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WO2018061034A1 - Novel process for the preparation of 1-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl-ethanamine - Google Patents

Novel process for the preparation of 1-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl-ethanamine Download PDF

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Publication number
WO2018061034A1
WO2018061034A1 PCT/IN2017/050439 IN2017050439W WO2018061034A1 WO 2018061034 A1 WO2018061034 A1 WO 2018061034A1 IN 2017050439 W IN2017050439 W IN 2017050439W WO 2018061034 A1 WO2018061034 A1 WO 2018061034A1
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Prior art keywords
formula
compound
apremilast
acid
alkyl
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PCT/IN2017/050439
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French (fr)
Inventor
Rajamannar Thennati
Shriprakash Dhar DWIVEDI
Kanaksinh Jesingbhai Jadav
Vimeshkumar Maganlal Patel
Krunalkumar Chetanbhai JOSHI
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Sun Pharmaceutical Industries Limited
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Publication of WO2018061034A1 publication Critical patent/WO2018061034A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide

Definitions

  • the present invention relates to a process for the preparation of l-(3-ethoxy-4-methoxy- phenyl)-2-methylsulfonyl-ethanamine, an intermediate used for the preparation of apremilast.
  • Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP), marketed in the United states under the brand name OTEZLA ® as oral tablets and indicated for the treatment of adult patients with active psoriatic arthritis and for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.
  • PDE4 phosphodiesterase 4
  • cAMP cyclic adenosine monophosphate
  • the corresponding 5 enantiomer can be isolated from the racemic compound by techniques known in the art.
  • the '638 patent discloses a process for the preparation of apremilast wherein it is synthesized from 3-acetamidophthalic anhydride and a chiral amino acid salt of (5)-l-(3-ethoxy-4- methoxyphenyl)-2-methanesulfonylethylamine.
  • the U. S. Pat. No. 9,187,417 discloses the processes for enantioselective preparation of (5)-l- (3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethanamine, an intermediate which is used for preparation of apremilast by using stoichiometric quantity of chiral auxiliary namely (R)-tert- butylsulfinamide or (S)-a-methylbenzylamine.
  • the U. S. Pat. No. 9,126,906 discloses the process for the enantiomerically enriched preparation of (5)-l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethanamine by reducing corresponding enamine via hydrogenation in the presence of a metal catalyst and a chiral ligand or a chiral metal catalyst/ligand complex.
  • the present invention provides a simple, scalable and economical process for the preparation of apremilast.
  • the present invention provides a process for the preparation of apremilast, comprising:
  • R is (Ci-C4)alkyl, (Ci-C4)haloalkyl, -0(Ci-C4)alkyl, or -Obenzyl, and L is a leaving group, with dimethylsulfone anion to obtain a compound of Formula IV
  • the present invention also provides a novel intermediate of compound of Formula Va
  • the processes of the present invention are economical and suitable for commercial production of apremilast.
  • (Ci-C4)aikyl refers to an straight or branched chain, saturated monovalent hydrocarbon residue containing 1-4 carbon atoms.
  • Examples of (Ci-C4)alkyl includes but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and tert- butyl.
  • -0(Ci-C4)alkyl refers to a group in which (Ci-C4)alkyl group as defined above, is attached to another group via an oxygen atom. Examples of -0(Ci-C4)alkyl includes but are not limited to methoxy, ethoxy, n-propoxy, n-butoxy, teri-butoxy and the like.
  • (Ci-C4)haloalkyl refers to C 1 -C4 alkyl group as defined above, wherein one or more hydrogen atoms of alkyl group is substituted by one or more halogens.
  • Examples of (Ci-C4)haloalkyl includes but are not limited to trifluromethyl, trichloromethyl.
  • halogen refers to chloro, bromo, iodo or fluoro.
  • the present invention provides a process for the preparation of apremilast, comprising:
  • R is (Ci-C4)alkyl, (Ci-C4)haloalkyl, -0(Ci-C4)alkyl, or -O-benzyl, and L is a leaving group, with dimethylsulfone anion to obtain a compound of Formula IV
  • R in the compound of Formula IV and V is selected from (Ci-C4)alkyl, (Ci-C 4 )haloalkyl, -0(Ci-C 4 )alkyl, and -O-benzyl; preferably R is -0(Ci-C 4 )alkyl; more preferably R is teri-butoxy.
