Field of Invention:
Present invention relates to an improved process for the preparation of Thalidomide which is less cumbersome and industrially applicable with no side products.
Background of invention:
Alpha-(N-phthalimido) glutarimide or Thalidomide is a glutamic acid derivative. The structure of the molecule is

Thalidomide
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. Cashexia, 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.

Thalidomicle 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 urea at 170 - 180°C. In the disclosed processes, yields are less.
US 5,605,914 by celgene discloses a process wherein N-carboxyphthalimide is reacted with L- glutamine in presence of Na2C03and water. The product N-pthalyl L-glutamine is converted to Thalidomide when reacted with carbonyldiimidazole and 4-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-carbethoxy pthalimide)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).
Summary of the invention:
The main objective of the present invention is to provide an improved process for the preparation of Thalidomide.

Accordingly in the present invention Thalidomide is prepared by reacting phthalic anhydride with L-glutamine to form N-phthaloyl L-glutamine inpresence of protic or aprotic solvents at a temperature of about 85 to 100 degC. In the second step N-phthaloyl L-glutamine is converted to Thalidomide in presence of aprotic or chlorinated solvents and a condensing agent.
Scheme-1

Thalidomide Detailed description of the invention:
Thus in accordance with the present invention preparation of Thalidomide comprises thi following steps;
• Preparing N-phthaloyl L-glutamine from phthalic anhydride and L-glutamine
• Converting the N-phthaloyl L-glutamine to thalidomide inpresence of a
condensing agent and a solvent selected from aprotic or chlorinated solvents.
In one embodiment, the present invention describes the preparation of N-phthaloyl L-glutamine, which involves reacting phthalic anhydride and L-glutamine in a solvent selected from Dimethylene propylene urea, Dimethylsulfoxide, acetic acid, 1,4 dioxane, N,N-Dimethylpropionamide, N,N-Dimethyl acrylamide, Dimethyl formamide and mixtures thereof This reaction is carried out at a temperature range of about 80 to 100 degC for about 3 hours to 5 hours.

The above obtained N-phthaloyl L-glutamine is converted to thalidomide in presence of a condensing agent and small amounts of catalyst such as N-dimethylamino pyridine in aprotic or chlorinated solvents selected from ethylacetate, acetonitrile, 1,4 dioxane, ethylenedichloride, methylenedichloride, chloroform, MEK, acetone etc and mixtures thereof. The reaction is carried out at a temperature range of about 40°C to 102°C, preferably at reflux temperature of the solvent used.
Condensing agents are used for the formation of amide bonds by means of elimination of water molecule and comprise the following carbodiimides such as active ingredients of inorganic acids for example esters or amides such as bis(4-nitrophenyl)-carbonate, carbonyl-diimidazole and l,l'dicarbonyl(l,2,4 triazole).
Thalidomide can be obtained in its pure form by slurrying the solid resulted at the end of the reaction with an insolubilizing organic solvent or a mixture thereof and such solvents are selected from methanol, ethanol, isopropanol, n-propanol and n-butanol.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
The invention is further illustrated with a few non-limiting examples Example 1: Preparation of N-Phthaloyl-L-glutamine:
To a dry three necked flask added dry DMF (60 ml) and L-glutamine (20g, 136mmole). Slowly heated to 40-45°C. To the resulting solution added phthalicanhydride (20 g, 135mmole) and heated to 90-95°C. Stirred for 3 hr at this temperature, cooled to 65 °C, and distilled DMF under vacuum. Charged DM water (120 ml). pH of the solution adjusted to 1.2 with 6N HCI. Stirred for 2 hr at 15°C. Filtered, washed with DM water (40 ml). Dried to get N-phthaloyl-Lglutamine (27 g, 97.8 mmole, 72%) as a white solid, m.p., 168-170 °C.

