WO2019058290A1 - Improved process for the preparation of ozanimod α-amino compound - Google Patents

Improved process for the preparation of ozanimod α-amino compound Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
nitro
methylbenzylamine
hydrogen
Prior art date
Application number
PCT/IB2018/057234
Other languages
French (fr)
Inventor
Rajendiran Chinnapillai
Nagarajan Periyandi
Venkateswaralu Jasti
Original Assignee
Suven Life Sciences Limited
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 Suven Life Sciences Limited filed Critical Suven Life Sciences Limited
Publication of WO2019058290A1 publication Critical patent/WO2019058290A1/en

Links

Classifications

    • 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:

Landscapes

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

Abstract

The present invention relates to an improved process for the preparation of optically chiral amino compound. The present invention particularly relates to the improved process for the preparation of (S)-1-amino-2,3-dihydro-1H-indene-4-carbonitrile, an important intermediate for the synthesis of ozanimod. The present invention more particularly relates to preparation of (S)-1-amino-2,3-dihydro-1H-indene-4- carbonitrile using 4-cyano-1-indanone and α-methylbenzylamine derivatives as starting materials. The present invention specifically relates to preparation of (S)-1- amino-2,3-dihydro-1H-indene-4-carbonitrile comprising diastereoselective chiral amine synthesis by protection with chiral auxiliary -methyl benzylamine derivatives followed by reduction and debenzylation.