  • L in the compound of Formula V is a leaving group selected from a group consisting of -S(0)2-(Ci-C 4 alkyl), -S(0)2-(Ci-C 4 haloalkyl), benzenesulfonyl, p- toluenesulfonyl, -0(Ci-C 4 )alkyl or halogen.
  • L is p-toluenesulfonyl group.
  • step a involve reaction of compound of Formula V with dimethylsulfone anion.
  • Dimethylsulfone anion can be prepared by reacting dimethylsulfone with a strong base. Strong base suitable for the purpose can be selected from sodium
  • the base is NaHMDS or NaH. In another embodiment, the base is NaHMDS.
  • Dimethylsulfone anion is reacted with compound of Formula V. The reaction can be carried out in presence of a solvent.
  • a suitable solvent for the reaction may be selected from a group comprising of ether solvents such as tetrahydrofuran (THF), Me-THF, diethylether, 1,4- dioxane; or halogenated solvents such as dichloromethane, dichloroe thane; or polar aprotic solvents such as acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methyl-2-pyrrolidone or a mixture thereof.
  • ether solvents such as tetrahydrofuran (THF), Me-THF, diethylether, 1,4- dioxane
  • halogenated solvents such as dichloromethane, dichloroe thane
  • polar aprotic solvents such as acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methyl-2-pyrrolidone or a mixture thereof.
  • compound of Formula V and dimethylsulfone may be mixed together in a solvent and then a base may be added thus generating the dimethylsulfone anion in-situ followed by reaction with the compound of Formula V.
  • the reaction may be carried out at a temperature ranging from about -78 °C to about 10 °C, more preferably at a temperature of about -40 °C to about 5 °C; most preferably at a temperature of about -10 °C to 0 °C.
  • the reaction may be carried out for a time sufficient enough to complete the reaction, for example about 30 minutes to 12 hours.
  • the compound of Formula IV may be isolated by the well known techniques in the art such as extraction by the solvent and then evaporation of the solvent under reduced pressure. The obtained compound of Formula IV may be further purified before subjecting it to reaction of step b.
  • Step b involves deprotecting the compound of Formula IV to obtain compound of Formula III.
  • the deprotection of compound of Formula IV may be carried out by a process known for the deprotection of amino protecting group, such as by using acids, bases or by hydrogenolysis.
  • Boc-deprotection of compound of Formula IV (when R is tert- butoxy) may be carried out by using reagents such as hydrochloric acid, trifluoroacetic acid, and the like.
  • Step c involves converting the compound of Formula III to apremilast.
  • the compound of Formula III can be converted to apremilast by a process comprising:
  • the compound of Formula III is reacted with a chiral acid HX wherein H is hydrogen and X is acid counterpart.
  • the chiral acid can be selected from amino acids or their derivatives.
  • a preferred chiral acid is N-acetyl-L-leucine.
  • the reaction can be conveniently carried out in presence of a solvent selected from C1-C4 alcohols, acetone and other equivalent ketones, halogenated solvents like dichloromethane and chloroform. In an embodiment the preferred solvent is methanol.
  • the reaction may be carried out at a temperature of 25 °C to reflux temperature of the solvent.
  • the acid addition salt may be separated from the reaction mass by the processes known to a person skilled in the art.
  • the acid addition salt obtained in above step is reacted with 3-acetamidophthalic acid or 3- acetamidophthalic anhydride in presence of a suitable solvent.
  • the solvent may be selected from acetone and other equivalent ketones, halogenated solvents like dichloromethane and chloroform, ethers like tetrahydrofuran and 1,4-dioxane or acids like acetic acid or formic acid.
  • the solvent is acetic acid.
  • an acid like acetic acid or dilute hydrochloric acid may be added to the reaction mixture.
  • the reaction may be carried out at temperature of about 25 °C to reflux temperature of the solvent used for a time sufficient for completion of the reaction. Apremilast may be isolated from the reaction mass as per the common processes known in the art. For instance, by distilling out the solvent to obtain crude and purifying the crude by means of crystallization.
