WO2011158257A1 - Preparation process of fesoterodine and intermediates - Google Patents

Preparation process of fesoterodine and intermediates Download PDF

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Publication number
WO2011158257A1
WO2011158257A1 PCT/IN2011/000403 IN2011000403W WO2011158257A1 WO 2011158257 A1 WO2011158257 A1 WO 2011158257A1 IN 2011000403 W IN2011000403 W IN 2011000403W WO 2011158257 A1 WO2011158257 A1 WO 2011158257A1
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formula
compound
acid
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PCT/IN2011/000403
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Rajesh Jain
Siripragada Mahender Rao
Jagadeeshwar R. Rao
Chandra Rao Madada
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Panacea Biotec Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • Fesoterodine is the adopted name of the drug compound chemically known as isobutyric acid 2- ((R)-3diisopropylammonium-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester and is represented by the following structural formula:
  • Fesoterodine is a competitive muscarinic receptor antagonist and is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. Fesoterodine was first disclosed in the year 1998 in WO 1999/058478 Al as a muscarinic receptor antagonist. This application discloses the synthesis of fesoterodine and its various intermediates. It discloses the synthesis of fesoterodine by the reaction between N, N diisopropyl acrylamide and methyl 3-bromo-4-methoxybenzoate leading to the formation of an intermediate B, which is further esterified to obtain fesoterodine. The process is represented by the following scheme:
  • R is hydrogen, a straight or branched Ci-C 6 alkyl carbonyl group or a phenyl carbonyl group by using turbo Grignard reagent.
  • Compound of the above formula are intermediates used in the synthesis of their phenolic monoesters which are pharmacologically active compounds.
  • One of the phenolic monoester of this compound is fesoterodine. This application also discloses the synthesis of fesoterodine from the above depicted intermediate by its esterification.
  • Formula B wherein R is selected from the group consisting of hydrogen, straight-chained and branched Ci-Cg alkyl, R' and R" can be same or different and are selected from the group consisting of straight-chained and branched C C 6 alkyl.
  • the 4 hydroxybenzoic acid esters are treated with cinnamic acid to form a 2-oxo-4-phenylchromane-6-carboxyllic acid ester compound, which is then resolved using cinchonidine and neutralized with an acid to obtain its pure enantiomer via an intermediate step of an acid chloride with continuing ester formation with alcohols.
  • the lactone group of pure enantiomer is reduced to lactol followed by reductively aminated with N, N diisopropylamine to obtain the compound of Formula B.
  • the ester group of the compound of Formula B is reduced to an alcohol group to obtain the compound of Formula C.
  • the compound of Formula E is synthesized by the reduction of the corresponding 2-oxo-6-carboxylic acid ester analogue.
  • WO 2007/138440 Al discloses a one pot reaction scheme for the synthesis of benzopyran-2- ol derivatives of Formula G:
  • Formula G wherein Y is selected from CH 3 , CH 2 OH, CH 2 CH 2 OH, CH 2 Br and Br;
  • N-methylpiperazine is particularly preferred because it produces good yields. It also discloses the synthesis of fesoterodine using the synthesized benzopyran-2-ol derivatives.
  • the benzopyran-2-ol compound is reductively aminated and subsequently resolved to obtain one enantiomer.
  • the pure enantiomer is acylated to produce fesoterodine.
  • the present invention provides an improved, commercially viable and industrially advantageous processes for the synthesis of 3,3 diphenylpropylamine derivatives and their pharmacologically active analogs.
  • the intermediates and the final end products obtained through the improved processes of this invention are obtained in a superior yield and high purity.
  • the present invention relates to an improved, commercially viable and industrially advantageous process for the synthesis of 3,3 dipheylpropylamines and further an improved, commercially viable and industrially advantageous process for the synthesis fesoterodine from 3,3 dipheylpropylamine intermediates.
  • R is selected from CI-CJO alkyl or aryl group
  • the present invention provides a process for the preparation of compounds of Formula ⁇
  • the present invention provides a process for the preparation of compounds of Formula Va or its pharmaceutically acceptable salts,
  • R 2 and R 3 are the same or different and are selected from Ci-Cio alkyl or aryl group; said process comprising;
  • R ⁇ , R 2 and R 3 are as defined above.
  • the present invention provides a process for the preparation of compounds of Formula V'a:
  • the present invention provides a process for the preparation of a compound of Formula VI or its pharmaceutically acceptable salts of Formula VII,
  • Formula VI wherein R 2 , R 3 and R4 are same or different and are selected from Ci-C 10 alkyl or aryl group and X is any salt;
  • the present invention provides a process for the preparation of fesoterodine of Formula VI' and its pharmaceutically acceptable fumarate salt VII', said process comprising:
  • the present invention is related to a process of synthesis of 3,3 dipheylpropylamines, which may be used as intermediates in the preparation of their pharmacologically active derivatives such as fesoterodine, tolterodine, their enantiomers, pharmaceutically acceptable salts and related compounds useful as antimuscarinic agents.
  • the present invention is related to the synthesis of 2 (3-dialkylamino)-l- phenylpropyl) 4-hydroxymethyl phenol compounds of general Formula Va from phenyl chroman derivatives of Formula I.
  • the present invention also discloses the synthesis of pharmacologically active compound such as fesoterodine using intermediates synthesized by the novel process of the instant invention.
  • alkyl refers to both straight, branched and cyclic Ci -C 20 radicals which include, for example, methyl, ethyl, n-propyl, isopropyl, 1-ethylpropyl, n-butyl, tert-butyl, isobutyl, 2,2-dimethylpropyl, pentyl, octyl and decyl.
  • aryl refers to aromatic moieties containing up to 18 carbon atoms such as phenyl, biphenyl, naphthyl and anthryl.
  • the term "resoluting acid” refers to L-(-)-Malic acid, D-(+)-Malic acid, L-(+)-Tartaric acid, D-(-)-Tartaric acid, N-Acetyl-L-Glutamic acid, N-Acetyl-D-Glutamic acid, (+)-Camphor sulfonic acid, (-)-Camphor sulfonic acid, S-(+)-Mandelic acid, R-(-)-Mandelic acid, (+)-2,3- Di benzoyl-D-tartaric acid, (-)-2,3-Di benzoyl-L-Tartaric acid, (-)-2,3-Di- -toluyl L-Tartaric acid, (+)-2,3-di /?-toluyl D-Tartaric acid, L-Aspartic acid, D-(+)-Glucuronic acid, R-(-)- Ace
  • alkylamine refers to compounds of general Formula NH(R 2 )(R 3 ), wherein R 2 and R 3 are same or different and are selected from alkyl or aryl as defined above.
  • aluminium hydride reducing agent refers to compounds selected from diisobutylaluminum hydride, sodium bis(2methoxyethoxy)aluminum hydride (vitride) , lithium tri-tert-butyoxyaluminohydride and the like.
  • aliphatic amine refers to trialkylamines with straight-chain or branched alkyl residues containing 1 to 20 carbon atoms.
  • alkyl residues examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert butyl, n-pentyl, n-hexyl and n-octyl.
  • the alkyl residues can be the same or different.
  • solvent refers to solvent selected from the group comprising of polar protic solvents such as n-Butanol, Isopropanol , n-Propanol, Ethanol, Methanol, water; polar aprotic solvents such as Dichloromethane, Tetrahydrofuran, Ethyl acetate, Acetone, Methyl Isobutyl Ketone, Dimethylformamide, Dimethylacetamide, Acetonitrile (MeCN), Dimethyl sulfoxide and non polar solvents such as Hexane, Benzene, Toluene, Xylene, N butylacetate, t-Amyl alcohol, 1,4-Dioxane, Dioxan, Chloroform, Diethyl ether, Methyl t-butyl ether. It may also include inorganic solvents such as ammonia (N3 ⁇ 4), concentrated sulfuric acid (H 2 S0 4 ) and the like.
