WO2006035296A1 - Procede de preparation d'un derive d'orlistat utile comme standard de reference dans la determination de la purete d'orlistat et procede de preparation d'orlistat - Google Patents

Procede de preparation d'un derive d'orlistat utile comme standard de reference dans la determination de la purete d'orlistat et procede de preparation d'orlistat Download PDF

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Publication number
WO2006035296A1
WO2006035296A1 PCT/IB2005/002864 IB2005002864W WO2006035296A1 WO 2006035296 A1 WO2006035296 A1 WO 2006035296A1 IB 2005002864 W IB2005002864 W IB 2005002864W WO 2006035296 A1 WO2006035296 A1 WO 2006035296A1
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WIPO (PCT)
Prior art keywords
orlistat
dodecyl ester
pure
formula
acid
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Application number
PCT/IB2005/002864
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English (en)
Inventor
Seema Kanwar
Killol Patel
Kaushal Nayyar
Keshav Deo
Mohan Prasad
Yatendra Kumar
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Ranbaxy Laboratories Limited
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Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2006035296A1 publication Critical patent/WO2006035296A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/10—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having one or more double bonds between ring members or between ring members and non-ring members
    • C07D305/12—Beta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the field of the invention relates to a leucine derivative, 2-N-[(S)-2-N- formylamino-4-methyl pentanoic acid (S)-l-[[3(S)-hydroxy-5-oxo-4-hexyl methyl] dodecyl 5 ester] amino-4-methyl pentanoic acid (S)-1-[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl]methyl] dodecyl ester of Formula I,
  • Formula I and process for producing it. More particularly, it relates to the preparation of pure orlistat and pharmaceutical compositions that include the pure orlistat. 0 The invention also relates to use of pure orlistat or dodecyl ester as reference standards or reference markers for checking the purity of orlistat.
  • Orlistat a tetrahydrolipstatin is a useful pancreatic lipase-inhibiting agent and can be used for the prevention and treatment of obesity and hyperlipaemia.
  • Chemically, orlistat 5 is (S)-2-Formylamino-4-methyl pentanoic acid (S)-I -[(2S, 3S)-3-hexyl-4-oxo-2- oxetanyl]methyl] dodecyl ester and is known from U.S. Patent No. 4,598,089.
  • a substantially pure compound of formula I which is chemically N-2[(S)-2-N-formylamino-4-methyl pentanoic acid (S)-1-[[3(S)- hydroxy-5-oxo-4-hexyl methyl] dodecyl ester] amino-4-methyl pentanoic acid (S)-1-[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl]niethyl] dodecyl ester (hereinafter referred to as dodecyl ester).
  • dodecyl ester as a reference standard for determination of the purity of orlistat.
  • a process for the isolation of dodecyl ester is provided.
  • a process for preparing pure orlistat includes deprotecting the compound of Formula II, wherein R is an amino protecting group, in the presence of methylene dichloride; adding formic acetic anhydride; and recovering the pure orlistat.
  • R is an amino protecting group
  • the solvent used in the deprotection reaction has a great impact on the purity of orlistat obtained.
  • Different solvents used in the deprotection reaction results in different amounts of compound of Formula I, as an impurity and therefore different purity of orlistat.
  • the use of methylene dichloride as a solvent in the deprotection reaction minimizes the formation of the impurity of Formula I and thus results in better purity of orlistat.
  • the process may include further drying of the product obtained.
  • the process may produce pure orlistat having less than 0.15% dodecyl ester. In particular, it may produce pure orlistat having less than 0.05% dodecyl ester. - A -
  • pure orlistat having less than 0.05% dodecyl ester.
  • a pharmaceutical composition that includes a therapeutically effective amount of pure orlistat having less than 0.15% dodecyl ester; and one or more pharmaceutically acceptable, carriers, excipients or diluents.
  • composition that includes a therapeutically effective amount of pure orlistat having less than 0.05% dodecyl ester; and one or more pharmaceutically acceptable, carriers, excipients or diluents.
  • a method of preventing and treating obesity and hyperlipaemia using therapeutically effective amount of pure orlistat having less than 0.15% dodecyl ester in another aspect there is provided a method of preventing and treating obesity and hyperlipaemia using therapeutically effective amount of pure orlistat having less than 0.05% dodecyl ester.
