WO2008132128A2 - Synthesis of a pharmaceutically active compound - Google Patents
Synthesis of a pharmaceutically active compound Download PDFInfo
- Publication number
- WO2008132128A2 WO2008132128A2 PCT/EP2008/054998 EP2008054998W WO2008132128A2 WO 2008132128 A2 WO2008132128 A2 WO 2008132128A2 EP 2008054998 W EP2008054998 W EP 2008054998W WO 2008132128 A2 WO2008132128 A2 WO 2008132128A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- process according
- acid
- anyone
- amino
- difluorocyclohexanoic
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 10
- 230000015572 biosynthetic process Effects 0.000 title description 14
- 238000003786 synthesis reaction Methods 0.000 title description 11
- 238000000034 method Methods 0.000 claims abstract description 83
- 230000008569 process Effects 0.000 claims abstract description 76
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- HYIUDFLDFSIXTR-UHFFFAOYSA-N 4,4-difluorocyclohexane-1-carboxylic acid Chemical compound OC(=O)C1CCC(F)(F)CC1 HYIUDFLDFSIXTR-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000000203 mixture Substances 0.000 claims abstract description 33
- 239000002253 acid Substances 0.000 claims abstract description 32
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 22
- SEQXIQNPMQTBGN-VIFPVBQESA-N (3s)-3-amino-3-phenylpropan-1-ol Chemical compound OCC[C@H](N)C1=CC=CC=C1 SEQXIQNPMQTBGN-VIFPVBQESA-N 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 150000002148 esters Chemical class 0.000 claims abstract description 16
- SEQXIQNPMQTBGN-UHFFFAOYSA-N 3-amino-3-phenylpropan-1-ol Chemical compound OCCC(N)C1=CC=CC=C1 SEQXIQNPMQTBGN-UHFFFAOYSA-N 0.000 claims abstract description 15
- GSNHKUDZZFZSJB-QYOOZWMWSA-N maraviroc Chemical compound CC(C)C1=NN=C(C)N1[C@@H]1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-QYOOZWMWSA-N 0.000 claims abstract description 15
- 229960004710 maraviroc Drugs 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 13
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000001376 precipitating effect Effects 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 25
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical group FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 18
- -1 difluorocyclohexanoic acid ester Chemical class 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000012025 fluorinating agent Substances 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 230000007062 hydrolysis Effects 0.000 claims description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- WSDQIHATCCOMLH-UHFFFAOYSA-N phenyl n-(3,5-dichlorophenyl)carbamate Chemical compound ClC1=CC(Cl)=CC(NC(=O)OC=2C=CC=CC=2)=C1 WSDQIHATCCOMLH-UHFFFAOYSA-N 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 7
- GSNHKUDZZFZSJB-HLMSNRGBSA-N 4,4-Difluoro-N-[(1S)-3-[(1R,5S)-3-[3-methyl-5-(propan-2-yl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]octan-8-yl]-1-phenylpropyl]cyclohexane-1-carboximidic acid Chemical compound CC(C)C1=NN=C(C)N1C1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-HLMSNRGBSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 238000005580 one pot reaction Methods 0.000 claims description 6
- AIQSXWLOKKCHFH-JTQLQIEISA-N (2s)-1-(4-methylphenyl)sulfonyl-5-oxopyrrolidine-2-carboxylic acid Chemical group C1=CC(C)=CC=C1S(=O)(=O)N1C(=O)CC[C@H]1C(O)=O AIQSXWLOKKCHFH-JTQLQIEISA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 230000002255 enzymatic effect Effects 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 5
- PJWULPCWPCVQKD-UHFFFAOYSA-N 4,4-difluorocyclohexane-1-carbonyl chloride Chemical compound FC1(F)CCC(C(Cl)=O)CC1 PJWULPCWPCVQKD-UHFFFAOYSA-N 0.000 claims description 4
- 102000004190 Enzymes Human genes 0.000 claims description 4
- 108090000790 Enzymes Proteins 0.000 claims description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical group F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 4
- 230000003213 activating effect Effects 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims description 4
- 238000002955 isolation Methods 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 108010093096 Immobilized Enzymes Proteins 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical group FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical group CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 2
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 2
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 claims description 2
- 239000012223 aqueous fraction Substances 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 239000012320 chlorinating reagent Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000001294 propane Substances 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims 2
- 230000003301 hydrolyzing effect Effects 0.000 claims 2
- KSNKQSPJFRQSEI-UHFFFAOYSA-N 3,3,3-trifluoropropanoic acid Chemical class OC(=O)CC(F)(F)F KSNKQSPJFRQSEI-UHFFFAOYSA-N 0.000 claims 1
- WTUCTMYLCMVYEX-UHFFFAOYSA-N 4,4,4-trifluorobutanoic acid Chemical class OC(=O)CCC(F)(F)F WTUCTMYLCMVYEX-UHFFFAOYSA-N 0.000 claims 1
- 239000012011 nucleophilic catalyst Substances 0.000 claims 1
- 230000020477 pH reduction Effects 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 abstract description 2
- HVFSJXUIRWUHRG-UHFFFAOYSA-N oic acid Natural products C1CC2C3CC=C4CC(OC5C(C(O)C(O)C(CO)O5)O)CC(O)C4(C)C3CCC2(C)C1C(C)C(O)CC(C)=C(C)C(=O)OC1OC(COC(C)=O)C(O)C(O)C1OC(C(C1O)O)OC(COC(C)=O)C1OC1OC(CO)C(O)C(O)C1O HVFSJXUIRWUHRG-UHFFFAOYSA-N 0.000 abstract 1
- 108090001060 Lipase Proteins 0.000 description 25
- 102000004882 Lipase Human genes 0.000 description 25
- 239000004367 Lipase Substances 0.000 description 25
- 235000019421 lipase Nutrition 0.000 description 25
- 239000003054 catalyst Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 108090000371 Esterases Proteins 0.000 description 12
- HZZDWLBBNSDYQM-UHFFFAOYSA-N ethyl 4,4-difluorocyclohexane-1-carboxylate Chemical compound CCOC(=O)C1CCC(F)(F)CC1 HZZDWLBBNSDYQM-UHFFFAOYSA-N 0.000 description 12
- 238000003682 fluorination reaction Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- ZXYAWONOWHSQRU-UHFFFAOYSA-N ethyl 4-oxocyclohexanecarboxylate Chemical compound CCOC(=O)C1CCC(=O)CC1 ZXYAWONOWHSQRU-UHFFFAOYSA-N 0.000 description 11
- IHJUKQGXHSICDZ-UHFFFAOYSA-N 4,4-bis(fluorooxycarbonyl)cyclohexane-1-carboxylic acid Chemical class FOC(=O)C1(CCC(CC1)C(=O)O)C(=O)OF IHJUKQGXHSICDZ-UHFFFAOYSA-N 0.000 description 10
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- 239000007787 solid Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 8
- RSWDZYJRBPVAHQ-UHFFFAOYSA-N ethyl 4,4-bis[(2,2,2-trifluoroacetyl)oxy]cyclohexane-1-carboxylate Chemical compound CCOC(=O)C1CCC(OC(=O)C(F)(F)F)(OC(=O)C(F)(F)F)CC1 RSWDZYJRBPVAHQ-UHFFFAOYSA-N 0.000 description 7
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000589774 Pseudomonas sp. Species 0.000 description 1
- 241000589614 Pseudomonas stutzeri Species 0.000 description 1
- 241000235545 Rhizopus niveus Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 241000142915 Streptomyces diastatochromogenes Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 241001147775 Thermoanaerobacter brockii Species 0.000 description 1
- 241000223258 Thermomyces lanuginosus Species 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical class [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 241000235015 Yarrowia lipolytica Species 0.000 description 1
- 241000179532 [Candida] cylindracea Species 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical group 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 150000001462 antimony Chemical class 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 238000010945 base-catalyzed hydrolysis reactiony Methods 0.000 description 1
- 239000011942 biocatalyst Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- YMEPHRXFRJPMOW-UHFFFAOYSA-N chloro carbonofluoridate Chemical class FC(=O)OCl YMEPHRXFRJPMOW-UHFFFAOYSA-N 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical group OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 230000009189 diving Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229960002089 ferrous chloride Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- XUCNUKMRBVNAPB-UHFFFAOYSA-N fluoroethene Chemical compound FC=C XUCNUKMRBVNAPB-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910000856 hastalloy Inorganic materials 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000001145 hydrido group Chemical group *[H] 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
- 159000000014 iron salts Chemical class 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- KYKUTNUWXQVSSU-UHFFFAOYSA-N marcfortine a Chemical compound O1C(C)(C)C=COC2=C1C=CC1=C2NC(=O)C1(C(C)(C)C1C2)CC31CN1CCCCC12C(=O)N3C KYKUTNUWXQVSSU-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- YPJUNDFVDDCYIH-UHFFFAOYSA-N perfluorobutyric acid Chemical compound OC(=O)C(F)(F)C(F)(F)C(F)(F)F YPJUNDFVDDCYIH-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 235000007686 potassium Nutrition 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical class Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 150000003608 titanium Chemical class 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine group Chemical class C(CCC)N(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention relates to improved synthesis of UK-427,857 (Maraviroc) which is a medicament under evaluation for treatment of HIV infections.
