WO2004031168A2 - Processes and intermediates for the preparation of optically active 3-amino-1-(2-thienyl)-1-propanol derivatives - Google Patents

Processes and intermediates for the preparation of optically active 3-amino-1-(2-thienyl)-1-propanol derivatives Download PDF

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WO2004031168A2
WO2004031168A2 PCT/EP2003/011073 EP0311073W WO2004031168A2 WO 2004031168 A2 WO2004031168 A2 WO 2004031168A2 EP 0311073 W EP0311073 W EP 0311073W WO 2004031168 A2 WO2004031168 A2 WO 2004031168A2
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thienyl
amino
keto
propanols
propanol
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WO2004031168A3 (en
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Rudolf Fuchs
Dominique Michel
Walter Brieden
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Lonza Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Definitions

  • the present invention refers to processes for the preparation of optically active 3-amino- 1 -(2-thienyl)- 1 -propanol derivatives and to salts of these derivatives with (-)-2,3 :4,6-di- O-isopropylidene-2-keto-L-gulonic acid and (+)-2,3:4,6-di-O-isopropylidene-2-keto- D-gulonic acid.
  • An example of an optically active 3 -amino-1 -(2-thienyl)- 1 -propanol derivative is (S)-3-N-methylamino-l -(2-thienyl)- 1 -propanol, which is an intermediate for the preparation of (S)-methyl-[3-(l-naphthyloxy)-3-(2-thienyl)-propyl]-amine (duloxetine), an agent for the treatment of depression and urinary incontinence (Huiling et al. Chirality 2000, 12, 26-29, Sorbera et al. Drugs of the Future 2000, 25(9), 907-916).
  • Huiling et al. (Chirality 2000, 12, 26-29) describes a preparation of (S)-3-N-methylamino- 1 -(2-thienyl)- 1 -propanol from thiophene.
  • Thiophene was converted with 3-chloropro ⁇ a- noyl chloride in the presence of tin tetrachloride in benzene to 3-chloro-l-(2-thienyl)- 1-propanone, which was reduced with sodium borohydride in ethanol to 3-chloro- 1 -(2-thienyl)- 1 -propanol.
  • Kinetic resolution by transesterification using vinyl butanoate and lipase B from Candida antarctica as catalyst in hexane yielded (S)-3-chloro-
  • Sorbera et al. (Drugs of the Future 2000, 25(9), 907-916) describes another preparation of (S)-3-N-methylamino-l -(2-thienyl)- 1 -propanol from thiophene, which is essentially the same as the one described by Huiling et al.
  • R and R independently of one another denote H, C ⁇ - 6 -alkyl, C 5 . -cycloalkyl, aralkyl or aryl, comprises the step of reducing a 3 -amino-1 -(2-thienyl)- 1-propanone of the formula
  • R and R are defined as above, using a hydrogen donor in the presence of a metal catalyst, an optically active nitrogen-containing ligand and optionally a base.
  • Enantiomerically enriched 3 -amino- 1 -(2-thienyl)- 1 -propanols are 3 -amino- 1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) having an enantiomeric excess (e.e.) of >0%, preferably >50%, more preferably >65%.
  • the e.e. of enantiomerically enriched 3 -amino-1 -(2-thienyl)- 1 -propanols can be determined by chiral HPLC, for example.
  • C ⁇ - 6 -alkyl can be branched or unbranched.
  • Examples of C ⁇ - 6 -alkyl are methyl, ethyl, propyl, isopropyl, butyl, -sec-butyl, tert-butyl, isobutyl, pentyl, isopentyl, 2 -methyl-butyl, 2,2-dimethyl-propyl (neopentyl), 2-pentyl, 3-methyl-2-butyl, 2-methyl-2 -butyl, 3-pentyl, hexyl, isohexyl, 3-methyl-pentyl, 3,3-dimethyl-butyl, 2-hexyl, 4-methyl-2-pentyl, 3,3-di- methyl-2-butyl and 3 -hexyl.
  • C 5 - -Cycloalkyl is cyclopentyl, cyclohexyl or cycloheptyl.
  • aralkyl examples include benzyl and 2-phenylethyl.
  • Aryl can be optionally substituted with C ⁇ -alkyl such as methyl, ethyl, propyl, isopropyl or butyl, with C ⁇ -alkoxy such as methoxy, ethoxy or propoxy, or with halogen such as chlorine, bromine or iodine.
  • Examples of aryl are phenyl, j?-tolyl, >-anisyl and j>-chlorophenyl.
  • R 1 denotes H, Ct- ⁇ -alkyl or aralkyl and R 2 denotes methyl. More preferably, R 1 denotes H, methyl or benzyl and R 2 denotes methyl. Most preferably, R 1 denotes H and R 2 denotes methyl.
  • the metal catalyst can be an organometal complex wherein the metal is selected from the group consisting of ruthenium, rhodium and iridium and wherein the organo ligand is selected from the group consisting of dienes, triarylphosphines, di-C ⁇ -alkyl sulfoxides and arenes.
  • the organometal complex can contain halogen atoms such as chlorine, bromine or iodine.
  • dienes are 1,5-hexadiene and 1,5-cyclooctadiene.
  • An example of a tri- arylphosphine is triphenylphosphine.
  • An example of a di-C ⁇ - 2 -alkyl-sulfoxide is dimethyl- sulfoxide.
  • the arene can be optionally substituted with at least one C ⁇ . -alkyl such as methyl, ethyl, propyl or isopropyl.
  • examples of arenes are benzene, toluene, ⁇ -xylene, -xylene, j3-xylene, ethylbenzene, mesitylene, 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, 2-ethyltoluene, 3-ethyltoluene, 4-ethyltoluene, propylbenzene, cumene, o-cymene, m-cymene, ?-cymene, 1,2-diethylbenzene, 1,4-diethylbenzene, 1,2,3,5-tetramethyl- benzene, 1,2,4,5-tetramethylbenzene, pentamethylbenzene and hexamethylbenzene.
  • metal catalysts are [Ru(p-cymene)Cl 2 ] 2 , [Ru(benzene)Cl 2 ] 2 , [Ru(mesityl- ene)Cl 2 ] 2 , [Ru(hexamethylbenzene)Cl 2 )] 2 , [Ru(PPh 3 ) 3 Cl 2 ], tr ⁇ «5 , -Ru(dimethyl- sulfoxide) 4 Cl 2 , [Ru(l,5-cyclooctadiene)Cl] 2 , [Rh(l,5-hexadiene)Cl] 2 , [Rh(l,5-cyclo- octadiene)Cl] , [Ir(l,5-hexadiene)Cl] and [Ir(l,5-cyclooctadiene)Cl] 2 .
  • the metal catalyst can be prepared by methods known in the art.
  • the organo Ru(II) complexes of the type [Ru(arene)X 2 ] 2 wherein X is halogen can be prepared from RuX 3 and the corresponding 1,3- or 1,4-cyclohexadiene derivative, for example Ru(p-cymene)Cl 2 ] 2 can be prepared from RuCl 3 and 5-isopropyl-2-methyl-l,3- cyclohexadiene (Bennett et al. J Chem. Soc; Dalton Trans 1974, 233-241).
  • organometal complexes of the type [metal(diene)X] 2 wherein metal is Rh(I) or Ir(I) can be prepared from [metal(cyclooctene) 2 X] 2 and diene (Mestroni et al. J. Organomet. Chem. 1977, 140, 63-72).
  • [Metal(cyclooctene) X] can be prepared from MC1 3 wherein M denotes metal and cyclooctene (Herde et al. Inorg. Nucl. Chem. Lett. 1971, 7, 1029-1031).
  • [Rh(l,5-cyclooctadiene)Cl] 2 can be prepared from RhCl 3 and 1,5-cyclooctadiene (Chatt et al. J Chem. Soc. 1957, 4735-4741).