  • the inventors have identified that the dodecyl ester is formed as an impurity during the synthesis of orlistat.
  • the inventors have isolated dodecyl ester, which can be used as a reference standard for determination of the purity of orlistat.
  • the process involves: a) stirring a mixture of crude orlistat in one or more solvents; b) adding water and separating orlistat enriched with dodecyl ester; c) subjecting the orlistat enriched with dodecyl ester to preparative HPLC and eluting with a gradient mobile phase to get eluent containing dodecyl ester; and d) isolating the substantially pure dodecyl ester from the eluent.
  • substantially pure herein refers to dodecyl ester having a purity of at least 92% by HPLC.
  • the crude orlistat may contain from about 20% to about 25 % of the dodecyl ester.
  • the mixture of crude orlistat and suitable solvent may be stirred by sonication for about 1 to 5 minutes.
  • the suitable solvent here represents any inert solvent, which does not react under reaction conditions.
  • the addition of water may be carried out till haziness appears and may be allowed to settle at the bottom.
  • the above step may be repeated twice or thrice for enrichment of dodecyl ester.
  • the enriched material may be loaded on to 8/LtHS silica (250 x 21.1 mm) column.
  • Mobile phase used may be a gradient of isopropyl alcohol and hexane.
  • the fractions containing the dodecyl ester may be further combined and concentrated to dryness.
  • the substantially pure dodecyl ester can then be further purified by crystallization or column chromatography.
  • the inventors also have developed a process for preparing pure orlistat by deprotecting the compound of Formula II, wherein R is an amino protecting group, in the presence of methylene dichloride; adding formic acetic anhydride; and recovering the pure orlistat.
  • the orlistat may be recovered by a technique which includes, for example, distillation, distillation under vacuum, cooling, evaporation, filtration, filtration under vacuum, decantation and centrifugation.
  • the orlistat thus recovered may be further purified or additionally purified, by employing commonly practiced recrystallization techniques using solvent / antisolvent mixture to obtain pure orlistat.
  • compositions that contain the pure orlistat having less than 0.15% dodecyl ester, for example, less than 0.05% dodecyl ester, in admixture with one or more solid or liquid pharmaceutical diluents, carriers and/or excipients. These pharmaceutical compositions may be used for preventing and treating obesity and hyperlipaemia.
  • the compound of formula II can be obtained by methods known in the art including methods described in U.S. Patent No. 4,983,746; J. Chem, Soc. Perkin. Trans. I, 1998, 17, 2679; and J. Org. Chem. 1991 , 56, 4714, which are incorporated herein by reference.
  • amino protecting group examples include alkyl, alkoxy, aralkyl, alkoxyalkyl, trialkylsily, benzyloxy, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, t-butoxycarbonyl, 9- fluorenylmethoxycarbony, alkyl-aminocarbonyloxy, phthalimides and sulfonamides.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, and tert-butyl groups.
  • aralkyl examples include benzyl or substituted benzyl.
  • Examples of substituted benzyl include p-nitro benzyl, p-methoxy benzyl, o-nitro benzyl, p-bromo benzyl or 2,4,6- trimethyl benzyl groups.
  • Examples of alkoxy include methoxy and ethoxy, isopropoxy, and tert-butoxy.
  • Examples of alkoxyalkyl include methoxymethyl, ethoxycarbonyl, isopropoxycarbonyl, and tert-butoxycarbonyl.
  • Examples of trialkylsilyl include trimethylsilyl and tert-butyldimethylsilyl groups.
  • Examples of alkyl-amino carbonyloxy include methyl aminocarbonyloxy and dimethyl aminocarbonyloxy.
  • the deprotection may be carried out by hydrogenation in the presence of a catalyst.
  • the hydrogenation catalysts are the customary hydrogenation catalysts known in organic chemistry, such as transition metal compounds.
  • transition metal compounds include palladium compounds such as palladium/carbon and palladium hydroxide, platinum compounds such as platinum oxide and platinum/carbon, ruthenium compounds such as ruthenium oxide, rhodium compounds such as rhodium/carbon and nickel compounds such as Raney nickel.
  • the hydrogenation reaction may be carried out at normal pressure, or at elevated pressure depending on the choice of a catalyst. In general, it may be carried out at a hydrogen pressure in the range from about 1 kg/cm 2 to about 10 kg/cm 2 , for example at a hydrogen pressure in the range from about 2 kg/cm 2 to about 4 kg/cm 2 .
