WO2015159170A2 - Improved process for the synthesis of 1-(4-methoxyphenyl) ethylamine and its isomers - Google Patents

Improved process for the synthesis of 1-(4-methoxyphenyl) ethylamine and its isomers Download PDF

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WO2015159170A2
WO2015159170A2 PCT/IB2015/052303 IB2015052303W WO2015159170A2 WO 2015159170 A2 WO2015159170 A2 WO 2015159170A2 IB 2015052303 W IB2015052303 W IB 2015052303W WO 2015159170 A2 WO2015159170 A2 WO 2015159170A2
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formula
compound
methoxyphenyl
acid
catalyst
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WO2015159170A3 (en
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Rajendiran Chinnapillai
Indrasena Reddy KONDAKINDI
Venkateswarlu Jasti
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Suven Life Sciences Limited
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    • 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
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/04—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms

Definitions

  • the present invention relates to an improved and efficient process for the preparation of highly useful and versatile chiral compound (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) and formula ( -R)
  • the present invention relates to an improved process for the preparation of optically pure compound of formula 1 from easily and commercially available materials.
  • (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) is useful as chiral resolving agent, chiral auxiliary, chiral base and catalyst for asymmetric synthesis of chiral amines such as (-)-(R)- Sitagliptin, Elarofiban, CXCR4 antagonist GSK812397, Docetaxel and phase- ⁇ , ⁇ , ⁇ molecules in pharmaceuticals and agrochemicals.
  • Various conventional techniques are reported in the literature for the preparation of (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1).
  • the process for the preparation of (S)-(-)-l-(4-methoxyphenyl)ethylamine involves reaction of 4-methoxyphenylacetic acid of the formula (2) with oxalylchloride for about 16 hrs, followed by reaction with lithium salt of (S)-4-benzyl-2-oxazolidinone at -78°C to give 4-(S)- benzyl-3-(4-methoxy)phenylacetyl-2-oxazolidinone of the formula (3), which is further alkylated with methyl iodide in the presence of LiHMDS at -78°C to give (2S, 4S)-4-benzyl-3-(l-oxo-2- (4-methoxyphenyl)propyl)-2-oxazolidinoe of the formula (4), which is further converted into (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) by subsequent reactions with LiOH, H
  • the process comprises condensation of 4-methoxy acetophenone of formula (5) with (lS,2R)-(+)- norephedrine of formula (6) in the presence of molecular sieve 4A in benzene as solvent to yield imine of formula (7), which is further reduced in the presence of Adam's catalyst followed by oxidative removal of the norephedrine carbons using sodium metaperiodate to yield (S)-(-)-l-(4- methoxyphenyl) ethylamine of formula (1) with 57% optical purity.
  • This process comprises the Lipase B enzyme catalyzed resolution of the compound formula of (9) to give (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) with 78% optical purity.
  • This method is not suitable for commercial scale due to the use of Lipase B enzyme and also the optical purity of compound of formula (1) is 78% only.
  • Scheme-5 The process involves the asymmetric hydroboration followed by amination of l-methoxy-4- vinyl-benzene compound of the formula (10) with rhodium complex of (S)-quinap in presence of Catecholborane, MeMgCI and H 2 NOS0 3 H to give (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) with 98% optical purity.
  • the optical purity of compound (1) by following this approach is good but this method is not feasible for commercial scale due to the use of highly expensive catalyst i.e rhodium complex of (S)-quinap and hazard chemicals like Catecholborane, MeMgCI and H 2 NOS0 3 H.
  • This process comprises the enantioselective hydrosilylation of ketimine of compound (11) with trichlorosilane in the presence of chiral N-picolinoylaminoalchols followed by catalytic hydrogenation with Pd/C to give (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1).
  • This method is not feasible for commercial scale due to the use highly expensive catalyst i.e chiral N- picolinoylaminoalchols and hazard chemicals like trichlorosilane.
  • Scheme-8 The disclosed process involves resolution of ( ⁇ )- 1 -(4-methoxyphenyl)ethylamine of formula (13) with (S)-2-(2-Naphthyl) glycolicacid followed treatment with hydrochloric acid gives (S)-(-)-l- (4-methoxyphenyl)ethylamine of formula (1) with 87% optical purity. This method is not feasible for commercial scale due to low optical purity and multiple recrystallizations are required to get 99% pure compound.
  • the main object of the present invention is to provide an improved process for the preparation of (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1).
  • Another object of the present invention is to provide an improved process for the preparation of (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) with optical purity above 99.5%.
  • a further object of the present invention is to provide an improved process for the preparation of (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) avoiding the use of hazardous chemicals like n-BuLi, BH 3 -THF, diphenylphosphorylazide, diethyl zinc.
  • Still another object of the present invention is to provide an improved process for the preparation of (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) avoiding the use of -78°C temperature.
  • Yet another objective of the present invention is to provide an improved process for the preparation of (S)-(-)-l-(4-Methoxyphenyl) ethylamine of formula (1) which can be readily scaled up to industrial level.
  • a further most important object of the present invention is that the process used for the preparation of (S)-(-)-l-(4-methoxyphenyl)ethylamine of formula (1) is applicable for the preparation of its isomer (R)-(+)-l-(4-methoxyphenyl) ethylamine of formula (1-R) from 4- methoxy acetophenone (14) and (R)-(+)-a-methylbenzylamine and (RS)-l-(4-Methoxyphenyl) ethylamine of the formula -RS) from 4-methoxy acetophenone and (RS)-a-methylbenzylamine.
  • the present invention provides an improved and efficient process for the preparation of (S)-(-)-l-(4-methoxyphenyl)ethylamine of formula (1)
  • (S)-(-)-l-(4-methoxyphenyl) ethylamine (1) prepared according to the present invention has optical purity above 99% .