  • the metal catalyst is an organometal complex wherein the metal is selected from the group consisting of ruthenium(II), rhodium(I) and iridium(I) and the organo ligand is an arene. More preferably, the metal is ruthenium(II) and the arene is selected from the group consisting of benzene, mesitylene and ?-cymene. Most preferably, the metal is ruthenium(II) and the organo ligand is ?-cymene.
  • the amount of metal catalyst used is preferably 0.001 to 0.05 mol equivalents, more preferably 0.001 to 0.01 mol equivalents, most preferably 0.001 to 0.005 mol equivalents, in respect to 3 -amino-1 -(2-thienyl)- 1-propanone (II).
  • the optically active nitrogen-containing ligand can be a bi-, tri- or tetradentate ligand comprising 2 to 4 heteroatoms which are capable of coordinating to the metal of the metal catalyst and which are selected from the group consisting of nitrogen, oxygen and phosphorus, wherein at least one of the heteroatoms is nitrogen.
  • bidentate optically active nitrogen-containing ligands are (S)-6-sec-buty ⁇ - 2,2'-bipyridine, (S)-3-(l ,2,2-trimethylpropyl)-l ,10-phenanthroline, (S)-(E)-(1 -phenyl- ethyl)pyridine-2-ylmethylene-amine, (S,S)-5,5'-diisopropyl-4,4',5,5'-tetrahydro-2,2'-bis- (oxazole), (S,S)-N,N-dimethyl-l,2-diphenyl-l,2-ethanediamine, (R,R)-1,1 '-bis[(methyl- amino)phenylmethyl]ferrocene, 1 , 1 -bis(4-methoxyphenyl)-3-phenyl-propane- 1 ,2-di- amine, (R,R)-N,N-bis(l-napht
  • tridentate optically active nitrogen-containing ligands are bis[2-((R)-4-phenyl-4,5-dihydrooxazolyl)-ethyl]amine, N,N-bis(2-hydroxy-2-phenyl- ethyl)-benzylamine, (R,R -2,6-bis[l-(diphenylphosphino)ethyl]pyridine, (S,S)-bis[(2-pyrrolidinyl)methyl]-phenyl-phosphine, (R,R)-bis[2-(4-phenyl-2-oxazolyl)- ethyl]-phenyl-phosphine and (R)-l-(diphenylphosphino)-2-((lR,2S,5R)-menthoxy)- 1 -(2-pyridyl)-ethane.
  • tetradentate optically active nitrogen-containing ligand is (S,S)-N,N- bis[o-(diphenylphosphino)benzyl]cyclohexane- 1 ,2-diamine.
  • the optically active nitrogen-containing ligand is a bidentate ligand comprising 2 heteroatoms which are capable of coordinating to the metal of the metal catalyst and which are selected from the group consisting of nitrogen, oxygen and phosphorus, wherein at least one of the heteroatoms is nitrogen.
  • the optically active nitrogen-containing ligand is selected from the group consisting of (S,S)-N,N -dimethyl- l,2-diphenyl-l,2-ethanediamine, (R,R)-1,1 '-bis[(memylamino)- phenylmethyljferrocene, 1 , 1 -bis(4-methoxyphenyl)-3-phenyl-propane- 1 ,2-diamine, (R,R)-N-tosyl- 1 ,2-diphenylethanediamine, (S,S)-N-tosyl- 1 ,2-diphenylethanediamine, (R,R)- 1 , 1' -(aminophenylmethyl)(tosylaminophenylmethyl)ferrocene, (R,R)-N-tosyl- cyclohexane-l,2-diamine, (lS,2R)-(-)-ct-?-
  • the optically active nitrogen- containing ligand is selected from the group consisting of lS,2R)-(-)-c/.s , -l-amino-2- indanol, ( 1 R,2S)-(+)-cis- 1 -amino-2-indanol, (S,S)-2-(methylamino)- 1 ,2-diphenylethanol and (lS,3R,4R)-3-(hydroxylmethyl)-2-azabicyclo[2.2.1]heptane.
  • the optically active nitrogen-containing ligand is (lS,2R)-(-)-c/5 , -l-amino-2-indanol or (lR,2S)-(+)-cz ' -y-l-amino-2-indanol.
  • the amount of optically active nitrogen-containing ligand used is preferably 0.005 to 0.100 mol equivalents, more preferably 0.010 to 0.050 mol equivalents, most preferably 0.010 to 0.020 mol equivalents, in respect to 3 -amino-1 -(2-thienyl)- 1-propanone (II).
  • the optically active nitrogen-containing ligand chelates to the metal catalyst to form an optically active metal catalyst.
  • the optically active nitrogen-containing ligand and the metal catalyst can be added separately to the reaction vessel and the optically active metal catalyst is formed in situ or the optically active nitrogen-containing ligand and the metal catalyst are premixed and the obtained optically active catalyst is added to the reaction vessel.
  • the optically active nitrogen-containing ligand and the metal catalyst are added separately to the reaction vessel.
  • the hydrogen donor can be an organic molecule which is itself oxidized upon transferring hydrogen to 3 -amino-1 -(2-thienyl)- 1-propanone (II) such as a suitable unsaturated hydrocarbon, a primary or secondary alcohol or formic acid.
  • Suitable unsaturated hydrocarbons are hydrocarbons which can be oxidized to an aromatic system. Examples of suitable unsaturated hydrocarbons are cyclohexene, 1,3-cyclohexadiene and 1,4-cyclo- hexadiene.
  • primary and secondary alcohols are methanol, ethanol, isopropanol and benzyl alcohol.
  • the hydrogen donor is isopropanol or formic acid. More preferably, the hydrogen donor is isopropanol.
  • a base is present.
  • the base can be an inorganic or organic base.
  • inorganic bases are alkali metal hydroxides such as sodium hydroxide and potassium hydroxide or alkali metal carbonates such as sodium carbonate or potassium carbonate.
  • organic bases are alkali metal alkoxides such as potassium tert-butanolate, potassium isopropoxide or sodium isopropoxide and amines such as diethylamine, triethylamine, butylamine or ethanolamine.
  • the base is an alkali metal hydroxide or an amine. More preferably the base is an alkali metal hydroxide.
  • the amount of base used is preferably 0.01 to 0.10 mol equivalents, more preferably 0.01 to 0.05 mol equivalents, in respect to 3-amino-l -(2-thienyl)- 1-propanone (II).
  • the solvent used in the reduction step can be any solvent or mixture of solvents that dissolves the reagents, namely a 3 -amino-1 -(2-thienyl)- 1-propanone (II), the hydrogen donor, the metal catalyst, the optically active nitrogen-containing ligand and the base, under the conditions used.
  • the solvent used in the reduction step is isopropanol or formic acid.
  • the reduction step can be carried out at a temperature from -40 to 110 °C, preferably at a temperature from 15 to 40 °C, more preferably at a temperature from 20 to 30 °C.
  • the reduction step is carried out in the absence of oxygen, e.g. under nitrogen or argon atmosphere.
  • the starting material, 3 -amino-1 -(2-thienyl)- 1-propanone (II), is obtained by treating a salt thereof with a base.
  • the base is as defined above.
  • the same base is used as the base employed in the reduction step.
  • a salt of a 3-amino-l -(2-thienyl)- 1 -propanone (II) can be an acid addition salt with an inorganic acid such as hydrochloric acid, hydrobromic acid or hydriodic acid.
  • a salt of a 3 -amino-1 -(2-thienyl)- 1-propanone (II) can be prepared by Mannich reaction from 2-acetylthiophene, formaldehyde and an acid addition salt of NHR ⁇ 2 , wherein R 1 and R 2 are defined as above, with an inorganic acid.