  • the hydrogenation temperature may be varied depending on the choice of a catalyst and/or pressure employed. For example, the hydrogenation may be carried out at a temperature range from about -2O 0 C to about 120 0 C, or at a temperature range from about O 0 C to about 80 0 C. In particular, it may be carried out at a temperature range from about 1O 0 C to about 35 0 C.
  • the protecting group When the protecting group is 9- fluorenylmethoxycarbony, it may be deprotected by a base catalyzed reaction. Examples of base include ammonia, piperidine, morpholine and 1,8- diazacyclo [5.4.0] undec-7-ene (DBU).
  • base examples include ammonia, piperidine, morpholine and 1,8- diazacyclo [5.4.0] undec-7-ene (DBU).
  • DBU 1,8- diazacyclo [5.4.0] undec-7-ene
  • the protecting group When the protecting group is silyl- protecting groups, it may be removed by treatment with fluoride. Other protecting groups may be removed by hydrolysis.
  • the hydrolysis is a reaction in which the protecting group is removed in the presence of water and acid or a base (alkali). Accordingly, hydrolysis may be acid or alkali hydrolysis.
  • Alkali hydrolysis may be carried out in the presence of organic and inorganic bases.
  • organic base include trimethylamine, triethylamine, tributylamine, triisopropylamine, diisopropylethylamine, 1,8-diazabicyclo- [5.4.0]-undec-7-ene (DBU), l,5-diazabicyclo-[4.3.0]-non-5-ene (DBN), 4-dimethylamino pyridine, morpholine, thiomorpholine, piperidine, pyrrolidine and mixtures thereof.
  • inorganic base include alkali metal carbonate, bicarbonate, hydroxide and mixtures thereof.
  • alkali metal carbonate include lithium carbonate, sodium carbonate and potassium carbonate.
  • alkali metal bicarbonate include sodium bicarbonate and potassium bicarbonate.
  • alkali metal hydroxide include sodium hydroxide and potassium hydroxide.
  • Acid hydrolysis may be carried out in the presence of an acid.
  • acid examples include hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid.
  • formic acetic anhydride may be carried out in the presence of a suitable solvent.
  • suitable solvents are inert organic solvents, which do not react under the reaction conditions.
  • solvents examples include chlorinated hydrocarbons such as methylene chloride, ethylene dichloride and carbon tetrachloride; alcohols such as methanol, ethanol, isopropanol and butanol; ketones such as acetone and methyl isobutyl ketone; esters such as ethylacetate and isopropylacetate; nitriles such as acetonitrile and benzonitrile; dipolar aprotic solvents such as dimethylsulfoxide and dimethylformamide; alkyl ethers such as diethylether, diisopropylether and dimethoxyethane; cyclic ethers such as dioxane and tetrahydrofuran, and mixtures thereof.
  • chlorinated hydrocarbons such as methylene chloride, ethylene dichloride and carbon tetrachloride
  • alcohols such as methanol, ethanol, isopropanol and butanol
  • ketones such as
  • the addition of formic acetic anhydride may be performed at temperatures of from about -2O 0 C to about 20°C for 30 minutes to 2 hours.
  • the addition may be carried out at about -10°C to about -5 0 C for 30 minutes to 40 minutes.
  • the reaction may be carried out at about -20 0 C to about 20 0 C for 30 minutes to 4 hours.
  • the reaction mixture may be stirred at about 0 0 C to about -5°C for 1 to 2 hours in some particular embodiments.
  • Formic acetic anhydride may be prepared by adding acetic anhydride to formic acid.
  • the pure orlistat may have purity of more than 99% having less than 0.15% by HPLC of compound of Formula I.
  • Example-1 Synthesis of (SV2-Formylamino-4-methyl pentanoic acid (S)-1-
  • Activated carbon (1 g) was then added to the methylene dichloride layer and stirred for 30 minutes.
  • the reaction mixture was filtered through hyflow bed and the bed was washed with methylene dichloride (50 ml).
  • the solvent was recovered completely under reduced pressure at 25 to 30°C.
  • hexane 25 ml was added and degassed completely under reduced pressure at 30 to 35°C.
  • the reaction mass was cooled at 20 to 25°C and the product was crystallized from hexane (350 ml).
  • the solid obtained was filtered and recrystallized twice from hexane (350 ml each) at 0 to 5 0 C to get pure orlistat.
  • Example-2 Synthesis of formic acetic anhydride Acetic anhydride (27.5 g) was added to formic acid (50 g) and the mixture was stirred at 45 to 50°C till acetic anhydride content was not more than 5%.
  • Example-3 Synthesis of N-2[(S)-2-N-formylamino-4-methyl pentanoic acid (S)-1-IT3(S)- hydroxy-5-oxo-4-hexyl methyl] dodecyl ester! amino-4-methyl pentanoic acid (S)-1-
  • the mixture of crude orlistat (5g, dodecyl ester: 23%) and acetonitrile (5ml) was sonicated for 2 minutes. Further, 0.5 ml water was added to the mixture and shaken, as the haziness appeared, it was allowed to settle.