  • Another aspect of the present invention relates to the preparation of (R)-(+)-l-(4- methoxyphenyl)ethylamine of formula (1-R).
  • the present invention provides an improved process for the preparation of (S)- (-)-l-(4-Methoxyphenyl) ethylamine (1)
  • Suitable solvent used in step (a) is selected from toluene, chloroform, dichlorome thane, EDC, CCI4, MTBE, methanol, THF, and the like or mixtures thereof, preferably toluene and the catalyst used is selected from para toluenesulfonic acid, acetic acid, hydrochloric acid, sulfuric acid and the like preferably para toluenesulfonic acid at ambient temperatures in the range from about 25 to 130°C preferably at 125-130°C.
  • the duration of the reaction may range from 1 to 10 hours, preferably from a period of 6 to 8 hours.
  • Suitable catalyst used in step (b) is selected from palladium on carbon, raney nickel, platinum oxide, palladium hydroxide on carbon, sodium borohydride, sodium cyanoborohydride, sodiumtriacetoxy borohydride or a mixture thereof, in combination with metal, preferably palladium on carbon and sodium borohydride, more preferable palladium on carbon under hydrogen gas.
  • the solvent used in this reaction may be selected from methanol, ethanol, IPA, ethyl acetate, isopropyl acetate, THF, 2-methyl THF, dimethoxy ethane and the like or mixture thereof, preferably methanol and ethyl acetate more preferably ethyl acetate.
  • the volume of the solvent used for the reaction may be in the range of 2-10 volumes more preferably 4.5 to 5 volumes.
  • the reaction is carried out at a temperature in the range from about 25 to 60°C more preferably at 35-38°C .
  • the duration of the reaction may range from 10 to 12 hours.
  • the hydrogen pressure is about 1 kg/cm 2 to 15 kg/cm 2 , preferably 8 kg/cm 2 to 12 kg/cm 2.
  • the acid used in the reaction may be organic and inorganic acids selected from para toluenesulfonic acid, oxalic acid hydrochloric acid, hydrobromic acid, sulfuric acid, preferably para toluenesulfonic acid.
  • the preferable salts of compound of formula (17) may be selected from para toluenesulfonic acid, oxalic acid hydrochloric acid, hydrobromic acid, sulfuric acid and the like.
  • Suitable catalyst used in step (c) is selected from palladium on carbon, raneynickel, platinum oxide, palladium hydroxide on carbon, more preferably palladium on carbon.
  • the solvent used in this reaction may be selected from methanol, ethanol, IPA, ethyl acetate, isopropyl acetate, THF, 2-methyl THF, more preferably methanol.
  • the volume of the solvent used for the reaction may be in the range of 5-15 volumes more preferably 12-13 volumes.
  • the reaction is carried out at a temperature in the range from about 25 to 60°C more preferably at 50-55°C .
  • the hydrogen pressure is about 1 kg/cm 2 to 15 kg/cm 2 , preferably 8 kg/cm 2 to 12 kg/cm 2.
  • the acid used in the reaction may be organic and inorganic acid selected from para toluenesulfonic acid, oxalic acid, hydrochloric acid, hydrobromic acid, sulfuric acid preferably hydrochloric acid in IPA and the base used is selected from inorganic or organic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethyl amine, disopropyl amine and the like, more preferably sodium carbonate.
  • the present invention provides a process for the synthesis of (R)-(+)-l- (4-methoxyphenyl) ethylamine of formula ( 1 -R)
  • the present invention provides a process for the synthesis of (RS)-l-(4- methoxyphenyl)ethylamine of formula (1-RS)
  • the present invention provides novel compounds
  • the process does not use highly hazardous chemicals like n-BuLi, LiHMDS, trichlorosilnae diphenylyphosphorylazide, and hence the process is safe for commercial scale.
  • this invention provides improved and efficient process for the synthesis of both the isomers of l-(4-Methoxyphenyl) ethylamine with chiral purity of >99%.
  • IR spectra were recorded on Perkin Elmer Spectrophotometer as KBr pellets or neat.
  • 1H-NMR, 13C-NMR spectra were recorded on a Bruker 400 MHz spectrometer with TMS as internal standard (chemical shift in ⁇ , ppm) and Mass spectra were measured on API 4000 model.
  • Chiral HPLC analysis was carried using Shimadzu with symmetry CI 8, 220nm. The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limited and relate to solutions which have been particularly effective on a bench scale.
  • Step-(a) Preparation of (S)-r i-(4-Methoxyphenyl)-ethylidenel-(l-phenylethyl)amine (16 ).
  • Mixture of 4-methoxyacetophenone (100 gm, 0.66 mole) and (S)-(-)-a-methylbenzylamine (100.8 gm, 0.83 mole) was refluxed in presence of p-toluenesulfonic acid (5 gm, 0.02 mole) in toluene (600 ml) for 10-12 hours, while the water formed during the progress of the reaction was separated azeotropically by using Dean-Stark trap which was connected to a refluxing condenser.
  • Step-(c) Preparation of (S)-(-)-l-(4-Methoxyphenyl)ethylamine (1).
  • IR (neat, cm “1 ): 3369, 3294, 2959, 2835, 1610, 1585, 1512, 1463, 1368, 1329, 1301, 1284, 1246, 1177, 1100, 1034, 917, 831, 701.
  • Step-(a) Preparation of (R)-[l-(4-Methoxyphenyl)-ethylidenel-(l-phenylethyl)amine (16-R ).