  • base refers to an organic base or an inorganic base.
  • Suitable organic base include, but are not limited to, lower alkyl amine such as triethylamine, diisopropylethylamine and the like.
  • Suitable inorganic base include, but are not limited to, an alkali metal carbonate and bicarbonates (for example, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate etc.), an alkali metal alkoxide (for example, potassium t-butoxide, sodium ethoxide, etc.), an alkali metal hydride (for example, potassium hydride, sodium hydride, etc.), or an alkali metal hydroxide (for example, potassium hydroxide, sodium hydroxide, etc.).
  • an alkali metal carbonate and bicarbonates for example, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate etc.
  • an alkali metal alkoxide for example, potassium t-butoxide, sodium ethoxide,
  • second amine compound refers to piperazine, N-methyl piperazine, morpholine, dibutylamine, dibenzylamine, diisopropylamine, diethylamine, piperidine and the like.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic inorganic or organic acids.
  • the salts may be prepared during the final isolation and purification of the compounds by making acidic addition salts.
  • Representative salts of basic compounds of the present invention can be prepared by reacting free base form of the compound with a suitable acid, including, but not limited to acetate, trifluoroacetate, adipate, citrate, aspartate, benzoate, benzenesulphonate, bisulfate, besylate, camphorsulphonate, hemisulfate, heptanoate, formate, fumarate, lactate, maleate, methanesulfonate, naphthylsulfonate, nicotinate, oxalate, picrate, pivalate, succinate, tartrate, trichloracetate, glutamate, p-toluenesulphonate, hydrochloric, hydrobromic, sulphate, acetate, adip
  • the present invention provides a process for the preparation of compounds of Formula I or its pharmaceutically acceptable salts,
  • Rl is selected from Ci-Cio alkyl or aryl group
  • the organic solvent that may be used in the above reaction is selected from the group consisting of toluene, xylene, methyl-t-butyl ether, dimethyl acetamide, cyclohexane, acetonitrile, N-butylacetate, dioxane and the like. Particularly, toluene is preferred.
  • the above reaction is carried out by adding the compound of formula II in the secondary amine compound at room temperature and heating the reaction mass to a higher temperature in the range from about 95°C to 115°C and slowly adding the compound of formula III at a temperature of about 60°C to 65°C and refluxing at that temperature to obtain the compound of formula I.
  • the present invention provides a process for the preparation of compounds of Formula ⁇
  • the present invention provides a process for the preparation of compound of Formula Va or its pharmaceutically acceptable salts,
  • R 2 and R 3 are the same or different and are selected from Ci-Ci 0 alkyl or aryl group; said process comprising;
  • Alkylamine that can be used in the above reaction step can be selected from the compounds of general formula NH(R 2 )(R 3 ), wherein R 2 and R 3 are the same or different and are selected from the group consisting of Ci-C 10 alkyl or aryl. Particularly, is preferred.
  • Solvents that can be used in the above reaction are selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, water, dichloromethane, tetrahydrofuran, ethylacetate and the like. Particularly, methanol is preferred.
  • the above reaction is carried out by adding the compound of Formula I obtained from the step (a) in a solvent, such as methanol and adding diisopropylamine and 10% Pd-C under hydrogen atmosphere to obtain the compound of Formula IV.
  • Step (c) involves reducing the compound of Formula IV with a reducing agent to obtain a compound of Formula V.
  • Reducing agents that can be used in the above reaction may be a aluminium hydride reducing agent such as diisobutylaluminium hydride, sodium dihydrobis(2-methoxyethoxy) aluminate (vitride), and lithium tri-tert-butyoxyaluminohydride. Particularly, sodium dihydrobis(2-methoxyethoxy) aluminate is preferred.
  • Solvents that may be used in the above reaction step may be selceted from non-polar solvents such as hexane, toluene, xylene, N-butylacetate, t-amylalcohol, dioxane, methyl-t- butyl ether and the like. Particularly, toluene is preferred.
  • the above reaction step is carried out by adding the vitride to a solvent at room temperature and cooling the reaction mass to a lower temperature of about 0°C to 10°C and adding the compound of Formula IV and raising the temperature to room temperature and maintaining for about 12 hours to obatin the compound of Formula V.
  • Step (d) involves resolving the compound of Formula V to its R enantiomer of Formula Va.
  • the above reaction step is carried out by reacting the compound of Formula V obtained in step (c) with a resoluting acid and recovering the pure enantiomer using a base and a suitable solvent.
  • Solvents used in step (d) may be selected from the group consisting of tetrahydrofuran, isopropyl alcohol, isoamyl alcohol, ethyl acetate, acetone, acetonitrile, methanol, ethanol, isopropyl ether and their mixtures and the like, preferably tetrahydrofuran or mixture of isopropyl alcohol and isopropyl ether.
  • the cokmpound of formula V obtained from step (c) was added to the solvent at room temperature and heated to about 50°C and the resoluting acid is added followed by the addition of a solvent. Later the reaction mass is cooled to room temperature to obatin the compound of Formula Va.
  • the present invention provides a process for the preparation of compounds of Formula Va:
  • the present invention provides a process for the preparation of a compound of Formula VI or its harmaceutically acceptable salts of Formula VII,
  • Formula VI wherein R 2 , R 3 and R4 are same or different and are selected from Ci-C 10 alkyl or aryl group and X is any salt;
  • Step (e) involves reacting the compound of Formula Va with an acylating agent in presence of a suitable base and solvent to obtain a compound of Formula VI.
  • step (e) can be carried in the presence of a suitable base such as aliphatic amines and a solvent which is a polar aprotic solvent.
  • Aliphatic amines that can be used at this step can be selected from trialkylamines with straight-chain or branched alkyl residues containing 1 to 20 carbon atoms.
  • alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and n-octyl.
  • the alkyl residues can be the same or different.
  • preferred aliphatic amine is triethylamine and disiopropylethyl amine.
  • Polar aprotic solvent that can be used at this step can be selected from dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate, acetone, dimethylformamide (DMF), acetonitrile, dimethylsulfoxide and the like. Particularly, preferred polar aprotic solvent is dichloromethane.
  • Step (f) involes optionally converting the compound of Formula VI to a pharmaceutically acceptable salt of Formula VII.
  • the salts of Formula VII may be prepared from pharmaceutically acceptable non-toxic inorganic or organic acids.
  • the salts may be prepared during the final isolation and purification of the compounds by making acidic addition salts.
  • Representative salts of basic compounds of the present invention can be prepared by reacting free base form of the compound of Formula VI with a suitable acid, including, but not limited to acetate, trifluoroacetate, adipate, citrate, aspartate, benzoate, benzenesulphonate, bisulfate, besylate, camphorsulphonate, hemisulfate, heptanoate, formate, fumarate, lactate, maleate, methanesulfonate, naphthylsulfonate, nicotinate, oxalate, picrate, pivalate, succinate, tartrate, trichloracetate, glutamate, p-toluenesulphonate, hydrochloric, hydrobromic, sulphuric, phosphoric and the like. Particularly, fumarate is preferred.
  • the present invention provides a process for the preparation of fesoterodine of Formula VI' and its pharmaceutically acceptable fumarate salt VII', said process comprising:
  • Example 1 Preparation of (4R, 4S)-2-(R, S)-Hydroxy-4-phenylchromane-6-carboxylic acid methyl ester ( ⁇ ).