Description

IMPROVED PROCESS FOR THE PREPARATION OF OZANIMOD a-
AMINO COMPOUND
FIELD OF THE INVENTION
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-
2,3-dihydro-lH-indene-4-carbonitrile using 4-cyano-l-indanone and a-methylbenzyl- amine derivatives as starting materials.
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.
BACKGROUND OF THE INVENTION
Ozanimod (RPC-1063) 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 C23H24N4O3, the molecular weight is 404.47 g/mol and the structural formula is:
Figure imgf000003_0001
Formula 1
US 4,000,197 A discloses a process for the preparation of [R,R]-(+) or [S,S]-(-) Substituted N-(a-phenethyl)phenylisopropylamine hydrochloride, which is shown in the scheme given below:
Ar-CH2CHCH3 +
Figure imgf000003_0002
[R,R]-(+) or [S,S]-
H?
Ar-CH2CHNH2 -HCI CH3
R-(-) or S-(+)
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:
Figure imgf000003_0003
.HCI
This patent also discloses preparation of (R)-(-)-5-(2-aminopropyl)-2-methoxy benzenesulfonamide hydrochloride, which is shown as given below:
Figure imgf000004_0001
US 5,932,749 A discloses the preparation of (R)-l-(benzo[d][l,3]dioxol-6- yl)butan-l -amine, which is shown as given below:
Figure imgf000004_0002
(R)-1 -(benzo[c ][1 ,3]dioxol-6-yl)butan-1 -amine
WO 2003/022785 A2 discloses asymmetric synthesis of (R)-(-)-8-Amino- 5,6,7,8-tetrahydroquinone, which is shown as given below:
Figure imgf000005_0001
NaBH4,EtOH, 0°C
93%
Figure imgf000005_0002
98% ee
WO 2006/030017 Al discloses synthesis of (2R)-4-phenyl-N-(R)-l -phenyl ethyl)butan-2-amine, which is shown as given below:
Figure imgf000005_0003
This application also discloses synthesis of (2R)-N-(R)-l-phenylethyl)octan-2-amine, which is shown as given below:
Figure imgf000005_0004
2-octanone Ra-Ni/H2, 120 psi R,R S,R
room temperature (major)
This application also discloses the synthesis of (lR)-2,2-dimethyl-N-(R)-l-p ethyl)cyclopentanamine, which is shown as given below:
Figure imgf000005_0005
(major) Nature Protocols, 2(11), 2759-2765, 2007 discloses the preparation of (R,R)- bis(a-phenyleth l)amine, which is shown as given below:
Figure imgf000006_0001
ou ene ( E,R)-i
1 . H2, Pd/C 10%
65psi, EtOAc
2. HCI
3. NaOH
Figure imgf000006_0002
(R,R)-2
US 8,309,724 B2 discloses a process for preparing Sitagliptin, which is shown as given below:
Figure imgf000006_0003
WO 2013/126360 A2 discloses process for preparing aminosulfones, which is shown as given below:
Figure imgf000007_0001
In US 9,382,217 and WO 2016/164180 described the process for the preparation of Ozanimod from 4-bromo-2,3-dihydro- lH-inden-l-one (2), which is shown as iven below:
Figure imgf000007_0002
In view of the importance acquired by Ozanimod intermediate, there is a great need for developing an alternate process for synthesizing Ozanimod intermediate. All the prior art references shows the reactions of aliphatic ketones, cyclic ketones with a-methylbenzylamine derivatives. None of the prior art references discloses the reactions between 4-cyano-l-indanone and a-methylbenzylamine derivatives.
It is therefore an object of the present invention to provide an improved process for the preparation of optically active chiral amine (S)-l-amino-2,3-dihydro-lH- indene-4-carbonitrile, an Ozanimod intermediate using 4-cyano-l-indanone and a- methylbenzylamine derivatives as starting materials.
OBJECTIVE OF INVENTION
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.
SUMMARY OF INVENTION
Accordingly, the present invention provides a novel process for preparing Ozanimod intermediate of Formula 6
Figure imgf000008_0001
Formula 6
which comprises reacting compound of Formula 3
Figure imgf000009_0001
Formula 3
with compound of Formula 13
Figure imgf000009_0002
Formula 13
wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups.
In a preferred aspect, the present invention provides an improved process for preparing compound of Formula 14
Figure imgf000009_0003
Formula 14
which comprises reacting compound of Formula 3
Figure imgf000009_0004
Formula 3
with compound of Formula 13
Figure imgf000009_0005
Formula 13
wherein 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.
In a preferred aspect, the present invention provides an improved process for preparing compound of Formula 15
Figure imgf000009_0006
Formula 15 which comprises reduction of compound of Formula 14
Figure imgf000010_0001
Formula 14
wherein 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.
In a preferred aspect, the present invention provides an improved process for preparing compound of Formula 16
Figure imgf000010_0002
rmula 16
wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, which comprises treatment of compound of Formula 15
Figure imgf000010_0003
Formula 15
wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, with suitable base.