  • Either isolated 3-amino-l-(2-thienyl)-l-propanone (II) can be employed as the starting material or 3-amino-l-(2-thienyl)-l-propanone (II) obtained in situ by treating a salt thereof with a base.
  • R 1 and R 2 independently denote H, C ⁇ -alkyl, C 5 . -cycloalkyl, aralkyl or aryl, comprises the steps of i) reducing a 3 -amino- 1 -(2-thienyl)- 1 -propanone of the formula
  • Enantiomerically pure 3 -amino-1 -(2-thienyl)- 1 -propanols are 3-amino- 1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) having an e.e. of >80%, preferably >90%, more preferably >95%.
  • the e.e. of enantiomerically pure 3 -amino-1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) can be determined by chiral HPLC, for example.
  • (-)-2,3:4,6-Di-O-isopropylidene-2-keto-L-gulonic acid (L-III) or (+)-2,3:4,6-di-O-isopro- pylidene-2-keto-D-gulonic acid (D-III) refer also to the hydrates of gulonic acids L-III or D-III.
  • enantiomerically enriched 3 -amino-1 -(2-thienyl)- 1 -propanols are treated with 0.50 to 3.00 mol equivalents (-)-2,3:4,6-di-O-isopropylidene-2-keto- L-gulonic acid (L-III) or (+)-2,3:4,6-di-O-isopropylidene-2-keto-D-gulonic acid (D-III) in respect to enantiomerically enriched 3 -amino- 1 -(2-thienyl)- 1 -propanols ((S)- ⁇ or (R)-I) to form the diastereomeric salts of the formulae (S)-L-IV and (R)-L-IN or (S)-D-IN and (R)-D-IN.
  • the solvent used in step ii) is preferably selected from the group consisting of water, alcohols, esters and mixtures thereof.
  • alcohols are methanol, ethanol, propanol, isopropanol, butanol and benzyl alcohol.
  • esters are ethyl acetate, butyl acetate and benzyl acetate.
  • the solvent used in step ii) is selected from the group of primary and secondary alcohols. Most preferably, the solvent used in step ii) is isopropanol.
  • Step ii) can be carried out at a temperature from 0 to 100 °C, preferably at 15 to 80 °C, more preferably at 15 to 40 °C.
  • Diastereomerically pure salts are salts (S)-L-IN or (R)-D-IN which liberate upon base treatment the corresponding 3 -amino-1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) having an e.e. of >80%, preferably >90% and more preferably >95%.
  • the diastereomerically pure salts (S)-L-IN or (R)-D-IN can be crystallized directly from the reaction mixture obtained in step ii) or after solvent exchange.
  • the solvent exchange can be performed by partially or completely removing the solvent used in step ii) and simultaneously or successively adding another solvent.
  • the diastereomerically pure salts (S)-L-IN or (R)-D-IV are crystallized directly from the reaction mixture obtained in step ii).
  • the diastereomerically pure salts (S)-L-IN or (R)-D-IV are isolated e. g. by filtration or centrifugation.
  • the diastereomeric pure salts (S)-L-IN or (R)-D-IN obtained in step iii) can be dissolved in water and treated with a water soluble base.
  • water soluble organic bases are trimethylamine, triethylamine and pyridine.
  • water soluble inorganic bases are sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and ammonium hydroxide.
  • the base is a water-soluble inorganic base. More preferably, the base is sodium hydroxide or potassium hydroxide.
  • the enantiomerically pure 3 -amino-1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) can be isolated e.
  • the solvent used for extracting 3-amino-l -(2-thienyl)- 1 -propanols is an ester or an ether. More preferably, this solvent is ethyl acetate or tert-butyl methyl ether.

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Abstract

Enantiomerically enriched 3-amino-1-(2-thienyl)-1-propanols of the formulae ((S)-I) or ((R)-I) wherein R1 and R2 independently denote H, C1-6-alkyl, C5-7-cycloalkyl, aralkyl or aryl, were prepared by reducing a 3-amino-1-(2-thienyl)-1-propanone of the formula (II) wherein R1 and R2 are defined as above, using a hydrogen donor in the presence of a metal catalyst, an optically active nitrogen-containing ligand and optionally a base.

Description

Processes and intermediates for the preparation of optically active 3-amino-l- (2-thienyl)-l-propanol derivatives
The present invention refers to processes for the preparation of optically active 3-amino- 1 -(2-thienyl)- 1 -propanol derivatives and to salts of these derivatives with (-)-2,3 :4,6-di- O-isopropylidene-2-keto-L-gulonic acid and (+)-2,3:4,6-di-O-isopropylidene-2-keto- D-gulonic acid.
An example of an optically active 3 -amino-1 -(2-thienyl)- 1 -propanol derivative is (S)-3-N-methylamino-l -(2-thienyl)- 1 -propanol, which is an intermediate for the preparation of (S)-methyl-[3-(l-naphthyloxy)-3-(2-thienyl)-propyl]-amine (duloxetine), an agent for the treatment of depression and urinary incontinence (Huiling et al. Chirality 2000, 12, 26-29, Sorbera et al. Drugs of the Future 2000, 25(9), 907-916).
Huiling et al. (Chirality 2000, 12, 26-29) describes a preparation of (S)-3-N-methylamino- 1 -(2-thienyl)- 1 -propanol from thiophene. Thiophene was converted with 3-chloroproρa- noyl chloride in the presence of tin tetrachloride in benzene to 3-chloro-l-(2-thienyl)- 1-propanone, which was reduced with sodium borohydride in ethanol to 3-chloro- 1 -(2-thienyl)- 1 -propanol. Kinetic resolution by transesterification using vinyl butanoate and lipase B from Candida antarctica as catalyst in hexane yielded (S)-3-chloro-
1 -(2-thienyl)- 1 -propanol, which was converted to (S)-3-iodo-l -(2-thienyl)- 1 -propanol using sodium iodide in acetone. Subsequent treatment with methylamine in tetrahydro- furan afforded (ιS)-3-N-methylamino-l -(2-thienyl)- 1 -propanol.
Sorbera et al. (Drugs of the Future 2000, 25(9), 907-916) describes another preparation of (S)-3-N-methylamino-l -(2-thienyl)- 1 -propanol from thiophene, which is essentially the same as the one described by Huiling et al. (Chirality 2000, 12, 26-29) except that 3-chloro-l-(2-thienyl)-l-propanone is directly asymmetrically reduced to (S)-3-chloro- 1 -(2-thienyl)- 1 -propanol using borane and catalytic amounts of (R)-3,3-diphenyl- l-methyltetrahydro-3H-pyrrolo[l,2-c][l,3,2]oxazaborole in tetrahydrofuran. This asymmetric reduction afforded (S)-3-chloro-l-(2-thienyl)-l-propanol in a yield of 86% from 3-chloro-l -(2-thienyl)- 1-propanone (Wheeler et al. J Label. Compd. Radiopharm. 1995, 36, 213-223). The drawbacks of above preparations of (S)-3-N-methylamino-l -(2-thienyl)- 1 -propanol are the use of toxic or carcinogenic compounds such as tin tetrachloride and benzene and the use of expensive compounds such as sodium borohydride or borane and sodium iodide, the latter being in addition difficult to dispose.
It is an object of the present invention to provide ecological and economical processes for the preparation of optically active 3 -amino-1 -(2-thienyl)- 1 -propanol derivatives. It is another object of the present invention to provide new amine addition salts of (-)-2,3:4,6- di-O-isopropylidene-2-keto-L-gulonic acid and of (+)-2,3:4,6-di-O-isopropylidene-2-keto- D-gulonic acid.
These objects are achieved by the processes according to claims 1 and 10 and by the compounds according to claims 13 to 16.