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

Abstract

The present invention relates to an improved and efficient process for the preparation of highly useful and versatile chiral compound (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) and formula (1-R) from novel chiral compounds (S)-[l-(4-Methoxyphenyl)-ethylidene]-(l-phenylethyl)amine of formula (16) and (R)-[l-(4-Methoxyphenyl)-ethylidene]-(l-phenylethyl)amine of formula (16-R) respectively.

Description

IMPROVED PROCESS FOR THE SYNTHESIS OF l-(4-METHOXYPHENYL)
ETHYLAMINE AND ITS ISOMERS
Field of the Invention
The present invention relates to an improved and efficient process for the preparation of highly useful and versatile chiral compound (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) and formula ( -R)
Figure imgf000002_0001
from novel chiral compounds (S)-[l-(4-Methoxyphenyl)-ethylidene]-(l-phenylethyl)amine of formula (16) and (R)-[l-(4-Methoxyphenyl)-ethylidene]-(l-phenylethyl)amine of formula (16-R) respectively.
Figure imgf000002_0002
More particularly, the present invention relates to an improved process for the preparation of optically pure compound of formula 1 from easily and commercially available materials.
Background of the Invention
(S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) is useful as chiral resolving agent, chiral auxiliary, chiral base and catalyst for asymmetric synthesis of chiral amines such as (-)-(R)- Sitagliptin, Elarofiban, CXCR4 antagonist GSK812397, Docetaxel and phase-Ι,ΙΙ,ΙΙΙ molecules in pharmaceuticals and agrochemicals. Various conventional techniques are reported in the literature for the preparation of (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1).
US patent No. 5,438, 118 describes a process for the preparation of (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1), which is as depicted in scheme-I given below:
Figure imgf000003_0001
Scheme- 1
Briefly, the process for the preparation of (S)-(-)-l-(4-methoxyphenyl)ethylamine involves reaction of 4-methoxyphenylacetic acid of the formula (2) with oxalylchloride for about 16 hrs, followed by reaction with lithium salt of (S)-4-benzyl-2-oxazolidinone at -78°C to give 4-(S)- benzyl-3-(4-methoxy)phenylacetyl-2-oxazolidinone of the formula (3), which is further alkylated with methyl iodide in the presence of LiHMDS at -78°C to give (2S, 4S)-4-benzyl-3-(l-oxo-2- (4-methoxyphenyl)propyl)-2-oxazolidinoe of the formula (4), which is further converted into (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) by subsequent reactions with LiOH, H202 and DPPA (diphenylphosporylazide) in the presence of TEA followed by catalytic hydrogenation with Pd/C.
The process disclosed in the above patent suffers from a serious drawback especially from commercial point of view like use of highly hazardous chemicals such as oxalyl chloride, n-BuLi, LiHMDS, H202, diphenylphosporylazide and -78°C temperature.
R.Sreekumar et al, Tetrahedron: Asymmetry Vol.4 (9), pp.2095-2100, 1993 discloses a process for the preparation of (S)-(-)-l-(4-methoxyphenyl)ethylamine as shown in scheme-2 given below:
Figure imgf000004_0001
Scheme 2
The process comprises condensation of 4-methoxy acetophenone of formula (5) with (lS,2R)-(+)- norephedrine of formula (6) in the presence of molecular sieve 4A in benzene as solvent to yield imine of formula (7), which is further reduced in the presence of Adam's catalyst followed by oxidative removal of the norephedrine carbons using sodium metaperiodate to yield (S)-(-)-l-(4- methoxyphenyl) ethylamine of formula (1) with 57% optical purity.
The drawback of this process is that the optical purity of compound of formula (1) is only 57% and also use of chemicals like (IS, 2R)-(+)-norephedrine, Adam's catalyst, benzene as solvent and molecular sieve 4A.
Zixing Shan et al, J.Org.Chem, Vol.71, pp.3998-4001, 2006 discloses a process for the preparation of compound of formula (1) as shown in scheme-3 given below:
Figure imgf000004_0002
Scheme 3 The process involves the asymmetric reduction of compound of the formula (8) by chiral spiroborate esters in presence of BH3-THF followed by silica gel chromatography purification to give (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) with 90% optical purity.
The process disclosed in the above publication suffers from a drawback especially from commercial point of view like use of selective chiral catalyst such as chiral spiroborate esters; highly hazardous chemical like BH3-THF and silica gel column chromatography to get 90% pure compound of formula (1). Use of column chromatography in a commercial scale is difficult and therefore the process is not suitable for commercial scale production.
Daniel T. Chapman et al., Chem. Communication pp.2415-2416-4001, 1996 discloses a biotransformation process for the synthesis of (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) as depicted in scheme-4.
Figure imgf000005_0001
Scheme-4
This process comprises the Lipase B enzyme catalyzed resolution of the compound formula of (9) to give (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) with 78% optical purity. This method is not suitable for commercial scale due to the use of Lipase B enzyme and also the optical purity of compound of formula (1) is 78% only.
John M. Brown et al, Chem.Commun., pp.173-174, 1997 discloses a process for the synthesis of compound (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) as shown in the scheme given below:
Figure imgf000006_0001
Scheme-5 The process involves the asymmetric hydroboration followed by amination of l-methoxy-4- vinyl-benzene compound of the formula (10) with rhodium complex of (S)-quinap in presence of Catecholborane, MeMgCI and H2NOS03H to give (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) with 98% optical purity. Although the optical purity of compound (1) by following this approach is good but this method is not feasible for commercial scale due to the use of highly expensive catalyst i.e rhodium complex of (S)-quinap and hazard chemicals like Catecholborane, MeMgCI and H2NOS03H.