In another preferred aspect, the present invention provides an improved process for preparing compound of Formula 6
Figure imgf000010_0004
Formula 6
which comprises debenzylation of Formula 16
Figure imgf000011_0001
rmula 16
wherein 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.
In another preferred aspect, 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
Figure imgf000011_0002
2 Formula 6
a) reacting compound of 4-cyano-l-indanone of Formula 3 with (S)-a- methylbenzylamine of Formula 13 using suitable catalyst or water scavenging agent or without catalyst in an organic solvent to form a new compound of Formula 14,
Figure imgf000011_0003
b) reducing compound of Formula 14 using suitable reagent in suitable solvents followed by treatment with organic and inorganic acid to obtain compound of Formula 15,
Figure imgf000011_0004
Formula 15
c) treating compound of Formula 15 with suitable base to obtain compound of Formula 16,
Figure imgf000012_0001
rmula 16
d) debenzylating of compound of Formula 16 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 hydrochloride of Formula 6,
Figure imgf000012_0002
Formula 6
e) converting compound of Formula 6 to Ozanimod.
In another preferred aspect, the present invention provides novel intermediates of Formulae 14, 15 and 16.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, 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.
In one embodiment, 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.
In one embodiment, Formula 3 is preferably 4-cyano-l-indanone.
In one embodiment, R in (S)-a-methylbenzylamine derivatives of Formula 13 represents hydrogen, halogen, nitro, alkyl, alkoxy groups.
The term halogen as used herein includes fluorine, chlorine, bromine and iodine.
The term 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. The term alkoxy as used herein includes but not limited to methoxy, ethoxy, propoxy, butoxy and acetoxy.
In one embodiment, (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.
In one embodiment, catalyst used in reacting Formula 3 with Formula 13 includes but not limited to p-toluenesulfonic acid, acetic acid, hydrochloric acid, sulfuric acid.
In one embodiment, 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.
In another embodiment, 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.
In another embodiment, 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.
In yet another preferred embodiment, 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.
In one embodiment, 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.
In one embodiment, 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.
In one embodiment, hydrogen pressure used is about 1 kg/cm2to 15 kg/cm2, preferably 5 kg/cm2 to 6 kg/cm2.
In another embodiment, reaction is carried out at a temperature in the range from about 25 to 100°C more preferably at 40-45°C.
In another embodiment, 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.
Yet another embodiment, the compound of Formula 15 is treated with suitable base to obtain compound of Formula 16.
In one embodiment, 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.
In yet another preferred embodiment, 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.
In one embodiment, catalyst is selected from palladium on carbon and palladium hydroxide on carbon.
In one embodiment, 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. In one embodiment, reaction is carried out at a temperature in the range from about 25 to 100°C more preferably at 70-75°C.
In one embodiment, 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.
In another preferred embodiment, 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.
In another embodiment, 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-
2,3-dihydro-lH-indene-4-carbonitrile of Formula 6, an important intermediate for the synthesis of Ozanimod.
Figure imgf000015_0001
2 Formula 6
which comprises reacting compound of Formula 3
Formula 3
with compound of Formula 13
Figure imgf000015_0002
Formula 13
wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups. In a preferred embodiment, the present invention provides an improved process for preparing compound of Formula 14
Figure imgf000016_0001
Formula 14
wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, which comprises reactingcompound of Formula 3
Figure imgf000016_0002
Formula 3
with compound of Formula 13
Figure imgf000016_0003
i Formula 13
wherein 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.
In yet another preferred embodiment, the present invention provides an improved process for preparing compound of Formula 15
Figure imgf000016_0004
Formula 15
wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, which comprises reduction of compound of Formula 14
Figure imgf000016_0005
Formula 14 wherein 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.