The process of the present invention for the preparation of enantiomerically enriched 3 -amino-1 -(2-thienyl)- 1-propanols of the formulae
Figure imgf000004_0001
wherein R and R independently of one another denote H, Cι-6-alkyl, C5. -cycloalkyl, aralkyl or aryl, comprises the step of reducing a 3 -amino-1 -(2-thienyl)- 1-propanone of the formula
Figure imgf000004_0002
wherein R and R are defined as above, using a hydrogen donor in the presence of a metal catalyst, an optically active nitrogen-containing ligand and optionally a base.
Enantiomerically enriched 3 -amino- 1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) are 3 -amino- 1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) having an enantiomeric excess (e.e.) of >0%, preferably >50%, more preferably >65%.
The e.e. of enantiomerically enriched 3 -amino-1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) can be determined by chiral HPLC, for example.
-6-Alkyl can be branched or unbranched. Examples of Cι-6-alkyl are methyl, ethyl, propyl, isopropyl, butyl, -sec-butyl, tert-butyl, isobutyl, pentyl, isopentyl, 2 -methyl-butyl, 2,2-dimethyl-propyl (neopentyl), 2-pentyl, 3-methyl-2-butyl, 2-methyl-2 -butyl, 3-pentyl, hexyl, isohexyl, 3-methyl-pentyl, 3,3-dimethyl-butyl, 2-hexyl, 4-methyl-2-pentyl, 3,3-di- methyl-2-butyl and 3 -hexyl. C5- -Cycloalkyl is cyclopentyl, cyclohexyl or cycloheptyl. Examples of aralkyl are benzyl and 2-phenylethyl. Aryl can be optionally substituted with C^-alkyl such as methyl, ethyl, propyl, isopropyl or butyl, with C^-alkoxy such as methoxy, ethoxy or propoxy, or with halogen such as chlorine, bromine or iodine. Examples of aryl are phenyl, j?-tolyl, >-anisyl and j>-chlorophenyl.
Preferably R1 denotes H, Ct-ό-alkyl or aralkyl and R2 denotes methyl. More preferably, R1 denotes H, methyl or benzyl and R2 denotes methyl. Most preferably, R1 denotes H and R2 denotes methyl.
The metal catalyst can be an organometal complex wherein the metal is selected from the group consisting of ruthenium, rhodium and iridium and wherein the organo ligand is selected from the group consisting of dienes, triarylphosphines, di-C^-alkyl sulfoxides and arenes. In addition, the organometal complex can contain halogen atoms such as chlorine, bromine or iodine. Examples of dienes are 1,5-hexadiene and 1,5-cyclooctadiene. An example of a tri- arylphosphine is triphenylphosphine. An example of a di-Cι-2-alkyl-sulfoxide is dimethyl- sulfoxide.
The arene can be optionally substituted with at least one Cι. -alkyl such as methyl, ethyl, propyl or isopropyl. Examples of arenes are benzene, toluene, ø-xylene, -xylene, j3-xylene, ethylbenzene, mesitylene, 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, 2-ethyltoluene, 3-ethyltoluene, 4-ethyltoluene, propylbenzene, cumene, o-cymene, m-cymene, ?-cymene, 1,2-diethylbenzene, 1,4-diethylbenzene, 1,2,3,5-tetramethyl- benzene, 1,2,4,5-tetramethylbenzene, pentamethylbenzene and hexamethylbenzene.
Examples of metal catalysts are [Ru(p-cymene)Cl2]2, [Ru(benzene)Cl2]2, [Ru(mesityl- ene)Cl2]2, [Ru(hexamethylbenzene)Cl2)]2, [Ru(PPh3)3Cl2], trα«5,-Ru(dimethyl- sulfoxide)4Cl2, [Ru(l,5-cyclooctadiene)Cl]2, [Rh(l,5-hexadiene)Cl]2, [Rh(l,5-cyclo- octadiene)Cl] , [Ir(l,5-hexadiene)Cl] and [Ir(l,5-cyclooctadiene)Cl]2.
The metal catalyst can be prepared by methods known in the art.
The organo Ru(II) complexes of the type [Ru(arene)X2]2 wherein X is halogen can be prepared from RuX3 and the corresponding 1,3- or 1,4-cyclohexadiene derivative, for example Ru(p-cymene)Cl2]2 can be prepared from RuCl3 and 5-isopropyl-2-methyl-l,3- cyclohexadiene (Bennett et al. J Chem. Soc; Dalton Trans 1974, 233-241).
The organometal complexes of the type [metal(diene)X]2 wherein metal is Rh(I) or Ir(I) can be prepared from [metal(cyclooctene)2X]2 and diene (Mestroni et al. J. Organomet. Chem. 1977, 140, 63-72).
[Metal(cyclooctene) X] can be prepared from MC13 wherein M denotes metal and cyclooctene (Herde et al. Inorg. Nucl. Chem. Lett. 1971, 7, 1029-1031). Alternatively, [Rh(l,5-cyclooctadiene)Cl]2 can be prepared from RhCl3 and 1,5-cyclooctadiene (Chatt et al. J Chem. Soc. 1957, 4735-4741). Preferably, the metal catalyst is an organometal complex wherein the metal is selected from the group consisting of ruthenium(II), rhodium(I) and iridium(I) and the organo ligand is an arene. More preferably, the metal is ruthenium(II) and the arene is selected from the group consisting of benzene, mesitylene and ?-cymene. Most preferably, the metal is ruthenium(II) and the organo ligand is ?-cymene.
The amount of metal catalyst used is preferably 0.001 to 0.05 mol equivalents, more preferably 0.001 to 0.01 mol equivalents, most preferably 0.001 to 0.005 mol equivalents, in respect to 3 -amino-1 -(2-thienyl)- 1-propanone (II).
The optically active nitrogen-containing ligand can be a bi-, tri- or tetradentate ligand comprising 2 to 4 heteroatoms which are capable of coordinating to the metal of the metal catalyst and which are selected from the group consisting of nitrogen, oxygen and phosphorus, wherein at least one of the heteroatoms is nitrogen.
Examples of bidentate optically active nitrogen-containing ligands are (S)-6-sec-buty\- 2,2'-bipyridine, (S)-3-(l ,2,2-trimethylpropyl)-l ,10-phenanthroline, (S)-(E)-(1 -phenyl- ethyl)pyridine-2-ylmethylene-amine, (S,S)-5,5'-diisopropyl-4,4',5,5'-tetrahydro-2,2'-bis- (oxazole), (S,S)-N,N-dimethyl-l,2-diphenyl-l,2-ethanediamine, (R,R)-1,1 '-bis[(methyl- amino)phenylmethyl]ferrocene, 1 , 1 -bis(4-methoxyphenyl)-3-phenyl-propane- 1 ,2-di- amine, (R,R)-N,N-bis(l-naphtylmethylene)-cyclohexane-l,2-diamine, (R,R)-N-tosyl- 1,2-diphenylethanediamine, (S,S)-N-tosyl-l,2-diphenylethanediamine, (R,R)-1,1 '-(a ino- phenylmethyl)(tosylaminophenylmethyl)ferrocene, (R,R)-N-tosyl-cyclohexane- 1 ,2-diamine, (lS,2R)-(-)-c/-s- 1 -amino-2-indanol, (lR,2S)-(+)-cis- 1 -amino-2-indanol, (S,S)-2-(methylamino)-l,2-diphenylethanol, (lS,3R,4R)-3-(hydroxylmethyl)-2-azabi- cyclo[2.2. l]heptane and (S)-2-(2-diphenylphosphinophenyl)-4-isopropyl-4,5-dihydro- oxazole.
