WO2017081701A1 - Procédé perfectionné pour la préparation de thalidomide - Google Patents

Procédé perfectionné pour la préparation de thalidomide Download PDF

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Publication number
WO2017081701A1
WO2017081701A1 PCT/IN2016/050006 IN2016050006W WO2017081701A1 WO 2017081701 A1 WO2017081701 A1 WO 2017081701A1 IN 2016050006 W IN2016050006 W IN 2016050006W WO 2017081701 A1 WO2017081701 A1 WO 2017081701A1
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WO
WIPO (PCT)
Prior art keywords
thalidomide
water
preparation
range
reaction
Prior art date
Application number
PCT/IN2016/050006
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English (en)
Inventor
Durga Prasad Konakanchi
Subba Rao Pula
Lakshmana Viswa Venkata Pavan Kumar MADDULA
Sandeep KARNAM
Kali Satya Bhujanga Rao Adibhatla
Venkaiah Chowdary Nannapaneni
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Natco Pharma Ltd
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Publication date
Application filed by Natco Pharma Ltd filed Critical Natco Pharma Ltd
Publication of WO2017081701A1 publication Critical patent/WO2017081701A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • 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.
  • Alpha-(N-phthalimido) glutarimide or thalidomide is a glutamic acid derivative.
  • the structure of the molecule is
  • 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.
  • TNF-alpha also called cachexin
  • 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.
  • 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.
  • 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.
  • high temperatures and vacuum distillations are involved.
  • EP 1,602,654 by Antibiotics S.P.A 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 .
  • pthaloylating agent claims phthalic anhydride and N- carboethoxy phthalimide
  • One aspect of the present invention is to provide a process for the preparation of Thalidomide comprising the steps of:
  • 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.
  • a process is provides for the preparation of thalidomide having high purity of more than 99.99% and impurity of less than 0.05%.
  • 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.
  • 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.
  • 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.
  • 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.
  • solvent used for the reaction is selected form protic or aprotic solvents preferably selected from acetic acid, Pyridine, dimethylformamide, dimethyl sulfoxide.
  • 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.
  • 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.
  • pyrophoric reagents such as Lithium aluminium hydride, sodium hydride, and triethyl silane and column chromatography for purification.
  • the present process is to provide an expedient process under normal conditions and no extreme reaction conditions are needed for the present process.
  • the present process is a simple and feasible for commercially large scale production preparation of high yield and high purity thalidomide.
  • Figure 1 Powder X Ray Diffractogram for crystalline anhydrous pure a-polymorphic form of thalidomide.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré de préparation de thalidomide de pureté élevée avec un rendement élevé. L'invention concerne également la préparation de la forme α polymorphe de thalidomide par cristallisation directe.
PCT/IN2016/050006 2015-11-12 2016-01-09 Procédé perfectionné pour la préparation de thalidomide WO2017081701A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN6099/CHE/2015 2015-11-12
IN6099CH2015 2015-11-12

Publications (1)

Publication Number Publication Date
WO2017081701A1 true WO2017081701A1 (fr) 2017-05-18

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PCT/IN2016/050006 WO2017081701A1 (fr) 2015-11-12 2016-01-09 Procédé perfectionné pour la préparation de thalidomide

Country Status (1)

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WO (1) WO2017081701A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110498788A (zh) * 2018-05-16 2019-11-26 欣凯医药化工中间体（上海）有限公司 一种高纯度沙利度胺α晶型的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5635517A (en) * 1996-07-24 1997-06-03 Celgene Corporation Method of reducing TNFα levels with amino substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxo-and 1,3-dioxoisoindolines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5635517A (en) * 1996-07-24 1997-06-03 Celgene Corporation Method of reducing TNFα levels with amino substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxo-and 1,3-dioxoisoindolines
US5635517B1 (en) * 1996-07-24 1999-06-29 Celgene Corp Method of reducing TNFalpha levels with amino substituted 2-(2,6-dioxopiperidin-3-YL)-1-oxo-and 1,3-dioxoisoindolines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RAVI VARALA ET AL.: "A Practical and Efficient Synthesis of Thalidomide via Na/Liquid NH3 Methodology", ORGANIC PROCESS RESEARCH AND DEVELOPMENT, vol. 9, no. 6, 20 October 2005 (2005-10-20), pages 853 - 856, XP055383240 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110498788A (zh) * 2018-05-16 2019-11-26 欣凯医药化工中间体（上海）有限公司 一种高纯度沙利度胺α晶型的制备方法
CN110498788B (zh) * 2018-05-16 2021-09-17 欣凯医药化工中间体（上海）有限公司 一种高纯度沙利度胺α晶型的制备方法

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