- the Maraviroc molecule contains one stereogenic centre with S-configuration. Enantiomeric purity of the target compound is therefore an important issue.
- Kellogg et al. Synthesis 2003, p. 1626-1638 proposes that racemic 3-amino-3-phenyl-l-propanols, unsubstituted or having 4-Br, 4-Cl, 4-OCH3 or 4-CH3 substituents on the phenyl ring can be resolved.
- 4-OCH3 can be resolved with M-mix.
- the present invention makes now available a more efficient process for the manufacture of Maraviroc in particular by providing efficient manufacture of enantiopure (S)-3-amino-3-phenylpropan- 1 -ol.
- the invention concerns in consequence a process for the manufacture of UK-427,857 (Maraviroc) which comprises a step wherein enantiopure (S)-3-amino-3-phenylpropan-l-ol is manufactured from a mixture of its enantiomers by crystallizing or precipitating from a solution containing the mixture of enantiomers of 3-amino-3-phenylpropan-l-ol, an enantiopure resolving agent and a solvent, a diastereomeric salt or complex of 3-amino-3- phenylpropan-1-ol with the resolving agent, said salt or complex being enriched in the (S)-enantiomer of 3-amino-3-phenylpropan-l-ol.
- the (S)-enantiomer of 3-amino-3- phenylpropan-1-ol is capable of forming a diastereomeric salt or complex with an enantiopure resolving agent, enabling for obtaining high optical purity and high yield of the required enantiomer for Maraviroc synthesis.
- the invention concerns also in consequence a crystallized or precipitated diastereomeric salt or diastereomeric complex of (S)-3-amino-3-phenylpropan-l- ol with an enantiopure resolving agent.
- Enantiopure (S)-3-amino-3- phenylpropan-1-ol can be recovered from this complex or this salt, e.g. by reaction with a strong acid such as a mineral acid e.g. aqueous HCl.
- enantiopure is intended to denote a chiral compound essentially composed of one enantiomer.
- Use is generally made of an enantiopure resolving agent having an enantiomeric excess of greater than or equal to 99 %. Preference is given to an enantiopure resolving agent having an enantiomeric excess of greater than or equal to 99.5 %.
- the enantiopure (S)-3-amino-3-phenylpropan-l-ol obtained in the present invention has generally an enantiomeric excess of greater than or equal to 90 %.
- enantiopure (S)-3-amino-3-phenylpropan-l- ol having an enantiomeric excess of greater than or equal to 99.5 %, more preferably of greater than or equal to 99.9 % can be obtained.
- the invention concerns also a method for obtaining enantiopure (S)-3-amino-3-phenylpropan-l-ol as described herein.
- the preferred resolving agent is enantiopure
- N-tosylpyroglutamic acid More preferably, the enantiopure N-tosylpyroglutamic acid has the (S)-conf ⁇ guration.
- Another preferred resolving agent is enantiopure N-sulphonyl pyroglutamic acid.
- the solvent used for providing the solution of the mixture of enantiomers of 3-amino-3-phenylpropan-l-ol and the resolving agent contains generally a polar organic solvent such as an ester and/or an alcohol, or an organic nitrile.
- a polar organic solvent such as an ester and/or an alcohol, or an organic nitrile.
- a mixture of ethyl acetate in particular water-saturated, and isopropanol is preferred for a primary crystallization or precipitation step, in particular with enantiopure N-tosylpyroglutamic acid.
- the crystallized or precipitated diastereomeric salt or diastereomeric complex of (S)-3-amino-3-phenylpropan-l-ol with an enantiopure resolving agent can be recrystallized.
- Acetonitrile has been found to give good results as recrystallization solvent in particular for recrystallizing diastereomeric salt or diastereomeric complex of (S)-3-amino-3-phenylpropan-l-ol with (S)- N- tosylpyroglutamic acid.
- the mixture of enantiomers of 3-amino-3-phenylpropan-l-ol is generally a racemic mixture. Such mixture is available commercially alternatively, it can be obtained by hydrogenation, e.g. with LiAlH 4 of 3-amino-3-phenylpropanoic acid.
- initiation is carried out by cooling the solution.
- initiation is carried out by introducing a seed material into the solution.
- seed material can be obtained by crystallization or precipitation of enantiopure (S)-3-amino-3-phenylpropan-l- ol which can be obtained e.g. according to the method of Fadvanis et al. discussed above with enantiopure resolving agent under the conditions of crystallization described herein.
- the enantiopure (S)-3-amino-3-phenylpropan-l-ol obtained as described herein before can be further converted to Maraviroc by further steps including reaction steps contemplated in WO-A-01/90106.
- the (S)-3-amino-3-phenylpropan-l-ol can be reacted with an activated 4,4-difluorocyclohexyl carboxylic acid species, preferably with 4,4-difluorocyclohexyl carboxylic acid chloride to produce (S)-4,4-difluorocyclohexyl carboxylic acid (l 'phenyl-3'-hydroxy- propane)amide.
- 4,4-difluorocyclohexyl carboxylic acid chloride can be advantageously produced by reacting 4,4-difluorocyclohexyl carboxylic acid with a chlorinating agent such as thionyl chloride in an organic solvent, preferably an aprotic organic solvent, having a boiling point of from 35°C to 80 0 C.
- a chlorinating agent such as thionyl chloride
- an organic solvent preferably an aprotic organic solvent, having a boiling point of from 35°C to 80 0 C.
- Methylene chloride is a suitable example.
- the (S)-4,4-difluorocyclohexyl carboxylic acid (l 'phenyl-3'-hydroxy- propane)amide can be further reacted with an activating agent to convert the 3 '-hydroxy group into a leaving group.
- a preferred activating agent is p- toluenesulphonic acid chloride, to produce (S)-4,4-difluorocyclohexyl carboxylic acid (1 'phenyl-3'-p-toluenesulphonyl-propane)amide.
- the leaving group can be substituted by 3-(3-isopropyl-5-methyl-4H- 1,2,4- triazol-4-yl)-exo-8-azabicyclo[3.2.1]octane to produce UK-427,857 (Maraviroc).
- the (S)-4,4-difluorocyclohexyl carboxylic acid (1 'phenyl- 3 '-hydroxy-propane)amide can be oxidized to the corresponding aldehyde and reacted with 3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl)-exo-8- azabicyclo[3.2.1]octane under reductive amination conditions to produce UK-427,857 (Maraviroc).
- 4,4-difluorocyclohexyl carboxylic acid species which can be used in the process for synthesis of Maraviroc according to the invention can be obtained using the procedure of co-pending European Patent application 07107158.3, the entire contents of which is incorporated by reference into the present application. A description of this process is described in the parts of the description here after. The process steps here after can be included in the process for the synthesis of Maraviroc described above.