Examples of tridentate optically active nitrogen-containing ligands are bis[2-((R)-4-phenyl-4,5-dihydrooxazolyl)-ethyl]amine, N,N-bis(2-hydroxy-2-phenyl- ethyl)-benzylamine, (R,R -2,6-bis[l-(diphenylphosphino)ethyl]pyridine, (S,S)-bis[(2-pyrrolidinyl)methyl]-phenyl-phosphine, (R,R)-bis[2-(4-phenyl-2-oxazolyl)- ethyl]-phenyl-phosphine and (R)-l-(diphenylphosphino)-2-((lR,2S,5R)-menthoxy)- 1 -(2-pyridyl)-ethane.
An examples of a tetradentate optically active nitrogen-containing ligand is (S,S)-N,N- bis[o-(diphenylphosphino)benzyl]cyclohexane- 1 ,2-diamine.
The above mentioned optically active nitrogen-containing ligands are described by Palmer et al. Tetrahedron: Asymmetry 1999, 10, 2045-2061.
Preferably, the optically active nitrogen-containing ligand is a bidentate ligand comprising 2 heteroatoms which are capable of coordinating to the metal of the metal catalyst and which are selected from the group consisting of nitrogen, oxygen and phosphorus, wherein at least one of the heteroatoms is nitrogen. More preferably, the optically active nitrogen-containing ligand is selected from the group consisting of (S,S)-N,N -dimethyl- l,2-diphenyl-l,2-ethanediamine, (R,R)-1,1 '-bis[(memylamino)- phenylmethyljferrocene, 1 , 1 -bis(4-methoxyphenyl)-3-phenyl-propane- 1 ,2-diamine, (R,R)-N-tosyl- 1 ,2-diphenylethanediamine, (S,S)-N-tosyl- 1 ,2-diphenylethanediamine, (R,R)- 1 , 1' -(aminophenylmethyl)(tosylaminophenylmethyl)ferrocene, (R,R)-N-tosyl- cyclohexane-l,2-diamine, (lS,2R)-(-)-ct-?-l-amino-2-indanol, (lR,2S)-(+)-ez'-?-l-amino-2- indanol, (S,S)-2-(methylamino)-l,2-diphenylethanol and (lS,3R,4R)-3-(hydroxylmethyl)- 2-azabicyclo[2.2.1]heptane. Even more preferably, the optically active nitrogen- containing ligand is selected from the group consisting of lS,2R)-(-)-c/.s,-l-amino-2- indanol, ( 1 R,2S)-(+)-cis- 1 -amino-2-indanol, (S,S)-2-(methylamino)- 1 ,2-diphenylethanol and (lS,3R,4R)-3-(hydroxylmethyl)-2-azabicyclo[2.2.1]heptane. Most preferably, the optically active nitrogen-containing ligand is (lS,2R)-(-)-c/5,-l-amino-2-indanol or (lR,2S)-(+)-cz'-y-l-amino-2-indanol.
The amount of optically active nitrogen-containing ligand used is preferably 0.005 to 0.100 mol equivalents, more preferably 0.010 to 0.050 mol equivalents, most preferably 0.010 to 0.020 mol equivalents, in respect to 3 -amino-1 -(2-thienyl)- 1-propanone (II).
The optically active nitrogen-containing ligand chelates to the metal catalyst to form an optically active metal catalyst. The optically active nitrogen-containing ligand and the metal catalyst can be added separately to the reaction vessel and the optically active metal catalyst is formed in situ or the optically active nitrogen-containing ligand and the metal catalyst are premixed and the obtained optically active catalyst is added to the reaction vessel. Preferably, the optically active nitrogen-containing ligand and the metal catalyst are added separately to the reaction vessel.
The hydrogen donor can be an organic molecule which is itself oxidized upon transferring hydrogen to 3 -amino-1 -(2-thienyl)- 1-propanone (II) such as a suitable unsaturated hydrocarbon, a primary or secondary alcohol or formic acid. Suitable unsaturated hydrocarbons are hydrocarbons which can be oxidized to an aromatic system. Examples of suitable unsaturated hydrocarbons are cyclohexene, 1,3-cyclohexadiene and 1,4-cyclo- hexadiene. Examples of primary and secondary alcohols are methanol, ethanol, isopropanol and benzyl alcohol.
Preferably, the hydrogen donor is isopropanol or formic acid. More preferably, the hydrogen donor is isopropanol.
Preferably, a base is present.
The base can be an inorganic or organic base. Examples of inorganic bases are alkali metal hydroxides such as sodium hydroxide and potassium hydroxide or alkali metal carbonates such as sodium carbonate or potassium carbonate. Examples of organic bases are alkali metal alkoxides such as potassium tert-butanolate, potassium isopropoxide or sodium isopropoxide and amines such as diethylamine, triethylamine, butylamine or ethanolamine. Preferably the base is an alkali metal hydroxide or an amine. More preferably the base is an alkali metal hydroxide.
The amount of base used is preferably 0.01 to 0.10 mol equivalents, more preferably 0.01 to 0.05 mol equivalents, in respect to 3-amino-l -(2-thienyl)- 1-propanone (II).
The solvent used in the reduction step can be any solvent or mixture of solvents that dissolves the reagents, namely a 3 -amino-1 -(2-thienyl)- 1-propanone (II), the hydrogen donor, the metal catalyst, the optically active nitrogen-containing ligand and the base, under the conditions used. Preferably, the solvent used in the reduction step is isopropanol or formic acid.
The reduction step can be carried out at a temperature from -40 to 110 °C, preferably at a temperature from 15 to 40 °C, more preferably at a temperature from 20 to 30 °C.
Preferably the reduction step is carried out in the absence of oxygen, e.g. under nitrogen or argon atmosphere.
Preferably, the starting material, 3 -amino-1 -(2-thienyl)- 1-propanone (II), is obtained by treating a salt thereof with a base. The base is as defined above. Preferably, the same base is used as the base employed in the reduction step.
A salt of a 3-amino-l -(2-thienyl)- 1 -propanone (II) can be an acid addition salt with an inorganic acid such as hydrochloric acid, hydrobromic acid or hydriodic acid. A salt of a 3 -amino-1 -(2-thienyl)- 1-propanone (II) can be prepared by Mannich reaction from 2-acetylthiophene, formaldehyde and an acid addition salt of NHR^2, wherein R1 and R2 are defined as above, with an inorganic acid. The preparation of 3-N,N-dimethylamino- 1 -(2-thienyl)- 1 -propanone hydrochloride from 2-acetylthiophene, dimethylamine hydrochloride and paraformaldehyde is described in EP 0 650 965 Al, for example.
Either isolated 3-amino-l-(2-thienyl)-l-propanone (II) can be employed as the starting material or 3-amino-l-(2-thienyl)-l-propanone (II) obtained in situ by treating a salt thereof with a base. The process of the present invention for the preparation of enantiomerically pure 3 -amino-1 -(2-thienyl)- 1 -propanol derivatives of the formulae
Figure imgf000011_0001
wherein R1 and R2 independently denote H, C^-alkyl, C5. -cycloalkyl, aralkyl or aryl, comprises the steps of i) reducing a 3 -amino- 1 -(2-thienyl)- 1 -propanone of the formula
Figure imgf000011_0002
using a hydrogen donor in the presence of a metal catalyst, an optically active nitrogen-containing ligand and optionally a base to yield enantiomerically enriched 3 -amino-1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I), ii) treating the enantiomerically enriched 3 -amino- 1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) obtained in step i) with (-)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid or (+)-2,3:4,6-di-O-isopropylidene-2-keto-D-gulonic acid of the formulae
Figure imgf000011_0003
to form the diastereomeric salts of the formulae
Figure imgf000012_0001
and
Figure imgf000012_0002
or the diastereomeric salts of the formulae
Figure imgf000012_0003
and
Figure imgf000012_0004
i ~ wherein R and R are defined as above, iii) crystallizing the diastereomerically pure salts (S)-L-IN or (R)-D-IN from the reaction mixture obtained in step ii), iv) treating the diastereomerically pure salts (S)-L-IN or (R)-D-IN obtained in step iii) with a base to liberate the enantiomerically pure 3 -amino-1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I).