  • the compound of Formula V used in the above process may be prepared by reacting 3- ethoxy-4-methoxybenzaldehyde (compound of Formula VIII), a compound of Formula VII and a compound of Formula VI in a suitable solvent (Scheme I)
  • L in the compound of Formula VI is selected from a group consisting of (C1-C4 alkyl)sulfinate, (C1-C4 haloalkyl)sulfinate, benzenesulfinate, p-toluenesulfinate, - 0(Ci-C4)alkyl or halogen; and the metal is selected from zinc (Zn), iron (Fe), sodium (Na), lithium (Li), potassium (K), calcium (Ca), magnesium (Mg), strontium (Sr) or titanium (Ti); and wherein n is an integer selected from 0 to 4, depending on the valency of metal ion selected.
  • the non-limiting examples of Metal + -(L) n " includes sodium benzenesulfinate, sodium p-toluenesulfinate, sodium methanesulfinate, sodium trifluoromethanesulfinate, zinc chloride, lithium bromide, ferric chloride, sodium methoxide, potassium teri-butoxide, titanium ethoxide and the like.
  • a suitable solvent for the reaction may be selected from alcoholic solvents such as methanol, ethanol; or aromatic hydrocarbon solvents such as toluene; or ether solvents such as tetrahydrofuran (THF), diethylether; or chlorinated hydrocarbons solvents such as dichlorome thane; or polar aprotic solvents such as acetonitrile, DMF; or ester solvents such as ethyl acetate; or water or a mixture thereof.
  • an acid such as formic acid or acetic acid may be added in the reaction mixture.
  • the reaction may be carried out at a temperature of about room temperature to about reflux temperature of the solvent for a time sufficient to complete the reaction.
  • the product may be isolated by the technique known in the art such as filtration or extraction by using organic solvent.
  • the present invention provides a process for the preparation of apremilast, wherein R in the compound of Formula V and IV is teri-butoxy and L in the compound of Formula V is p-toluenesulfonyl group; the process comprises:
  • the steps a, b and c can be performed as per the process disclosed earlier in the specification.
  • the present invention provides a compound of Formula Va
  • the compound of Formula Va can be prepared by one pot process comprising mixing 3- ethoxy-4-methoxybenzaldehyde, teri-butyl carbamate and alkali metal p-toluenesulfinate such as sodium p-toluenesulfinate in a suitable solvent.
  • a suitable solvent for the reaction may be selected from alcoholic solvents such as methanol, ethanol; or aromatic hydrocarbon solvents such as toluene; or ether solvents such as tetrahydrofuran (THF), diethylether; or chlorinated hydrocarbons solvents such as dichlorome thane; or polar aprotic solvents such as acetonitrile, DMF; or ester solvents such as ethyl acetate; or water or a mixture thereof.
  • the preferred solvent is water.
  • the reaction is carried out in presence of an acid such as formic acid.
  • the reaction may be carried out at a temperature of about room temperature to about 60 °C, more preferably at room temperature, for a time sufficient to complete the reaction.
  • L is a leaving group
  • R is (C -C,)alkyl, -0(C -C,)alkyl, or -O-benzyl

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Abstract

The present invention relates to a process for the preparation of 1-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl-ethanamine, an intermediate for the preparation of apremilast via a compound of Formula (V) wherein R is (C1-C4)alkyl, (C1-C4)haloalkyl, -O(C1-C4)alkyl, or –O-benzyl, and L is a leaving group.

Description

NOVEL PROCESS FOR THE PREPARATION OF l-(3-ETHOXY-4-METHOXY- PHENYL)-2-METHYLSULFONYL-ETHANAMINE
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of l-(3-ethoxy-4-methoxy- phenyl)-2-methylsulfonyl-ethanamine, an intermediate used for the preparation of apremilast.
BACKGROUND OF THE INVENTION
Apremilast chemically known as N-[2-[(15)-l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-iH-isoindol-4-yl]acetamide is represented by the compound of Formula I:
Figure imgf000002_0001
Formula I
Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP), marketed in the United states under the brand name OTEZLA® as oral tablets and indicated for the treatment of adult patients with active psoriatic arthritis and for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.