  • the obtained crude product was dissolved in isopropyl ether (750 ml) and 5% H 2 S0 4 solution (800 ml) was added to it and stirred for 30-45 minutes.
  • the aqueous and organic layers were separated and the aqueous layer was washed with isopropyl ether (750 ml).
  • the aqueous layer was basified with 10% NaOH solution (250 ml) to make reaction mass at pH 9-10 below 20°C and extracted with ethyl acetate (700 ml) twice.
  • the ethyl acetate layers were combined and washed with water.
  • the organic layer was separated and concentrated to dryness under reduced pressure to obtain the title compound IV (260 g, 0.706 mol).
  • the Malic acid salt was purified in 1:1 IPA/IPE solution to get the title compound (2.35 g, 0.0068 mol). Yield: 36.15 % (Chiral purity: 98%)

Abstract

The present invention relates to a process of synthesis of 3,3 dipheylpropylamines, which may be used as pharmaceutical intermediates in the preparation of their pharmacologically active derivatives such as fesoterodine, tolterodine, their enantiomers, pharmaceutically acceptable salts and related compounds useful as antimuscarinic agents.

Description

PREPARATION PROCESS OF FESOTERODINE AND
INTERMEDIATES
FIELD OF INVENTION:
The present invention is related to the field of synthetic chemistry. It is related to a process of synthesis of 3,3 dipheylpropylamines, which may be used as pharmaceutical intermediates in the preparation of their pharmacologically active derivatives such as fesoterodine, tolterodine, their enantiomers, pharmaceutically acceptable salts and related compounds useful as antimuscarinic agents. The invention also provides process for the synthesis of fesoterodine and related compounds using the intermediate.
BACKGROUND:
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Fesoterodine is the adopted name of the drug compound chemically known as isobutyric acid 2- ((R)-3diisopropylammonium-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester and is represented by the following structural formula:
Figure imgf000002_0001
Fesoterodine is a competitive muscarinic receptor antagonist and is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. Fesoterodine was first disclosed in the year 1998 in WO 1999/058478 Al as a muscarinic receptor antagonist. This application discloses the synthesis of fesoterodine and its various intermediates. It discloses the synthesis of fesoterodine by the reaction between N, N diisopropyl acrylamide and methyl 3-bromo-4-methoxybenzoate leading to the formation of an intermediate B, which is further esterified to obtain fesoterodine. The process is represented by the following scheme:
Figure imgf000003_0001
Formula A
wherein R is hydrogen, a straight or branched Ci-C6 alkyl carbonyl group or a phenyl carbonyl group by using turbo Grignard reagent. Compound of the above formula are intermediates used in the synthesis of their phenolic monoesters which are pharmacologically active compounds. One of the phenolic monoester of this compound is fesoterodine. This application also discloses the synthesis of fesoterodine from the above depicted intermediate by its esterification.
US 6,809,214 B2 discloses the preparation of 3,3 diarylpropylamines of general Formula B and C using 4-hydroxybenzoic acid esters as the starting material:
Figure imgf000004_0001
Formula B Formula C wherein R is selected from the group consisting of hydrogen, straight-chained and branched Ci-Cg alkyl, R' and R" can be same or different and are selected from the group consisting of straight-chained and branched C C6 alkyl.
In the process disclosed, the 4 hydroxybenzoic acid esters are treated with cinnamic acid to form a 2-oxo-4-phenylchromane-6-carboxyllic acid ester compound, which is then resolved using cinchonidine and neutralized with an acid to obtain its pure enantiomer via an intermediate step of an acid chloride with continuing ester formation with alcohols. The lactone group of pure enantiomer is reduced to lactol followed by reductively aminated with N, N diisopropylamine to obtain the compound of Formula B. In the final step, the ester group of the compound of Formula B is reduced to an alcohol group to obtain the compound of Formula C.
WO 2007/144097 Al discloses the synthesis of compounds of general Formula E:
Figure imgf000005_0001
Formula E
and their use in the synthesis of fesoterodine and related compounds .The compound of Formula E is synthesized by the reduction of the corresponding 2-oxo-6-carboxylic acid ester analogue.
WO 2007/138440 Al discloses a one pot reaction scheme for the synthesis of benzopyran-2- ol derivatives of Formula G:
Figure imgf000005_0002
Formula G wherein Y is selected from CH3, CH2OH, CH2CH2OH, CH2Br and Br;
by the reaction between trans-cinnamaldehyde and compound of Formula F;
Figure imgf000005_0003
Formula F
wherein OX is hydroxy or 0"M+, in which M+ is a cation selected from Li+, Na+ and K+ and Y is as defined above; in the presence of a piperazine compound.
It is disclosed that N-methylpiperazine is particularly preferred because it produces good yields. It also discloses the synthesis of fesoterodine using the synthesized benzopyran-2-ol derivatives. The benzopyran-2-ol compound is reductively aminated and subsequently resolved to obtain one enantiomer. The pure enantiomer is acylated to produce fesoterodine. There still exists a need to provide a simple and convenient process for the preparation of Fesoterodine and its intermediates. The present invention provides an improved, commercially viable and industrially advantageous processes for the synthesis of 3,3 diphenylpropylamine derivatives and their pharmacologically active analogs. The intermediates and the final end products obtained through the improved processes of this invention are obtained in a superior yield and high purity. SUMMARY OF THE INVENTION
The present invention relates to an improved, commercially viable and industrially advantageous process for the synthesis of 3,3 dipheylpropylamines and further an improved, commercially viable and industrially advantageous process for the synthesis fesoterodine from 3,3 dipheylpropylamine intermediates.
In one embodiment, the present invention provides a process for the preparation of compounds of Formula I or its pharmaceutically acceptable salts,
Figure imgf000006_0001
Formula I wherein R) is selected from CI-CJO alkyl or aryl group;
said process comprising:
reacting a compound of Formula II
Figure imgf000007_0001
wherein Ri is as defined above;
with a compound of Formula III
Figure imgf000007_0002
Formula lit in the presence of a secondary amine compound.
In a specific embodiment, the present invention provides a process for the preparation of compounds of Formula Γ
Figure imgf000007_0003
Formula I'
comprising reacting a compound of Formula ΙΓ
Figure imgf000007_0004
Formula II* with a compound of Formula III
Figure imgf000008_0001
Formula III in the presence of N-methyl piperazine.
In another embodiment, the present invention provides a process for the preparation of compounds of Formula Va or its pharmaceutically acceptable salts,
Figure imgf000008_0002
Formula Va
wherein R2 and R3 are the same or different and are selected from Ci-Cio alkyl or aryl group; said process comprising;
(a) reacting a compound of Formula II
Figure imgf000008_0003
Formula II
with a compound of Formula HI
Figure imgf000009_0001
Formula III
in the presence of a secondary amine compound to obtain a compound of Formula I;
Figure imgf000009_0002
Formula I
(b) reductively aminating the compound of Formula I with an alkylamine to obtain compound of Formula IV;
Figure imgf000009_0003
Formula IV
wherein R\, R2 and R3 are as defined above.
(c) reducing the compound of Formula IV with a reducing agent to obtain a compound of Formula V; and
Figure imgf000009_0004
Formula V (d) resolving the compound of Formula V to its R enantiomer of Formula Va.