All definitions given for the process for the preparation of enantiomerically enriched 3-amino-l-(2-thienyl)-l-propanols ((S)-I or (R)-I) apply, when appropriate, accordingly to this process.
Enantiomerically pure 3 -amino-1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) are 3-amino- 1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) having an e.e. of >80%, preferably >90%, more preferably >95%.
The e.e. of enantiomerically pure 3 -amino-1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) can be determined by chiral HPLC, for example.
(-)-2,3:4,6-Di-O-isopropylidene-2-keto-L-gulonic acid (L-III) or (+)-2,3:4,6-di-O-isopro- pylidene-2-keto-D-gulonic acid (D-III) refer also to the hydrates of gulonic acids L-III or D-III.
Preferably, enantiomerically enriched 3 -amino-1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) are treated with 0.50 to 3.00 mol equivalents (-)-2,3:4,6-di-O-isopropylidene-2-keto- L-gulonic acid (L-III) or (+)-2,3:4,6-di-O-isopropylidene-2-keto-D-gulonic acid (D-III) in respect to enantiomerically enriched 3 -amino- 1 -(2-thienyl)- 1 -propanols ((S)-ϊ or (R)-I) to form the diastereomeric salts of the formulae (S)-L-IV and (R)-L-IN or (S)-D-IN and (R)-D-IN.
The solvent used in step ii) is preferably selected from the group consisting of water, alcohols, esters and mixtures thereof. Examples of alcohols are methanol, ethanol, propanol, isopropanol, butanol and benzyl alcohol. Examples of esters are ethyl acetate, butyl acetate and benzyl acetate. More preferably, the solvent used in step ii) is selected from the group of primary and secondary alcohols. Most preferably, the solvent used in step ii) is isopropanol.
Step ii) can be carried out at a temperature from 0 to 100 °C, preferably at 15 to 80 °C, more preferably at 15 to 40 °C.
Diastereomerically pure salts (S)-L-IN or (R)-D-IN are salts (S)-L-IN or (R)-D-IN which liberate upon base treatment the corresponding 3 -amino-1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) having an e.e. of >80%, preferably >90% and more preferably >95%.
The diastereomerically pure salts (S)-L-IN or (R)-D-IN can be crystallized directly from the reaction mixture obtained in step ii) or after solvent exchange. The solvent exchange can be performed by partially or completely removing the solvent used in step ii) and simultaneously or successively adding another solvent. Preferably the diastereomerically pure salts (S)-L-IN or (R)-D-IV are crystallized directly from the reaction mixture obtained in step ii). The diastereomerically pure salts (S)-L-IN or (R)-D-IV are isolated e. g. by filtration or centrifugation.
The diastereomeric pure salts (S)-L-IN or (R)-D-IN obtained in step iii) can be dissolved in water and treated with a water soluble base. Examples of water soluble organic bases are trimethylamine, triethylamine and pyridine. Examples of water soluble inorganic bases are sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and ammonium hydroxide. Preferably, the base is a water-soluble inorganic base. More preferably, the base is sodium hydroxide or potassium hydroxide. The enantiomerically pure 3 -amino-1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) can be isolated e. g. by extraction with a suitable organic solvent such as an ester or an ether. Examples of esters are given above. Examples of ethers are diethyl ether, tert-butyl methyl ether and diisopropyl ether. Preferably, the solvent used for extracting 3-amino-l -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) is an ester or an ether. More preferably, this solvent is ethyl acetate or tert-butyl methyl ether. The following compounds are also part of the invention:
(S)-3 -NN-Dimethylammonio- 1 -(2-thienyl)- 1 -propanol 2,3 :4,6-di-O-isopropylidene- 2-keto-L-gulonate of the formula
Figure imgf000015_0001
and the mirror image thereof.
(R)-3 -NN-Dimethylammonio- 1 -(2-thienyl)- 1 -propanol 2,3 :4,6-di-O-isopropylidene- 2-keto-L-gulonate of the formula
Figure imgf000015_0002
and the mirror image thereof.
(S)-3-N-Benzyl-N-methylammonio-l-(2-thienyl)-l-propanol 2,3:4,6-di-O-isopropylidene- 2-keto-L-gulonate of the formula
Figure imgf000016_0001
and the mirror image thereof.
(R)-3-N-Benzyl-N-methylammonio- 1 -(2-thienyl)- 1 -propanol 2,3 :4,6-di-O-isopropylidene- 2-keto-L-gulonate of the formula
Figure imgf000016_0002
and the mirror image thereof. Example 1
Preparation of 3 -N-methylamino- 1 -(2-thienyl)- 1 -propanone hydrochloride
A mixture of 2-acetylthiophene (25.5 g, 200 mmol), methylamine hydrochloride (14.9 g, 220 mmol), paraformaldehyde (8.2 g, 280 mmol) and ethanol (100 mL) was heated in an autoclave at 110 °C for 9 h. The obtained light brown solution was cooled to 20 °C and part of the ethanol (50 mL) was removed by distillation under vacuum. Ethyl acetate (200 mL) was added to the residue to afford a thick suspension, which was cooled to 0 °C and kept for 45 min at that temperature. The obtained precipitate was isolated by filtration and dried yielding 3 -N-methylamino- 1 -(2-thienyl)- 1-propanone hydrochloride (content: 71%, 41.3 g, yield: 71%) as a slightly yellow powder.
Example 2
Preparation of enantiomerically enriched (S)-3-N-methylamino-l-(2-thienyl)-l-propanol
A mixture of (lS,2R)-(-)-c/-y-l-amino-2-indanol (17.7 mg, 0.119 mmol), (p-cymene)- ruthenium(II) chloride dimer (20.0 mg, 0.032 mmol) and degassed isopropanol (10 mL) was stirred for 20 min at 85 °C under nitrogen atmosphere and then cooled to 20 °C. A mixture of 3 -N-methylamino- 1 -(2-thienyl)- 1-propanone hydrochloride obtained as described in example 1 (content: 71%, 2.10 g, 7.24 mmol), sodium hydroxide (content: 98%, 0.44 g, 10.78 mmol) and degassed isopropanol (78 mL) was stirred for 1 h at 20 °C under nitrogen atmosphere, and then the above catalyst solution was added. The reaction mixture was stirred for 4 h at 20 °C under nitrogen atmosphere. After this time, the starting material, 3 -N-methylamino- 1 -(2-thienyl)- 1-propanone, had completely reacted (as determined by 1H-ΝMR) . (S)-3 -N-Methylamino- 1 -(2-thienyl)- 1 -propanol having an e.e. of 70% (as determined by chiral HPLC) was formed in a yield of 39% (as determined by 1H-ΝMR).
Example 3 Preparation of enantiomerically enriched (S)-3-NN-dimethylamino-l-(2-thienyl)-l-pro- panol
A mixture of (lS,2R)-(-)-c/-s-l-amino-2 -indanol (15.1 mg, 0.101 mmol), (p-cymene)- ruthenium(II) chloride dimer (15.6 mg, 0.026 mmol) and degassed isopropanol (8 mL) was stirred for 20 min at 85 °C under nitrogen atmosphere and then cooled to 20 °C. This solution was added to a mixture of 3 -NN-dimethylamino-1 -(2-thienyl)- 1-propanone (1.83 g, 10.00 mmol), potassium hydroxide (0.1 Ν solution in isopropanol, 2.5 mL, 0.25 mmol) and degassed isopropanol (90 mL). The reaction mixture was stirred for 4 h at 20 °C under nitrogen atmosphere. After this time, the starting material, 3 -NN-dimethylamino-1 -(2-thienyl)- 1-propanone, had completely reacted (as determined by 1H-ΝMR). (S)-3-NN-Dimethylamino-l-(2-thienyl)-l-propanol having an e.e. of 67.5% (as determined by chiral HPLC) was formed in a yield of 70% (as determined by 1H-ΝMR).
