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WO2022034427A1 - Processus amélioré de préparation de 4-oxoisotrétinoïne - Google Patents

Processus amélioré de préparation de 4-oxoisotrétinoïne Download PDF

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Publication number
WO2022034427A1
WO2022034427A1 PCT/IB2021/057015 IB2021057015W WO2022034427A1 WO 2022034427 A1 WO2022034427 A1 WO 2022034427A1 IB 2021057015 W IB2021057015 W IB 2021057015W WO 2022034427 A1 WO2022034427 A1 WO 2022034427A1
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WIPO (PCT)
Prior art keywords
oxoisotretinoin
acid
compound
formula
mixtures
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/IB2021/057015
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English (en)
Inventor
Natarajan Senthilkumar
Karumanchi KISHORE
Vanchanagiri Krishna
Moturu VENKATA RAMAKRISHNA MURTHY
Sivakumaran Meenakshisunderam
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.)
Aurobindo Pharma Ltd
Original Assignee
Aurobindo Pharma Ltd
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Filing date
Publication date
Application filed by Aurobindo Pharma Ltd filed Critical Aurobindo Pharma Ltd
Publication of WO2022034427A1 publication Critical patent/WO2022034427A1/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
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/20—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to an improved process for the preparation and purification of 4-Oxoisotretinoin.
  • the present invention also relates to a crystalline polymorph of 4-Oxoisotretinoin.
  • 4-Oxoisotretinoin is chemically known as (2Z,4E,6E,8E)-3,7-dimethyl-9- (2,6,6-trimethyl-3-oxocyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid, as shown below a Compound of Formula (I).
  • 4-OxoIsotretinoin is a metabolite of Isotretinoin.
  • 4-Oxoisotretinoin (I) disclosed in GB 2156676, and discloses a process for the preparation of 4-Oxoisotretinoin, wherein esterification of 4-oxo-11,13-di-cis retinoic acid (A) with methanol to produce 4-oxo-11,13-di-cis retinoic acid methyl ester (B). Isomerization of the obtained ester to 4-Oxoisotretinoin methyl ester, which is hydrolyzed to 4-Oxoisotretinoin (I).
  • Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
  • New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional polymorphs of 4-Oxoisotretinoin.
  • the main objective of the present invention is an improved process for the preparation of 4-Oxoisotretinoin (I), and its intermediates with high purity and good yield on commercial scale.
  • BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 – Shows a PXRD of crystalline 4-Oxoisotretinoin (I)
  • the present invention provides a crystalline form of 4- Oxoisotretinoin (I) having a Powder X-ray Diffraction (PXRD) pattern shown in
  • the present invention provides an improved process for the preparation of 4-Oxoisotretinoin (I): which comprises: (i) oxidation of Isotretinoin alkyl ester of a compound of Formula (III) using an oxidizing agent in presence of an acid; to produce 4-Oxoisotretinoin alkyl ester of a Compound of Formula (IV); wherein R is a carboxyl protecting group comprises substituted or unsubstituted alkyl group; (ii) optionally, hydrolysis of a Compound of Formula (IV) to produce 4- Oxoisotretinoin of a Compound
  • the present invention provides an improved process for the preparation of 4-Oxoisotretinoin (I): which comprises: (i) oxidation of Isotretinoin alkyl ester of a compound of Formula (III) using an alpha form of MnO 2 ; to produce 4-Oxoisotretinoin alkyl ester of a Compound of Formula (IV); wherein R is a carboxyl protecting group comprises substituted or unsubstituted alkyl group; (ii) optionally addition of an acid; (iii) hydrolysis of a Compound of Formula (IV) to produce 4-Oxoisotretinoin of a Compound of Formula (I).
  • the present invention provides purification process of 4-Oxoisotretinoin (I): which comprises: (a) providing a solution of 4-Oxoisotretinoin (I) in a suitable solvent; (b) optionally, filtering the resulting solution; (c) adding an anti-solvent to the resulting solution; and (d) isolating the pure 4-Oxoisotretinoin (I).
  • the present invention provides a crystalline form of 4- Oxoisotretinoin (I):
  • crystalline form of 4- Oxoisotretinoin (I) is characterized by Powder X-ray diffraction pattern, made using CuK ⁇ l radiation, which comprises peaks at degrees 2 ⁇ ( ⁇ 0.02 degrees) as shown in FIG.1.
  • the crystalline form of 4-Oxoisotretinoin (I) is characterized by DSC (determined via DSC; evaluated as onset -temperature; heating rate 10 K/min). The obtained DSC curve is shown in FIG.2.
  • the present invention provides an improved process for the preparation of 4-Oxoisotretinoin (I): which comprises: (i) esterification of Isotretinoin (II); to produce Isotretinoin alkyl ester of a compound of Formula (III); wherein R is a carboxyl protecting group comprises substituted or unsubstituted alkyl group; (ii) oxidation of Isotretinoin alkyl ester of a compound of Formula (III) using an oxidizing agent in presence of an acid to produce 4- Oxoisotretinoin alkyl ester of a Compound of Formula (IV); (iii) hydrolysis of a Compound of Formula (IV) to produce 4-Oxoisotretinoin (I).