In another preferred embodiment, the present invention provides an improved process for preparing compound of Formula 16
Figure imgf000017_0001
ormula 16
wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, which comprises treatment of compound of Formula 15.
Figure imgf000017_0002
Formula 15
wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, with suitable base.
In another preferred embodiment, the present invention provides an improved process for preparing compound of Formula 6
Figure imgf000017_0003
2 Formula 6
which comprises debenzylation of Formula 16
Figure imgf000017_0004
ormula 16
wherein 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. In yet another preferred embodiment, the present invention provides an improved process for the preparation of (S)-l-amino-2,3-dihydro-lH-indene-4- carbonitrile of Formula 6
Figure imgf000018_0001
a) reacting compound of 4-cyano-l-indanone of Formula 3 with (S)-a- methyl benzylamine of Formula 13 using of suitable catalyst or water scavenging agent or without catalyst in an organic solvent to form a new compound of Formula 14,
Figure imgf000018_0002
Formula 13 Formula 14
b) reducing compound of Formula 14 using suitable reagent in suitable solvents followed by treatment with organic and inorganic acid to obtain compound of Formula 15,
Figure imgf000018_0003
Formula 15
c) treating compound of Formula 15 with suitable base to obtain compound of Formula 16,
Figure imgf000018_0004
ormula 16
d) debenzylating of compound of Formula 16 using suitable acid 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,
Figure imgf000019_0001
2 Formula 6
e) converting compound of Formula 6 to Ozanimod.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. EXAMPLES
Example 1: Preparation of l-{[(lS)-l-(4-methoxyphenyl)ethyl]imino}-2,3 dihydro-lH-indene-4-carbonitrile, a compound of Formula 14:
To the stirred mixture of 50.0 gm of 4-cyano-l-indanone (Formula 3) (0.318 moles) and 500 ml of heptane, 60 gm of (S)-(-)-l-(4-methoxyphenyl)ethylamine (Formulal3) (0.398 moles, 1.25eq.) was added at ambient temperature. The resulting mixture was heated to 100-105°C and water was removed azeotropically. After 15.0 hrs, the reaction mass was cooled to 25-30°C and stirred for 1.0 hr. The product was filtered, washed with heptane and dried to obtain a light brown solid of compound of Formulal4(84.0 g, 90.93% yield) with HPLC purity 94.35% & SOR -72° (c=0.1 in CHC13 at 20°C).
MR: 130.4-132.1°C; IR (KBr, cm"1): 2226, 1661, 1611, 1513, 1245, 1030; 1H- NMR(CDC13): δ 8.11-8.09 (d, 1H, J=7.74Hz), 7.66-7.64 (d, 1H, J=7.47Hz),7.41-7.89 (m, 3H), 6.89-6.87 (d, 2H, J=8.50Hz), 4.66-4.61 (q, 1H, J=6.46, 12.96 Hz), 3.79 (s, 3H), 3.26-3.21 (m, 2H), 2.90-2.88 (m, 1H), 2.78-2.73 (m, 1H), 1.56-1.55 (d, 3H, J=6.49Hz);13C-NMR(CDCl3): 169.99, 158.48, 152.56, 141.66, 137.59, 134.28, 127.72, 127.66 (2C),127.15,117.12, 113.87(2C), 109.93, 61.56, 55.32, 27.85, 27.67, 24.77;MS (m/z): 291.1 [M+l]+. Example 2: Preparation of (lS)-l-{[(lS)-l-(4-methoxyphenyl)ethyl]amino}-2,3- dihydro-lH-indene-4-carbonitrile p-toluenesulfonic acid salt, a compound of Formula 15:
To the stirred mixture 80.0 gm of Imine (0.2756 moles) (Formula 14)and 1040 ml of ethyl acetate in autoclave vessel, 8.0 gm of 10% Pd/C (-50% wet)was added at ambient temperature. The autoclave was evacuated with nitrogen gas and 5.0 kg of hydrogen Gas was applied. The reaction mass was heated to 40-45°C and maintained for 8-10hrs. After completion, the reaction mass was cooled to 25-30°C and filtered to remove the Pd/C through celite. 46.0 gm of p-toluenesulfonic acid monohydrate was added to the filtrate at 25-30°C and stirred for 2.0hrs. The product was filtered, washed with ethyl acetate and dried to obtain a light brown solid of compound of Formula 15 (99.0 g, 77.34% yield) with HPLC purity 99.66%, Chiral HPLC Purity (SS) 99.67% & (RS) 0.13% & SOR -71° (c=0.1 in MeOH at 25°C).
MR: 190.4-192.1°C; IR (KBr, cm-1): 3077, 2227, 1611, 1514, 1249, 1227, 1171; 1H-NMR (DMSO-d6): δ 9.20-9.08 (brd, 2H), 7.95-7.93 (d, 1H, J=7.76Hz),7.85- 7.83 (d,lH, J=7.65Hz), 7.56-7.53 (d, 1H, J=8.56Hz), 7.52-7.47 (m, 3H),7.14-7.12 (d, 2H, J=7.87Hz), 7.03-7.01 (d, 2H, J=8.56Hz), 4.81(br, 1H), 4.57-4.55 (m, 1H), 3.78 (s, 3H), 3.26-3.18 (m, 1Η),3.05-2.97 (m, 1H), 2.46-2.36 (m, 1H), 2.30 (s, 3H), 2.24-2.18 (m,lH), 1.62-1.61 (d, 3H, J=6.65Hz); 13C-NMR(CDC13): 160.16, 149.25, 145.90, 139.75, 138.27, 133.42, 131.33, 129.80 (2C), 129.48, 128.59 (2C), 128.37, 125.94 (2C), 117.64, 114.78 (2C), 108.78, 60.23, 56.02, 55.73, 30.04, 28.73, 21.25, 19.57; MS (m/z): 293.1 [M+l]+.
Example 3: Preparation of (lS)-l-{[(lS)-l-(4-methoxyphenyl)ethyl]amino}-2,3- dihydro-lH-indene-4-carbo-nitrile, a compound of Formula 16:
To the stirred mixture 90.0 gm of amine PTSA salt (0.1937 moles) (Formula 15) and 450 ml of water was added 50% sodium hydroxide solution to get pH~l 1. The product was extracted with ethyl acetate. The organic layers was combined, washed with brine solution and concentrated to obtain a light brown liquid on standing become solid of compound of Formula 16 (55.8 gm, 98.51% yield) with HPLC Purity 98.60%, Chiral HPLC Purity (SS)100.0% & SOR -123° (c=0.1 in MeOH at 25°C).
IR (KBr, cm"1): 2962, 2227, 1610, 1511, 1465, 1451, 1244; 1H NMR(CDC13): δ 7.58-7.56 (d, 1H, J=7.52Hz), 7.47-7.45 (d, 1H, J=7.64Hz),7.32-7.30 (d,lH, J=8.40Hz), 7.28-7.25 (m, 1H), 6.90-6.88 (d, 2H, J=8.52Hz), 4.19-4.16(t, 1H, J=6.70Hz), 4.01-3.97 (q, 1H, J=6.48, 12.92Hz), 3.80 (s, 3H), 3.16-3.09 (m, 1H), 2.92- 2.83 (m, 1H), 2.35-2.26 (m, 1H), 1.79-1.70 (m, 1H), 1.37-1.35 (d, 3H,J=6.48Hz); 13C- NMR(CDC13): 158.71, 147.84, 147.70, 138.02, 130.77, 128.74, 127.72 (2C), 127.02, 117.87,113.94 (2C), 108.96, 60.95, 55.92, 55.31, 34.65, 29.94, 24.49; MS (m/z): 293.1 [M+l]+.
Example 4:Preparation of (S)-l-amino-2,3-dihydro-lH-indene-4-carbonitrile hydrochloride, a compound of Formula 6:
48.0 gm of amine (Formula 16) was added to 288.0 of trifluoroacetic acid at ambient temperature and heated the reaction mass to 70-75°C. The reaction mass was refluxed for 16.0 hr. After completion, TFA was distilled out under vacuum at 40- 50°C and cooled to 25-30°C. The residue was diluted with water and washed with toluene. The aqueous layer was basified with sodium hydroxide solution and the product was extracted with ethyl acetate. The organic layer was washed with brine and concentrated under vacuum at 40-45°C to get crude amine. The amine was diluted with 240ml of ethyl acetate and stirred. 48 ml of IPA-HCl (-13%) was added and stirred for l.Ohr. The product was filtered, washed with ethyl acetate and dried to obtain off-white solid of compound of Formula 6 (26.0 gm, 81.35% yield) with HPLC Purity 98.27%, Chiral HPLC Purity (S) 100.0% & SOR -45° (c=l in Methanol at 25°C).
MR: Not melted up to 270°C; IR (KBr, cm-1): 2229, 1497, 1370, 1127; 1H- NMR (DMSO-d6): δ 8.91 (br, 3H), 8.07-8.05 (d, 1H, J=7.68Hz), 7.81-7.79 (d, 1H, J=7.63Hz), 7.51-7.47 (t, 1H, J=7.71Hz), 4.80-4.77 (t, 1H, J=6.27Hz), 3.24-3.20 (m, 1H), 3.07-3.01 (m, 1H), 2.56-2.53 (m, 1H), 2.16-2.12(m, 1H); 13C-NMR (DMSO- d6): 148.59, 141.64, 132.96, 130.86, 128.36, 117.77, 108.53, 54.87, 39.96, 30.14; MS (m/z): 159.0 [M+l]+, 142.0 [M-NH2].
Example 5: Preparation of (S)-tert-butyl 4-cyano-2,3-dihydro-lH-inden-l- ylcarbamate, a compound of Formula 7:
To a stirred solution of 30.0 gm of amine.HCl (Formula 6) (0.154 moles) and 300.0 of dichloromethane, 31.2 gm of triethyl amine (0.308 moles, 2.0 eq.)was added at 5-15°C. 43.47 gm of Boc anhydride (85%) (0.169 moles, 1.1 eq.) was added and warmed to ambient temperature. The reaction mass was stirred for 2.0hrs. After completion, the reaction mass was washed with water and brine solution. The organic layer was concentrated, cooled and stirred with hexane. The product was filtered, washed with hexane and dried to obtain off-white solid of Formula 7(36.9 gm, 92.71% yield) with HPLC Purity 96.93% & SOR -122° (c=l in CHC13 at 25°C).
MR: 129.7-132.1°C; IR (KBr, cm"1): 3364, 2979, 2225, 1677, 1514, 1169; 1H- NMR(CDC13): δ 7.56-7.50 (m, 2H), 7.33-7.29 (t, 1H, J=7.64Hz), 5.25-5.23 (m, 1H), 4.76-4.74 (d, 1H, J=6.24Hz) , 3.20-3.14 (m, 1H), 2.99 (m, 1H), 2.68-2.64 (m, 1H), 1.89-1.83 (m, 1H), 1.49 (s, 9H); 13C-NMR(CDC13): 155.55, 147.03, 145.44, 131.34, 128.72, 127.56, 117.50, 109.01, 79.84, 55.79, 33.51, 29.62, 28.37(3C); MS (m/z): 259.0 [M+l]+, 203.1 [M-C(CH3)3] +.
Example 6: Preparation of (S)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl-(4- cyano-2,3-dihydro-lH-inden-l-ylcarbamate, a compound of Formula 9:
To a stirred solution of 20.0 gm of Formula 7 (0.0774 moles) and 200.0 of DMF under nitrogen atmosphere at 0-10°C,11.6 gm of sodium hydride (60%) (0.232 moles, 3.0eq.)was added at below 10°C. The reaction mixture was stirred for 2.0 hrs at 0-10°C. 37.0 gm of (2-bromoethoxy)-tert-butyldimethylsilane (Formula 8) (0.155 moles, 2.0eq.) was added and stirred for 8.0 hrs at 0-10°C. After completion, the reaction was quenched by the addition of saturated NaHCO3 and the product was extracted with ethyl acetate. The organic layer was concentrated and purify through column chromatography by using ethyl acetate/hexane to obtain a light brown liquid of Formula 9 (24.2 gm, 75.01% yield) with HPLC Purity 99.95% & SOR -80.0° (c=0.1 in CHC13 at 25°C).
IR (Neat, cm-1): 2955, 2930, 2229, 1695, 1454, 1404, 1253, 1155, 1102, 837, 778; 1H-NMR(CDC13): δ 7.50-7.48 (d, 1H, J=7.53Hz), 7.41-7.34 (m, 1H), 7.29-7.25 (m, 1H), 5.72 (brs, 0.5H), 5.23 (brs, 0.5H) 3.81-3.44 (m, 3H), 3.24-3.18 (m, 2H), 3.01- 2.92 (m, 1.5H), 2.48 (brs, 1H), 2.35-2.19 (m, 1H), 1.50 (brs, 4.5Hz), 1.23 (brs, 4.5Hz), 0.85 (s, 9H), 0.03-0.01 (d, 6H); 13C-NMR(CDC13): 155.86, 155.06, 147.23, 146.57, 145.51, 144.33, 131.18, 130.78, 128.40, 128.15, 127.24, 127.08, 117.59, 109.25, 108.97, 80.17, 79.90, 63.99, 61.91, 61.48, 60.36, 49.79, 46.82, 30.31, 29.73, 28.46, 28.15, 25.90, 18.28, 14.19, -5.36; MS (m/z): 417.3 [M+l]+, 361.1 [M-C(CH3)3] + , 317.2 [M-Boc] +.