Example 4
Preparation of enantiomerically enriched (S)-3-N-benzyl-N-methylamino-l-(2-thienyl)- 1 -propanol
A mixture of (lS,2R)-(-)-cts-l-amino-2-indanol (15.1 mg, 0.101 mmol), ( -cymene)- ruthenium(II) chloride dimer (15.6 mg, 0.026 mmol) and degassed isopropanol (8 mL) was stirred for 20 min at 85 °C under nitrogen atmosphere and then cooled to 20 °C. This solution was added to a mixture of 3 -N-benzyl-N-methylamino-1 -(2-thienyl)- 1-propanone (2.29 g, 8.84 mmol), potassium hydroxide (0.1 Ν solution in isopropanol, 2.5 mL, 0.25 mmol) and degassed isopropanol (90 mL). The reaction mixture was stirred for 4 h at 20 °C under nitrogen atmosphere. After this time, the starting material, 3-N-benzyl- methylamino-1 -(2-thienyl)- 1-propanone, had completely reacted (as determined by 1H-ΝMR). (S)-(-)-3-N-Benzyl-N-methylamino-l -(2-thienyl)- 1 -propanol having an e.e. of 67.5% (as determined by chiral HPLC) was formed in a yield of 50% (as determined by 1H-ΝMR).
Example 5
Preparation of enantiomerically pure (S)-3 -N-methylamino- 1 -(2-thienyl)- 1 -propanol
(-)-2,3:4,6-Di-O-isopropylidene-2-keto-L-gulonic acid (2.00 g, 6.85 mmol) was added to the reaction mixture obtained as described in example 2 (67.0 g) containing
(S)-3 -N-methylamino- 1 -(2-thienyl)- 1 -propanol (0.48 g, 2.82 mmol). After stirring the mixture for 20 h at 20 °C, the formed precipitate was isolated by filtration and dried to yield (S)-3 -N-methylammonio- 1 -(2-thienyl)- 1 -propanol 2,3 :4,6-di-O-isopropylidene- 2-keto-L-gulonate (0.72 g, 1.56 mmol). Sodium hydroxide (0.43 g of a 30% aqueous solution) was added to a solution of (S)-3-N-methylammonio-l -(2-thienyl)- 1 -propanol 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonate (0.72 g, 1.56 mmol) in water (15 mL). tert-Butyl methyl ether (15 mL) was added. The two phases were separated and the aqueous one was extracted with tert-butyl methyl ether (2 x 15 mL). The collected organic phases were dried over sodium sulfate, filtrated and concentrated to yield a colorless oil which crystallized spontaneously affording (S)-(-)-3-N-methylamino- 1 -(2-thienyl)- 1 -propanol (0.22 g, 85%) as a white solid having an e.e. of >99% as determined by chiral HPLC.

Claims

Claims
1. A process for the preparation of enantiomerically enriched 3-amino-l-(2-thienyl)- 1 -propanols of the formulae
Figure imgf000020_0001
wherein R1 and R2 independently of one another denote H, Cι-6-alkyl, C5-7-cyclo- alkyl, aralkyl or aryl, comprising the step of reducing a 3-amino-l-(2-thienyl)- 1 -propanone of the formula
Figure imgf000020_0002
wherein R1 and R2 are defined as above, using a hydrogen donor in the presence of a metal catalyst, an optically active nitrogen-containing ligand and optionally a base.
2. The process of claim 1 wherein the metal catalyst is an organometal complex wherein the metal is selected from the group consisting of ruthenium(II), rhodium(I) and iridium(I) and the organo ligand is an arene.
3. The process of claim 2 wherein the metal is ruthenium(II) and the arene is selected from the group consisting of benzene, mesitylene and >-cymene.
4. The process of any of claims 1 to 3 wherein the optically active nitrogen-containing ligand is a bidentate ligand comprising 2 heteroatoms which are capable of coordinating to the metal of the metal catalyst and which are selected from the group consisting of nitrogen, oxygen and phosphorus, and wherein at least one of the heteroatoms is nitrogen.
5. The process of any of claims 1 to 4 wherein R1 denotes H, Cι-6-alkyl or aralkyl and R denotes methyl.
6. The process of claim 5 wherein R denotes H, methyl or benzyl and R denotes methyl.
7. The process of any of claims 1 to 6 wherein the hydrogen donor is isopropanol or formic acid.
8. The process of any of claims 1 to 7 wherein a base is present.
9. The process of any of claims 1 to 8 wherein 3 -amino-1 -(2-thienyl)- 1-propanone (II) is obtained by treating a salt thereof with a base.
10. A process for the preparation of enantiomerically pure 3 -amino-1 -(2-thienyl)- 1 -propanols of the formulae
Figure imgf000021_0001
wherein R1 and R2 independently of one another denote H, Ci-β-alkyl, C5. -cyclo- alkyl, aralkyl or aryl, comprising the steps of reducing a 3 -amino- 1 -(2-thienyl)- 1 -propanone of the formula
Figure imgf000022_0001
using a hydrogen donor in the presence of a metal catalyst, an optically active nitrogen-containing ligand and optionally a base to yield enantiomerically enriched 3 -amino-1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I), treating the enantiomerically enriched 3 -amino- 1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) obtained in step i) with (-)-2,3:4,6-di-O-isopropylidene-2-keto-L-gu- lonic acid or (+)-2,3:4,6-di-O-isopropylidene-2-keto-D-gulonic acid of the formulae
Figure imgf000022_0002
to form the diastereomeric salts of the formulae
Figure imgf000022_0003
and
Figure imgf000023_0001
or the diastereomeric salts of the formulae
Figure imgf000023_0002
and
Figure imgf000023_0003
wherein R1 and R2 are defined as above, iii) crystallizing the diastereomerically pure salts (5)-L-IN or (R)-D-IV from the reaction mixture obtained in step ii), and iv) treating the diastereomerically pure salts (S)-L-IV or (R)-D-IN obtained in step iii) with a base to liberate the enantiomerically pure 3-amino-l-(2-thienyl)-
1 -propanols ((S)-I or (R)-I).
11. The process of claim 10 wherein in step ii) 0.5 to 3.0 mol equivalents of (-)-2,3:4,6- di-O-isopropylidene-2-keto-L-gulonic acid or (+)-2,3:4,6-di-O-isopropylidene-2- keto-D-gulonic acid of the formulae L-III or D-III in respect to enantiomerically enriched 3 -amino-1 -(2-thienyl)- 1 -propanols ((S)-I or (R)-I) are used.
12. The process of claim 10 or 11 wherein in step iv) a water soluble inorganic base is used.
13. (S)-3 -NN-Dimethylammonio- 1 -(2-thienyl)- 1 -propanol 2,3 :4,6-di-O-isopropylidene- 2-keto-L-gulonate of the formula
Figure imgf000024_0001
and the mirror image thereof.
14. (R)-3-NN-Dimethylammonio- 1 -(2-thienyl)- 1 -propanol 2,3 :4,6-di-O-isopropylidene- 2-keto-L-gulonate of the formula
Figure imgf000024_0002
and the mirror image thereof.
15. (S)-3 -N-Benzyl-N-methylammonio- 1 -(2-thienyl)- 1 -propanol 2,3 :4,6-di-O-iso- propylidene-2-keto-L-gulonate of the formula
Figure imgf000025_0001
and the mirror image thereof.