Hongjie et, al., Tet.Lett. 48, pp.7934-7937, 2007 discloses synthesis of (S)-(-)-l-(4- methoxyphenyl)ethylamine of formula (1) by enantioselective hydrosilylation of ketimine as shown in scheme-6 given below:
Figure imgf000006_0002
(1 1 ) (1 )
Scheme-6
This process comprises the enantioselective hydrosilylation of ketimine of compound (11) with trichlorosilane in the presence of chiral N-picolinoylaminoalchols followed by catalytic hydrogenation with Pd/C to give (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1). This method is not feasible for commercial scale due to the use highly expensive catalyst i.e chiral N- picolinoylaminoalchols and hazard chemicals like trichlorosilane. Yong Qin et al, Org.Lett., 8(1), pp.139-142, 2006 discloses a method for the synthesis of (S)-(-)- 1 -(4-Methoxyphenyl) ethylamine of formula (1) as shown in scheme-7 given below:
Figure imgf000007_0001
(12)
Scheme-7
This process involves the selective reduction of the tert-butanesulfinyl ketimine of formula (12) with diethylzinc in the presence of catalytic Ni(acac)2 followed by hydrolysis with hydrochloric acid to yield (S)-(-)-l -(4-Methoxyphenyl) ethylamine of formula (1). The process disclosed in the above publication suffers from a drawback especially from commercial point of view like the use of selective catalyst i.e Ni(acac)2 and expensive chemicals like (S)-(-)-2-methyl-2-propanesulfinamide and diethylzinc, therefore the process is not suitable for commercial scale production. US patent No. 6,342,636 describes a process for the preparation of (S)-(-)-l -(4-Methoxyphenyl) ethylamine of formula (1) as shown in scheme-8 given below:
Figure imgf000007_0002
(13) (1 )
Scheme-8 The disclosed process involves resolution of (±)- 1 -(4-methoxyphenyl)ethylamine of formula (13) with (S)-2-(2-Naphthyl) glycolicacid followed treatment with hydrochloric acid gives (S)-(-)-l- (4-methoxyphenyl)ethylamine of formula (1) with 87% optical purity. This method is not feasible for commercial scale due to low optical purity and multiple recrystallizations are required to get 99% pure compound.
In addition to the above methods, there were also reports for the synthesis of (S)-(-)-l-(4- methoxyphenyl) ethylamine of formula (1) by Robert A. Moss et al., J.Org.Chem., 39(8), pp.1083- 1089, 1974; R.D. Guthrie et al., J.Am.Chem.Soc, pp.2971-2977, 1973 using resolution of (±)-l- (4-methoxyphenyl)ethylamine of formula (13) with optically active tartaric acid to get (S)-(-)-l-(4- methoxyphenyl) ethylamine of formula (1). The processes disclosed in these publications suffers a drawback especially from commercial point of view that the low optical purity and multiple recrystalisations are required to get 99% optically pure compound. However, all the processes of the prior art for the preparation of (S)-(-)-l-(4-methoxyphenyl) ethylamine (1) have evident disadvantages such as ,
(i) handling of hazardous chemicals like n-BuLi, LiHMDS, diphenylyphosphorylazide, trichlorosilnae,
(ii) -78°C temperature,
(iii) use of expensive chiral catalysts,
(iv) resolution process by using enzyme, which is industrially not feasible,
(v) low optical purity,
(vi) separation of isomers using Si-gel chromatography, which is industrially not feasible. Hence, there is a need to provide an improved process that would avoid the aforementioned steps like resolution, expensive chiral catalysts, hazardous chemicals like n-BuLi, LiHMDS, BH3-THF, diphenylphoporylazide and Silica gel purification and that could be well applicable on industrial scale. The present invention provides an improved process for the preparation of (S)-(-)-l-(4- methoxyphenyl) ethylamine of formula (1) which addresses the problems associated with the prior art.
Objective of the Invention
The main object of the present invention is to provide an improved process for the preparation of (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1).
Figure imgf000009_0001
Another object of the present invention is to provide an improved process for the preparation of (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) with optical purity above 99.5%.
Yet another object of the present invention is to be prepare a novel compounds of the formula (16) and (16-R) employing readily available and easy to handle reagents. Yet another object of the present invention is to provide an improved process for the preparation of (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) employing readily available and easy to handle reagents.
A further object of the present invention is to provide an improved process for the preparation of (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) avoiding the use of hazardous chemicals like n-BuLi, BH3-THF, diphenylphosphorylazide, diethyl zinc.
Still another object of the present invention is to provide an improved process for the preparation of (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) avoiding the use of -78°C temperature.
Yet another object of the present invention is to provide an improved process for the preparation of (S)-(-)-l-(4-methoxyphenyl)ethylamine of formula (1) avoiding the use of enzyme and chiral catalysts. Still another object of the present invention is to provide an improved process for the preparation of (S)-(-)-l-(4-methoxyphenyl)ethylamine of formula (1) avoiding the resolution process and silica gel purification.
Yet another objective of the present invention is to provide an improved process for the preparation of (S)-(-)-l-(4-Methoxyphenyl) ethylamine of formula (1) which can be readily scaled up to industrial level.
A further most important object of the present invention is that the process used for the preparation of (S)-(-)-l-(4-methoxyphenyl)ethylamine of formula (1) is applicable for the preparation of its isomer (R)-(+)-l-(4-methoxyphenyl) ethylamine of formula (1-R) from 4- methoxy acetophenone (14) and (R)-(+)-a-methylbenzylamine and (RS)-l-(4-Methoxyphenyl) ethylamine of the formula -RS) from 4-methoxy acetophenone and (RS)-a-methylbenzylamine.
