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WO2009090663A1 - Nouveau polymorphe cristallin de l'armodafinil et procédé perfectionné permettant de le préparer - Google Patents

Nouveau polymorphe cristallin de l'armodafinil et procédé perfectionné permettant de le préparer Download PDF

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Publication number
WO2009090663A1
WO2009090663A1 PCT/IN2008/000373 IN2008000373W WO2009090663A1 WO 2009090663 A1 WO2009090663 A1 WO 2009090663A1 IN 2008000373 W IN2008000373 W IN 2008000373W WO 2009090663 A1 WO2009090663 A1 WO 2009090663A1
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WO
WIPO (PCT)
Prior art keywords
armodafinil
acetic acid
benzhydrylsulfinyl
preparation
crystalline anhydrous
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IN2008/000373
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English (en)
Inventor
Rajesh Kumar Thaper
Manoj Devilalji Prabhavat
Devendra Kumar Paramsukh Varma
Runjhun Gupta
Dinesh Jyantibhai Paghdar
Navanath Janardhan Kawade
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lupin Ltd
Original Assignee
Lupin 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 Lupin Ltd filed Critical Lupin Ltd
Publication of WO2009090663A1 publication Critical patent/WO2009090663A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/06—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a novel crystalline polymorph of armodafinil.
  • the invention relates to an improved process for preparation of the novel polymorph of armodafinil.
  • Provigil ® is indicated for the treatment of excessive sleepiness associated with narcolepsy, shift work sleep disorder, and obstructive sleep apnea/hyponea syndrome.
  • the R enantiomer of modafinil is known as armodafinil and has the chemical name 2-[(R) -(diphenylmethyl) sulfinyl] acetamide, and has the following chemical structure:
  • the present invention relates to novel crystalline anhydrous form of armodafinil characterized by Powder XRD pattern having peaks at about 6.6, 10.4, 13.3, 14.0, 16.5, 17.4, 17.7, 19.0, 19.4, 20.0, 20.8, 21.1 , 21.4,22.3, 22.8, 23.5, 25.6, 26.0, 26.0, 26.8, 27.6, 28.3, 28.6, 29.1 , 29.8, 31.9, 34.3, 35.2, 39.3 + 0.2 degrees 2- theta as depicted in Figure 1.
  • the present invention relates to an improved process for preparing the novel crystalline polymorph of armodafinil, which is cost effective and industrially applicable.
  • FIGURES Figure 1 Powder X Ray Diffractogram for crystalline anhydrous armodafinil of the present invention.
  • Figure 2 TGA thermogram for crystalline anhydrous armodafinil of the present invention.
  • Figure 3 DSC thermogram for crystalline anhydrous armodafinil of the present invention.
  • Polymorphism is a property of some molecules wherein the solids arising out of this property have distinct physical properties such as melting point, X-ray diffraction pattern, infrared absorption spectra and NMR spectra. The differences in the physical properties of polymorphs result from the orientation and intermolecular interactions of adjacent molecules in the bulk solid.
  • polymorphs are distinct solids sharing the same molecular formula yet have distinct physical properties compared to other forms of the same molecule.
  • One of the most important physical properties of pharmaceutical polymorph is their solubility in aqueous solution, particularly in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment.
  • the present invention relates to novel crystalline polymorph for armodafinil and a novel process for preparing the same.
  • the invention encompasses a novel crystalline form of armodafinil characterized by a powder XRD pattern having peaks at about 6.6, 10.4, 13.3, 14.0, 16.5, 17.4, 17.7, 19.0, 19.4, 20.0, 20.8, 21.1 , 21.4,22.3, 22.8, 23.5, 25.6, 26.0, 26.0, 26.8, 27.6, 28.3, 28.6, 29.1 , 29.8, 31.9, 34.3, 35,2, 39.3 + 0.2 degrees 2- theta; depicted in Figure 1.