16. (R)-3-N-Benzyl-N-methylammonio- 1 -(2-thienyl)- 1 -propanol 2,3 :4,6-di-O-iso- propylidene-2-keto-L-gulonate of the formula
Figure imgf000025_0002
and the mirror image thereof.
PCT/EP2003/011073 2002-10-07 2003-10-07 Processes and intermediates for the preparation of optically active 3-amino-1-(2-thienyl)-1-propanol derivatives WO2004031168A2 (en)

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WO2007098250A2 (en) * 2006-02-21 2007-08-30 Teva Pharmaceutical Industries Ltd. Process for the preparation of (s)-(-)-n,n-dimethyl-3-(2-thienyl)-3-hydroxypropanamine, a duloxetine intermediate
EP1836185A1 (en) * 2005-01-05 2007-09-26 Basf Aktiengesellschaft Method for purifying (1s)-3-methylamino-1-(2-thienyl)-1-propanol
WO2008004191A2 (en) 2006-07-03 2008-01-10 Ranbaxy Laboratories Limited Process for the preparation of enantiomerically pure salts of n-methyl-3- ( 1-naphthaleneoxy) -3- (2-thienyl) propanamine
WO2008077645A1 (en) * 2006-12-22 2008-07-03 Synthon B.V. Process for making duloxetine and related compounds
WO2008078124A1 (en) * 2006-12-22 2008-07-03 Richter Gedeon Nyrt. A process for the preparation of duloxetin and new key intermediates for use therein
WO2010003942A2 (en) * 2008-07-07 2010-01-14 Krka, D.D. Novo Mesto Preparation of duloxetine and its pharmaceutically acceptable salts by the use of asymmetric transfer hydrogenation process
US7842717B2 (en) 2005-09-22 2010-11-30 Teva Pharmaceutical Industries Ltd. DNT-maleate and methods of preparation thereof
WO2011033366A2 (en) 2009-09-16 2011-03-24 Jubilant Life Sciences Limited Process for the preparation of duloxetine hydrochloride and its precursors
WO2011128370A1 (en) 2010-04-13 2011-10-20 Krka, D.D., Novo Mesto Synthesis of duloxetine and/or pharmaceutically acceptable salts thereof
EP2426116A1 (en) 2010-08-30 2012-03-07 Saltigo GmbH Method for producing (S)-3-N-Methylamino-1-(2-thienyl)-1-propanol
US8288141B2 (en) 2008-08-27 2012-10-16 Codexis, Inc. Ketoreductase polypeptides for the production of 3-aryl-3-hydroxypropanamine from a 3-aryl-3-ketopropanamine
US8426178B2 (en) 2008-08-27 2013-04-23 Codexis, Inc. Ketoreductase polypeptides for the production of a 3-aryl-3-hydroxypropanamine from a 3-aryl-3-ketopropanamine
CN105061393A (en) * 2015-08-07 2015-11-18 浙江华义医药有限公司 Synthetic method for (S)-(-)-3-methylamino-1-(2-thienyl)-1-propanol
CN111793056A (en) * 2020-07-27 2020-10-20 广州康瑞泰药业有限公司 Preparation method of duloxetine intermediate

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EP1836185A1 (en) * 2005-01-05 2007-09-26 Basf Aktiengesellschaft Method for purifying (1s)-3-methylamino-1-(2-thienyl)-1-propanol
US7842717B2 (en) 2005-09-22 2010-11-30 Teva Pharmaceutical Industries Ltd. DNT-maleate and methods of preparation thereof
WO2007098250A3 (en) * 2006-02-21 2007-11-01 Teva Pharma Process for the preparation of (s)-(-)-n,n-dimethyl-3-(2-thienyl)-3-hydroxypropanamine, a duloxetine intermediate
US7560573B2 (en) 2006-02-21 2009-07-14 Teva Pharmaceutical Industries Ltd Process for the preparation of (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropananine, a duloxetine intermediate
WO2007098250A2 (en) * 2006-02-21 2007-08-30 Teva Pharmaceutical Industries Ltd. Process for the preparation of (s)-(-)-n,n-dimethyl-3-(2-thienyl)-3-hydroxypropanamine, a duloxetine intermediate
WO2008004191A2 (en) 2006-07-03 2008-01-10 Ranbaxy Laboratories Limited Process for the preparation of enantiomerically pure salts of n-methyl-3- ( 1-naphthaleneoxy) -3- (2-thienyl) propanamine
EA015828B1 (en) * 2006-12-22 2011-12-30 Рихтер Гедеон Нирт. A process for the preparation of duloxetin and new key intermediates for use therein
WO2008077645A1 (en) * 2006-12-22 2008-07-03 Synthon B.V. Process for making duloxetine and related compounds
WO2008078124A1 (en) * 2006-12-22 2008-07-03 Richter Gedeon Nyrt. A process for the preparation of duloxetin and new key intermediates for use therein
US7928250B2 (en) 2006-12-22 2011-04-19 Synthon Bv Process for making duloxetine and related compounds
WO2010003942A2 (en) * 2008-07-07 2010-01-14 Krka, D.D. Novo Mesto Preparation of duloxetine and its pharmaceutically acceptable salts by the use of asymmetric transfer hydrogenation process
WO2010003942A3 (en) * 2008-07-07 2010-07-22 Krka, D.D. Novo Mesto Preparation of duloxetine and its pharmaceutically acceptable salts by the use of asymmetric transfer hydrogenation process
US8673607B2 (en) 2008-08-27 2014-03-18 Codexis, Inc. Ketoreductase polypeptides for the production of a 3-aryl-3-hydroxypropanamine from a 3-aryl-3-ketopropanamine
US8877475B2 (en) 2008-08-27 2014-11-04 Codexis, Inc. Polynucleotides encoding engineered ketoreductase polypeptides
US11512332B2 (en) 2008-08-27 2022-11-29 Codexis, Inc. Engineered ketoreductase polypeptides
US10752926B2 (en) 2008-08-27 2020-08-25 Codexis, Inc. Engineered ketoreductase polypeptides
US8288141B2 (en) 2008-08-27 2012-10-16 Codexis, Inc. Ketoreductase polypeptides for the production of 3-aryl-3-hydroxypropanamine from a 3-aryl-3-ketopropanamine
US8426178B2 (en) 2008-08-27 2013-04-23 Codexis, Inc. Ketoreductase polypeptides for the production of a 3-aryl-3-hydroxypropanamine from a 3-aryl-3-ketopropanamine
US10006069B2 (en) 2008-08-27 2018-06-26 Codexis, Inc. Engineered ketoreductase polypeptides
US9657320B2 (en) 2008-08-27 2017-05-23 Codexis, Inc. Engineered ketoreductase polypeptides
US9228213B2 (en) 2008-08-27 2016-01-05 Codexis, Inc. Polynucleotides encoding engineered ketoreductase polypeptides
WO2011033366A2 (en) 2009-09-16 2011-03-24 Jubilant Life Sciences Limited Process for the preparation of duloxetine hydrochloride and its precursors
WO2011128370A1 (en) 2010-04-13 2011-10-20 Krka, D.D., Novo Mesto Synthesis of duloxetine and/or pharmaceutically acceptable salts thereof
WO2012028545A1 (en) 2010-08-30 2012-03-08 Saltigo Gmbh Process for preparing (s)-3-n-methylamino-1-(2-thienyl)-1-propanol
EP2426116A1 (en) 2010-08-30 2012-03-07 Saltigo GmbH Method for producing (S)-3-N-Methylamino-1-(2-thienyl)-1-propanol
CN105061393A (en) * 2015-08-07 2015-11-18 浙江华义医药有限公司 Synthetic method for (S)-(-)-3-methylamino-1-(2-thienyl)-1-propanol
CN111793056A (en) * 2020-07-27 2020-10-20 广州康瑞泰药业有限公司 Preparation method of duloxetine intermediate

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