In a specific embodiment, the present invention provides a process for the preparation of compounds of Formula V'a:
Figure imgf000010_0001
Formula V'a
comprising
(a) reacting a compound of Formul
Figure imgf000010_0002
with a compound of Formula III
Figure imgf000010_0003
Formula Ml
in the presence of a secondary amine compound to obtain a compound of Formula Γ;
Figure imgf000011_0001
Formula
(b) reductively aminating the compound of Formula Γ , to obtain compound of Formula IV;
Figure imgf000011_0002
Formula (V
(c) reducing the compound of Formula IV' with a reducing agent to obtain a compound of Formula V:
Figure imgf000011_0003
Formula V"
(d) resolving the compound of Formula V to its R enantiomer of Formula V'a.
In yet another embodiment, the present invention provides a process for the preparation of a compound of Formula VI or its pharmaceutically acceptable salts of Formula VII,
Figure imgf000012_0001
Formula VI Formula VII wherein R2, R3 and R4 are same or different and are selected from Ci-C10 alkyl or aryl group and X is any salt;
said process comprising:
(a) reacting a compound of Formula II
Figure imgf000012_0002
Formula II
with a compound of Formula III
Figure imgf000012_0003
Formula III
in the presence of a secondary amine compound to obtain a compound of Formula I;
Figure imgf000013_0001
Formula I
(b) reductively aminating the compound of Formula I with an alkylamine to obtain compound of Formula IV;
Figure imgf000013_0002
Formula IV
(c) reducing the compound of Formula IV with a reducing agent to obtain a compound of Formula V;
Figure imgf000013_0003
Formula V
(d) resolving the compound of Formula V to its R enantiomer of Formula Va;
Figure imgf000013_0004
Formula Va (e) reacting the the compound of Formula Va with an acylating agent in the presence of a suitable base and solvent to obtain a compound of Formula VI; and
Figure imgf000014_0001
Formula VI
(f) optionally converting the compound of Formula VI to a pharmaceutically acceptable salt of Formula VII.
In a specific embodiment, the present invention provides a process for the preparation of fesoterodine of Formula VI' and its pharmaceutically acceptable fumarate salt VII', said process comprising:
(a) preparing a compound of Formula Γ
Figure imgf000014_0002
Formula I'
by reacting a compound of Formula IF
Figure imgf000014_0003
Formula ΙΓ
with a compound of Formula III
Figure imgf000015_0001
Formula III
in the presence of a N methyl piperazine ;
(b) reductively aminating the compound of Formula Γ with Diisopropylamine to compound of Formula IV;
Figure imgf000015_0002
Formula IV
(c) reducing the compound of Formula IV with vitride to obtain a compound of Formula V
Figure imgf000015_0003
Formula V
(d) resolving the compound of Formula V to compound of Formula Va using L(-)malic acid or D(+)-Malic acid or L (+)-Tartaric acid
Figure imgf000016_0001
Formula V'a
(e) acylating the compound of Formula V'a with isobutyryl chloride to obtain a compound of Formula VI';
Figure imgf000016_0002
Formula VP
(f) optionally converting the compound of Formula VI' to its fumarate salt of Formula VII'
Figure imgf000016_0003
Formula VII'
These and other features, aspects, and advantages of the present subject matter will become better understood with reference to the following description and appended claims. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to limit the scope of the claimed subject matter. DETAILED DESCRIPTION OF THE INVENTION
The present invention is related to a process of synthesis of 3,3 dipheylpropylamines, which may be used as intermediates in the preparation of their pharmacologically active derivatives such as fesoterodine, tolterodine, their enantiomers, pharmaceutically acceptable salts and related compounds useful as antimuscarinic agents.
In particular the present invention is related to the synthesis of 2 (3-dialkylamino)-l- phenylpropyl) 4-hydroxymethyl phenol compounds of general Formula Va from phenyl chroman derivatives of Formula I. The present invention also discloses the synthesis of pharmacologically active compound such as fesoterodine using intermediates synthesized by the novel process of the instant invention.
DEFINITIONS:
The invention is described herein in detail using the terms defined below unless otherwise specified.
The term "alkyl" refers to both straight, branched and cyclic Ci -C20 radicals which include, for example, methyl, ethyl, n-propyl, isopropyl, 1-ethylpropyl, n-butyl, tert-butyl, isobutyl, 2,2-dimethylpropyl, pentyl, octyl and decyl.
The term "aryl" refers to aromatic moieties containing up to 18 carbon atoms such as phenyl, biphenyl, naphthyl and anthryl.
The term "resoluting acid" refers to L-(-)-Malic acid, D-(+)-Malic acid, L-(+)-Tartaric acid, D-(-)-Tartaric acid, N-Acetyl-L-Glutamic acid, N-Acetyl-D-Glutamic acid, (+)-Camphor sulfonic acid, (-)-Camphor sulfonic acid, S-(+)-Mandelic acid, R-(-)-Mandelic acid, (+)-2,3- Di benzoyl-D-tartaric acid, (-)-2,3-Di benzoyl-L-Tartaric acid, (-)-2,3-Di- -toluyl L-Tartaric acid, (+)-2,3-di /?-toluyl D-Tartaric acid, L-Aspartic acid, D-(+)-Glucuronic acid, R-(-)- Acetoxy Mandelic acid, R (+)-2-(4-Hydroxyphenoxy)propionic acid, Mucic acid.
The term "alkylamine" refers to compounds of general Formula NH(R2)(R3), wherein R2 and R3 are same or different and are selected from alkyl or aryl as defined above.
The term "aluminium hydride reducing agent" refers to compounds selected from diisobutylaluminum hydride, sodium bis(2methoxyethoxy)aluminum hydride (vitride) , lithium tri-tert-butyoxyaluminohydride and the like. The term "aliphatic amine" refers to trialkylamines with straight-chain or branched alkyl residues containing 1 to 20 carbon atoms. Examples of such alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert butyl, n-pentyl, n-hexyl and n-octyl. In such trialkylamines, the alkyl residues can be the same or different.
The term " solvent" refers to solvent selected from the group comprising of polar protic solvents such as n-Butanol, Isopropanol , n-Propanol, Ethanol, Methanol, water; polar aprotic solvents such as Dichloromethane, Tetrahydrofuran, Ethyl acetate, Acetone, Methyl Isobutyl Ketone, Dimethylformamide, Dimethylacetamide, Acetonitrile (MeCN), Dimethyl sulfoxide and non polar solvents such as Hexane, Benzene, Toluene, Xylene, N butylacetate, t-Amyl alcohol, 1,4-Dioxane, Dioxan, Chloroform, Diethyl ether, Methyl t-butyl ether. It may also include inorganic solvents such as ammonia (N¾), concentrated sulfuric acid (H2S04) and the like.
The term "base" refers to an organic base or an inorganic base. Suitable organic base include, but are not limited to, lower alkyl amine such as triethylamine, diisopropylethylamine and the like. Suitable inorganic base include, but are not limited to, an alkali metal carbonate and bicarbonates (for example, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate etc.), an alkali metal alkoxide (for example, potassium t-butoxide, sodium ethoxide, etc.), an alkali metal hydride (for example, potassium hydride, sodium hydride, etc.), or an alkali metal hydroxide (for example, potassium hydroxide, sodium hydroxide, etc.).
The term "secondary amine compound" refers to piperazine, N-methyl piperazine, morpholine, dibutylamine, dibenzylamine, diisopropylamine, diethylamine, piperidine and the like.
The term "salts" or "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic inorganic or organic acids. The salts may be prepared during the final isolation and purification of the compounds by making acidic addition salts. Representative salts of basic compounds of the present invention can be prepared by reacting free base form of the compound with a suitable acid, including, but not limited to acetate, trifluoroacetate, adipate, citrate, aspartate, benzoate, benzenesulphonate, bisulfate, besylate, camphorsulphonate, hemisulfate, heptanoate, formate, fumarate, lactate, maleate, methanesulfonate, naphthylsulfonate, nicotinate, oxalate, picrate, pivalate, succinate, tartrate, trichloracetate, glutamate, p-toluenesulphonate, hydrochloric, hydrobromic, sulphuric, phosphoric and the like.