  • novel crystalline form of armodafinil of the present invention is characterized by TGA as depicted in Figure 2.
  • the novel crystalline form of armodafinil of the present invention is characterized by DSC thermogram having onset peak at 163.39 0 C as depicted in Figure 3.
  • the invention provides a novel process for preparing crystalline armodafinil.
  • the inventors of the present invention have reacted the benzhydrol with thioglycolic acid in dichloromethane and catalytic amount of p-toluene sulfonic acid and avoided use of trifluoro acetic acid.
  • the prior art processes used trifluoro acetic acid, which is not only hazardous on industrial scale but also not commercially viable, as it requires distillation of TFA. Further the product obtained had impurities and required purification.
  • the distinctiveness of the process of the present invention resides in oxidation of the benzhydryl thioacetic acid using acetonitrile as the solvent with hydrogen peroxide.
  • the formation of the sulfone impurity by the process of the invention is very low and hence results in high yield and high quality product.
  • the prior art processes used hydrogen peroxide in methanol as a solvent, which resulted in over oxidized product and ester formation.
  • the crude armodafinil is crystallized in ethanol, denatured with 5% acetone.
  • the product thus obtained is anhydrous crystalline armodafinil.
  • the product is characterized by XRD peaks at about 6.6, 10.4, 13.3, 14.0, 16.5, 17.4, 17.7, 19.0, 19.4, 20.0, 20.8, 21.1 , 21.4,22.3, 22.8, 23.5, 25.6, 26.0, 26.0, 26.8, 27.6, 28.3, 28.6, 29.1, 29.8, 31.9, 34.3, 35.2, 39.3 + 0.2 degrees 2-theta; depicted in Figure 1 ; a TGA thermogram; as depicted in figure 2; and a DSC thermogram as depicted in Figure 3; which shows that the product is essentially anhydrous.
  • Step I Preparation of the benzhvdryl thio acetic acid from benzhvdrol: Benzhydrol (10 g), Thioglycolic acid (7.8 g) and pTSA (0.2g) were charged in 100 mL of dichloromethane at room temperature. The reaction mixture was refluxed azeotropically till benzhydrol is not more than 1 %. 50 mL of DM water was added and the organic layers separated. The solvent was distilled out under vacuum till slurry is formed. 100 mL of cyclohexane was added to the slurry to get a solid, which was filtered and dried, under vacuum at 40-45 0 C. Yield: 8.5 g Purity: 98-99%
  • Step II Oxidation of the benzhvdryl thio acetic acid with hydrogen per oxide and acetic acid in acetonitrile to obtain benzhvdryl sulfinyl acetic acid:
  • Step III Resolution of the benzhvdrylsulfinyl acetic acid with (-)- ⁇ - methylbenzylamine to obtain the (-) isomer of benzhydrylsulfinyl acetic acid: 10 g of benzhydryl sulfinyl acetic acid is charged in 200 mL of DM water. 4.8g of (-)- ⁇ -methylbenzylamine were added to the reaction mixture and heated up to 75-80 0 C to get a clear solution. Filtered the hot solution and heated again to 70-75 0 C followed by cooling at 64-65 0 C and seeded the solution with pure salt of R-isomer.
  • Step IV Esterification of the (-) benzhvdrylsulfinyl acetic acid CH3I/K2CO3 10 g of the (-) benzhydrylsulfinyl acetic acid was added to 600 mL of acetone, 5.4 g of K 2 CO 3 and 7.7 g of methyl iodide in four lots over four hours under reflux and the reaction was monitored to obtain reaction mixture wherein benzhydryl sulfinyl acetic acid was not more than 1%. The solvent was distilled out under vacuum. Reaction mixture was extracted with dichloromethane. The organic layer was washed with DM water. The organic layer was distilled off to obtain a residual mass. The product was isolated by 100 mL of diiso propyl ether (DIPE).
  • DIPE diiso propyl ether
  • Step V Amidification of the methyl (-) benzhydrylsulfinyl acetate with ammonical methanol

