preferably at reflux temperature of the solvent used. Thalidomide can be obtained in its pure form by slurring the solid resulted at the end of the reaction with a quenching of the reaction in water or insolubihzing organic solvent or a mixture thereof and such solvents are selected from methanol, ethanol, isopropanol, n-propanol and n-butanol. 3-Aminopiperidine-2, 6-dione HCl to phthalic anhydride is typically in the mole ratio range of 1.0:0.8 tol.0: 1.40, preferably in the ratio range of 1.0: 0.90 tol.0: 1.10, and more preferably in the range of 1.0: 1.0.

3-Aminopiperidine-2, 6-dione HCl to triethyl amine in the mole ratios is typically in the ratio range of 1.0: 1.50 to 1.0: 1.30, preferably in the ratio range of 1.0:2.0 to 1.0:2.40, and more preferably in the range of 1.0:2.20.

The ratio of 3-Aminopiperidine-2, 6-dione HCl to acetic acid is typically in the range of 1:5.0 w/v to 1: 15 w/v; preferably in the range of 1 : 7.5 w/v to 1 : 12.5 w/v, and more preferably in the range of 1: 10 w/v.

The reaction temperature is typically in the range of 50 to 130 °C, preferably in the range of about 100 to 125 °C, and more preferably in the range of 115-120°C.

The reaction time is typically in the range of about 1 hour to 6 hours, preferably in the range of about 2 to 5 hours, and more preferably in the range of 3 to 4 hours.

Another embodiment of the present invention is to provide purification of thalidomide comprising recrystallizing thalidomide from dimethylsulfoxide and water mixture or dimethylformamide and water mixture, or acetic acid and water and mixtures thereof.

According to the present invention crude thalidomide is dissolved in dimethylsulfoxide and water mixture or dimethylformamide and water mixture, or acetic acid and water and mixtures and stirred. Solid is filtered and washed with water. Wet compound was dried under vacuum to get pure thalidomide.

The ratio of Thalidomide to dimethylsulfoxide is typically in the range of 1:3.0 w/v to 1 : 7 w/v; preferably in the range of 1: 4 w/v to 1 :6 w/v, and more preferably in the range of 1:5 w/v. Thalidomide dissolution temperature is typically in the range of 50 to 90 °C, preferably in the range of about 60 to 80 °C, and more preferably in the range of 65-75°C.

The ratio of dimethyl sulfoxide to water is typically in the range of 1 :2.5 w/v to 1 : 12.5 w/v; preferably in the range of 1: 5 w/v to 1 : 10 w/v, and more preferably in the range of 1:7.5 w/v.

Thalidomide drying temperature is typically in the range of 40 to 90 °C, preferably in the range of about 50 to 70 °C, and more preferably in the range of 55-65°C.

According to the present invention solvent used for the reaction is selected form protic or aprotic solvents preferably selected from acetic acid, Pyridine, dimethylformamide, dimethyl sulfoxide.

Advantages of the present process:

1. The present process is to provide an expedient commercially viable and useful process for the preparation of thalidomide using commercially available chief raw materials of 3- amino-piperidine-2, 6-dione hydrochloride and phthalic anhydride.

2. The present process is to provide an environmentally friendly process without using pyrophoric reagents such as Lithium aluminium hydride, sodium hydride, and triethyl silane and column chromatography for purification.

3. The present process is to provide an expedient process under normal conditions and no extreme reaction conditions are needed for the present process.

4. The present process is a simple and feasible for commercially large scale production preparation of high yield and high purity thalidomide.

Brief description of drawings:

• Figure 1 : Powder X Ray Diffractogram for crystalline anhydrous pure a-polymorphic form of thalidomide.

• Figure 2: DSC thermogram for crystalline anhydrous pure a-polymorphic form of thalidomide. The following examples are provided for illustrative purpose only and are not intended to limit the scope of the invention in any way.

Example- 1: Preparation of crude thalidomide

Crude Thalidomide

To a stirred solution of 150 g (0.91 mol) of 3-amino-piperidine-2, 6-dione hydrochloride in 1500 ml of acetic acid was added 135.0 g (0.91 mol) of phthalic anhydride and 202.6 g (2 mol) of triethyl amine. Reaction mixture was heated to reflux and further stirred at reflux for 3 hours. The progress and completion of reaction was monitored by HPLC till 3-amino-piperidine-2, 6-dione hydrochloride absent. Reaction mass was cooled to 25-30°C and further stirred for 1 hour at 25- 30°C. Solid was filtered and washed the wet cake with 750 ml of water. Wet compound was slurred in 2250 ml of water and suspension mass was further stirred for 1 hour. Solid was filtered and washed the wet cake with 750 ml of water. Dried under vacuum at 55-60°C under vacuum to give 223.5 g (95% yield) of crude thalidomide with a purity 99.9% by HPLC.