- the present invention consequently relates also to a process for preparing difluorocyclohexanoic acid derivatives.
- DFCHCA 4,4-difluorocyclohexanoic acid
- US 4,792,618 discloses a process comprising formation of a chloro-substituted cyclohexenoate via Diels-Alder reaction and subsequent fluorination of said substituted chlorohexenoate.
- performance of the Diels-Alder reaction is unsatisfactory, as it may lead to by-products which are difficult to separate.
- An additional shortcoming of this process consists in the difficult access to one of the starting materials, i.e., a suitably substituted 1,3-diene.
- a process for the preparation of 4,4-difluorocyclohexanoic acid is disclosed in Tetrahedron Letters, 46 (2005) 5005-5007 and involves fluorination of ethyl 4-oxo-cyclohexanoate by means of a sulfur type fluorinating agent, namely DAST (diethylaminosulfur trifluoride). Said fluorination however results in the formation of a 1:1 mixture of the desired difluoro compound and of an inseparable vinyl fluoride by-product. An additional dihydroxylation step of said by-product is required in order to allow isolation of ethyl 4,4-difluorocyclohexanoate, and the overall yield of the process is anyway compromised.
- EP 1 364 938 discloses a two steps process applicable for producing
- JP63054331A discloses a process for the production of 1,1 -difluorocyclohexane, wherein cyclohexanone is reacted with trifluoroacetic anhydride and the resulting l,l-bis(trifluoroacetoxy)cyclohexane is reacted with hydrogen fluoride to obtain the desired product.
- JP63041443A and JP63044536A disclose single steps of the same process, whereas JP63054332A discloses a process comprising additional oxidation steps to obtain fluorobenzene.
- none of the above mentioned documents discloses a process for preparing difluorocyclohexanoic acid derivatives.
- the present invention concerns in consequence also a process for preparing a difluorocyclohexanoic acid derivative, which comprises a) reacting an oxocyclohexanoic acid ester of formula
- a further embodiment of the present invention concerns a process in which step a) is catalyzed by means of an amine.
- a further embodiment of the present invention is a process having an improved efficiency, wherein step a) and b) are carried out one-pot, in a single reaction vessel. In this way, a one-pot preparation of difluorocyclohexanoic acid derivatives is carried out.
- a further embodiment of the present invention is a process comprising a step c) of hydrolysis of the difluorocyclohexanoic acid ester recovered from step b), to afford the difluorocyclohexanoic acid.
- Said hydrolysis can be advantageously performed at neutral pH by using an enzymatic catalyst.
- the process of the present invention allows for selective and high yield manufacture of difluorocyclohexanoic acid derivative. The formation of undesirable by-products can be substantially avoided. Once a reaction of a step is completed, the resulting product can be easily recovered and be used for the next step without or only minimal efforts for purification.
- Another advantage of the process according to a preferred embodiment of the present invention consists in that it allows to obtain the desired products in more time efficient manner, due to improved reaction times of step a).
- Still another advantage of the process according to the present invention consists in that each step can be carried out under conditions and with materials allowing to avoid e.g. corrosiveness problems.
- ⁇ figure 1 shows the performance of the reaction of conversion of ethyl 4-oxocyclohexanoate into ethyl 4,4-bis(trifluoroacetoxy)cyclohexanoate, without catalyst, at 25°C and at 40 0 C ;
- Ri in the ester is generally chosen so that the ester group remains substantially stable when reacted with a fluorinating agent.
- Ri substituents include hydrocarbon residues such as alkyl, alkaryl or aryl groups which can be optionally be substituted and/or contain catenary or annular heteroatoms such as in particular oxygen atoms.
- Ri is preferably selected from substituents consisting of carbon and hydrogen in particular alkyl, alkaryl or aryl substituents containing from 1 to 12, more preferably from 1 to 7 carbon atoms. Most preferably Ri is selected from methyl, ethyl, propyl or butyl.
- the above formula (1) represents cyclohexanoic acid esters bearing the oxo group in the position 2, 3 or 4 of the ring, with respect to the position of the carboxylic function.
- the process according to the invention is applicable to starting compounds such as 2-oxocyclohexanoic acid esters or 3-oxocyclohexanoic acid esters, in order to prepare 2,2-difluoro or 3,3-difluorocyclohexanoic acid derivatives.
- the starting compound is a 4-oxocyclohexanoic acid ester (Ia), so that the resulting products are 4,4-difluorocyclohexanoic acid derivatives.
- step a) of the process an oxocyclohexanoic acid ester of formula (1) or (Ia) is reacted with an activated fluorocarboxylic acid derivative in order to obtain conversion into a bis(fluorocarboxy)cyclohexanoic acid derivative (2) or (2a).
- Said activated fluorocarboxylic acid derivative may, for example, be a fluorocarboxylic anhydride or halide, for example a chloride or fluoride, often a chloride.
- a fluorocarboxylic anhydride is preferred.
- said activated derivative is selected from derivatives of hydro fluorocarboxylic acids, chlorofluorocarboxylic acids, hydrochlorofluorocarboxylic acids and perfluorocarboxylic acids. It is preferably selected from derivatives of perfluorocarboxylic acids, in particular containing 1 to 10 carbon atoms in the perfluoroalkyl group. It is more preferably selected from derivatives of trifluoroacetic, perfluoropropionic and perfluorobutyric acid.
- said activated derivative is a trifluoroacetic derivative, such as trifluoroacetic chloride, trifluoroacetic fluoride or trifluoroacetic anhydride.
- said activated derivative is trifluoroacetic anhydride.
- This reagent is particularly advantageous since it has been found that its reaction with oxocyclohexanoic acid esters is extremely selective and leads to the desired product in particularly high yield.
- it has the additional advantage that the excess of trifluoroacetic anhydride can be easily removed for example by vacuum evaporation and can be reused in a next batch or recycled to the reaction medium in a continuous process.
- the molar ratio of the activated fluorocarboxylic acid derivative with respect to the oxocyclohexanoic acid ester is preferably from 1.5:1 to 30:1 and more preferably from 2: 1 and 20:1, in particular when trifluoroacetic anhydride is employed.
- step (a) of the process according to the invention can be carried out in the absence of catalyst.
- Figure 1 shows that in this case, when working at 40 0 C, the complete conversion of the starting material is reached after 168 hours. After the same time, at 25°C, a conversion of about 90 % is observed.
- Acid catalysts can be selected for example from Lewis acids such as for example Lewis acid metal salts.
- Lewis acid metal salts can be selected from transition metal salts such as iron salts, in particular iron trichloride or ferrous chloride, titanium salts such as titanium tetrachloride. They can also be selected from main group metal salts such as aluminum salts, for example aluminium trichloride, antimony salts such as chlorides or tin salts, in particular tin chlorides.
- Basic catalysts are preferred. It has been found that these catalysts have a significant effect on the reaction kinetics in a large scale.
- amine or phosphine catalysts such as triphenylphosphine [P(Ph) 3 ] are preferred.
- Amine catalysts are more preferred.
- tertiary alkyl amines such as triethylamine or tributylamines and aromatic amines such as pyridine and dimethylaminopyridine [DMAP] give good results. Particularly preferred is pyridine.
- Figure 2 shows the results of some tests which were carried out by measuring the time of conversion of ethyl 4-oxocyclohexanoate with trifluoroacetic anhydride at 40 0 C under the effect of different catalysts.
- the catalyst is generally applied in an amount from 0.005 to 0.1 moles per mole of the starting compound.
- the amount of the catalyst equal to or greater than 0.01 moles per mole of the starting compound.
- the amount of the catalyst is equal to or lower than 0.05 moles per mole of the starting compound. It has been found, surprisingly, that in particular when the catalyst concentration is in the range described here before, good results can be obtained in step (b) without any need for purification of the product obtained in step (a).
- Preferred reaction temperatures are from 0 0 C to 100 0 C. More preferred are temperatures from 20 0 C to 60 0 C.