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Abstract

L'invention porte sur un dérivé de leucine, N-2[(S)-2-N-formylamino-4-methyl acide pentanoïque (S)-1-[[3(S)-hydroxy-5-oxo-4-hexyl methyl] ester dodécylique] amino-4-methyl acide pentanoïque (S)-1-[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl]methyl ester dodécylique représenté par la formule (I), et sur un procédé d'isolation de celui-ci. Plus précisément, l'invention porte sur la préparation d'orlistat pur, qui consiste en (S)-2-Formylamino-4-methyl acide pentanoïque (S)-1-[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl]methyl] ester dodécylique. Cette invention se rapporte aussi à l'utilisation du composé de la formule (I) en tant que standard de référence ou marqueur de référence afin de vérifier la pureté d'orlistat.
PCT/IB2005/002864 2004-09-27 2005-09-27 Procede de preparation d'un derive d'orlistat utile comme standard de reference dans la determination de la purete d'orlistat et procede de preparation d'orlistat WO2006035296A1 (fr)

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IN1853DE2004 2004-09-27
IN1853/DEL/2004 2004-09-27

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4931463A (en) * 1984-12-21 1990-06-05 Hoffmann-La Roche Inc. Oxetanones
US20020035089A1 (en) * 2000-07-28 2002-03-21 Pierre Barbier Orlistat compositions
WO2005005403A2 (fr) * 2003-07-15 2005-01-20 Ranbaxy Laboratories Limited Procede de preparation d'oxetan-2-ones

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4931463A (en) * 1984-12-21 1990-06-05 Hoffmann-La Roche Inc. Oxetanones
US20020035089A1 (en) * 2000-07-28 2002-03-21 Pierre Barbier Orlistat compositions
WO2005005403A2 (fr) * 2003-07-15 2005-01-20 Ranbaxy Laboratories Limited Procede de preparation d'oxetan-2-ones

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHADHA ET AL: "Synthesis of tetrahydrolipstatin", J. ORG. CHEM., vol. 56, 1991, pages 4714 - 4718, XP002355693 *
I.FLEMING, N.J. LAWRENCE: "Stereocontrol in organic synthesis using silicon-containing compounds. A synthesis of (-)-tetrahydrolipstatin using the alkylation of a beta-silyl ester and the hydroboration of an allylsilane", J. CHEM. SOC. PERKIN TRANS. 1, 1998, pages 2679 - 2686, XP002355692 *
T.W. GREENE, P. WUTS: "Protective groups in organic synthesis", 1991, WILEY&SONS, NEW YORK, XP002355761 *

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