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention porte sur un nouveau polymorphe cristallin de l'armodafinil. Sous un autre aspect, l'invention porte sur un procédé perfectionné pour la préparation du nouveau polymorphe de l'armodafinil.
PCT/IN2008/000373 2008-01-15 2008-06-13 Nouveau polymorphe cristallin de l'armodafinil et procédé perfectionné permettant de le préparer Ceased WO2009090663A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN108/KOL/2008 2008-01-15
IN108KO2008 2008-01-15

Publications (1)

Publication Number Publication Date
WO2009090663A1 true WO2009090663A1 (fr) 2009-07-23

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2008/000373 Ceased WO2009090663A1 (fr) 2008-01-15 2008-06-13 Nouveau polymorphe cristallin de l'armodafinil et procédé perfectionné permettant de le préparer

Country Status (1)

Country Link
WO (1) WO2009090663A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102276588A (zh) * 2011-05-05 2011-12-14 四川科伦药物研究有限公司 一种制备拉呋替丁的新工艺
US8318979B2 (en) 2003-09-19 2012-11-27 Cephalon France Process for enantioselective synthesis of single enantiomers of modafinil by asymmetric oxidation
CN103058900A (zh) * 2012-12-14 2013-04-24 重庆康乐制药有限公司 一种r-二苯甲基亚硫酰乙酸的制备方法
US8729305B2 (en) 2002-12-20 2014-05-20 Teva Sante Process for the preparation of and crystalline forms of optical enantiomers of modafinil

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2849029A1 (fr) * 2002-12-20 2004-06-25 Lafon Labor Procede de preparation et formes cristallines des enantiomeres optiques du modafinil.
WO2005077894A1 (fr) * 2004-02-06 2005-08-25 Cephalon, Inc. Compositions a base de modafinil
WO2007103221A2 (fr) * 2006-03-01 2007-09-13 Teva Pharmaceutical Industries Ltd. Procede ameliore pour la preparation de l'armodafinil

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2849029A1 (fr) * 2002-12-20 2004-06-25 Lafon Labor Procede de preparation et formes cristallines des enantiomeres optiques du modafinil.
WO2005077894A1 (fr) * 2004-02-06 2005-08-25 Cephalon, Inc. Compositions a base de modafinil
WO2007103221A2 (fr) * 2006-03-01 2007-09-13 Teva Pharmaceutical Industries Ltd. Procede ameliore pour la preparation de l'armodafinil

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DAHLBOM R ET AL: "DIPHENYLMETHOXYACETIC ACID AND SOME RELATED COMPOUNDS", ACTA CHEMICA SCANDINAVICA, MUNKSGAARD, COPENHAGEN, DK, vol. 2, 1 January 1948 (1948-01-01), pages 856 - 860, XP009018806, ISSN: 0904-213X *
PRISINZANO T ET AL: "Synthesis and determination of the absolute configuration of the enantiomers of modafinil", TETRAHEDRON ASYMMETRY, PERGAMON, OXFORD; GB, vol. 15, no. 6, 22 March 2004 (2004-03-22), pages 1053 - 1058, XP004494506, ISSN: 0957-4166 *
TERNOIS ET AL: "Asymmetric synthesis of modafinil and its derivatives by enantioselective oxidation of thioethers: comparison of various methods including synthesis in ionic liquids", TETRAHEDRON ASYMMETRY, PERGAMON, OXFORD; GB, vol. 18, no. 24, 21 December 2007 (2007-12-21), pages 2959 - 2964, XP022400759, ISSN: 0957-4166 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8729305B2 (en) 2002-12-20 2014-05-20 Teva Sante Process for the preparation of and crystalline forms of optical enantiomers of modafinil
US8975442B2 (en) 2002-12-20 2015-03-10 Teva Sante Process for the preparation of and crystalline forms of optical enantiomers of modafinil
US9382200B2 (en) 2002-12-20 2016-07-05 Teva Sante Process for the preparation of and crystalline forms of optical enantiomers of modafinil
US8318979B2 (en) 2003-09-19 2012-11-27 Cephalon France Process for enantioselective synthesis of single enantiomers of modafinil by asymmetric oxidation
US8759583B2 (en) 2003-09-19 2014-06-24 Teva Sante Process for enantioselective synthesis of single enantiomers of modafinil by asymmetric oxidation
CN102276588A (zh) * 2011-05-05 2011-12-14 四川科伦药物研究有限公司 一种制备拉呋替丁的新工艺
CN102276588B (zh) * 2011-05-05 2014-05-21 四川科伦药物研究有限公司 一种拉呋替丁的制备方法
CN103058900A (zh) * 2012-12-14 2013-04-24 重庆康乐制药有限公司 一种r-二苯甲基亚硫酰乙酸的制备方法
CN103058900B (zh) * 2012-12-14 2014-11-26 重庆康乐制药有限公司 一种r-二苯甲基亚硫酰乙酸的制备方法

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