- the pressure can vary. It is preferred to perform the reaction under autogenous pressure.
- the bis(fluorocarboxy)cyclo- hexanoic acid derivative (2) or (2a), formed in step a) of the process can be used without any purification for step b).
- step b) of the process the bis(fluorocarboxy)cyclohexanoic acid derivative (2) or (2a) resulting from step a) is reacted with a fluorinating agent to produce difluorocyclohexanoic acid ester.
- any fluorinating agent can be used in step b) of the process, where by fluorinating agents is meant in particular those fluorinating agents in which the fluoride ion serves as a reaction active species.
- the preferred fluorinating agent to be used is HF.
- a reaction with HF is preferably carried out in the substantial absence of catalyst. This embodiment gives particularly good results.
- Fluorination catalysts may also be used to catalyze the reaction with the fluorinating agent in particular HF.
- the molar ratio of hydrogen fluoride to the bis(fluorocarboxy)cyclo- hexanoic acid derivative (2) or (2a) is generally from 2:1 to 200:1. Preferably, said ratio is from 3:1 to 20 : 1. More preferably, said ratio is from 4:1 to 10:1.
- the reaction temperature is generally from -50 0 C and 150 0 C.
- the reaction is advantageously performed at moderate temperatures such as room temperature or temperatures ranging from 10 to 40 0 C preferably about 25°C. This embodiment allows for particularly selective reaction.
- the reaction is performed at higher temperatures. Typical temperatures range from 40 0 C to 150 0 C, preferably from 50 0 C to 100 0 C. This embodiment, while giving good selectivity, allows for increased time-space yield and is particularly useful when the reaction is carried out in continuous mode.
- the reaction can also be carried out continuously.
- one or more continuously stirred tank reactor, a plug-flow reactor or combinations thereof can be used.
- the residence time defined as the ratio of used volume of the reactor to the volume flow of reactants is generally from 30 minutes to 3 hours and preferably from 60 to 120 minutes.
- a residence time of from 70 to 100 minutes gives good results.
- product is withdrawn in a liquid phase. Withdrawal can be carried out, for example, with a dip tube.
- a liquid phase obtained in this embodiment can be treated for example, by distillation or evaporation notably of optionally present unreacted HF. Unreacted HF and optional other starting materials recovered can be recycled to the reaction.
- the liquid phase obtained in this embodiment can also be treated with an aqueous solution followed by phase separation. Water can be used as aqueous phase. A potassium, sodium or calcium carbonate or hydrogencarbonate solution is preferred as aqeuous solution.
- steps a) and b) may be carried out in a solvent.
- Suitable solvents are for example hydrocarbon solvents, ether solvents, halogenated hydrocarbon solvents.
- the reactions of step (a) and/or step (b) are performed in the absence of solvent.
- steps a) and b) of the process may be carried out one- pot.
- the oxocyclohexanoic acid ester of formula (1) or (Ia) the activated fluorocarboxylic acid derivative and the fluorinating agent are introduced into a single reaction vessel.
- Recovery of the difluorocyclohexanoic acid derivative can be carried out by an isolation procedure comprising treating at least a fraction of the reaction mixture from step (b) with an aqueous solution, preferably water or a solution as described above, and subsequently extracting an aqueous fraction obtained from the treatment with the aqueous solution with an organic solvent.
- the difluorocyclohexanoic acid derivative may be purified by separation methods, such as distillation, as illustrated in example 5.
- step (b) is carried out under conditions where hydrolysis or, where possible, transesterification of difluorocyclohexanoic acid ester can occur.
- This embodiment is suitable in particular when the desired final product is the difluorocyclohexanoic acid.
- the process may comprise a step c) of hydrolysis of the difluorocyclohexanoic acid ester recovered from step b), to afford the difluorocyclohexanoic acid.
- step c) may be optionally carried out on said mixture.
- Said hydrolysis optionally performed in step c) of the process according to the invention may be catalysed by acid or basic catalyst.
- said hydrolysis can be performed by using an enzymatic catalyst advantageously at neutral pH, such as pH 5 to pH 8, preferably about 7.
- Enzymes which can be used for the hydrolysis of the difluorocyclohexanoic acid esters include for example Esterase from Bacillus sp., Esterase from Bacillus stearothermophilus, Esterase from Bacillus thermoglucosidasius, Esterase from horse liver, Esterase from Mucor miehei, Esterase from porcine liver, Esterase from rabbit liver, Esterase from Rhizopus oryzae, Esterase from Saccharomyces cerevisiae, Esterase from Thermoanaerobium brockii, Esterase Isoenzyme 1 from hog liver, Esterase Streptomyces diastatochromogenes, Lipase A from Candida antarctica, Cholesterol Esterase from porcine pancreas, Cholesterol Esterase from
- Lipase B from Candida antarctica Lipase from Aspergillus niger, Lipase from Aspergillus oryzae, Lipase from Burkholderia sp., Lipase from Candida cylindracea, Lipase from Candida lipolytica, Lipase from Candida rugosa, Lipase from Chromobacterium viscosum, Lipase from human pancreas, Lipase from Mucor javanicus BioChemika, Lipase from Mucor javanicus, Lipase from Mucor miehei 1, Lipase from Penicillium roqueforti, Lipase from porcine pancreas, Lipase from Pseudomonas cepacia, Lipase from Pseudomonas fluorescens, Lipase from Pseudomonas sp.
- Type XIII Lipase from Pseudomonas stutzeri, Lipase from Rhizomucor miehei, Lipase from Rhizopus arrhizus, Lipase from Rhizopus niveus, Lipase from wheat germ, Lipase from Thermomyces lanuginosus, Lipase from Penicillium camemberti, Lipase from Rhizopus oryzae.
- Immobilized enzymes are preferred since it has been found that the reaction performs quite rapidly, with very good yields, under mild conditions.
- the immobilization has also the advantage of easy recycling of the biocatalyst.
- the difluorocyclohexanoic acid is preferably recovered from the reaction mixture by filtration, and then it is heat-dried.
- the aminophenylpropanol was partitioned between 250 ml water containing Na 2 CO 3 and 500 ml dichloromethane.
- the bilayered system was cooled down to 0 ⁇ 5°C.
- the dichloromethane solution of the chloride acid was then added gradually into the bilayered system under vigorous stirring by keeping the pH between 10.5 and 11.0.
- the reaction mixture was further stirred at room temperature at least 1 A h.
- the separated organic layer was washed once with 400 ml aqueous Na 2 CO 3 5 %, 400 ml water, 400 ml aqueous NaCl 5 % containing 10.9 g KHSO 4 , and finally with 400 ml water.
- Example 3 Preparation of ethyl 4,4-bis(trifluoroacetoxy)cyclohexanoate Reaction without catalyst at room temperatur and at 40 0 C
- Example 5 Fluorination of ethyl 4,4-bis(trifluoroacetoxy)cyclohexanoate (Bis-TFA ester) by HF, followed by aqueous work up
- the organic phase was washed once with water and once with a solution of NaHCO 3 . 114 g of organic were obtained, having a content of ethyl 4,4-difluorocyclohexanoate of 85 %.
- the organic phase was distilled and 70.3 g ethyl 4,4-difluorocyclohexanoate with a purity of 98.7 % were obtained.
- the bis-TFA-ester was placed in a 500 ml three-neck PTFE round bottom flask equipped with a cooler (-10 0 C) and tube to introduce the HF.
- the synthesis was carried out in the apparatus described in the previous example by introducing consecutively ethyl 4-oxocyclohexanoate (18.6 g, 0.11 mol), the HF (25.0 g, 1.25 mol) and trifluoroacetic chloride (31.0 g, 0.23 mol) after cooling down the reactor and evacuation.
- the conversion of the ketone was estimated to be 75 % after 16 h of stirring at ambient temperature.
- the selectivity to ethyl 4,4-difluorocyclohexanoate was 50 %.
- the main by- products were chlorinated compounds.
