WO2019058290A1 - Procédé amélioré pour la préparation d'un composé a-amino d'azanimod - Google Patents

Procédé amélioré pour la préparation d'un composé a-amino d'azanimod Download PDF

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Publication number
WO2019058290A1
WO2019058290A1 PCT/IB2018/057234 IB2018057234W WO2019058290A1 WO 2019058290 A1 WO2019058290 A1 WO 2019058290A1 IB 2018057234 W IB2018057234 W IB 2018057234W WO 2019058290 A1 WO2019058290 A1 WO 2019058290A1
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Prior art keywords
formula
compound
nitro
methylbenzylamine
hydrogen
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PCT/IB2018/057234
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English (en)
Inventor
Rajendiran Chinnapillai
Nagarajan Periyandi
Venkateswaralu Jasti
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Suven Life Sciences Limited
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Publication of WO2019058290A1 publication Critical patent/WO2019058290A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/61—Carboxylic acid nitriles containing cyano groups and nitrogen atoms being part of imino groups bound to the same carbon skeleton

Definitions

  • the present invention specifically relates to improved process for the preparation of optically chiral amino compound.
  • the present invention particularly relates to the improved process for the preparation of (S)-l-amino-2,3-dihydro-lH-indene-4-carbonitrile, an important intermediate for the synthesis of ozanimod.
  • the present invention more particularly relates to preparation of (S)-l-amino-
  • the present invention specifically relates to preparation of (S)-l-amino-2,3- dihydro-lH-indene-4-carbonitrile comprising diastereo selective chiral amine synthesis by protection with chiral auxiliary a-methylbenzylamine derivatives followed by reduction and debenzylation.
  • Ozanimod is an investigational immunomodulatory drug in development for the potential treatment of relapsing multiple sclerosis (RMS), ulcerative colitis (UC) and Crohn's Disease. It acts as a sphingosine-l- phosphate (SlPl) receptor agonist that induces peripheral lymphocyte sequestration, potentially decreasing the number of activated lymphocytes circulating to the gastrointestinal tract.
  • Ozanimod is chemically represented as 5- [3- [(IS)- 1 -(2- hydroxyethylamino)-2,3-dihydro-lH-inden-4-yl]-l,2,4-oxadiazol-5-yl]-2-propan-2- yloxybenzonitrile.
  • the chemical formula is C23H 24 N 4 O3, the molecular weight is 404.47 g/mol and the structural formula is:
  • EP 0 380 144 Bl discloses a process for the preparation of 2R,lR-2-methoxy- 5-[2-(l-methylbenzylamino)propyl]benzenesulfonamide hydrochloride, which is shown as given below:
  • WO 2003/022785 A2 discloses asymmetric synthesis of (R)-(-)-8-Amino- 5,6,7,8-tetrahydroquinone, which is shown as given below:
  • WO 2006/030017 Al discloses synthesis of (2R)-4-phenyl-N-(R)-l -phenyl ethyl)butan-2-amine, which is shown as given below:
  • WO 2013/126360 A2 discloses process for preparing aminosulfones, which is shown as given below:
  • the main objective of the present invention is to provide an improved process for the preparation of Ozanimod intermediate.
  • Another objective of the present invention is to provide improved process for the preparation of (S)-l-amino-2,3-dihydro-lH-indene-4-carbonitrile, an important intermediate for the preparation of Ozanimod.
  • Still another objective of the present invention is to provide synthesis of (S)-l- amino-2,3-dihydro-lH-indene-4-carbonitrile using 4-cyano-l-indanone and a- methylbenzylamine derivatives as starting materials.
  • Yet another objective of the present invention is to provide preparation of (S)- l-amino-2,3-dihydro-lH-indene-4-carbonitrile comprising diastereo selective chiral amine preparation by protection with chiral auxiliary a-methyl benzylamine derivatives followed by reduction and debenzylation.
  • the present invention provides a novel process for preparing Ozanimod intermediate of Formula 6
  • R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups.
