WO2008035378A2 - Procédé amélioré de préparation de thalidomide - Google Patents

Procédé amélioré de préparation de thalidomide Download PDF

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Publication number
WO2008035378A2
WO2008035378A2 PCT/IN2007/000413 IN2007000413W WO2008035378A2 WO 2008035378 A2 WO2008035378 A2 WO 2008035378A2 IN 2007000413 W IN2007000413 W IN 2007000413W WO 2008035378 A2 WO2008035378 A2 WO 2008035378A2
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WO
WIPO (PCT)
Prior art keywords
thalidomide
glutamine
process according
phthaloyl
preparation
Prior art date
Application number
PCT/IN2007/000413
Other languages
English (en)
Other versions
WO2008035378A3 (fr
Inventor
Purna Chandra Ray
Jagan Mohana Chary Tummanepally
Jebaraj Rathinapandian
Om Dutt Tyagi
Original Assignee
Matrix Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Matrix Laboratories Ltd filed Critical Matrix Laboratories Ltd
Publication of WO2008035378A2 publication Critical patent/WO2008035378A2/fr
Publication of WO2008035378A3 publication Critical patent/WO2008035378A3/fr

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Classifications

    • 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

  • Present invention relates to an improved process for the preparation of Thalidomide which is less cumbersome and industrially applicable with no side products.
  • Alpha-(N-phthaIimido) 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.
  • Thalidomide 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.
  • TNF-alpha also called cachexin
  • 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.
  • 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 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 Na 2 CO 3 and 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.
  • 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-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).
  • the main objective of the present invention is to provide an improved process for the preparation of Thalidomide.
  • 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.
  • N-phthaloyl L-glutamine is converted to Thalidomide in presence of aprotic or chlorinated solvents and a condensing agent.
  • Thalidomide which comprises, reacting phthalic anhydride with L-glutamine to give N-phthaloyl L-glutamine, which is further subjecting to cyclization reaction in the presence of condensing agent to give Thalidomide.
  • 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° C for about 3 hours to 5 hours.
  • N-phthaloyl L-glutamine is subjected to cyclization reaction in en 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, methyl ethyl ketone, acetone etc or mixtures thereof.
  • the reaction is carried out at a temperature range of about 40° C to 102 0 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 1,1 'dicarbonyl( 1,2,4 triazole).
  • carbodiimides such as active ingredients of inorganic acids for example esters or amides such as bis(4-nitrophenyl)-carbonate, carbonyl-diimidazole and 1,1 'dicarbonyl( 1,2,4 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.

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

Abstract

La présente invention concerne un procédé amélioré permettant de préparer de la Thalidomide, un inhibiteur du TNF-alpha, par conversion de N-phthaloyle L-glutamine en présence d'un ingrédient actif de sels d'acides inorganiques tel que le 1,1-Carbonyldi(1,2,4-triazole) comme agent de condensation.
PCT/IN2007/000413 2006-09-20 2007-09-13 Procédé amélioré de préparation de thalidomide WO2008035378A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1716CH2006 2006-09-20
IN1716/CHE/2006 2006-09-20

Publications (2)

Publication Number Publication Date
WO2008035378A2 true WO2008035378A2 (fr) 2008-03-27
WO2008035378A3 WO2008035378A3 (fr) 2009-09-24

Family

ID=39200978

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2007/000413 WO2008035378A2 (fr) 2006-09-20 2007-09-13 Procédé amélioré de préparation de thalidomide

Country Status (1)

Country Link
WO (1) WO2008035378A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102260241A (zh) * 2010-05-26 2011-11-30 重庆医药工业研究院有限责任公司 一种沙利度胺α晶型的工业化制备方法
WO2011154739A1 (fr) * 2010-06-09 2011-12-15 Generics [Uk] Limited Formes cristallines de thalidomide et procédés pour leur préparation
CN102924432A (zh) * 2012-11-09 2013-02-13 常州制药厂有限公司 一种高纯度沙利度胺的制备方法
CN114890988A (zh) * 2022-04-28 2022-08-12 浙江工业大学 一种沙利度胺的化学合成方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1602654A1 (fr) * 2004-06-01 2005-12-07 Antibioticos S.p.A. Procédé de préparation de thalidomide

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1602654A1 (fr) * 2004-06-01 2005-12-07 Antibioticos S.p.A. Procédé de préparation de thalidomide

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102260241A (zh) * 2010-05-26 2011-11-30 重庆医药工业研究院有限责任公司 一种沙利度胺α晶型的工业化制备方法
WO2011154739A1 (fr) * 2010-06-09 2011-12-15 Generics [Uk] Limited Formes cristallines de thalidomide et procédés pour leur préparation
CN103068812A (zh) * 2010-06-09 2013-04-24 基因里克斯(英国)有限公司 沙利度胺晶型及其制备方法
JP2013528206A (ja) * 2010-06-09 2013-07-08 ジェネリクス・［ユーケー］・リミテッド 結晶形態のサリドマイド及びその調製方法
AU2011263493B2 (en) * 2010-06-09 2015-08-06 Generics [Uk] Limited Crystalline forms of thalidomide and processes for their preparation
CN102924432A (zh) * 2012-11-09 2013-02-13 常州制药厂有限公司 一种高纯度沙利度胺的制备方法
CN114890988A (zh) * 2022-04-28 2022-08-12 浙江工业大学 一种沙利度胺的化学合成方法

Also Published As

Publication number Publication date
WO2008035378A3 (fr) 2009-09-24

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