- Example 10 Base-catalyzed hydrolysis of ethyl 4,4-difluorocyclohexanoate
- Example 11 Enzyme-catalyzed hydrolysis of ethyl 4,4-difluorocyclohexanoate A suspension of 15.7 g ethyl 4,4-difluorocyclohexanoate (6.3 mmol), 2.1 g
- Example 12 Reaction at elevated temperature in batch :
- Example 13 Reaction at elevated temperature in continuous mode : In a 500 ml autoclave, 25O g of bis-TFA-ester and 60 g of HF were introduced at RT. The autoclave was then stirred over night. The next day the temperature was increased to 90 0 C and it was stirred for additional 3h. After that time a sample was taken and analyzed by GC. The conversion of that sample was complete. By doing so a start solution for the continuous process was prepared.
- Solid PCI5 (109.1 g) was introduced in a three-necked flask provided with a mechanical stirrer and a CaCl 2 cartridge. The flask was cooled down with an ice/water mixture bath and ethyl 4-oxocyclohexanoate (71.6 g) was added slowly. During that time the mixture became homogenous. After stirring overnight, 20Og of ice were slowly added. The crude was extracted trice by 200 ml of petroleum ether (60-80 0 C). The organic layer was washed by means of a saturated solution of NaHCOs and dried on MgSO 4 . The solvent was evaporated in a rotavapor. 63.7 g were isolated and analyzed by GC.
- composition of the mixture was the following : 24.6 % of ethyl 4,4-dichlorocyclohexanoate, 72.4 % of 4-chlorocyclohexene ethyl carboxylate. Three other chlorinated species were also identified. Comparative example 2 : Fluorination
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Abstract
Process for the manufacture of UK- 427,857 ( Maraviroc ) which comprises a step wherein enantiopure (S)-3-amino-3-phenylpropan-1-ol is manufactured from a mixture of its enantiomers by crystallizing or precipitating from a solution containing the mixture of enantiomers of 3-amino-3-phenylpropan-1-ol, an enantiopure resolving agent and a solvent, a diastereomeric salt or complex of 3-amino-3-phenylpropan-1-ol with the resolving agent, said salt or complex being enriched in the (S)-enantiomer of 3-amino-3-phenylpropan-1-ol. Difluorocyclohexan oic acid derivatives useful in the process can be obtained by a process comprising subjecting an oxocyclohexanoic acid ester to reaction with an activated fluorocarboxylic acid derivative and fluorinating the obtained intermediate to obtain a difluorocyclo hexanoic acid ester.
Description
Synthesis of a pharmaceutically active compound
The present invention relates to improved synthesis of UK-427,857 (Maraviroc) which is a medicament under evaluation for treatment of HIV infections.
Formula (I) - UK-427,857 (Maraviroc)
The Maraviroc molecule contains one stereogenic centre with S-configuration. Enantiomeric purity of the target compound is therefore an important issue.
The patent application WO-A-01/90106 the contents of which is incorporated by reference into the present application discloses a multiplicity of synthesis pathways for manufacturing 3-(3-isopropyl-5-methyl-4H-l,2,4-triazol- 4-yl)-exo-8-azabicyclo[3.2.1 Joctane derivatives. That reference mentions enantiomerically pure (S)-3-amino-3-phenyl-l-propanol as intermediate.
Such material has been obtained according to Fadvanis et al. Tetrahedron Asymm. (2006) p. 240-244 by enzymatic resolution with immobilized penicillin G acylase of N-phenylacetyl protected 3-amino-3-phenyl-l-propanol. Industrial use of such method would be expensive.
Torre et al.Tetrahedron Asymm. (2006) p. 860-866 showed that enantiomeric separation of 3-amino-3-phenyl-l-propanol by direct enzymatic acylation with different enzymes failed to provide acceptable enantiomeric excess. A particular protecting group strategy is required to achieve a maximum
enantiomeric excess of 95 %
Kellogg et al. Synthesis 2003, p. 1626-1638 proposes that racemic 3-amino-3-phenyl-l-propanols, unsubstituted or having 4-Br, 4-Cl, 4-OCH3 or 4-CH3 substituents on the phenyl ring can be resolved. For example, 4-OCH3 can be resolved with M-mix.
The present invention makes now available a more efficient process for the manufacture of Maraviroc in particular by providing efficient manufacture of enantiopure (S)-3-amino-3-phenylpropan- 1 -ol.
The invention concerns in consequence a process for the manufacture of UK-427,857 (Maraviroc) which comprises a step wherein enantiopure (S)-3-amino-3-phenylpropan-l-ol is manufactured from a mixture of its enantiomers by crystallizing or precipitating from a solution containing the mixture of enantiomers of 3-amino-3-phenylpropan-l-ol, an enantiopure resolving agent and a solvent, a diastereomeric salt or complex of 3-amino-3- phenylpropan-1-ol with the resolving agent, said salt or complex being enriched in the (S)-enantiomer of 3-amino-3-phenylpropan-l-ol.
It has been found, surprisingly, that the (S)-enantiomer of 3-amino-3- phenylpropan-1-ol is capable of forming a diastereomeric salt or complex with an enantiopure resolving agent, enabling for obtaining high optical purity and high yield of the required enantiomer for Maraviroc synthesis.
The invention concerns also in consequence a crystallized or precipitated diastereomeric salt or diastereomeric complex of (S)-3-amino-3-phenylpropan-l- ol with an enantiopure resolving agent. Enantiopure (S)-3-amino-3- phenylpropan-1-ol can be recovered from this complex or this salt, e.g. by reaction with a strong acid such as a mineral acid e.g. aqueous HCl.
The term "enantiopure" is intended to denote a chiral compound essentially composed of one enantiomer. The enantiomeric excess (ee) is defined : ee (%) = 100(xi -X2V(Xi-X2) with xi>x2 ; X1 and x2 represent the content of enantiomer 1 or 2 respectively in the mixture. Use is generally made of an enantiopure resolving agent having an enantiomeric excess of greater than or equal to 99 %. Preference is given to an enantiopure resolving agent having an enantiomeric excess of greater than or equal to 99.5 %.
The enantiopure (S)-3-amino-3-phenylpropan-l-ol obtained in the present invention has generally an enantiomeric excess of greater than or equal to 90 %.
In particular after recrystallization, enantiopure (S)-3-amino-3-phenylpropan-l-
ol having an enantiomeric excess of greater than or equal to 99.5 %, more preferably of greater than or equal to 99.9 % can be obtained.
The invention concerns also a method for obtaining enantiopure (S)-3-amino-3-phenylpropan-l-ol as described herein. In the present invention, the preferred resolving agent is enantiopure
N-tosylpyroglutamic acid. More preferably, the enantiopure N-tosylpyroglutamic acid has the (S)-confϊguration. Another preferred resolving agent is enantiopure N-sulphonyl pyroglutamic acid.
In the present invention, the solvent used for providing the solution of the mixture of enantiomers of 3-amino-3-phenylpropan-l-ol and the resolving agent contains generally a polar organic solvent such as an ester and/or an alcohol, or an organic nitrile. A mixture of ethyl acetate in particular water-saturated, and isopropanol is preferred for a primary crystallization or precipitation step, in particular with enantiopure N-tosylpyroglutamic acid. If desired the crystallized or precipitated diastereomeric salt or diastereomeric complex of (S)-3-amino-3-phenylpropan-l-ol with an enantiopure resolving agent can be recrystallized. Acetonitrile has been found to give good results as recrystallization solvent in particular for recrystallizing diastereomeric salt or diastereomeric complex of (S)-3-amino-3-phenylpropan-l-ol with (S)- N- tosylpyroglutamic acid.
The mixture of enantiomers of 3-amino-3-phenylpropan-l-ol is generally a racemic mixture. Such mixture is available commercially alternatively, it can be obtained by hydrogenation, e.g. with LiAlH4 of 3-amino-3-phenylpropanoic acid.