Example 7: Preparation of (S)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl-(4- (N-hydroxy carbamimidoyl)-2,3-dihydro-lH-inden-l-ylcarbamate, a compound of Formula 10:
To a solution of 20.0 gm of Formula 9 (0.048 moles) and 200.0 of ethanol at ambient temperature, 10.0 gm of hydroxylamine hydrochloride (0.144 moles, 3.0eq.) and 14.6 gm of triethylamine (0.144 moles, 3.0eq.)was added. The reaction mass was heated to 80-85°C and stirred for 2.0hrs. After completion, the reaction mass was concentrated and diluted with dichloromethane. The organic layer was washed with water and brine. The organic layer was concentrated to obtain a brown liquid of compound of Formula 10 (21.5 gm, 99.63% yield) with SOR -45.0° (c=l in CHC13 at 25°C).
IR (KBr, cm"1): 2930, 1679, 758; 1H-NMR(CDC13): δ 7.40-7.38 (d, 1H, J=7.48Hz), 7.31-7.16 (m, 2H), 5.76 (brs, 0.5H), 5.35(brs, 0.5H), 4.88 (s, 2H), 3.80- 3.38 (m, 2H), 3.27-3.17 (m, 2H), 2.98-2.90 (m, 2H), 2.39-2.04 (m, 2H), 1.53 (brs, 4.5Hz), 1.33 (brs, 4.5H), 0.91 (brs,9H), 0.04-0.01 (brd, 6H);13C-NMR(CDC13): 156.26, 155.65, 144.69, 143.72, 141.81, 141.21, 129.49, 126.88, 126.52, 126.17, 125.18, 124.88, 79.96, 79.73, 63.27, 61.92, 61.62, 61.13, 48.36, 46.06, 36.69, 30.79, 30.29, 28.57, 28.31, 25.98, 24.72, 18.34, 1.05, -5.31; MS (m/z): 450.2 [M+l]+, 350.2 [M-Boc]. 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:
To a solution of 9.6 gm of 3-cyano-4-(propan-2-yloxy)benzoic acid (Formula 11) (0.0467 moles) in 210.0ml of DMF,9.08 gm of Ι, Ι'-carbonyldiimidazole (0.056 moles, 1.2eq.) was added at ambient temperature. After 2.0hrs stirring, 21.0 gm of compound of Formula 10(0.0467 moles, l.Oeq.) was added and the reaction was stirred for 4.0 hrs. TLC showed the complete conversion of compound of Formula 11 to the intermediate. The reaction mass was heated gradually to 90-95°C and stirred for lO.Ohrs. After complete cyclization, the reaction mass was concentrated and diluted with dichloromethane. The organic layer was washed with water and brine. The layer was concentrated to obtain brown liquid of Formulas 12a&12b (27.1 gm).
Example 9: Preparation of Ozanimod or (S)-5-(3-(2-(2-hydroxyethylamino)-2,3- dihydro-lH-inden-4-yl)-l,2,4-oxadiazol-5-yl)-2-isopropxybenzonitrile, a compound of Formula 1:
To a solution of 27.0 gm of compound of Formulas 12a & 12b and 130 ml of dioxane, 130 ml of dioxane-HCl (4N) was added at ambient temperature and stirred for 3.0 hrs. After completion, the product was diluted with 130 ml of ether and stirred. The product was filtered, washed with ether and dried to obtain 11.4 gm of crude hydrochloride salt. The crude hydrochloride salt was recrystallized from methanol to obtain hydrochloride salt of Formula 1(11.2 gm, 52.91% (Overall from 9) with HPLC Purity 99.75% , Chiral HPLC Purity (S) 100% & SOR -30.0°(c=0.1 in MeOH at 25°C).
MR: 236.4-240.3°C; IR (KBr, cm"1): 3265, 2947, 2733, 2229, 1620, 1286; 1H- NMR(DMSO-d6): δ 9.29 (brs, 2H), 8.53-8.52 (d, 1H, J=1.86Hz), 8.43-8.40 (dd, 1H, J=8.9, 2.0Hz), 8.17-8.16 (d, 1H, J=7.67Hz), 7.99-7.97 (d, 1H, J=7.61Hz), 7.59-7.56 (m, 2H), 5.30-5.28 (t, 1H, J=5.0Hz), 5.00-4.97 (m, 1H), 4.91 (brs, 1H), 3.74-3.70 (q, 2H, J=5.0Hz), 3.49-3.37 (m, 1H), 3.31-3.25 (m, 1H), 3.06-3.00 (m, 2H), 2.55-2.53(m, 1H), 2.33-2.30 (m, 1H), 1.39-1.38 (d, 6H, J=6.0Hz); 13C-NMR(CDC13): 173.73, 168.42, 163.01, 145.07, 139.75, 135.05, 134.26, 129.78, 129.61, 127.93, 23.31, 116.33, 115.71, 115.38, 102.94, 73.03, 61.56, 57.09, 47.04, 32.17, 28.22, 21.95 (2C); MS (m/z): 405.2 [M+l]+.
To a slurry solution of 2.0 gm of Formula 1 hydrochloride salt and 20 ml of water, 4M sodium hydroxide solution was added to get pH~8-9. The product was extracted with dichloromethane. The organic layer was washed with water and concentrated. The product was isolated in heptane and dried to obtain off-white solid of Formula 1 (1.8 gm, 98.36% yield) with HPLC Purity 99.85%, Chiral HPLC Purity (S) 100% & SOR -31.0° (c=0.1 in MeOH at 25°C)
MR: 134.2-135.9°C; IR (KBr, cm-1): 3291, 2926, 2230, 1616, 1284, 1101, 1045, 763; 1H-NMR(DMSO-d6): δ 8.51-8.50 (d, 1H, J=2.0Hz), 8.42-8.39 (dd, 1H, J=8.9, 2.0Hz), 7.99-7.97 (d, 1H, J=7.6Hz), 7.57-7.54 (m, 1H), 7.44-7.40 (t, 1H, J=7.6Hz), 5.00-4.95 (m, 1H), 4.51-4.49 (t, 1H, J=5.3Hz, D2O exchangeable), 4.25- 4.22 (t, 1H, J=6.6Hz), 3.52-3.47 (q, 2H, J=5.6Hz), 3.32-3.29 (m,lH), 3.09-3.05 (m, 1H), 2.70-2.66 (m, 2H), 2.39-2.35 (m, 1H), 1.85-1.81 (m, 1H), 1.40-1.38 (d, 6H, J=6.0Hz);13C-NMR(CDCl3): 173.44, 168.81, 162.90, 147.94, 143.45, 134.45, 134.15, 127.67 (2C), 127.78, 116.45, 115.72, 115.28, 102.89, 72.98, 62.86, 61.36, 49.59, 33.10, 31.90, 21.94 (2C); MS (m/z): 405.1 [M+l]+.