Apremilast is first disclosed in United States Patent No. 7,427,638 (the '638 patent).
Many processes for the preparation of N-[2-[(15)-l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-iH-isoindol-4-yl]acetamide or apremilast are reported. Generally, racemic 2-[l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4- acetylaminoisoindoline-l,3-dione can be prepared using the methods described in United States Patent No. 6,020,358. The corresponding 5 enantiomer can be isolated from the racemic compound by techniques known in the art. The '638 patent discloses a process for the preparation of apremilast wherein it is synthesized from 3-acetamidophthalic anhydride and a chiral amino acid salt of (5)-l-(3-ethoxy-4- methoxyphenyl)-2-methanesulfonylethylamine.
The U. S. Pat. No. 9,187,417 discloses the processes for enantioselective preparation of (5)-l- (3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethanamine, an intermediate which is used for preparation of apremilast by using stoichiometric quantity of chiral auxiliary namely (R)-tert- butylsulfinamide or (S)-a-methylbenzylamine.
The U. S. Pat. No. 9,126,906 discloses the process for the enantiomerically enriched preparation of (5)-l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethanamine by reducing corresponding enamine via hydrogenation in the presence of a metal catalyst and a chiral ligand or a chiral metal catalyst/ligand complex.
Although these methods are enabling and useful for preparing apremilast, there is a need for developing a process which is commercially efficient.
The present invention provides a simple, scalable and economical process for the preparation of apremilast.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of apremilast, comprising:
(a) reacting a compound of Formula V,
Figure imgf000003_0001
Formula V wherein R is (Ci-C4)alkyl, (Ci-C4)haloalkyl, -0(Ci-C4)alkyl, or -Obenzyl, and L is a leaving group, with dimethylsulfone anion to obtain a compound of Formula IV
Figure imgf000004_0001
Formula IV wherein R is as defined above,
(b) deprotecting the compound of Formula IV to obtain a compound of Formula III
Figure imgf000004_0002
Formula III
, and
(c) converting the compound of Formula III to apremilast.
The present invention also provides a novel intermediate of compound of Formula Va
Figure imgf000004_0003
Formula Va its enantiomers or acid addition salts thereof.
The processes of the present invention are economical and suitable for commercial production of apremilast.
DEFINITIONS
The term "(Ci-C4)aikyl" as used herein refers to an straight or branched chain, saturated monovalent hydrocarbon residue containing 1-4 carbon atoms. Examples of (Ci-C4)alkyl includes but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and tert- butyl. The term "-0(Ci-C4)alkyl" as used herein refers to a group in which (Ci-C4)alkyl group as defined above, is attached to another group via an oxygen atom. Examples of -0(Ci-C4)alkyl includes but are not limited to methoxy, ethoxy, n-propoxy, n-butoxy, teri-butoxy and the like.
The term "(Ci-C4)haloalkyl" as used herein refers to C1-C4 alkyl group as defined above, wherein one or more hydrogen atoms of alkyl group is substituted by one or more halogens. Examples of (Ci-C4)haloalkyl includes but are not limited to trifluromethyl, trichloromethyl.
The term "halogen" as used herein refers to chloro, bromo, iodo or fluoro.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of apremilast, comprising:
(a) reacting a compound of Formula V
Figure imgf000005_0001
Formula V wherein R is (Ci-C4)alkyl, (Ci-C4)haloalkyl, -0(Ci-C4)alkyl, or -O-benzyl, and L is a leaving group, with dimethylsulfone anion to obtain a compound of Formula IV
Figure imgf000005_0002
Formula IV wherein R is as defined above,
(b) deprotecting the compound of Formula IV to obtain a compound of Formula III
Figure imgf000006_0001
Formula III
, and
(c) converting the compound of Formula III to apremilast.
In one embodiment, R in the compound of Formula IV and V is selected from (Ci-C4)alkyl, (Ci-C4)haloalkyl, -0(Ci-C4)alkyl, and -O-benzyl; preferably R is -0(Ci-C4)alkyl; more preferably R is teri-butoxy.