  • the present invention provides an improved process for preparing compound of Formula 14
  • R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, in the presence of suitable catalyst or water scavenging agent or without catalyst in organic solvents.
  • the present invention provides an improved process for preparing compound of Formula 15
  • R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, using a reducing agent in suitable solvents followed by treatment with organic and inorganic acid.
  • the present invention provides an improved process for preparing compound of Formula 16
  • R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, which comprises treatment of compound of Formula 15
  • R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, with suitable base.
  • the present invention provides an improved process for preparing compound of Formula 6
  • R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, in the presence of suitable catalyst in suitable solvents followed by treatment with organic and inorganic acid.
  • the present invention provides an improved process for the preparation of (S)-l-amino-2,3-dihydro-lH-indene-4-carbonitrile hydrochloride of Formula 6
  • the present invention provides novel intermediates of Formulae 14, 15 and 16.
  • the present invention provides an improved process for the preparation of optically active chiral amine (S)-l-amino-2,3-dihydro-lH-indene-4- carbonitrile, a key intermediate for the drug Ozanimod which is an agonist of the sphingosine- 1 -phosphate receptor.
  • Formula 3 is reacted with Formula 13in the presence of suitable catalyst or water scavenging agent or without catalyst in an organic solvent to form a new compound of Formula 14.
  • Formula 3 is preferably 4-cyano-l-indanone.
  • R in (S)-a-methylbenzylamine derivatives of Formula 13 represents hydrogen, halogen, nitro, alkyl, alkoxy groups.
  • halogen as used herein includes fluorine, chlorine, bromine and iodine.
  • alkyl as used herein includes but not limited to C ⁇ -Ce alkyl such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and allyl.
  • alkoxy as used herein includes but not limited to methoxy, ethoxy, propoxy, butoxy and acetoxy.
  • (S)-a-methylbenzylamine derivatives includes but not limited to (S)-a-methylbenzylamine, (S)-2-methoxy-a-methylbenzylamine, (S)-4- methoxy-a-methylbenzylamine, (S)-2-chloro-a-methyl-benzylamine, (S)-2-bromo-a- methylbenzylamine, (S)-4-chloro-a-methylbenzylamine, (S)-4-bromo-a- methyl benzylamine, (S)-2-nitro-a-methylbenzylamine, (S)-4-nitro-a-methylbenzyl amine, (S)-a,2-dimethylbenzylamine, (S)-a,4-dimethylbenzylamine, (S)-2-nitro-a-methyl- benzylamine, (S)-4-nitro-a-methylbenzylamine and more preferably (S)-4-methoxy- a-methyl-benzylamine
  • catalyst used in reacting Formula 3 with Formula 13 includes but not limited to p-toluenesulfonic acid, acetic acid, hydrochloric acid, sulfuric acid.
  • water scavenger used in reacting Formula 3 with Formula 13 includes but not limited to titanium tetraethoxide, copper sulphate and triisopropyl borate and more preferably without any catalyst or scavenger.
  • solvents used in reacting Formula 3 with Formula 13 includes but not limited to toluene, chloroform, dichloromethane, ethylene dichloride, carbon tetrachloride, methyl tert-butyl ether, heptane, hexane, o-xylene, cyclohexane, methanol, THF, and the like or mixtures thereof and more preferably the solvent is heptane.
  • reaction conditions used for reacting Formula 3 with Formula 13 is the reaction temperature may range from 40 to 145°C and preferable temperature in the range of 100-105°C.
  • reduction of compound of Formula 14 is carried out using suitable reagent in suitable solvents followed by treatment with organic and inorganic acid to obtain compound of Formula 15.
  • reagent used in reducing Formula 14 into Formula 15 includes but not limited to palladium on carbon, Raney nickel, platinum on carbon, palladium hydroxide on carbon, ruthenium on carbon, sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, more preferable palladium on carbon under hydrogen gas.