Figure imgf000010_0001
Summary of the Invention
Accordingly, the present invention provides an improved and efficient process for the preparation of (S)-(-)-l-(4-methoxyphenyl)ethylamine of formula (1)
Figure imgf000010_0002
comprising the steps of,
(i) reaction of 4-methoxyacetophenone of formula (14)
Figure imgf000010_0003
with (S)-(-)-a-methylbenzylamine of formula (15),
Figure imgf000011_0001
in presence of a catalyst in organic solvent to obtain a new compound of formula (16),
Figure imgf000011_0002
(ii) catalytic reduction of a compound of formula (16) in the presence of a catalyst in a solvent followed by treatment with an acid to obtain compound of formula (17)
Figure imgf000011_0003
wherein X represent acid addition salt,
(iii) reduction of compound of formula (S,S-17) in the presence of a catalyst in solvent to optically pure compound of formula (1).
In another aspect, (S)-(-)-l-(4-methoxyphenyl) ethylamine (1) prepared according to the present invention has optical purity above 99% . Another aspect of the present invention relates to the preparation of (R)-(+)-l-(4- methoxyphenyl)ethylamine of formula (1-R).
Yet another aspect of the present invention relates to the preparation of (RS)-l-(4- methoxyphenyl) ethylamine of the formula (1-RS). Detailed Description of the Invention
In an embodiment, the present invention provides an improved process for the preparation of (S)- (-)-l-(4-Methoxyphenyl) ethylamine (1)
Figure imgf000012_0001
(1 )
comprising the steps of;
(i) reaction of 4-methoxyacetophenone of formula (14),
Figure imgf000012_0002
(14)
with (S)-(-)-a-methylbenzylamine of formula (15),
Figure imgf000012_0003
(15)
in the presence of suitable catalyst in organic solvent to obtain a new compound of formula (16),
Figure imgf000012_0004
(16)
(ii) catalytic reduction of a compound of formula (16) in the presence of suitable catalyst in suitable solvents followed by treatment with organic and inorganic acid to obtain compound of formula (17) wherein X preferably represent organic and inorganic salt.
Figure imgf000013_0001
(iii) catalytic reduction of compound of formula (17) in the presence of suitable catalyst in suitable solvents followed by treatment with acid base treatment to obtain compound of formula (1) with above 99% of optical purity.
Suitable solvent used in step (a) is selected from toluene, chloroform, dichlorome thane, EDC, CCI4, MTBE, methanol, THF, and the like or mixtures thereof, preferably toluene and the catalyst used is selected from para toluenesulfonic acid, acetic acid, hydrochloric acid, sulfuric acid and the like preferably para toluenesulfonic acid at ambient temperatures in the range from about 25 to 130°C preferably at 125-130°C. The duration of the reaction may range from 1 to 10 hours, preferably from a period of 6 to 8 hours.
Suitable catalyst used in step (b) is selected from palladium on carbon, raney nickel, platinum oxide, palladium hydroxide on carbon, sodium borohydride, sodium cyanoborohydride, sodiumtriacetoxy borohydride or a mixture thereof, in combination with metal, preferably palladium on carbon and sodium borohydride, more preferable palladium on carbon under hydrogen gas. The solvent used in this reaction may be selected from methanol, ethanol, IPA, ethyl acetate, isopropyl acetate, THF, 2-methyl THF, dimethoxy ethane and the like or mixture thereof, preferably methanol and ethyl acetate more preferably ethyl acetate. The volume of the solvent used for the reaction may be in the range of 2-10 volumes more preferably 4.5 to 5 volumes. The reaction is carried out at a temperature in the range from about 25 to 60°C more preferably at 35-38°C .The duration of the reaction may range from 10 to 12 hours. The hydrogen pressure is about 1 kg/cm 2 to 15 kg/cm 2 , preferably 8 kg/cm 2 to 12 kg/cm 2. The acid used in the reaction may be organic and inorganic acids selected from para toluenesulfonic acid, oxalic acid hydrochloric acid, hydrobromic acid, sulfuric acid, preferably para toluenesulfonic acid. In another embodiment, the preferable salts of compound of formula (17) may be selected from para toluenesulfonic acid, oxalic acid hydrochloric acid, hydrobromic acid, sulfuric acid and the like. Suitable catalyst used in step (c) is selected from palladium on carbon, raneynickel, platinum oxide, palladium hydroxide on carbon, more preferably palladium on carbon. The solvent used in this reaction may be selected from methanol, ethanol, IPA, ethyl acetate, isopropyl acetate, THF, 2-methyl THF, more preferably methanol. The volume of the solvent used for the reaction may be in the range of 5-15 volumes more preferably 12-13 volumes. The reaction is carried out at a temperature in the range from about 25 to 60°C more preferably at 50-55°C .The duration of the reaction in the range of 1-20 hours more preferably range from 10 to 12 hours. The hydrogen pressure is about 1 kg/cm 2 to 15 kg/cm 2 , preferably 8 kg/cm 2 to 12 kg/cm 2. The acid used in the reaction may be organic and inorganic acid selected from para toluenesulfonic acid, oxalic acid, hydrochloric acid, hydrobromic acid, sulfuric acid preferably hydrochloric acid in IPA and the base used is selected from inorganic or organic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethyl amine, disopropyl amine and the like, more preferably sodium carbonate.
In another embodiment, the present invention provides a process for the synthesis of (R)-(+)-l- (4-methoxyphenyl) ethylamine of formula ( 1 -R)
Figure imgf000014_0001
comprising the steps of,
(i) reaction of 4-methoxyacetophenone of formula (14)
Figure imgf000014_0002
with (R)-(+)-a-methylbenzylamine of formula (15-R),
Figure imgf000015_0001
in presence of a catalyst in organic solvent to obtain a new compound of formula (16-R),
Figure imgf000015_0002
(ii) catalytic reduction of a compound of formula (16-R) in the presence of a catalyst in a solvent followed by treatment with an acid to obtain compound of formula (17-R)
Figure imgf000015_0003
wherein X represent acid addition salt,
(iii) reduction of compound of formula (17-R) in the presence of a catalyst in solvent to obtain optically pure compound of formula (1-R).