In another embodiment, L in the compound of Formula V is a leaving group selected from a group consisting of -S(0)2-(Ci-C4 alkyl), -S(0)2-(Ci-C4 haloalkyl), benzenesulfonyl, p- toluenesulfonyl, -0(Ci-C4)alkyl or halogen. In a preferred embodiment L is p-toluenesulfonyl group.
Accordingly, step a involve reaction of compound of Formula V with dimethylsulfone anion. Dimethylsulfone anion can be prepared by reacting dimethylsulfone with a strong base. Strong base suitable for the purpose can be selected from sodium
Figure imgf000006_0002
(NaHMDS), lithium Ws<trimethylsilyl)amide (LiHMDS), «-butyl lithium («-BuLi), sodium hydride or hydroxide like potassium hydroxide. In one embodiment, the base is NaHMDS or NaH. In another embodiment, the base is NaHMDS. Dimethylsulfone anion is reacted with compound of Formula V. The reaction can be carried out in presence of a solvent. A suitable solvent for the reaction may be selected from a group comprising of ether solvents such as tetrahydrofuran (THF), Me-THF, diethylether, 1,4- dioxane; or halogenated solvents such as dichloromethane, dichloroe thane; or polar aprotic solvents such as acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methyl-2-pyrrolidone or a mixture thereof. The most preferred solvent is tetrahydrofuran. Alternatively, compound of Formula V and dimethylsulfone may be mixed together in a solvent and then a base may be added thus generating the dimethylsulfone anion in-situ followed by reaction with the compound of Formula V. The reaction may be carried out at a temperature ranging from about -78 °C to about 10 °C, more preferably at a temperature of about -40 °C to about 5 °C; most preferably at a temperature of about -10 °C to 0 °C. The reaction may be carried out for a time sufficient enough to complete the reaction, for example about 30 minutes to 12 hours. The compound of Formula IV may be isolated by the well known techniques in the art such as extraction by the solvent and then evaporation of the solvent under reduced pressure. The obtained compound of Formula IV may be further purified before subjecting it to reaction of step b.
Step b involves deprotecting the compound of Formula IV to obtain compound of Formula III. The deprotection of compound of Formula IV may be carried out by a process known for the deprotection of amino protecting group, such as by using acids, bases or by hydrogenolysis. For instance Boc-deprotection of compound of Formula IV (when R is tert- butoxy) may be carried out by using reagents such as hydrochloric acid, trifluoroacetic acid, and the like.
Step c involves converting the compound of Formula III to apremilast. The compound of Formula III can be converted to apremilast by a process comprising:
(i) reacting the compound of Formula III with a chiral acid HX, to form an acid addition salt of following formula
Figure imgf000007_0001
Acid addition salt
wherein H is hydrogen and X is acid counterpart, and
(ii) reacting the acid addition salt with 3-acetamidophthalic acid or 3-acetamidophthalic anhydride to obtain apremilast.
The compound of Formula III is reacted with a chiral acid HX wherein H is hydrogen and X is acid counterpart. The chiral acid can be selected from amino acids or their derivatives. A preferred chiral acid is N-acetyl-L-leucine. The reaction can be conveniently carried out in presence of a solvent selected from C1-C4 alcohols, acetone and other equivalent ketones, halogenated solvents like dichloromethane and chloroform. In an embodiment the preferred solvent is methanol. The reaction may be carried out at a temperature of 25 °C to reflux temperature of the solvent. The acid addition salt may be separated from the reaction mass by the processes known to a person skilled in the art.
The acid addition salt obtained in above step is reacted with 3-acetamidophthalic acid or 3- acetamidophthalic anhydride in presence of a suitable solvent. The solvent may be selected from acetone and other equivalent ketones, halogenated solvents like dichloromethane and chloroform, ethers like tetrahydrofuran and 1,4-dioxane or acids like acetic acid or formic acid. In a preferred embodiment the solvent is acetic acid. When the solvent is other than acid, an acid like acetic acid or dilute hydrochloric acid may be added to the reaction mixture. The reaction may be carried out at temperature of about 25 °C to reflux temperature of the solvent used for a time sufficient for completion of the reaction. Apremilast may be isolated from the reaction mass as per the common processes known in the art. For instance, by distilling out the solvent to obtain crude and purifying the crude by means of crystallization.