In the process according to the invention, it is often desirable to initiate the crystallization or precipitation. In one embodiment, initiation is carried out by cooling the solution. In another embodiment, initiation is carried out by introducing a seed material into the solution. Such seed material can be obtained by crystallization or precipitation of enantiopure (S)-3-amino-3-phenylpropan-l- ol which can be obtained e.g. according to the method of Fadvanis et al. discussed above with enantiopure resolving agent under the conditions of crystallization described herein.
The enantiopure (S)-3-amino-3-phenylpropan-l-ol obtained as described herein before can be further converted to Maraviroc by further steps including reaction steps contemplated in WO-A-01/90106. For example, the (S)-3-amino-3-phenylpropan-l-ol can be reacted with an activated 4,4-difluorocyclohexyl carboxylic acid species, preferably with
4,4-difluorocyclohexyl carboxylic acid chloride to produce (S)-4,4-difluorocyclohexyl carboxylic acid (l 'phenyl-3'-hydroxy- propane)amide.
It has been found that petroleum ether allows for particularly efficient isolation of 4,4-difluorocyclohexyl carboxylic acid (1 'phenyl-3'-hydroxy- propane)amide in solid form.
It has been found that 4,4-difluorocyclohexyl carboxylic acid chloride can be advantageously produced by reacting 4,4-difluorocyclohexyl carboxylic acid with a chlorinating agent such as thionyl chloride in an organic solvent, preferably an aprotic organic solvent, having a boiling point of from 35°C to 800C. Methylene chloride is a suitable example.
The (S)-4,4-difluorocyclohexyl carboxylic acid (l 'phenyl-3'-hydroxy- propane)amide can be further reacted with an activating agent to convert the 3 '-hydroxy group into a leaving group. A preferred activating agent is p- toluenesulphonic acid chloride, to produce (S)-4,4-difluorocyclohexyl carboxylic acid (1 'phenyl-3'-p-toluenesulphonyl-propane)amide.
The leaving group can be substituted by 3-(3-isopropyl-5-methyl-4H- 1,2,4- triazol-4-yl)-exo-8-azabicyclo[3.2.1]octane to produce UK-427,857 (Maraviroc).
In another embodiment, the (S)-4,4-difluorocyclohexyl carboxylic acid (1 'phenyl- 3 '-hydroxy-propane)amide can be oxidized to the corresponding aldehyde and reacted with 3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl)-exo-8- azabicyclo[3.2.1]octane under reductive amination conditions to produce UK-427,857 (Maraviroc).
4,4-difluorocyclohexyl carboxylic acid species which can be used in the process for synthesis of Maraviroc according to the invention can be obtained using the procedure of co-pending European Patent application 07107158.3, the entire contents of which is incorporated by reference into the present application. A description of this process is described in the parts of the description here after. The process steps here after can be included in the process for the synthesis of Maraviroc described above. The present invention consequently relates also to a process for preparing difluorocyclohexanoic acid derivatives.
It is known that difluorocyclohexanoic acid derivatives are useful intermediates in the synthesis of pharmaceuticals. In particular, 4,4-difluorocyclohexanoic acid (DFCHCA) is a building block for the anti HIV drug Maraviroc.
Methods for the preparation of such derivatives are already known. For the preparation of 4,4-difluorocyclohexanoic acid esters, a number of synthetical processes have been described.
US 4,792,618 discloses a process comprising formation of a chloro-substituted cyclohexenoate via Diels-Alder reaction and subsequent fluorination of said substituted chlorohexenoate. However, performance of the Diels-Alder reaction is unsatisfactory, as it may lead to by-products which are difficult to separate. An additional shortcoming of this process consists in the difficult access to one of the starting materials, i.e., a suitably substituted 1,3-diene.
A process for the preparation of 4,4-difluorocyclohexanoic acid is disclosed in Tetrahedron Letters, 46 (2005) 5005-5007 and involves fluorination of ethyl 4-oxo-cyclohexanoate by means of a sulfur type fluorinating agent, namely DAST (diethylaminosulfur trifluoride). Said fluorination however results in the formation of a 1:1 mixture of the desired difluoro compound and of an inseparable vinyl fluoride by-product. An additional dihydroxylation step of said by-product is required in order to allow isolation of ethyl 4,4-difluorocyclohexanoate, and the overall yield of the process is anyway compromised. EP 1 364 938 discloses a two steps process applicable for producing
4,4-difluorocyclohexanoic acid esters. In the first step of the process, ethyl 4-oxocyclohexanoate is reacted with phosphorus pentachloride and the resulting product comprises a mixture of ethyl 4,4-dichlorocyclohexanoate and an olefin by-product in a ratio of about 1 :2. In the second step, fluorination of ethyl 4,4-dichlorocyclohexanoate yields the target 4,4-difluorocyclohexanoic acid ester. However, the overall yield of the process is poor. In addition, also the second step reaction is not efficient, since the reported yield of the sole fluorination step is low.
JP63054331A discloses a process for the production of 1,1 -difluorocyclohexane, wherein cyclohexanone is reacted with trifluoroacetic anhydride and the resulting l,l-bis(trifluoroacetoxy)cyclohexane is reacted with hydrogen fluoride to obtain the desired product. JP63041443A and JP63044536A disclose single steps of the same process, whereas JP63054332A discloses a process comprising additional oxidation steps to obtain fluorobenzene.
However, none of the above mentioned documents discloses a process for preparing difluorocyclohexanoic acid derivatives.
It was therefore desirable to solve the above discussed problems of the prior art processes. In particular, it was desirable to provide a process for preparing difluorocyclohexanoic acid derivatives, which affords the desired product with high yield and in high purity.
The present invention concerns in consequence also a process for preparing a difluorocyclohexanoic acid derivative, which comprises a) reacting an oxocyclohexanoic acid ester of formula
(1 ) wherein COORi is an ester group with an activated fluorocarboxylic acid derivative to produce a compound of formula (2),
(2) wherein COORi is as defined above and R2 is a fluorocarbon substituent and b) reacting said compound of formula (2) with a fluorinating agent to produce a difluorocyclohexanoic acid ester of formula (3),
(3) wherein COORi is as defined above.
The process according to the invention is especially suitable to produce 4,4-difluorocyclohexanoic acid derivatives (3a) starting from a 4-oxocyclohexanoic acid ester (Ia) as shown in the following reaction schema :
(1 a) (2a) (3a) . A further embodiment of the present invention concerns a process in which step a) is catalyzed by means of an amine.
A further embodiment of the present invention is a process having an improved efficiency, wherein step a) and b) are carried out one-pot, in a single reaction vessel. In this way, a one-pot preparation of difluorocyclohexanoic acid derivatives is carried out.
A further embodiment of the present invention is a process comprising a step c) of hydrolysis of the difluorocyclohexanoic acid ester recovered from step b), to afford the difluorocyclohexanoic acid. Said hydrolysis can be advantageously performed at neutral pH by using an enzymatic catalyst. Surprisingly, the process of the present invention allows for selective and high yield manufacture of difluorocyclohexanoic acid derivative. The formation of undesirable by-products can be substantially avoided. Once a reaction of a step is completed, the resulting product can be easily recovered and be used for the next step without or only minimal efforts for purification. Another advantage of the process according to a preferred embodiment of the present invention consists in that it allows to obtain the desired products in more time efficient manner, due to improved reaction times of step a).
Still another advantage of the process according to the present invention consists in that each step can be carried out under conditions and with materials allowing to avoid e.g. corrosiveness problems.
The process according to the present invention will be described in detail in the following, with reference to the attached drawings, wherein : ■ figure 1 shows the performance of the reaction of conversion of ethyl 4-oxocyclohexanoate into ethyl 4,4-bis(trifluoroacetoxy)cyclohexanoate,
without catalyst, at 25°C and at 400C ;
■ figure 2 shows the influence of different catalysts on step a) of the reaction ; In the process according to the present invention the substituent Ri in the ester is generally chosen so that the ester group remains substantially stable when reacted with a fluorinating agent. Examples of such Ri substituents include hydrocarbon residues such as alkyl, alkaryl or aryl groups which can be optionally be substituted and/or contain catenary or annular heteroatoms such as in particular oxygen atoms. Ri is preferably selected from substituents consisting of carbon and hydrogen in particular alkyl, alkaryl or aryl substituents containing from 1 to 12, more preferably from 1 to 7 carbon atoms. Most preferably Ri is selected from methyl, ethyl, propyl or butyl.