In another embodiment, the present invention provides a process for the synthesis of (RS)-l-(4- methoxyphenyl)ethylamine of formula (1-RS)
Figure imgf000015_0004
comprising the steps of,
(i) reaction of 4-methoxyacetophenone of formula (14)
Figure imgf000015_0005
with (RS)-a-methylbenzylamine of formula (15-RS),
Figure imgf000016_0001
in presence of a catalyst in organic solvent to obtain a compound of formula (16-RS),
Figure imgf000016_0002
(16-RS)
(ii) catalytic reduction of a compound of formula (16-RS) in the presence of a catalyst in a solvent followed by treatment with an acid to obtain compound of formula (17-RS)
Figure imgf000016_0003
wherein X represent acid addition salt,
(iii) reduction of compound of formula (17-RS) in the presence of a catalyst in solvent to obtain racemic compound of formula (1-RS).
In another embodiment, the present invention provides novel compounds
(S)-[ 1 -(4-Methoxyphenyl)-ethylidene] -( 1 -phenylethyl)amine
(S,S)-[l-(4-methoxyphenyl)-ethyl]-(l-phenylethyl)amine PTSA salt
(R)-[l-(4-Methoxyphenyl)-ethylidene]-(l-phenylethyl)amine
(R,R)-[ 1 -(4-methoxyphenyl)-ethyl] -( 1 -phenylethyl)amine PTSA salt
Advantages of the present invention
The aforementioned process for the preparation of (S)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1) has the following advantages:
(i) the process does not use highly hazardous chemicals like n-BuLi, LiHMDS, trichlorosilnae diphenylyphosphorylazide, and hence the process is safe for commercial scale.
(ii) the process does not use any expensive chiral catalysts, and hence the process is economical. (iii) the resolution process by using enzyme and chemicals to get pure (S)-(-)-l-(4- methoxyphenyl) ethylamine of formula ( 1 ) is avoided.
(iv) there is no Si-gel chromatographic purification required to get pure (S)-(-)-l-(4- methoxyphenyl) ethylamine of formula (1) and hence the process can be used commercially. (v) moreover the present process requires commercially available low cost and non toxic chemicals and hence the process is safe and economical for industrial purpose,
(vi) this invention provides improved and efficient process for the synthesis of both the isomers of l-(4-Methoxyphenyl) ethylamine with chiral purity of >99%. IR spectra were recorded on Perkin Elmer Spectrophotometer as KBr pellets or neat. 1H-NMR, 13C-NMR spectra were recorded on a Bruker 400 MHz spectrometer with TMS as internal standard (chemical shift in δ, ppm) and Mass spectra were measured on API 4000 model. Chiral HPLC analysis was carried using Shimadzu with symmetry CI 8, 220nm. The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limited and relate to solutions which have been particularly effective on a bench scale.
Example-1
Preparation of (S)-(-)-l-(4-methoxyphenyl)ethylamine (1).
Step-(a) : Preparation of (S)-r i-(4-Methoxyphenyl)-ethylidenel-(l-phenylethyl)amine (16 ). Mixture of 4-methoxyacetophenone (100 gm, 0.66 mole) and (S)-(-)-a-methylbenzylamine (100.8 gm, 0.83 mole) was refluxed in presence of p-toluenesulfonic acid (5 gm, 0.02 mole) in toluene (600 ml) for 10-12 hours, while the water formed during the progress of the reaction was separated azeotropically by using Dean-Stark trap which was connected to a refluxing condenser. Slowly cooled the reaction mixture to room temperature and washed with 10% sodium carbonate solution followed by brine solution. Separated the organic layer, dried over Na2S04 and concentrated under reduced pressure to get 180 gm of title compound (16) as syrup. The resulting compound of formula (16) was directly used for the next step. Step-(b): Preparation of (S,S)-r i-(4-methoxyphenyl)-ethyll-(l-phenylethyl)amine PTSA salt (17). Mixture of compound of formula (16) (180.0 gm) in ethyl acetate (800 ml) was stirred with 10% Pd/C (7.2 gm) under hydrogen atmosphere at 35-40°C for 10-12 hrs. Cooled the reaction mass to room temperature, filtered the catalyst on celite bed and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure to give crude compound (150 gm) as liquid. The resulting crude compound was dissolved in ethyl acetate (600 ml) and stirred with p- tolunesulfonic acid (135 gm, 0.70 mole) at 45-50°C for 30 min. Cooled the reaction mass to 5- 10°C, stirred for about 6 hrs and the solid formed was filtered, washed with ethyl acetate and dried to obtain the compound of formula (S,S)-17 as white crystalline solid.
Output: 125.0 gm;
m.p: 181.7-182.9°C.
[a]25: -75° (c=0.25 in MeOH),
Chiral purity: 99.5 %(by HPLC).
IR (KBr): 3007, 2837, 2523, 1613, 1586, 1518, 1477, 1250, 1232, 1159, 1034, 1010, 828, 809, 681, 566.
Step-(c): Preparation of (S)-(-)-l-(4-Methoxyphenyl)ethylamine (1).
To the suspension of compound (17) (120 gm, 0.28 mole) in water (950 ml) was added 10% sodium hydroxide solution (250 ml) to reach pH basic and it was extracted with MDC (2 x 350 ml). The combined organic layers were dried over Na2S04 and concentrated under reduced pressure to give free base 75 gm of compound (17).