The compound of Formula V used in the above process, may be prepared by reacting 3- ethoxy-4-methoxybenzaldehyde (compound of Formula VIII), a compound of Formula VII and a compound of Formula VI in a suitable solvent (Scheme I)
Scheme I
Figure imgf000008_0001
Formula VIII Formula V
wherein, R in the compound of Formula VII and V and L in the compound of Formula V are as defined above; L in the compound of Formula VI is selected from a group consisting of (C1-C4 alkyl)sulfinate, (C1-C4 haloalkyl)sulfinate, benzenesulfinate, p-toluenesulfinate, - 0(Ci-C4)alkyl or halogen; and the metal is selected from zinc (Zn), iron (Fe), sodium (Na), lithium (Li), potassium (K), calcium (Ca), magnesium (Mg), strontium (Sr) or titanium (Ti); and wherein n is an integer selected from 0 to 4, depending on the valency of metal ion selected. The non-limiting examples of Metal+-(L)n " (Formula VI) includes sodium benzenesulfinate, sodium p-toluenesulfinate, sodium methanesulfinate, sodium trifluoromethanesulfinate, zinc chloride, lithium bromide, ferric chloride, sodium methoxide, potassium teri-butoxide, titanium ethoxide and the like.
A suitable solvent for the reaction may be selected from alcoholic solvents such as methanol, ethanol; or aromatic hydrocarbon solvents such as toluene; or ether solvents such as tetrahydrofuran (THF), diethylether; or chlorinated hydrocarbons solvents such as dichlorome thane; or polar aprotic solvents such as acetonitrile, DMF; or ester solvents such as ethyl acetate; or water or a mixture thereof. Optionally an acid such as formic acid or acetic acid may be added in the reaction mixture. The reaction may be carried out at a temperature of about room temperature to about reflux temperature of the solvent for a time sufficient to complete the reaction. The product may be isolated by the technique known in the art such as filtration or extraction by using organic solvent.
In a preferred embodiment, the present invention provides a process for the preparation of apremilast, wherein R in the compound of Formula V and IV is teri-butoxy and L in the compound of Formula V is p-toluenesulfonyl group; the process comprises:
(a) reacting a compound of Formula
Figure imgf000009_0001
Formula Va
with dimethylsulfone anion to obtain la IVa
Figure imgf000009_0002
Formula IVa
(b) deprotecting the compound of Formula IVa to obtain a compound of Formula III
Figure imgf000010_0001
Formula III
, and
(c) converting the compound of Formula III to apremilast.
In another embodiment, the steps a, b and c can be performed as per the process disclosed earlier in the specification.
In another aspect, the present invention provides a compound of Formula Va
Figure imgf000010_0002
Formula Va its enantiomers or salts thereof.
The compound of Formula Va can be prepared by one pot process comprising mixing 3- ethoxy-4-methoxybenzaldehyde, teri-butyl carbamate and alkali metal p-toluenesulfinate such as sodium p-toluenesulfinate in a suitable solvent. A suitable solvent for the reaction may be selected from alcoholic solvents such as methanol, ethanol; or aromatic hydrocarbon solvents such as toluene; or ether solvents such as tetrahydrofuran (THF), diethylether; or chlorinated hydrocarbons solvents such as dichlorome thane; or polar aprotic solvents such as acetonitrile, DMF; or ester solvents such as ethyl acetate; or water or a mixture thereof. The preferred solvent is water. Preferably the reaction is carried out in presence of an acid such as formic acid. The reaction may be carried out at a temperature of about room temperature to about 60 °C, more preferably at room temperature, for a time sufficient to complete the reaction.
The complete process for the preparation of apremilast of the present invention can be depicted as in Scheme below:
Figure imgf000011_0001
Formula V
L is a leaving group
R is (C -C,)alkyl, -0(C -C,)alkyl, or -O-benzyl
Figure imgf000011_0002
Formula I Acid addition salt
The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respect as illustrative and are not intended to limit the scope of the claimed invention.