  • solvent used in reducing Formula 14 into Formula 15 includes but not limited to methanol, ethanol, isopropyl alcohol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane and the like or mixture thereof, more preferably ethyl acetate.
  • hydrogen pressure used is about 1 kg/cm 2 to 15 kg/cm 2 , preferably 5 kg/cm 2 to 6 kg/cm 2 .
  • reaction is carried out at a temperature in the range from about 25 to 100°C more preferably at 40-45°C.
  • acid used for the purification is selected from organic and inorganic acids preferably p- toluenesulfonic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, hydrochloric acid, hydrobromic acid, sulfuric acid and the like or mixture thereof, preferably p-toluenesulfonic acid.
  • the compound of Formula 15 is treated with suitable base to obtain compound of Formula 16.
  • base is selected from but not limited to inorganic or organic base such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine and the like, more preferably sodium hydroxide.
  • debenzylation of compound of Formula 16 is carried out using suitable catalyst in suitable solvents followed by treatment with organic and inorganic acid to obtain (S)-l-amino-2,3-dihydro-lH-indene-4- carbonitrile of Formula 6.
  • catalyst is selected from palladium on carbon and palladium hydroxide on carbon.
  • solvent used is selected from methanol, ethanol, isopropyl alcohol, ethyl acetate, acetic acid, trifluoroacetic acid and the like or mixture thereof, more preferably trifluoroacetic acid without any catalyst.
  • reaction is carried out at a temperature in the range from about 25 to 100°C more preferably at 70-75°C.
  • acid used for the making salt may be organic and inorganic acids selected from para toluenesulfonic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, hydrochloric acid, hydrobromic acid, sulfuric acid trichloroacetic acid ,trifluoroacric acid and the like or mixture thereof preferably trifluoroacetic acid.
  • the compounds of Formula 3, 13, 14, 15, 16 or their salts used in the present invention may be isolated or not. Any of the above reactions may be carried out in- situ reactions to obtain Formula 6 or its pharmaceutically acceptable salts.
  • the present invention provides an improved process for the preparation of Ozanimod compound of Formula 1 using chiral amine of Formula 6 prepared by the process of the present invention.
  • the present invention provides an improved process for preparing (S)-l-amino-
  • R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups.
  • the present invention provides an improved process for preparing compound of Formula 14
  • R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, which comprises reactingcompound of Formula 3
  • R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, in the presence of suitable catalyst or water scavenging agent or without catalyst in organic solvents.
  • the present invention provides an improved process for preparing compound of Formula 15
  • R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, which comprises reduction of compound of Formula 14
  • R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, using a suitable reagent in suitable solvents followed by treatment with organic and inorganic acid.
  • the present invention provides an improved process for preparing compound of Formula 16
  • R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, which comprises treatment of compound of Formula 15.
  • R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, with suitable base.
  • the present invention provides an improved process for preparing compound of Formula 6
  • the present invention provides an improved process for the preparation of (S)-l-amino-2,3-dihydro-lH-indene-4- carbonitrile of Formula 6
  • Example 8 Preparation (S)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl-(4-(5- (3-cyano-4-isopropoxy phenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l- yl)carbamate (12a) and (S)-tert-butyl (4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4- oxadiazol-3-yl)-2,3-dihydro-lH-ind-en-l-yl)carbamate, a compound of Formula 12b:

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

Abstract

La présente invention concerne un procédé amélioré pour la préparation d'un composé amino chiral optiquement actif. La présente invention concerne en particulier un procédé amélioré pour la préparation de (S)-1-amino-2,3-dihydro-1H-indène-4-carbonitrile, un intermédiaire important pour la synthèse d'ozanimod. La présente invention concerne plus particulièrement la préparation de (S)-1-amino-2,3-dihydro-1H-indène-4-carbonitrile à l'aide de 4-cyano-1-indanone et de dérivés d'alpha-méthylbenzylamine en tant que matières premières. La présente invention concerne particulièrement la préparation de (S)-1-amino-2,3-dihydro-1H-indène-4-carbonitrile comprenant une synthèse d'amine chirale diastéréosélective par protection avec des dérivés de -méthyle benzylamine auxiliaires chiraux suivi d'une réduction et d'une débenzylation.
PCT/IB2018/057234 2017-09-20 2018-09-20 Procédé amélioré pour la préparation d'un composé a-amino d'azanimod WO2019058290A1 (fr)

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IN201741033398 2017-09-20
IN201741033398 2017-09-20

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110229067A (zh) * 2019-06-05 2019-09-13 南京焕然生物科技有限公司 一种2-氨基茚制备方法
WO2020064818A1 (fr) * 2018-09-25 2020-04-02 Química Sintética, S.A. Procédé de préparation d'un agoniste du récepteur de la sphingosine-1-phosphate
WO2021084068A1 (fr) 2019-10-31 2021-05-06 Idorsia Pharmaceuticals Ltd Combinaison d'un antagoniste de cxcr7 avec un modulateur du récepteur s1p1
EP4212156A1 (fr) 2022-01-13 2023-07-19 Abivax Combinaison de 8-chloro-n-(4-(trifluorométhoxy)phényl)quinolin-2-amine et de ses dérivés avec un modulateur de récepteur de s1p

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011060392A1 (fr) * 2009-11-13 2011-05-19 Receptos, Inc. Modulateurs sélectifs du récepteur de sphingosine-1-phosphate et procédés de synthèse chirale
WO2015066515A1 (fr) * 2013-11-01 2015-05-07 Receptos, Inc. Modulateurs sélectifs des récepteurs de la sphingosine-1-phosphate et traitement combiné les utilisant
WO2016164180A1 (fr) * 2015-04-06 2016-10-13 Auspex Pharmaceuticals, Inc. Oxadiazoles substitués par du deutérium

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011060392A1 (fr) * 2009-11-13 2011-05-19 Receptos, Inc. Modulateurs sélectifs du récepteur de sphingosine-1-phosphate et procédés de synthèse chirale
WO2015066515A1 (fr) * 2013-11-01 2015-05-07 Receptos, Inc. Modulateurs sélectifs des récepteurs de la sphingosine-1-phosphate et traitement combiné les utilisant
WO2016164180A1 (fr) * 2015-04-06 2016-10-13 Auspex Pharmaceuticals, Inc. Oxadiazoles substitués par du deutérium

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Title
SUSANNE HARTMANNA ET AL.: "EPC syntheses and structure-activity relationships of hypoglycaemic semicyclic amidines", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 35, no. 4, 2000, pages 377392, XP004330422 *
THOMAS C. NUGENT ET AL.: "Asymmetric Reductive Amination: Convenient Access to Enantioenriched Alkyl-Alkyl or Aryl-Alkyl Substituted a-Chiral Primary Amines", ADVANCED SYNTHESIS & CATALYSIS, vol. 348, no. 10-11, 2006, pages 1289 - 1299, XP055584187, ISSN: 1615-4150, DOI: 10.1002/adsc.200606073 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020064818A1 (fr) * 2018-09-25 2020-04-02 Química Sintética, S.A. Procédé de préparation d'un agoniste du récepteur de la sphingosine-1-phosphate
US11465977B2 (en) 2018-09-25 2022-10-11 Química Sintética, S.A. Process for the preparation of sphingosine-1-phosphate receptor agonist
CN110229067A (zh) * 2019-06-05 2019-09-13 南京焕然生物科技有限公司 一种2-氨基茚制备方法
WO2021084068A1 (fr) 2019-10-31 2021-05-06 Idorsia Pharmaceuticals Ltd Combinaison d'un antagoniste de cxcr7 avec un modulateur du récepteur s1p1
EP4212156A1 (fr) 2022-01-13 2023-07-19 Abivax Combinaison de 8-chloro-n-(4-(trifluorométhoxy)phényl)quinolin-2-amine et de ses dérivés avec un modulateur de récepteur de s1p
WO2023135207A1 (fr) 2022-01-13 2023-07-20 Abivax Combinaison de 8-chloro-n-(4-(trifluorométhoxy)phényl)quinolin-2-amine et de ses dérivés avec un modulateur du récepteur s1p

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