Claims

We Claims:
1. An improved process for preparing Ozanimod intermediate of Formula 6
Figure imgf000026_0001
2 Formula 6
which comprises reacting compound of Formula 3
Figure imgf000026_0002
Formula 3
with compound of Formula 13
Figure imgf000026_0003
Formula 13
wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups.
The process for preparation of com ound of Formula 6 as claimed in claim 1,
Figure imgf000026_0004
2 Formula 6
wherein the process comprising:
a) reacting compound of 4-cyano-l-indanone of Formula 3 with (S)-a- methylbenzylamine of Formula 13 using suitable catalyst or water scavenging agent or without catalyst in an organic solvent to form a new compound of Formula 14,
Figure imgf000026_0005
b) reducing compound of Formula 14 using suitable reagent in suitable solvents followed by treatment with organic and inorganic acid to obtain compound of Formula 15,
Figure imgf000027_0001
Formula 15
c) treating compound of Formula 15 with suitable base to obtain compound of Formula 16, and
Figure imgf000027_0002
ormula 16
d) debenzylating of compound of Formula 16 using suitable catalyst in suitable solvents followed by treatment with organic and inorganic acid to obtain (S)- 1 -amino-2,
3-dihydro- lH-indene-4-carbonitrile hydrochloride of Formula 6.
Figure imgf000027_0003
2 Formula 6
The process for preparing compound of Formula 14 as claimed in claim 2,
Figure imgf000027_0004
Formula 14
wherein the process comprises reactin compound of Formula 3
Figure imgf000027_0005
Formula 3
with compound of Formula 13
Figure imgf000027_0006
Formula 13 wherein 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.
4. Theprocess for preparing compound of Formula 15 as claimed in claim 2,
Figure imgf000028_0001
Formula 15
wherein the process comprises reduction of compound of Formula 14
Figure imgf000028_0002
Formula 14
wherein 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.
5. The process for preparing compound of Formula 16 as claimed in claim 2,
Figure imgf000028_0003
rmula 16
wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, comprises treatment of compound of Formula 15
Figure imgf000028_0004
Formula 15
wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, with suitable base.
6. The process for preparing compound of Formula 6 as claimed in claim 2,
Figure imgf000029_0001
comprises debenzylation of Formula 16
Figure imgf000029_0002
rmula 16
wherein 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 process for preparing compound of Formula 6 as claimed in claim 1, claim 2 and claim 6, further convertin into Ozanimodcompound of Formula 1.
Figure imgf000029_0003
Formula 1
The process as claimed in claim 2, wherein the (S)-a-methylbenzylamine derivatives are selected from (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 .
The process as claimed in claim 2 and claim 3, wherein the water scavenger is selected from titanium tetraethoxide, copper sulphate and triisopropyl borate and more preferably without any catalyst or scavenger.
The process as claimed in claim 2-3, wherein the catalyst used as herein selected from palladium on carbon and palladium hydroxide on carbon.
11. The process as claimed in claim 5, wherein the base used as herein 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.
12. The process as claimed claim 2-4 and claim 6, wherein the solvent used as herein is selected from 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.
13. The process as claimed in Claim 2 and claim 4, the reducing agents used as herein 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 triacetoxyborohydride, more preferable palladium on carbon under hydrogen gas.
14. Novel intermediates of Formula 14, 15 and 16.
ormula 14
Formula 15
Figure imgf000030_0001
rmula 16
wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups
PCT/IB2018/057234 2017-09-20 2018-09-20 Improved process for the preparation of ozanimod α-amino compound WO2019058290A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201741033398 2017-09-20
IN201741033398 2017-09-20

Publications (1)

Publication Number Publication Date
WO2019058290A1 true WO2019058290A1 (en) 2019-03-28

Family

ID=65810114

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2018/057234 WO2019058290A1 (en) 2017-09-20 2018-09-20 Improved process for the preparation of ozanimod α-amino compound

Country Status (1)

Country Link
WO (1) WO2019058290A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110229067A (en) * 2019-06-05 2019-09-13 南京焕然生物科技有限公司 A kind of 2- amino indenes preparation method
WO2020064818A1 (en) * 2018-09-25 2020-04-02 Química Sintética, S.A. Process for the preparation of sphingosine-1-phosphate receptor agonist
WO2021084068A1 (en) 2019-10-31 2021-05-06 Idorsia Pharmaceuticals Ltd Combination of a cxcr7 antagonist with an s1p1 receptor modulator
EP4212156A1 (en) 2022-01-13 2023-07-19 Abivax Combination of 8-chloro-n-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and its derivatives with a s1p receptor modulator