It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. As well, the terms "a" (or "an"), "one or more" and "at least one" can be used interchangeably herein. It is also to be noted that the terms "comprising", "including", "characterized by" and "having" can be used interchangeably.
In one embodiment, the present invention provides a process for the preparation of compounds of Formula I or its pharmaceutically acceptable salts,
Figure imgf000019_0001
Formula I wherein Rl is selected from Ci-Cio alkyl or aryl group;
said process comprising;
(a) reacting a compound of Formula II
Figure imgf000019_0002
Formula II
wherein Ri is as defined above; with a compound of Formula III
Figure imgf000020_0001
Formula III in the presence of a secondary amine compound.,
The details of the above embodiment is as follows:
The above reaction between the compound of formula II and compound of formula III can be carried out in the presence of an organic solvent.
The organic solvent that may be used in the above reaction is selected from the group consisting of toluene, xylene, methyl-t-butyl ether, dimethyl acetamide, cyclohexane, acetonitrile, N-butylacetate, dioxane and the like. Particularly, toluene is preferred.
The secondary amine compound used in the above reaction may be selected from the group coonsisiting of piperazine, N-methyl piperazine, morpholine, dibutylamine, dibenzylamine, diisopropylamine, diethylamine, piperidine and the like. Particularly N-methyl piperazine is preferred.
In an embodiment, the above reaction is carried out by adding the compound of formula II in the secondary amine compound at room temperature and heating the reaction mass to a higher temperature in the range from about 95°C to 115°C and slowly adding the compound of formula III at a temperature of about 60°C to 65°C and refluxing at that temperature to obtain the compound of formula I. In a specific embodiment, the present invention provides a process for the preparation of compounds of Formula Γ
Figure imgf000021_0001
Formula
comprising, reacting a compound of Formula ΙΓ
Figure imgf000021_0002
Formula Ι compound of Formula III
Figure imgf000021_0003
Formula III in the presence of N-methyl piperazine.
In another embodiment, the present invention provides a process for the preparation of compound of Formula Va or its pharmaceutically acceptable salts,
Figure imgf000021_0004
Formula Va
wherein R2 and R3 are the same or different and are selected from Ci-Ci0alkyl or aryl group; said process comprising;
(a) reacting a compound of Formula II
Figure imgf000022_0001
Formula II
with a compound of Formula III
Figure imgf000022_0002
Formula III
in the presence of a secondary amine compound, to obtain a compound of Formula I;
Figure imgf000022_0003
Formula I
(b) reductively aminating the compound of Formula I with an alkylamine to obtain compound of Formula IV;
Figure imgf000022_0004
Formula IV
wherein Ri, R2 and R3 are as defined above; (c) reducing the compound of Formula IV with a reducing agent to obtain a compound of Formula V; and
Figure imgf000023_0001
Formula V
(d) resolving the compound of Formula V to its R enantiomer of Formula Va.
The details of the above embodiment is as follows:
Step (a) involves the reaction between compound of Formula II and compound of Formula III. The reaction is detailed in the previous embodiment. Step (b) involves reductively aminating the compound of Formula I with an alkylamine to obtain compound of Formula IV.
The reaction of step (b) is carried out in the presence of a reducing agent and an alkyl amine. Reducing agents that can be used in this step may be selected from the group consisting of H2/Pd-C, sodium borohydride, sodium acetoxy borohydride, ammonium formate/Pd-C and the like. Particularly, H2/Pd-C is preferred.
Alkylamine that can be used in the above reaction step can be selected from the compounds of general formula NH(R2)(R3), wherein R2 and R3 are the same or different and are selected from the group consisting of Ci-C10 alkyl or aryl. Particularly,
Figure imgf000023_0002
is preferred. Solvents that can be used in the above reaction are selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, water, dichloromethane, tetrahydrofuran, ethylacetate and the like. Particularly, methanol is preferred.
In an embodiment, the above reaction is carried out by adding the compound of Formula I obtained from the step (a) in a solvent, such as methanol and adding diisopropylamine and 10% Pd-C under hydrogen atmosphere to obtain the compound of Formula IV. Step (c) involves reducing the compound of Formula IV with a reducing agent to obtain a compound of Formula V.
Reducing agents that can be used in the above reaction may be a aluminium hydride reducing agent such as diisobutylaluminium hydride, sodium dihydrobis(2-methoxyethoxy) aluminate (vitride), and lithium tri-tert-butyoxyaluminohydride. Particularly, sodium dihydrobis(2-methoxyethoxy) aluminate is preferred.
Solvents that may be used in the above reaction step may be selceted from non-polar solvents such as hexane, toluene, xylene, N-butylacetate, t-amylalcohol, dioxane, methyl-t- butyl ether and the like. Particularly, toluene is preferred.
In an embodiment, the above reaction step is carried out by adding the vitride to a solvent at room temperature and cooling the reaction mass to a lower temperature of about 0°C to 10°C and adding the compound of Formula IV and raising the temperature to room temperature and maintaining for about 12 hours to obatin the compound of Formula V. Step (d) involves resolving the compound of Formula V to its R enantiomer of Formula Va. The above reaction step is carried out by reacting the compound of Formula V obtained in step (c) with a resoluting acid and recovering the pure enantiomer using a base and a suitable solvent.
Resoluting acids that can be used in this step can be selected from the group consisting of L- (-)-Malic acid, D-(+)-Malic acid, L-(+)-Tartaric acid, D-(-)-Tartaric acid, N-Acetyl-L- Glutamic acid, N-Acetyl-D-Glutamic acid, (+)-Camphor sulfonic acid, (-)-Camphor sulfonic acid, S-(+)-Mandelic acid, R-(-)-Mandelic acid, (+)-2,3-Di benzoyl-D-Tartaric acid, (-)-2,3- Di benzoyl-L-Tartaric acid, (-) Di-p-toluyl L(-) Tartaric acid, (+)-Di ?-toluyl D-Tartaric acid, L-Aspartic acid, D-(+)-Glucuronic acid, R-(-)-Acetoxy Mandelic acid, R-(+)-2-(4- Hydroxyphenoxy)propionic acid, Mucic acid and the like. Particularly, D-(+)-Malic acid or L-(-)-Malic acid and L-(+)-Tartaric acid are preferred.
Suitable bases that can be usedin this step can be selected from the group consisting of hydroxides, carbonates, bicarbonates, alkoxides and oxides of alkali or alkaline earth metals. The preferred alkali metal compounds are those of lithium, sodium and potassium, more preferred being those of sodium and potassium. Some examples of bases are sodium hydroxide, potassium hydroxide, magnesium hydroxide, magnesium oxide^ sddium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert- butoxide and potassium tert-butoxide. Particularly, sodium bicarbonate is preferred.
Solvents used in step (d) may be selected from the group consisting of tetrahydrofuran, isopropyl alcohol, isoamyl alcohol, ethyl acetate, acetone, acetonitrile, methanol, ethanol, isopropyl ether and their mixtures and the like, preferably tetrahydrofuran or mixture of isopropyl alcohol and isopropyl ether.
In an embodiment, the cokmpound of formula V obtained from step (c) was added to the solvent at room temperature and heated to about 50°C and the resoluting acid is added followed by the addition of a solvent. Later the reaction mass is cooled to room temperature to obatin the compound of Formula Va.