Example-2: Preparation of crude thalidomide

To a stirred solution of 50 g (0.30 mol) of 3-amino-piperidine-2, 6-dione hydrochloride in 250 ml of pyridine was added 45.0 g (0.30 mol) of phthalic anhydride and 67.5 g (2.2 mol) of triethyl amine. Reaction mixture was heated to reflux and further stirred at reflux for 3 hours. The progress and completion of reaction was monitored by HPLC till 3-amino-piperidine-2, 6-dione hydrochloride absent. Reaction mass was cooled to 25-30°C and quenched the reaction mass in 2500 ml of water. Stirred the mass for 1 hour at 25-30°C. Solid was filtered and washed the wet cake with 250 ml of water. Wet compound was slurred in 750 ml of water and suspension mass was further stirred for 1 hour. Solid was filtered and washed the wet cake with 250 ml of water. Dried at 55-60°C under vacuum to give 53.1 g (67.7 % yield) of crude thalidomide with a purity 99.9% by HPLC.

Example-3: Preparation of crude thalidomide

To a stirred solution of 50 g (0.30 mol) of 3-amino-piperidine-2, 6-dione hydrochloride in 250 ml of dimethylformamide was added 45.0 g (0.30 mol) of phthalic anhydride and 67.5 g (2.2 mol) of triethyl amine. Reaction mixture was heated to reflux and further stirred at 115-120°C for 3 hours. The progress and completion of reaction was monitored by HPLC till 3-amino-piperidine-2, 6- dione hydrochloride absent. Reaction mass was cooled to 25-30°C and quenched the reaction mass in 2500 ml of water. Stirred the mass for 1 hour at 25-30°C. Solid was filtered and washed the wet cake with 250 ml of water. Wet compound was slurred in 750 ml of water and suspension mass was further stirred for 1 hour. Solid was filtered and washed the wet cake with 250 ml of water. Dried at 55-60°C under vacuum to give 39.0 g (49.7 % yield) of crude thalidomide with a purity 99.9% by HPLC.

Example-4: Preparation of crude thalidomide

To a stirred solution of 50 g (0.30 mol) of 3-amino-piperidine-2, 6-dione hydrochloride in 250 ml of dimethylsulfoxide was added 45.0 g (0.30 mol) of phthalic anhydride and 67.5 g (2.2 mol) of triethyl amine. Reaction mixture was heated to reflux and further stirred at 115-120°C for 3 hours. The progress and completion of reaction was monitored by HPLC till 3-amino-piperidine-2, 6- dione hydrochloride absent. Reaction mass was cooled to 25-30°C and quenched the reaction mass in 2500 ml of water. Stirred the mass for 1 hour at 25-30°C. Solid was filtered and washed the wet cake with 250 ml of water. Wet compound was slurred in 750 ml of water and suspension mass was further stirred for 1 hour. Solid was filtered and washed the wet cake with 250 ml of water. Dried at 55-60°C under vacuum to give 56.5 g (72.0 % yield) of crude thalidomide with a purity 99.97% by HPLC.

Example-5: Preparation of pure thalidomide

Crude Thalidomide Pure Thalidomide

200 g of crude thalidomide was dissolved in 1000 ml dimethyl sulfoxide at 70-75 C and 40 g of activated carbon was charged and further stirred at 70-75°C for 20-30 min. Filtered the carbon on micro filter paper and filtrate was added to 7500 ml of water. The precipitated solid mass was further stirred at 25-30 °C for 2 hours. Solid was filtered and washed the wet cake with 1000 ml of water. Wet compound was slurred in 2500 ml of water and suspension mass was further stirred for 1 hour. Solid was filtered and washed the wet cake with 500 ml of water. Dried under vacuum at 55-60°C under vacuum to give 192 g (96 % yield) thalidomide -USP grade with a purity 99.99 % by HPLC. The P-XRD spectrum shows the pure a-polymorphic form of Thalidomide. Thalidomide a -polymorphic form X-RD 2 Θ values: 11.33, 14.35, 19.15, 22.88, 26.12 and 30.32.

Example-6: Preparation of pure thalidomide

Crude Thalidomide Pure Thalidomide 50 g of thalidomide technical grade was dissolved in 500 ml dimethylformamide at 70-75 C and 10 g of activated carbon was charged and further stirred at 70-75°C for 20-30 min. Filtered the carbon on micro filter paper and filtrate was added to 3600 ml of water. The precipitated solid mass was further stirred at 25-30 °C for 2 hours. Solid was filtered and washed the wet cake with 500 ml of water. Wet compound was slurred in 500 ml of water and suspension mass was further stirred for 1 hour. Solid was filtered and washed the wet cake with 100 ml of water. Dried at 55- 60°C under vacuum to give 45.4 g (91 % yield) thalidomide -USP grade with a purity 99.99 % by HPLC. The P-XRD spectrum shows the pure a-polymorphic form of Thalidomide. Thalidomide a -polymorphic form X-RD 2 Θ values: 11.33, 14.35, 19.15, 22.88, 26.12 and 30.32.

Claims

We claim:

1. A process for the preparation of Thalidomide comprising the steps of:

a) reacting phthalic anhydride with 3-amino-piperidine-2, 6-dione hydrochloride in presence of triethyl amine and solvent to obtain thalidomide,

2. The process according to claim 1, wherein solvent is selected from acetic acid, Pyridine, dimethylformamide, dimethyl sulfoxide.

3. A process for purification of thalidomide comprising recrystallizing thalidomide from dimethylsulfoxide and water mixture or dimethylformamide and water mixture, or acetic acid and water and mixtures thereof.

4. The process according to any preceding claims, wherein thalidomide obtained is a- polymorphic form of thalidomide.

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