The compound obtained above (17) (75 gm, 0.75 mole) in methanol (750 ml) was stirred with 10% Pd/C (6.0 gm) under hydrogen atmosphere at 50-55°C for 10-12 hrs. Cooled the reaction mass to room temperature, filtered the catalyst on celite bed and washed with methanol (100 ml). The combined filtrate was concentrated under reduced pressure to give crude compound (45 gm) as syrup mass. IPA (100 ml), 14% IPA/HC1 (125.2 gm) were added to the crude product at 25- 30°C and stirred the reaction mixture for about 30 min at the same temperature, concentrated under reduced pressure and crystallized from ethyl acetate (90 ml) to get hydrochloride salt of compound (1) as white crystalline solid
Output: 55.0 gm:
m.p: 156.1-160.4°C; [af3: -6.8U (c=0.5 in MeOH),
Chiral purity: 99.8% (by HPLC).
To the solution of hydrochloride salt of compound (1) 55.0 gm in water (225 ml) was added sodium carbonate (35.5 gm) to get pH basic, and extracted with MDC (2x100 ml). The combined organic layers were washed with brine solution, dried over Na2S04 and concentrated under reduced pressure to give compound of (1) as liquid.
Output: 42 gm;
Chiral purity: 100% (by HPLC).
[a]20: -34.6° (neat),
IR (neat, cm"1): 3369, 3294, 2959, 2835, 1610, 1585, 1512, 1463, 1368, 1329, 1301, 1284, 1246, 1177, 1100, 1034, 917, 831, 701.
1H-NMR(400MHz,CDCl3):51.33(d,J=6.5Hz,3H),1.47(S,2H),3.75(S,3H),4.02(q,J=6.5Hz,lH), 6.84(d,J=8.4Hz,2H),7.23(d,J=8.5Hz,2H).13C-NMR(400MHz,CDCl3): δ 25.8, 50.6, 55.1, 113.7, 126.7, 140.0, 158.4.
Example-2
Preparation of (R)-(+)-l-(4-methoxyphenyl)ethylamine (1-R)
Step-(a) : Preparation of (R)-[l-(4-Methoxyphenyl)-ethylidenel-(l-phenylethyl)amine (16-R ).
Mixture of 4-methoxyacetophenone (100.0gm,0.66mole) and (R)-(+)-a-methylbenzylamine (100.8 gm, 0.83 mole) was refluxed in presence of p-toluenesulfonic acid (5 gm, 0.02 mole) in toluene (600 ml) for 10-12 hours, while the water formed during the progress of the reaction was separated azeotropically by using Dean-Stark trap which was connected to a refluxing condenser.
Slowly cooled the reaction mixture to room temperature and washed with 10% sodium carbonate solution followed by brine solution. Separated the organic layer, dried over Na2S04 and concentrated under reduced pressure to get 188 gm of title compound (16-R) as syrup. The resulting compound of formula (16-R) was directly used for the next step.
Step-(b): Preparation of (R,R)-ri-(4-methoxyphenyl)-ethyll-(l-phenylethyl)amine PTSA salt (17-R.R).
Mixture of compound of formula (16-R) (188.0 gm) in ethyl acetate (800 ml) was stirred with 10% Pd/C (7.6 gm) under hydrogen atmosphere at 35-40°C for 6-8 hrs. Cooled the reaction mass to room temperature, filtered the catalyst on celite bed and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure to give crude compound (158 gm) as liquid. The resulting crude compound was dissolved in ethyl acetate (624 ml) and stirred with p- tolunesulfonic acid (139.6 gm, 0.70 mole) at 45-50°C for 30 min. Cooled the reaction mass to 5- 10°C, stirred for about 6 hrs and the solid formed was filtered, washed with ethyl acetate and dried to obtain the compound of formula (R,R)-17 as white crystalline solid.
Output: 105.0 gm;
m.p: 178.2-180.0°C.
[a]25: +79° (c=0.25 in MeOH),
Chiral purity: 100% (by HPLC).
IR (KBr): 3006, 2837, 2523, 1613, 1586, 1518, 1478, 1250, 1232, 1158, 1034, 1010, 828, 808, 681, 565.
Step-(c): Preparation of (R)-(+)-l-(4-Methoxyphenyl)ethylamine (1-R)
To the suspension of compound (17-R,R) (182 gm, 0.42 mole) in water (1800 ml) was added 10% sodium hydroxide solution to reach pH basic and it was extracted with MDC (3 x 500 ml). The combined organic layers were dried over Na2S04 and concentrated under reduced pressure to give free base 104.0 gm of compound (17-R,R).
The compound obtained above (17-R,R) (104 gm, 0.407 mole) in methanol (1040 ml) was stirred with 10% Pd/C (8.6 gm) under hydrogen atmosphere at 50-55°C for 10-12 hrs. Cooled the reaction mass to room temperature, filtered the catalyst on celite bed and washed with methanol (2x100 ml). The combined filtrate was concentrated under reduced pressure to give crude compound (62 gm) as syrup mass. IPA (150 ml), 14% IPA/HC1 (172.0 gm) were added to the crude product at 25-30°C and stirred the reaction mixture for about 30 min at the same temperature, concentrated under reduced pressure and crystallized from ethyl acetate (150 ml) to get hydrochloride salt of compound ( 1 -R) as white crystalline solid
Output: 61.0 gm:
m.p: 150.4-153.9°C.
[a]25: +6.7° (c=0.5 in MeOH),
Chiral purity: 99.6% (by HPLC). To the solution of hydrochloride salt of compound (1-R) 61.0 gm in water (295 ml) was added sodium carbonate (39.5 gm) to get pH basic, and extracted with MDC (2x150 ml). The combined organic layers were washed with brine solution, dried over Na2S04 and concentrated under reduced pressure to give compound of ( 1 -R) as liquid.