In a specific embodiment, the present invention provides a process for the preparation of compounds of Formula Va:
Figure imgf000025_0001
Formula Ι
with a compound of Formula III
Figure imgf000026_0001
Formula III
in the presence of a secondary amine compound to obtain a compound of Formula Γ;
Figure imgf000026_0002
Formula
(b) reductively aminating the compound of Formula Γ , to obtain compound of Formula IV;
Figure imgf000026_0003
Formula IV
(c) reducing the compound of Formula IV with a reducing agent to obtain a compound of Formula V;
Figure imgf000026_0004
Formula Ve
(d) resolving the compound of Formula V to its R enantiomer V'a In yet another embodiment, the present invention provides a process for the preparation of a compound of Formula VI or its harmaceutically acceptable salts of Formula VII,
Figure imgf000027_0001
Formula VI Formula VII wherein R2, R3 and R4 are same or different and are selected from Ci-C10 alkyl or aryl group and X is any salt;
said process comprising:
(a) reacting a compound of Formula II
with a compound of Formula III
Figure imgf000027_0002
Formula III
in the presence of a secondary amine compound to obtain a compound of Formula I;
Figure imgf000028_0001
Formula I
(b) reductively aminating the compound of Formula I with an alkylamine to obtain a compound of Formula IV;
Figure imgf000028_0002
Formula IV
(c) reducing the compound of Formula IV with a reducing agent to obtain a compound of Formula V;
Figure imgf000028_0003
Formula V
(d) resolving the compound of Formula V to its R enantiomer of Formula Va;
Figure imgf000028_0004
Formula Va (e) reacting the compound of Formula Va with an acylating agent in the presence of a suitable base and solvent to obtain a compound of Formula VI; and
Figure imgf000029_0001
Formula VI
(f) optionally converting the compound of Formula VI to a pharmaceutically acceptable salt of Formula VII.
The details of the above embodiment is as follows:
The reactions of steps (a)-(d) are detailed in the previous embodiments. The further reaction steps are explained below:
Step (e) involves reacting the compound of Formula Va with an acylating agent in presence of a suitable base and solvent to obtain a compound of Formula VI.
The acylating agents that may be used in this step may be any acid chloride. Particularly isobutyrylchloride is preferred.
The reaction of step (e) can be carried in the presence of a suitable base such as aliphatic amines and a solvent which is a polar aprotic solvent.
Aliphatic amines that can be used at this step can be selected from trialkylamines with straight-chain or branched alkyl residues containing 1 to 20 carbon atoms. Examples of such alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and n-octyl. In such trialkylamines, the alkyl residues can be the same or different. Particularly, preferred aliphatic amine is triethylamine and disiopropylethyl amine.
Polar aprotic solvent that can be used at this step can be selected from dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate, acetone, dimethylformamide (DMF), acetonitrile, dimethylsulfoxide and the like. Particularly, preferred polar aprotic solvent is dichloromethane.
Step (f) involes optionally converting the compound of Formula VI to a pharmaceutically acceptable salt of Formula VII.
The salts of Formula VII may be prepared from pharmaceutically acceptable non-toxic inorganic or organic acids.
The salts may be prepared during the final isolation and purification of the compounds by making acidic addition salts.
Representative salts of basic compounds of the present invention can be prepared by reacting free base form of the compound of Formula VI with a suitable acid, including, but not limited to acetate, trifluoroacetate, adipate, citrate, aspartate, benzoate, benzenesulphonate, bisulfate, besylate, camphorsulphonate, hemisulfate, heptanoate, formate, fumarate, lactate, maleate, methanesulfonate, naphthylsulfonate, nicotinate, oxalate, picrate, pivalate, succinate, tartrate, trichloracetate, glutamate, p-toluenesulphonate, hydrochloric, hydrobromic, sulphuric, phosphoric and the like. Particularly, fumarate is preferred.
In a specific embodiment, the present invention provides a process for the preparation of fesoterodine of Formula VI' and its pharmaceutically acceptable fumarate salt VII', said process comprising:
(a) preparing a compound of Formula Γ
Figure imgf000030_0001
Formula
by reacting a compound of Formula Ι
Figure imgf000031_0001
Formula II"
a compound of Formula III
Figure imgf000031_0002
Formula III
in the presence of a N-methyl piperazine ;
(b) reductively aminating the compound of Formula Γ with Diisopropylamine to obtain compound of Formula IV;
Figure imgf000031_0003
Formula IV
(c) reducing the compound of Formula IV with vitride to obtain a compound of Formula V;
Figure imgf000031_0004
Formula V
(d) resolving the compound of Formula V to compound of Formula V'a using L(-)Malic acid or D(+)-Malic acid or L (+)-Tartaric acid;
Figure imgf000032_0001
Formula V'a
(e) acylating the compound of Formula V'a with isobutyryl chloride to obtain a compound of
Formula VI'; and
Figure imgf000032_0002
Formula VII'
EXAMPLES: The invention is further described by reference to the following examples which are given solely for the purpose of illustration only and therefore should not be construed to limit the scope of the invention. Example 1: Preparation of (4R, 4S)-2-(R, S)-Hydroxy-4-phenylchromane-6-carboxylic acid methyl ester (Γ).
To a stirring solution of 4-Hydroxy methyl benzoate (200 g, 1.314 mol) (compound ΙΓ) in toluene (2000 ml), N-methyl piperazine (195 g, 1.97 mol) was added at 25-30°C and heated the reaction mass to 100-110°C in a Dean stark apparatus. t-Cinnamaldehyde (350 g, 2.64 mol) (compound III) was slowly added to the reaction mass at 60-65 °C and refluxed for 4- 5h. After completion of the reaction, the reaction mass was cooled to 25-30°C and diluted with aqueous hydrochloric acid (2000 ml). The organic layer was separated and washed with 5% sodium bicarbonate followed by water. The organic layer was concentrated to dryness to obtain the title compound Γ (280 g, 0.985 mol). Yield: 75%
Example 2: Preparation of (R,S)-3-(3-Diisopropylamino-l-phenylpropyl)-4- hydroxybenzoic acid methyl ester) (IV)
To a stirring solution of the Compound Γ (280 g, 0.985 mol) obtained from Example 1 in methanol (1400 ml) in an autoclave vessel, N,N-Diisopropylamine (149 g, 1.47 mol) and 10% Pd/C (14 g) was added at 25-30°C. The mass was stirred under hydrogen atmosphere with 200 psi pressure at 45-50°C. After completion of the reaction, the reaction mass was filtered through celite and washed with methanol (280 ml). The filtrate was concentrated to dryness under reduced pressure. The obtained crude product was dissolved in isopropyl ether (750 ml) and 5% H2S04 solution (800 ml) was added to it and stirred for 30-45 minutes. The aqueous and organic layers were separated and the aqueous layer was washed with isopropyl ether (750 ml). The aqueous layer was basified with 10% NaOH solution (250 ml) to make reaction mass at pH 9-10 below 20°C and extracted with ethyl acetate (700 ml) twice. The ethyl acetate layers were combined and washed with water. The organic layer was separated and concentrated to dryness under reduced pressure to obtain the title compound IV (260 g, 0.706 mol). Yield: 71.62 % (HPLC purity: 96.78%) Example 3: Preparation of (R,S)-2-(3-Diisopropylamino-l-phenylpropyl)-4-hydroxy methyl phenol (V')
Compound IV (290 g, 0.785 mol) obtained ftom example 2 was dissolved in toluene (2320 ml) and the reaction mass was cooled to 0-10°C under argon atmosphere. To this, Vitride solution in toluene (460 ml, 1.37 mol) (60% in toluene) was added at 10-20°C and the addition line was rinsed with toluene (580 ml). After addition, the reaction mass was allowed to room temperature and stirred for 15 min after which the temperature was raised to 25-30°C and continued for 10-12 hrs at 25-30°C. After completion of the reaction, the reaction mass was again cooled and diluted with ethyl acetate (100 ml). 5% sodium hydroxide solution and water (1160 ml) was added to the reaction mass and stirred for 15-30 min. The aqueous and organic layers were separated and the aqueous layer was washed with ethyl acetate (200 ml). All the organic layers were combined and washed with 5% sodium bicarbonate solution followed by 200 ml of water wash. The organic layer was concentrated to dryness under reduced pressure to obtain crude material. The crude material was dissolved in ethyl acetate (290 ml) at 45-50°C under stirring and pet ether (1740 ml) was added to the reaction mass at the same temperature slowly over 30 min. The reaction mass was cooled to room temperature and stirred for 12-14 hrs. The solid was filtered, washed with 290 ml of pet ether and dried in vacuum oven at 40-45°C for 8-10 hrs to obtain the title compound V (174 g, 0.51 mol). Yield: 65.1% (HPLC purity: 98.87%)
Example 4: Preparation of (R)-(+)-2-(3-Diisopropylamino-l-phenylpropyl)-4-hydroxy methyl phenol (V'a)
Compound V (6.5 g, 0.019 mol) obtained from example 3 was added to isopropyl alcohol (65 ml) at 25-30°C and the reaction mass was heated to 50°C under stirring. To this, L-(-) Malic acid (2.55 g, 0.019 mol) was added and the reaction mass was stirred for 2-3 hrs at the same temperature followed by the addition of Diisopropylether (13 ml). The reaction mass was slowly cooled to room temperature and stirred for 12-16 hrs at the same temperature. The solid was filtered under vacuum and washed with 1 :1 IPA/IPE solution (10 ml) and the ML's were collected, concentrated to dryness and pH was adjusted to 10 using 10% sodium bicarbonate solution followed by washing with ethyl acetate (50 ml). The organic layer was separated and washed with water (20 ml), followed by its concentration to dryness to obtain the title compound. Weight of the compound: 3.0 g; chiral purity: 83%.