  • step (i) is carried out using an alkylating agent and a dehydrating agent in presence of a base and a solvent.
  • alkylating agent comprises methanol, ethanol, propanol, isopropanol, 2-butanol and dehydrating agent comprises aluminum phosphate, Burgess reagent, calcium oxide, cyanuric chloride, N,N'- cicyclohexylcarbodiimide, Iron(III) chloride, ortho formic acid, Phosphorus pentoxide, phosphoryl chloride, sulfuric acid.
  • R is an alkyl group comprises methyl, ethyl, propyl, isopropyl, butyl.
  • solvent comprises dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, acetone, ethyl acetate, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, methylene chloride (CH 2 Cl2) and/or mixtures thereof.
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • THF tetrahydrofuran
  • acetonitrile acetone
  • ethyl acetate benzene
  • toluene 1,4-dioxane
  • chloroform chloroform
  • diethyl ether methylene chloride
  • CH 2 Cl2 methylene chloride
  • the base comprises 4-dimethylaminopyridine (DMAP), pyridine; diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and/or mixtures thereof.
  • DMAP 4-dimethylaminopyridine
  • pyridine diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and/or mixtures thereof.
  • DMAP 4-dimethylaminopyridine
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • oxidizing agent used in step (ii) of conversion of Isotretinoin alkyl ester of a compound of Formula (III) to 4-Oxoisotretinoin alkyl ester of a compound of Formula (IV) comprises Oxygen (O 2 ), hydrogen peroxide (H 2 O 2 ), potassium permanganate (KMnO 4 ), sodium dichromate (Na 2 Cr 2 O 7 ), peroxydisulfuric acid (H 2 S 2 O 8 ), peroxymonosulfuric acid (H 2 SO5), MnO 2 and/or alpha form of MnO 2 .
  • step (ii) is carried out in presence of an acid to produce 4-Oxoisotretinoin alkyl ester of a compound of Formula (IV).
  • acid comprises oxalic acid, hydrochloric acid, sulfuric acid or nitric acid.
  • step (ii) reaction is carried out at a temperature ranging from about 0 degrees Celsius to about 80 degrees Celsius depending upon the solvent used in the reaction for a time period of 1-4 hours
  • hydrolysis of a compound of Formula (IV) in step (iii) is carried out using an alkali or an acid or metal alkoxides in a suitable solvent.
  • alkali comprises sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, or acid comprises hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, metal alkoxides comprises sodium methoxide, sodium ethoxide and/or mixtures thereof.
  • the solvent used in hydrolysis comprises water; a lower alcohol comprises methanol, ethanol, propanol, isopropyl alcohol; a water soluble organic solvent such as acetone, tetrahydrofuran, dioxane and the like, and a mixture of solvents selected from the same can be illustrated.
  • the hydrolysis reaction may be performed usually at from 0° C to a boiling point of used solvent for 30 minutes to 48 hours, and then 4-Oxoisotretinoin (I) can be obtained by a usual procedure.
  • pH can be adjusted by adding appropriate acid / base.
  • the present invention provides purification process of 4-Oxoisotretinoin (I): which comprises: (a) providing a solution of 4-Oxoisotretinoin (I) in a suitable solvent; (b) optionally, filtering the resulting solution; (c) adding an anti-solvent to the resulting solution; and
  • suitable solvent used in step (a) comprises, methylene chloride, ethylene chloride, methyl tert-butyl ether (MTBE), dimethyl sulfoxide (DMSO), N,N-dimethylacetamide, N-methyl-pyrrolidine, tetrahydrofuran, or N,N-dimethylformamide and/or mixtures thereof.
  • anti-solvent used in step (c) comprises acetonitrile, ethanol, methanol, isopropyl alcohol, n-butanol and/or mixtures thereof.
  • suitable solvent in step (a) heating the reaction mixture to 10-50°C, preferable 20-30°C and further stirred the reaction mixture up to 30 minutes, preferable 20 minutes. Filtering the resulting solution.
  • anti-solvent in step (c) stirred the reaction mixture up to 1-2 hours, preferably 1 hour and cooled to 20-30°C.
  • the present invention provides 4- Oxoisotretinoin (I) obtained is in crystalline form.
  • Oxalic acid (8.3 g) and ⁇ -MnO 2 (250 g) were added to a stirred solution of Isotretinoin methyl ester (III) (11 g) in methylene chloride (1000 ml), at 20-30°C.
  • the resultant slurry was stirred for 4 h at 20-30°C.
  • the insolubles were removed by filtration and washed with methylene chloride (5 ⁇ 200 ml).
  • the wet cake was unloaded and suspended in methylene chloride (1000 ml).
  • the resultant slurry was stirred for 30 min.
  • the solvent was removed from the reaction mass under reduced pressure.
  • the pH of the reaction mass was adjusted to 3.0-3.5 with ⁇ 5% w/w aqueous hydrochloric acid.
  • the product was extracted twice with ethyl acetate (2 ⁇ 100 ml).
  • the organic layers were combined and washed with DM water (50 ml).
  • the organic layer was concentrated completely under reduced pressure.
  • Ethyl acetate (20 ml) was added to the concentrated mass.
  • the slurry was stirred for 1 h at 20-30°C.
  • the resultant slurry was cooled to 0-5°C and stirred for 2 h.
  • the product was filtered under nitrogen atmosphere and dried to afford 4-oxoisotretinoin (5 g).