The above formula (1), represents cyclohexanoic acid esters bearing the oxo group in the position 2, 3 or 4 of the ring, with respect to the position of the carboxylic function. For example, the process according to the invention is applicable to starting compounds such as 2-oxocyclohexanoic acid esters or 3-oxocyclohexanoic acid esters, in order to prepare 2,2-difluoro or 3,3-difluorocyclohexanoic acid derivatives.
According to a preferred embodiment of the process according to the invention, the starting compound is a 4-oxocyclohexanoic acid ester (Ia), so that the resulting products are 4,4-difluorocyclohexanoic acid derivatives.
In step a) of the process, an oxocyclohexanoic acid ester of formula (1) or (Ia) is reacted with an activated fluorocarboxylic acid derivative in order to obtain conversion into a bis(fluorocarboxy)cyclohexanoic acid derivative (2) or (2a). Said activated fluorocarboxylic acid derivative may, for example, be a fluorocarboxylic anhydride or halide, for example a chloride or fluoride, often a chloride. A fluorocarboxylic anhydride is preferred. Often, said activated derivative is selected from derivatives of hydro fluorocarboxylic acids, chlorofluorocarboxylic acids, hydrochlorofluorocarboxylic acids and perfluorocarboxylic acids. It is preferably selected from derivatives of perfluorocarboxylic acids, in particular containing 1 to 10 carbon atoms in the perfluoroalkyl group. It is more preferably selected from derivatives of trifluoroacetic, perfluoropropionic and perfluorobutyric acid.
Even more preferably, said activated derivative is a trifluoroacetic derivative, such as trifluoroacetic chloride, trifluoroacetic fluoride or trifluoroacetic anhydride. Most preferably said activated derivative is
trifluoroacetic anhydride. This reagent is particularly advantageous since it has been found that its reaction with oxocyclohexanoic acid esters is extremely selective and leads to the desired product in particularly high yield. In addition, it has the additional advantage that the excess of trifluoroacetic anhydride can be easily removed for example by vacuum evaporation and can be reused in a next batch or recycled to the reaction medium in a continuous process.
It is preferable to apply a molar excess of said activated fluorocarboxylic acid derivative with respect to the oxocyclohexanoic acid ester of formula (1) or (Ia). The molar ratio of the activated fluorocarboxylic acid derivative with respect to the oxocyclohexanoic acid ester is preferably from 1.5:1 to 30:1 and more preferably from 2: 1 and 20:1, in particular when trifluoroacetic anhydride is employed.
The reaction of step (a) of the process according to the invention can be carried out in the absence of catalyst. Figure 1 shows that in this case, when working at 400C, the complete conversion of the starting material is reached after 168 hours. After the same time, at 25°C, a conversion of about 90 % is observed.
The reaction of step (a) of the process according to the invention can be carried out in the presence of a catalyst. Both acid and basic catalysts are useful. Acid catalysts can be selected for example from Lewis acids such as for example Lewis acid metal salts. Such Lewis acid metal salts can be selected from transition metal salts such as iron salts, in particular iron trichloride or ferrous chloride, titanium salts such as titanium tetrachloride. They can also be selected from main group metal salts such as aluminum salts, for example aluminium trichloride, antimony salts such as chlorides or tin salts, in particular tin chlorides.
Basic catalysts are preferred. It has been found that these catalysts have a significant effect on the reaction kinetics in a large scale. Among these, amine or phosphine catalysts, such as triphenylphosphine [P(Ph)3], are preferred. Amine catalysts are more preferred. Among the amine catalysts, tertiary alkyl amines such as triethylamine or tributylamines and aromatic amines such as pyridine and dimethylaminopyridine [DMAP] give good results. Particularly preferred is pyridine.
Figure 2 shows the results of some tests which were carried out by measuring the time of conversion of ethyl 4-oxocyclohexanoate with trifluoroacetic anhydride at 400C under the effect of different catalysts.
The catalyst is generally applied in an amount from 0.005 to 0.1 moles per mole of the starting compound. Preferably, the amount of the catalyst equal to or greater than 0.01 moles per mole of the starting compound. Preferably, the amount of the catalyst is equal to or lower than 0.05 moles per mole of the starting compound. It has been found, surprisingly, that in particular when the catalyst concentration is in the range described here before, good results can be obtained in step (b) without any need for purification of the product obtained in step (a).
Preferred reaction temperatures are from 00C to 1000C. More preferred are temperatures from 200C to 600C.
The pressure can vary. It is preferred to perform the reaction under autogenous pressure.
Surprisingly, in a preferred embodiment, the bis(fluorocarboxy)cyclo- hexanoic acid derivative (2) or (2a), formed in step a) of the process, can be used without any purification for step b).
In step b) of the process, the bis(fluorocarboxy)cyclohexanoic acid derivative (2) or (2a) resulting from step a) is reacted with a fluorinating agent to produce difluorocyclohexanoic acid ester.
Basically any fluorinating agent can be used in step b) of the process, where by fluorinating agents is meant in particular those fluorinating agents in which the fluoride ion serves as a reaction active species.
The preferred fluorinating agent to be used is HF. A reaction with HF is preferably carried out in the substantial absence of catalyst. This embodiment gives particularly good results. Fluorination catalysts may also be used to catalyze the reaction with the fluorinating agent in particular HF.
Complexes between HF and amines may also be used.
The molar ratio of hydrogen fluoride to the bis(fluorocarboxy)cyclo- hexanoic acid derivative (2) or (2a) is generally from 2:1 to 200:1. Preferably, said ratio is from 3:1 to 20 : 1. More preferably, said ratio is from 4:1 to 10:1.
In step (b), the reaction temperature is generally from -500C and 1500C.
In a first embodiment, the reaction is advantageously performed at moderate temperatures such as room temperature or temperatures ranging from 10 to 400C preferably about 25°C. This embodiment allows for particularly selective reaction.
In a second embodiment, the reaction is performed at higher temperatures. Typical temperatures range from 400C to 1500C, preferably from 500C to 1000C. This embodiment, while giving good selectivity, allows for increased time-space yield and is particularly useful when the reaction is carried out in continuous mode.
It is preferred to perform the reaction under autogenous pressure.
The reaction can also be carried out continuously. In this case, one or more continuously stirred tank reactor, a plug-flow reactor or combinations thereof can be used. In a continuous process, the residence time defined as the ratio of used volume of the reactor to the volume flow of reactants is generally from 30 minutes to 3 hours and preferably from 60 to 120 minutes. A residence time of from 70 to 100 minutes gives good results.
Generally, in the continuous process, product is withdrawn in a liquid phase. Withdrawal can be carried out, for example, with a dip tube.
A liquid phase obtained in this embodiment can be treated for example, by distillation or evaporation notably of optionally present unreacted HF. Unreacted HF and optional other starting materials recovered can be recycled to the reaction. The liquid phase obtained in this embodiment can also be treated with an aqueous solution followed by phase separation. Water can be used as aqueous phase. A potassium, sodium or calcium carbonate or hydrogencarbonate solution is preferred as aqeuous solution.
The reactions of steps a) and b) may be carried out in a solvent. Suitable solvents are for example hydrocarbon solvents, ether solvents, halogenated hydrocarbon solvents. Advantageously, the reactions of step (a) and/or step (b) are performed in the absence of solvent.
The above illustrated steps a) and b) of the process may be carried out one- pot. In this case, the oxocyclohexanoic acid ester of formula (1) or (Ia), the activated fluorocarboxylic acid derivative and the fluorinating agent are introduced into a single reaction vessel.