The Malic acid salt was purified in 1:1 IPA/IPE solution to get the title compound (2.35 g, 0.0068 mol). Yield: 36.15 % (Chiral purity: 98%)
Example 5: Preparation of (R)-(+)-2-(3-Diisopropylamino-l-phenylpropyl)-4-hydroxy methyl phenol (V'a)
Compound V (5.0 g, 0.0146 mol) obtained from example 3 was added to isopropyl alcohol (150 ml) at 25-30°C and the reaction mass was heated to 80°C under stirring. To this, D (+) Malic acid (1.96 g, 0.0146 mol) was added and the reaction mass was stirred for 2-3 hrs at the same temperature. The reaction mass was cooled to room temperature and stirred for 12- 16 hrs at the same temperature. Diisopropylether (25 ml) was added and stirred for 4-5 hrs. The solid was filtered and washed with 1 :1 IPA/IPE solution (10 ml). The obtained solid was dissolved in water and the pH was adjusted to 10 using 10% sodium bicarbonate solution followed by extraction with ethyl acetate (50 ml). The organic layer was separated and washed with water (20 ml) followed by its concentration to dryness to obtain the title compound (2.01 g, 0.0059 mol). Yield: 40.2%; chiral purity: 95%. Example 6: Preparation of (R)-(+)-2-(3-Diisopropylamino-l-phenylpropyl)-4-hydroxy methyl phenol (V'a)
Compound V (50 g,0.146 mol) obtained from example 3 was dissolved in tetrahydrofuran (1250 ml) at 25-30°C and D(+) Malic acid (19.63 g,0.146 mol) was added at 25-30°C. The reaction mass was stirred for 2-3 hrs at 55-60°C followed by cooling the reaction mass to 25-30°C and stirred for 15-20 hrs. The precipitated product was filtered and washed with chilled tetrahydrofuran (100 ml). The obtained solid was dissolved in water (200 ml) and the pH was adjusted to 10 using 10% sodium bicarbonate solution followed by extraction with ethyl acetate (375 ml). The organic layer was separated and washed with water (200 ml) followed by its concentration to dryness to obtain the title compound V'a (13 g, 0.038 mol). Yield: 26.0%; chiral purity 98%. Example 7: Preparation of (R)-(+)-2-(3-Diisopropylamino-l-phenylpropyl)-4-hydroxy methyl phenol (V'a)
Compound V (5 g, 0.0146 mol) obtained from example 3 was added to tetrahydrofuran (125 ml) at 25-30°C and the reaction mass was heated to 50°C under stirring. To this L-(+)- Tartaric acid (2.2 g, 0.0146 mol) was added and the reaction mass was stirred for 2-3 hrs at the same temperature. The obtained solid was filtered and washed with tetrahydrofuran (10 ml). The solid was dissolved in water and the pH was adjusted to 10 using 10% Sodium Bicarbonate solution followed by extraction with 50 ml of ethyl acetate. The organic layer was separated and washed with water (20 ml) followed by its concentration to dryness to obtain the title compound (0.72 g, 0.002 mol). Yield: 14.4%
Example 8: Preparation of (R)-(+)-2-(3-Diisopropylammo-l-phenylpropyl)-4-hydroxy methyl phenol (V'a)
Compound V (10 g, 0.0293 mol) obtained from example 3 was added to ethyl acetate (200 ml) at 25-30°C and the reaction mass was heated to 55°C under stirring. To this of R-(-)- Acetoxy phenyl acetic acid (2.84 g, 0.0146 mol) in ethyl acetate (30 ml) was added and addition line was washed with ethyl acetate (20 ml). The reaction mass was stirred for 5-6 hrs at the same temperature and allowed the reaction mass to 25-30°C. The obtained solid was filtered and washed with 10 ml of ethyl acetate. The solid was dissolved in water (20 ml) and pH was adjusted to 10 by using 10% potassium carbonate solution followed by extraction with ethyl acetate (75 ml). The organic layer was separated and washed with water (50 ml) followed by its concentration to dryness to obtain the title compound (3.45 g, 0.101 mol). Yield: 34.5%; chiral purity: 98%.
Example 9: Preparation of R-(+)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxy methylphenol isobutyrate ester (VI')
This preparation is done as per the method described in US 6858650 or US7384980 which is inserted herein by reference. Example 10: Preparation of R-(+)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxy methylphenol isobutyrate ester hydrogen Fumarate (VII')
This preparation is done as per the method described in US 6858650 which is inserted herein by reference.
The general reaction scheme of one of the embodiments of the instant invention can be schematically represented as follows:
Figure imgf000037_0001
Fesoterodine Fumarate

Claims

We Claim:
1. A process for the preparation of compounds of Formula I or its pharmaceutically acceptable salts,
Figure imgf000038_0001
Formula I wherein
Figure imgf000038_0002
is selected from C Cio alkyl or aryl group;
said process comprising:
reacting a compound of Formula II
Figure imgf000038_0003
Formula II
wherein Rj is as defined above;
with a compound of Formula III
Figure imgf000039_0001
Formula III in the presence of a secondary amine compound.
2. The process of claim 1, wherein the secondary amine compound is selected from the group consisting of N-methyl piperazine, morpholine, dibutylamine, dibenzylamine, diisopropylamine, diethylamine and piperidine.
3. A process for the preparation of compounds of Formula Γ
Figure imgf000039_0002
Formula I'
comprising, reacting a compound of Formula ΙΓ
Figure imgf000039_0003
Formula Ι with a compound of Formula III
Figure imgf000040_0001
Formula III in the presence of N-methyl piperazine.