EXAMPLES:
Example 1: Preparation of tert-butyl N-[(3-ethoxy-4-methoxy-phi toly
Figure imgf000011_0003
A solution of 3-ethoxy-4-methoxybenzaldehyde, ieri-butyl carbamate and sodium p- toluenesulfinate in water was stirred at 25-30 °C. Formic acid was added into the reaction mixture and stirred for 48 hours at 25-30 °C. After completion of reaction, the reaction mixture was filtered to obtain the solid product, washed with methanol: water (1:9) mixture and dried in vacuum oven. Yield: 90 %. ¾ NMR (400 MHz, DMSO-d6) δ 8.63-8.66 (d, 1H), 7.73-7.75 (d, 2H), 7.46-7.48 (d, 2H), 7.29 (s, 1H), 7.12-7.15 (dd, 1H), 6.97-7.12 (d, 1H), 5.89-5.91(d, 2H), 4.02-4.07 (q, 2H), 3.82 (s, 3H), 2.43 (s, 3H), 1.36-1.40 (t, 3H), 1.25 (s, 9H). Example 2: Preparation of tert-butyl N-[l-(3-ethoxy-4-methoxy-phenyl)-2- methylsulfonyl-ethyljc
Figure imgf000012_0001
A mixture of dimethylsulfone in dry tetrahydrofuran was cooled to -5 °C to 0 °C and was added a solution of NaHMDS in THF (35 % solution). The resulting suspension was stirred at -5 °C to 0 °C for 1 hour. A solution of teri-butyl N-[(3-ethoxy-4-methoxy-phenyl)-(p- tolylsulfonyl)methyl]carbamate in dry dichloromethane was added into the reaction mass at - 5 °C to 0 °C and stirred fori hour. After completion of reaction, the reaction mixture was quenched with water and diluted with dichloromethane. The organic layer was separated and concentrated under reduced pressure to afford the crude product, which was triturated with isopropanol and hexane mixture to yield off-white solid of title compound. Yield: 90 %. ¾ NMR (400MHZ, CDCb) δ 6.83-6.88 (m, 3H), 5.59-5.60 (broad d, 1H), 5.13-5.14 (broad d, 1H), 4.02-4.26 (q, 2H), 3.84-3.89 (s, 3H), 3.63-3.66 (m, 1H), 3.37-3.41 (m, 1H), 2.61-2.66 (s, 3H), 1.41-1.46 (m, 12H).
Example 3: Preparation of l-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl- ethanamine
Figure imgf000012_0002
To a solution of teri-butyl N-[l-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl- ethyl]carbamate in acetonitrile was added isopropyl alcohol hydrochloride solution (IPA- HC1, 14 %) at 25-30 °C. The resultant reaction mixture was stirred for 12 hours at the same temperature. After completion of the reaction, the reaction mass was concentrated under reduced pressure and partitioned between 10 % aq. NaOH solution and dichloromethane. The organic layer was separated and concentrated under reduced pressure to afford the title compound as white solid. Yield: 95 %. Example 4: Preparation of (S)-2-(3-ethoxy-4-methoxy-phenyl)-2-(methylsulfonyl)-eth- 2-ylamine-N-ace
Figure imgf000013_0001
To 1 liter round bottom flask , l-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl-ethanamine, N-acetyl-L-leucine and methanol were charged and the suspension was stirred at 60 °C to 65 °C for 1 hour, the suspension was cooled to room temperature and stirred for another 3 hours. The solid was filtered and dried under reduced pressure to obtain the title compound with chiral purity of 85 % desired isomer. Yield: 40 %.
It was further purified by methanol to give pure title compound having chiral purity 99.5%.
Example 5: Apremilast
To a 500 mL RBF the product of example 4, 3-acetamidophthalic anhydride and acetic acid were charged and stirred at 110 °C to 115 °C for 1 hour and the solution was cooled to 60-65 °C. Acetic acid was distilled off completely and the residue was dissolved in dichloromethane. The dichloromethane layer was washed with water followed by washing with aq. sodium bicarbonate solution. The dichloromethane layer was separated and distilled off completely. The product was isolated by recrystallization in acetone:ethanol mixture to give apremilast as a light yellow solid with chiral purity of 99.9 % and HPLC purity of 99.8 %. Yield: 75 %.