1H NMR (dmso-de): 5 13.20 (br s, 1H, COOH), 8.05-7.75 (m, 4H, Ar), 7.22 (s, 1H, CONH2), 6.72 (s,lH, CONH2), 4.72 (dd, 1H,CH), 2.50-1.95 (m,4H, CH2CH2), 2.15-2.00 (m, 1H, CH2).
13C NMR (dmso-de): 8 173.0, 170.4, 167.3, 134.7, 131.2, 123.3, 51.2, 31.3, 23.9. Example 2: Preparation of Thalidomide: (using CDT as cyclising reagent)
To a dry three necked flask added ethylacetate (30 ml) and N-phthaloyl-L-glutamine (5 g, 18.1 mmole). The slurry was stirred and added l,l'-carbonyldi(l,2,4-triazole) (3,95 g, 24 mmole) followed by 4-dimethylamino- pyridine ( 10 mg, 0.08 mmole) as catalyst. The resulting solution was heated to reflux for 4 hr. The reaction mixture was cooled to 25-27°C, filtered and the solid was washed with ethylacetate (8 ml). The solid slurried in methanol (15 ml), stirred for 15 min., filtered and washed with methanol (8 ml). Dried the product under vacuum at 60 °C for 5 hr to afford 3.8 g (81.3%) of Thalidomide as a white powder, m.p. 273-275 °C.
1H NMR (dmso-d6): 8 11.13 (s, 1H, NH), 7.95-7.80 (br, s, 4H, Ar), 5.18 (dd, 1H, CHCO), 2.96-2, 85 (m, 1H, CH2CO), 2.63-2.50 (m, 2H, CH2CH2), 2.09-2.05(m, 1H, CH2).
13C NMR (dmso-de): 8 172.8, 169.18, 134.9, 131.2, 123.4, 49.0, 30.9, 22.0. Example 3: Preparation of Thalidomide: (using CDI in acetonitrile)
A stirred mixture of N-phthaloyl-L-glutamine (20 g, 72.4 mmole), l,l'-Carbonyl-di-imidazole (15.85 g, 97.7 mmole) and 4-dimethylamino-pyridine (40 mg, 0.32 mmole) in acetonitrile (60 ml)was heated to reflux for 5-6 hr. The reaction slurry was filtered and the solid was washed with acetonitrile (20 ml). The crude solid was slurried in methanol (40 ml), filtered and washed with fresh methanol (20 ml). The solid was air dried and then dried in vacuum at 60 °C to afford 17.1 g (91%) of Thalidomide as a white powder, m.p. 272-274 °C.
1H NMR (dmso-d6): 8 11.13 (s, 1H, NH), 7.95-7.80 (br, s, 4H, Ar), 5.17 (dd, 1H, CHCO), 2.92-2.84 (m, 1H, CH2CO), 2.64-2.50(m, 2H, CH2CH2), 2.10-2.07 (m, 1H, CH2).
13C NMR (dmso-d6): 8 172.8, 169.18, 134.9, 131.2, 123.4, 49.0, 30.9, 22.0.

We claim:
1. A process for the preparation of Thalidomide comprising
• Preparing N-phthaloyl L-glutamine from phthalic anhydride and L-glutamine
• Converting the N-phthaloyl L-glutamine to thalidomide inpresence of a
condensing agent
2. The process as claimed in claim 1, wherein the condensation of phthalic anhydride
and L-glutamine is carried out in a solvent selected from Dimethyl propylene urea, Dimethylethylene urea, Dimethylsulfoxide, acetic acid, 1,4 dioxane, N,N-Dimethyl propionamide, N,IM-Dimethyl acrylamide, N,N-Dimethyl formamide and mixtures thereof.
3. The process claimed in claim 1, wherein the condensing agent is active
ingredient(s) of organic acid(s).
4. The process claimed in claim 4, wherein the active ingredient(s) of organic acid(s)
are esters or amides.
5. The process claimed in claim 5, wherein the condensing agent is selected from
bis(4-nitrophenyl)-carbonate carbonyl-diimidazole, l,l-carbonyldi(l,2,4-triazole) and 1,1-carbonyldiimidazole
6. The process claimed in claim 1, wherein the Conversion of N-phthaloyl L-
glutamine to thalidomide is carried out in aprotic or chlorinated solvents.
7. The process claimed in claim 7, wherein the aprotic solvent is selected from ethyl
acetate, acetonitrile, 1,4-dioxane, acetone, MEK and mixtures thereof

8. The process claimed in claim 7, wherein the chlorinated solvents is selected from ethylene dichloride, methylene dichloride, chloroform and mixtures thereof.
Dated: 18-09-2006 Hyderabad