4. A process for the preparation of compounds of Formula Va or its pharmaceutically acceptable salts,
Figure imgf000040_0002
Formula Va
wherein R2 and R3 are the same or different and are selected from Q-Cio alkyl or aryl group;
said process comprising;
(a) reacting a compound of Formula II
Figure imgf000040_0003
wherein Ri is selected form Ci-Cio alkyl or aryl;
with a compound of Formula III
Figure imgf000041_0001
Formula III
in the presence of a secondary amine compound to obtain a compound of Formula I;
Figure imgf000041_0002
Formula I
(b) reductively aminating the compound of Formula I with an alkylamine to obtain compound of Formula IV
Figure imgf000041_0003
Formula IV
wherein Ri, R2 and R3 are as defined above;
(c) reducing the compound of Formula IV with a reducing agent to obtain a compound of Formula V; and
Figure imgf000041_0004
Formula V (d) resolving the compound of Formula V to its R enantiomer of Formula Va.
5. A process according to claim 4, wherein the step (b) is carried out in the presence of a reducing agent.
6. A process according to claim 5, wherein the reducing agent used in step (b) is selected from the group consisting of H2/Pd-C, sodium borohydride, sodium acetoxy borohydride and ammonium formate/Pd-C.
7. A process according to claim 4, wherein the alkylamine used in step (b) is selected from the compounds of general formula NH(R2)(R3), wherein R2 and R3 are the same or different and are selected from the group consisting of Ci-C|0 alkyl or aryl.
8. A process according to claim 4, wherein the reducing agent used in step (c) is selected from aluminium hydride reducing agent such as diisobutylaluminium hydride, sodium dihydrobis(2-methoxyethoxy) aluminate (vitride), and lithium tri- tert-butyoxyaluminohydride.
9. A process according to claim 4, wherein the step (d) is carried out in the presence of a resoluting acid, a base and a solvent.
10. A process according to claim 9, wherein the resoluting acid is selected from the group consisting of L-(-)-Malic acid, D-(+)-Malic acid, L-(+)-Tartaric acid, D-(-)- Tartaric acid, N-Acetyl-L-Glutamic acid, N-Acetyl-D-Glutamic acid, (+)-Camphor sulfonic acid, (-)-Camphor sulfonic acid, S-(+)-Mandelic acid, R-(-)-Mandelic acid, (+)-2,3-Di benzoyl-D-tartaric acid, (-)-2,3-Di benzoyl-L-Tartaric acid, (-)-2,3-Di-p- toluyl L-Tartaric acid, (+)-2,3-di 7-toluyl D-Tartaric acid, L-Aspartic acid, D-(+)- Glucuronic acid, R-(-)-Acetoxy Mandelic acid, R (+)-2-(4- Hydroxyphenoxy)propionic acid and Mucic acid.
11. A process according to claim 9, wherein the base is selected from the group consisting of hydroxides, carbonates, bicarbonates, alkoxides and oxides of alkali or alkaline earth metals.
12. A process according to claim 9, wherein the solvent is selected from the group consisting of tetrahydrofuran, isopropyl alcohol, isoamyl alcohol, ethyl acetate, acetone, acetonitrile, methanol, ethanol, isopropyl ether and their mixtures.
13. A process according to claim 12, wherein the solvent is tetrahydrofuran or mixture of isopropyl alcohol and isopropyl ether.
14. A process for the preparation of compounds of Formula V'a:
Figure imgf000043_0001
Formula If
with a compound of Formula III
Figure imgf000043_0002
Formula III
in the presence of a secondary amine compound to obtain a compound of Formula Γ;
Figure imgf000043_0003
Formula (b) reductively aminating the compound of Formula Γ, to obtain compound of Formula IV;
Figure imgf000044_0001
Formula IV
(c) reducing the compound of Formula IV with a reducing agent to obtain a compound of Formula V; and
Figure imgf000044_0002
Formula V*
(d) resolving the compound of Formula V to its R enantiomer of Formula Va.
15. A process for the preparation of a compound of Formula VI or its pharmaceutically acce table salts of Formula VII,
Figure imgf000044_0003
Formula VI Formula VII wherein R2, R3 and R4 are same or different and are selected from CpCio alkyl or aryl group and X is any salt;
said process comprising: (a) reacting a compound of Formula II
Figure imgf000045_0001
Formula II
with a compound of Formula III
Figure imgf000045_0002
Formula III
in the presence of a secondary amine compound to obtain a compound of Formula I;
Figure imgf000045_0003
Formula I
(b) reductively aminating the compound of Formula I with an alkylamine to obtain a compound of Formula IV;
Figure imgf000045_0004
Formula IV
(c) reducing the compound of Formula IV with a reducing agent to obtain a compound of Formula V;
Figure imgf000046_0001
Formula V
(d) resolving the compound of Formula V to its R enantiomer of Formula Va;
Figure imgf000046_0002
Formula Va
(e) reacting the compound of Formula Va with an acylating agent in the presence of a suitable base and a solvent to obtain a compound of Formula VI; and
Figure imgf000046_0003
Formula VI
(f) optionally converting the compound of Formula VI to a pharmaceutically acceptable salt of Formula VII.
16. A process according to claim 15, wherein the acylating agent used in step (e) is an acid chloride.
17. A process according to claim 16, wherein the acid chloride is isobutyrylchloride.
18. A process according to claim 15, wherein the base used in step (e) is selected from an aliphatic amine.
19. A process according to claim 18, wherein the aliphatic amine used in step (e) is selected from trialkylamines with straight-chain or branched alkyl residues containing 1 to 20 carbon atoms.
20. A process according to claim 15, wherein the solvent is a polar aprotic solvent.
21. A process according to claim 15, wherein the salt in step (f) is selected from acetate, trifluoroacetate, adipate, citrate, aspartate, benzoate, benzenesulphonate, bisulfate, besylate, camphorsulphonate, hemisulfate, heptanoate, formate, fumarate, lactate, maleate, methanesulfonate, naphthylsulfonate, nicotinate, oxalate, picrate, pivalate, succinate, tartrate, trichloracetate, glutamate, p-toluenesulphonate, hydrochloric, hydrobromic, sulphuric and phosphoric.
22. A process according to claim 21, wherein the salt is fumarate.
23. A process for the preparation of fesoterodine of Formula VI' and its fumarate salt of Formula VII', said process comprising:
(a) preparing a compound of Formula Γ
Figure imgf000047_0001
Formula
by reacting a compound of Formula ΙΓ
Figure imgf000047_0002
Formula IP
with a compound of Formula III
Figure imgf000048_0001
Formula III
in the presence of a N methyl piperazine;
(b) reductively aminating the compound of Formula Γ with Diisopropyl obtain compound of Formula IV;
Figure imgf000048_0002
Formula IV
(c) reducing the compound of Formula IV with vitride to obtain a compound of Formula V;
Figure imgf000048_0003
Formula V
(d) resolving the compound of Formula V to compound of Formula V'a using L(- )malic acid or D(+)-Malic acid or L (+)-Tartaric acid;
Figure imgf000049_0001
Formula V'a
(e) acylating the compound of Formula V'a with isobutyryl chloride to obtain a compound of Formula VI';
Figure imgf000049_0002
Formula VI'
(f optionally converting the compound of Formula VI' to the its fumarate salt of Formula VII'.
Figure imgf000049_0003
Formula VII'
PCT/IN2011/000403 2010-06-18 2011-06-15 Preparation process of fesoterodine and intermediates WO2011158257A1 (en)

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