Example 6: Apremilast
To a 500 mL RBF the product of example 4, 3-acetamidophthalic acid and acetic acid were charged and stirred at 110 °C to 115 °C for 1 hour and the solution was cooled to 60-65 °C. Acetic acid was distilled off completely and the residue was dissolved in dichloromethane. The dichloromethane layer was washed with water followed by washing with aq. sodium bicarbonate solution. The dichloromethane layer was separated and distilled off completely. The product was isolated by recrystallization in acetone :ethanol mixture to give apremilast as a light yellow solid with HPLC purity of 99.9 %. Yield: 75 %.

Claims

Claims:
1. A process for the preparation of apremilast, comprising
(a) reacting a compound of Formu
Figure imgf000014_0001
Formula V wherein R is (Ci-C4)alkyl, (Ci-C4)haloalkyl, -0(Ci-C4)alkyl, or -O-benzyl, and L is a leaving group, with dime thylsulf one anion to obtain a compound of Formula IV
Figure imgf000014_0002
Formula IV wherein R is as defined above,
(b) deprotecting the compound of Formula IV to obtain a compound of Formula III
Figure imgf000014_0003
Formula III
, and
(c) converting the compound of Formula III to apremilast.
2. The process as claimed in claim 1, wherein L is a leaving group selected from a group consisting of -S(0)2-(Ci-C4 alkyl), -S(0)2-(Ci-C4 haloalkyl), benzenesulfonyl, p- toluenesulfonyl, -0(Ci-C4)alkyl or halogen.
3. The process as claimed in claim 1, wherein R is teri-butoxy and L is p-toluenesulfonyl.
4. The process as claimed in claim 1, wherein in step c, the compound of Formula III is converted to apremilast by a process comprising:
(i) reacting the compound of Formula III with a chiral acid HX, to form an acid addition salt of following formula
Figure imgf000015_0001
Acid addition salt
wherein H is hydrogen and X is acid counterpart, and
(ii) reacting the acid addition salt with 3-acetamidophthalic acid or 3- acetamidophthalic anhydride to obtain apremilast.
5. The process as claimed in claim 4, wherein the chiral acid HX is N-acetyl-L-leucine.
6. A compound of Formula Va
Figure imgf000015_0002
Formula Va its enantiomers or acid addition salts thereof.
7. A process for the preparation of apremilast, comprising:
(a) reacting a compound of Formu
Figure imgf000015_0003
Formula Va
with dimethylsulfone anion to obtain a compound of Formula IVa
Figure imgf000016_0001
Formula IVa
(b) deprotecting the compound of Formula IVa to obtain a compound of Formula III
Figure imgf000016_0002
Formula III
, and
(c) converting the compound of Formula III to apremilast.
PCT/IN2017/050439 2016-09-30 2017-09-29 Novel process for the preparation of 1-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl-ethanamine WO2018061034A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018184933A1 (en) * 2017-04-04 2018-10-11 Quimica Sintetica, S. A. Racemic beta-aminosulfone compounds
EP3929179A1 (en) * 2020-06-22 2021-12-29 Biohorm, S.L. Anti-inflammatory compounds and methods for their manufacture

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130217918A1 (en) * 2012-02-21 2013-08-22 Celgene Corporation Processes for the preparation of (s)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine
CN104447445A (en) * 2014-12-05 2015-03-25 新发药业有限公司 Preparation method for synthesizing apremilast intermediate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130217918A1 (en) * 2012-02-21 2013-08-22 Celgene Corporation Processes for the preparation of (s)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine
CN104447445A (en) * 2014-12-05 2015-03-25 新发药业有限公司 Preparation method for synthesizing apremilast intermediate

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018184933A1 (en) * 2017-04-04 2018-10-11 Quimica Sintetica, S. A. Racemic beta-aminosulfone compounds
EP3929179A1 (en) * 2020-06-22 2021-12-29 Biohorm, S.L. Anti-inflammatory compounds and methods for their manufacture
WO2021259860A1 (en) * 2020-06-22 2021-12-30 Biohorm, S.L. Anti-inflammatory compounds and methods for their manufacture

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