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011060392A1 (en) * 2009-11-13 2011-05-19 Receptos, Inc. Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis
WO2015066515A1 (en) * 2013-11-01 2015-05-07 Receptos, Inc. Selective sphingosine 1 phosphate receptor modulators and combination therapy therewith
WO2016164180A1 (en) * 2015-04-06 2016-10-13 Auspex Pharmaceuticals, Inc. Deuterium-substituted oxadiazoles

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011060392A1 (en) * 2009-11-13 2011-05-19 Receptos, Inc. Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis
WO2015066515A1 (en) * 2013-11-01 2015-05-07 Receptos, Inc. Selective sphingosine 1 phosphate receptor modulators and combination therapy therewith
WO2016164180A1 (en) * 2015-04-06 2016-10-13 Auspex Pharmaceuticals, Inc. Deuterium-substituted oxadiazoles

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
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 (en) * 2018-09-25 2020-04-02 Química Sintética, S.A. Process for the preparation of sphingosine-1-phosphate receptor agonist
US11465977B2 (en) 2018-09-25 2022-10-11 Química Sintética, S.A. Process for the preparation of sphingosine-1-phosphate receptor agonist
CN110229067A (en) * 2019-06-05 2019-09-13 南京焕然生物科技有限公司 A kind of 2- amino indenes preparation method
WO2021084068A1 (en) 2019-10-31 2021-05-06 Idorsia Pharmaceuticals Ltd Combination of a cxcr7 antagonist with an s1p1 receptor modulator
EP4212156A1 (en) 2022-01-13 2023-07-19 Abivax Combination of 8-chloro-n-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and its derivatives with a s1p receptor modulator
WO2023135207A1 (en) 2022-01-13 2023-07-20 Abivax Combination of 8-chloro-n-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and its derivatives with a s1p receptor modulator

Similar Documents

Publication Publication Date Title
WO2019058290A1 (en) Improved process for the preparation of ozanimod α-amino compound
WO2005095343A1 (en) Dpp-iv inhibitors
JP2006523700A (en) Methods and intermediates for the preparation of pyrrolidinecarboxylic acids
JP2011520966A (en) Methods for the preparation of orexin receptor antagonists
WO2015131773A1 (en) Piperidine derivatives as orexin receptor antagonist
CN105801572A (en) Preparation method of rivaroxaban
OA10863A (en) 3-Azetidinylalkylpiperidines or-pyrrolidines as tachykinin antagonists
Nammalwar et al. Efficient syntheses of substituted (±)-3-oxoisoindoline-1-carbonitriles and carboxamides using OSU-6
FI120259B (en) A process for preparing the epoxide
ZA200408193B (en) Process for 5-ÄÄ2(R)-Ä3,5-bis(trifluoromethyl)phenylÜethoxyÜ-3(S)-(4-fluorophenyl)-4-morpholinylÜmethylÜ-1,2-dihydro-3H-1,2,4-triazol-3-one
WO2006036498A2 (en) A process for the preparation of 1,3,5-trisubstituted pyrazoles via [3+2] cycloaddition
US10053460B2 (en) Process for the preparation of tert-butyl 4-((2S ,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate and analogs thereof
WO2008000818A1 (en) Fluorinated indoleamides useful as ligands of the orl-1 receptor
JPWO2006123767A1 (en) Preparation of asymmetric tetrasubstituted carbon atom-containing compounds
US8703939B2 (en) Method for preparing (R)-3-(3-fluoro-4-(1-methyl-5,6-dihydro-1,2,4-triazin-4(1H)-yl)phenyl)-5-(substituted methyl)oxazolidin-2-one derivatives
JP7292517B2 (en) Process and intermediates for the preparation of oxetan-2-ylmethanamine
Hu et al. Copper (I)-catalyzed intramolecular CN coupling reactions to form 1-cyanobenzimidazoles
Karlsson et al. Diastereoselective addition of chiral azomethine ylides to cyclic α, β-unsaturated N-enoylbornanesultams
TW200403222A (en) Process for the preparation of amino-pyrrolidine derivatives
TWI825323B (en) Processes and intermediates for the preparation of 2-(2,6-dichlorophenyl)-1-[(1s,3r)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1h)-yl]ethanone
TWI631120B (en) Acridine derivative as an appetite hormone receptor antagonist
WO2001096332A1 (en) Process for the preparation of a piperazine derivative
CA2479819A1 (en) Process for the preparation of morpholine derivatives and intermediates therefore
CN111094270A (en) Optically active pyrrolidine compound and process for producing the same
WO2004078714A2 (en) Processes for preparing imidazoquinoxalinones, heterocyclic-substituted imidazopyrazinones, imidazouinoxalines and heterocyclic-substituted imidazopyrazines

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18858758

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18858758

Country of ref document: EP

Kind code of ref document: A1