Output: 47.2 gm;
Chiral purity: 100% (by HPLC).

Claims

We Claim:
1. An improved and efficient process for the preparation of (S)-(-)-l-(4-methoxyphenyl) ethylamine (1),
Figure imgf000022_0001
(1 )
which comprises the steps of:
(a) reaction of 4-methoxyacetophenone of formula (14),
Figure imgf000022_0002
(14)
with (S)-(-)-a-methylbenzylamine of formula (15),
Figure imgf000022_0003
(15)
in presence of s catalyst in organic solvent to obtain a compound of formula (16),
Figure imgf000022_0004
(1 6)
(b) catalytic reduction of a compound of formula (16) in the presence of catalyst in a solvent followed by treatment with an acid to obtain compound of formula (17)
Figure imgf000022_0005
wherein X represent acid addition salt, (iii) reduction of compound of formula (17) in the presence of a catalyst in a solvent to obtain optically pure compound of formula (1).
2. The process of claim 1, wherein solvent used in step (a) is selected from group comprising of toluene, chloroform, dichlorome thane, EDC, CC14, MTBE, methanol, THF or mixtures thereof.
3. The process of claim 1, wherein catalyst used in step (a) is selected from para toluenesulfonicacid, acetic acid, hydrochloric acid and sulfuric acid.
4. The process of claim 1, wherein the reaction in step (a) is carried at a temperature range of 25- 130°C.
5. The process of claim 1, wherein solvent used in step (b) is selected from group comprising of methanol, ethanol, IPA, ethyl acetate, isopropyl acetate, THF, 2-methyl THF and, dimethoxy ethane or mixture thereof..
6. The process of claim 1, wherein reduction catalyst used in step (b) is selected from palladium on carbon, raney nickel, platinum oxide, and palladium hydroxide on carbon, sodium borohydride, sodium cyanoborohydride and sodiumtriacetoxy borohydride or a mixtu re thereof.
7. The process of claim 1, wherein the reaction in step (b) is carried at a temperature range about 25 to 60°C.
8. The process of claim 1, wherein acid used in the step (b) selected from para toluenesulfonic acid, oxalic acid, hydrochloric acid, hydrobromic acid and, sulfuric acid.
9. The process of claim 1, wherein solvent used in step (c) is selected from group comprising of methanol, ethanol, IPA, ethyl acetate, isopropyl acetate, THF and, 2-methyl THF or mixtures thereof.
10. The process of claim 1, wherein catalyst used in step (c) is selected from palladium on carbon, raney nickel, platinum oxide and palladium hydroxide on carbon.
11. The process of claim 1 , wherein the reaction in step (c) is carried at a temperature range about from about 25 to 60°C.
12. In another embodiment, the preferable salts of compound of formula (17) may be selected para toluenesulfonic acid, oxalic acid hydrochloric acid, hydrobromic acid, sulfuric acid and the like.
13. A process for the synthesis of (R)-(-)-l-(4-methoxyphenyl) ethylamine of formula (1-R)
Figure imgf000024_0001
comprising the steps of,
(i) reaction of 4-methoxyacetophenone of formula (14)
Figure imgf000024_0002
with (R)-(+)-a-methylbenzylamine of formula (15-R),
Figure imgf000024_0003
in presence of a catalyst in organic solvent to obtain a compound of formula (16-R),
Figure imgf000024_0004
(ii) catalytic reduction of a compound of formula (16-R) in the presence of a catalyst in a solvent followed by treatment with an acid to obtain compound of formula (17-R)
Figure imgf000025_0001
wherein X represent acid addition salt,
(iii) reduction of compound of formula (17-R) in the presence of a catalyst in solvent to obtain optically pure compound of formula (1-R).
14. A process for the synthesis of (RS)-l-(4-methoxyphenyl)ethylamine of formula (1-RS)
Figure imgf000025_0002
comprising the steps of,
(i) reaction of 4-methoxyacetophenone of formula (14)
Figure imgf000025_0003
with (RS)-a-methylbenzylamine of formula (15-RS),
Figure imgf000025_0004
in presence of a catalyst in organic solvent to obtain a compound of formula (16-RS),
Figure imgf000025_0005
(16-RS)
(ii) catalytic reduction of a compound of formula (16-RS) in the presence of a catalyst in a solvent followed by treatment with an acid to obtain compound of formula (17-RS)
Figure imgf000026_0001
wherein X represent acid addition salt,
(iii) reduction of compound of formula (17-RS) in the presence of a catalyst in solvent to obtain racemic compound of formula (1-RS).
15. A compound selected from
(S)-[ 1 -(4-Methoxyphenyl)-ethylidene]-( 1 -phenylethyl)amine;
(S,S)-[l-(4-methoxyphenyl)-ethyl]-(l-phenylethyl)amine PTSA salt ;
(R)-[l-(4-Methoxyphenyl)-ethylidene]-(l-phenylethyl)amine
(R,R)-[l-(4-methoxyphenyl)-ethyl]-(l-phenylethyl)amine PTSA salt.
16. The process for the preparation of (S)-(-)-l-(4-methoxyphenyl) ethylamine (1) substantially pure as herein described with reference to the example 1.
17. The process for the preparation of (R)-(+)-l-(4-methoxyphenyl) ethylamine (1-R) substantially pure as herein described with reference to the example 2.
18. The process according to claim 1, 13, 14 and 15 wherein the compound of formula I is further converted to Sitagliptin, Elarofiban, CXCR4 antagonist, GSK812397, Docetaxel and its pharmaceutically acceptable salts.
PCT/IB2015/052303 2014-04-18 2015-03-28 Improved process for the synthesis of 1-(4-methoxyphenyl) ethylamine and its isomers WO2015159170A2 (en)

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