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

Abstract

La présente invention concerne un processus amélioré de préparation de 4-oxoisotrétinoïne et un processus de purification de 4-oxoisotrétinoïne (I) et une forme cristalline de 4-oxoisotrétinoïne (I).
PCT/IB2021/057015 2020-08-14 2021-07-31 Processus amélioré de préparation de 4-oxoisotrétinoïne Ceased WO2022034427A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202041035037 2020-08-14
IN202041035037 2020-08-14

Publications (1)

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WO2022034427A1 true WO2022034427A1 (fr) 2022-02-17

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190002411A1 (en) * 2014-11-20 2019-01-03 University Of Maryland, Baltimore 13-Cis-RAMBA RETINAMIDES THAT DEGRADE MNKs FOR TREATING CANCER

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190002411A1 (en) * 2014-11-20 2019-01-03 University Of Maryland, Baltimore 13-Cis-RAMBA RETINAMIDES THAT DEGRADE MNKs FOR TREATING CANCER

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AI-HE YU ET AL.: "Synthesis and Characterization of Novel 4-Hydroxy-(4-solanesylaminophenyl) Retinoate", ADVANCED MATERIALS RESEARCH, vol. 236-238, no. 238.2794, 2011, Retrieved from the Internet <URL:https://doi.org/10.4028/www.scientific.net/AMR.236> [retrieved on 20111205] *
SERRA STEFANO, SERRA STEFANO: "MnO 2 /TBHP: A Versatile and User-­Friend­ly Combination of Reagents for the Oxidation of Allylic and Benzylic Methylene Functional Groups : MnO 2 /TBHP: A Combination of Reagents for Allylic Oxidation", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, WILEY-VCH, DE, vol. 2015, no. 29, 1 September 2015 (2015-09-01), DE , pages 6472 - 6478, XP055908384, ISSN: 1434-193X, DOI: 10.1002/ejoc.201500829 *

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