Recovery of the difluorocyclohexanoic acid derivative can be carried out by an isolation procedure comprising treating at least a fraction of the reaction mixture from step (b) with an aqueous solution, preferably water or a solution as described above, and subsequently extracting an aqueous fraction obtained from the treatment with the aqueous solution with an organic solvent. After that, the
difluorocyclohexanoic acid derivative may be purified by separation methods, such as distillation, as illustrated in example 5.
In a particular embodiment, step (b) is carried out under conditions where hydrolysis or, where possible, transesterification of difluorocyclohexanoic acid ester can occur. This embodiment is suitable in particular when the desired final product is the difluorocyclohexanoic acid.
Since in many cases the final desired product is the free acid, the process may comprise a step c) of hydrolysis of the difluorocyclohexanoic acid ester recovered from step b), to afford the difluorocyclohexanoic acid. In the case that a mixture of difluorocyclohexanoic acid and ester is recovered from the two first steps of the process, then step c) may be optionally carried out on said mixture.
Said hydrolysis optionally performed in step c) of the process according to the invention, may be catalysed by acid or basic catalyst.
In a preferred embodiment of the invention, said hydrolysis can be performed by using an enzymatic catalyst advantageously at neutral pH, such as pH 5 to pH 8, preferably about 7.
Enzymes which can be used for the hydrolysis of the difluorocyclohexanoic acid esters include for example Esterase from Bacillus sp., Esterase from Bacillus stearothermophilus, Esterase from Bacillus thermoglucosidasius, Esterase from horse liver, Esterase from Mucor miehei, Esterase from porcine liver, Esterase from rabbit liver, Esterase from Rhizopus oryzae, Esterase from Saccharomyces cerevisiae, Esterase from Thermoanaerobium brockii, Esterase Isoenzyme 1 from hog liver, Esterase Streptomyces diastatochromogenes, Lipase A from Candida antarctica, Cholesterol Esterase from porcine pancreas, Cholesterol Esterase from
Pseudomonas fluorescens, Lipase B from Candida antarctica, Lipase from Aspergillus niger, Lipase from Aspergillus oryzae, Lipase from Burkholderia sp., Lipase from Candida cylindracea, Lipase from Candida lipolytica, Lipase from Candida rugosa, Lipase from Chromobacterium viscosum, Lipase from human pancreas, Lipase from Mucor javanicus BioChemika, Lipase from Mucor javanicus, Lipase from Mucor miehei 1, Lipase from Penicillium roqueforti, Lipase from porcine pancreas, Lipase from Pseudomonas cepacia, Lipase from Pseudomonas fluorescens, Lipase from Pseudomonas sp. Type XIII, Lipase from Pseudomonas stutzeri, Lipase from Rhizomucor miehei, Lipase from Rhizopus arrhizus, Lipase from Rhizopus niveus, Lipase from wheat germ, Lipase from
Thermomyces lanuginosus, Lipase from Penicillium camemberti, Lipase from Rhizopus oryzae.
Immobilized enzymes are preferred since it has been found that the reaction performs quite rapidly, with very good yields, under mild conditions. The immobilization has also the advantage of easy recycling of the biocatalyst.
The difluorocyclohexanoic acid is preferably recovered from the reaction mixture by filtration, and then it is heat-dried.
The examples here after are intended to illustrate the invention without however limiting it. Example 1
On one side, 6.16 g of racemic aminophenylpropanol (NMR 94 %) was dissolved in 160 ml ethyl acetate (satured by water) and 8 ml isopropanol. On the other side, 13.32 g of p-Tos (D)pGlu-OH was dissolved in the same mixture. Both solutions were mixed, and seed crystals of p-Tos(D)pGlu- OH.(S)aminophenylpropanol previously obtained were added. After about 16 hours at room temperature, the suspension was filtered. The crystals were then washed twice with 25 ml ethyl acetate, dried under vacuum (45°C). The first crystallization yielded 5g of p-Tos(D)p-Glu-OH. (S)aminophenylpropanol with 9.8:90.2 % ratio. Second step crystallization
2 g of pTos(D)pGlu-OH.(S)aminophenylpropanol having 97.5 % ee was suspended in 18 ml acetonitrile. By heating the suspension (600C) and adding 0.95 ml water, a solution was obtained. Stirring at 600C was maintained for about 1A h then the solution was first cooled down at room temperature and then put into the fridge (10-50C). After few hours at 10-50C, the crystals were filtered and dried under vacuum. After drying, we obtained 1.12 g crystals with the ratio 0.1 :99.9. Example 2
Coupling step between difluorocyclohexylcarboxylic acid (DFCHA) and aminophenylpropanol
Thionyl chloride was added, at room temperature, to a solution of difluorocyclohexylcarboxylic acid, obtained according to the procedure disclosed in European Patent application 07107158.3, in 170 ml dichloromethane containing catalytic amount of dimethylformamide. After stirring the solution at least 8 hours, the reaction mixture was concentrated in vacuo, retaken two times in 150 ml dichloromethane and further concentrated in order to eliminate the
remaining thionyl chloride. (At the end of the concentration, the chloride acid begins to crystallize). The solid was dissolved in 100 ml dichloromethane. The aminophenylpropanol was partitioned between 250 ml water containing Na2CO3 and 500 ml dichloromethane. The bilayered system was cooled down to 0 ± 5°C. The dichloromethane solution of the chloride acid was then added gradually into the bilayered system under vigorous stirring by keeping the pH between 10.5 and 11.0. At the end of the addition, the reaction mixture was further stirred at room temperature at least 1A h. After checking the completion of the reaction by HPLC, the separated organic layer was washed once with 400 ml aqueous Na2CO3 5 %, 400 ml water, 400 ml aqueous NaCl 5 % containing 10.9 g KHSO4, and finally with 400 ml water. After concentrating the washed organic layer in vacuo, the resulting precipitate was diluted by 250 ml petroleum ether. The suspension was stirred at 0 ± 5°C for at least Vi h, then filtered, dried under vacuum at 45°C. This step yielded to 20.5 g of slightly yellow solid (84.5 %).
Example 3 : Preparation of ethyl 4,4-bis(trifluoroacetoxy)cyclohexanoate Reaction without catalyst at room temperatur and at 400C
Ethyl-4-oxocyclohexanoate (84.1g ; 0.49 mol) and trifluoroacetic anhydride (TFAH : 256.7g, 1.22 mol ; 3.47 eq.) were placed in a 500 ml round bottom flask. The solution was stirred at RT (room temperature) during
166 hours (an identical trial was run at 400C during 168 hours). The conversion of the starting compound into ethyl 4,4-bis(trifluoroacetoxy)cyclohexanoate was determined by GC analysis (see Figure 1). After stirring for the mentioned time, the excess of TFAH was removed in a rotavapor (500C, 40 mbar). 187 g were obtained. The composition of the final mixture was the following : 77.7 % of ethyl 4,4-bis(trifluoroacetoxy)cyclohexanoate (bis-TFA-ester), 3 % of TFAH and 17 % of ethyl-4-oxocyclohexanoate. The mixture was used without further purification as starting material in a fluorination reaction corresponding to step (b). Example 4 : Preparation of ethyl 4,4-bis(trifluoroacetoxy)cyclohexanoate Reaction with catalyst
Ethyl-4-oxocyclohexanoate (119.6g ; 0.703mol), trifluoroacetic anhydride (TFAH : 256.7g, 1.22 mol ; 2.47eq) and pyridine (0.57g ; 7 mmol ; O.Oleq) were placed in a 500 ml round bottom flask. The solution was stirred at 55°C (reflux) during 45 hours. The conversion of the starting compound into ethyl
4,4-bis(trifluoroacetoxy)cyclohexanoate was determined by GC analysis
(see Figure 2). The excess of TFAH was removed in a rotavapor. 29O g were obtained. The composition of the final mixture was the following : 88 % of bis-TFA-ester, 3.2 % of ethyl-4-oxocyclohexanoate, 1.3 % of TFAH. The mixture was used without further purification as starting material in a fluorination reaction corresponding to step (b).
Example 5 : Fluorination of ethyl 4,4-bis(trifluoroacetoxy)cyclohexanoate (Bis-TFA ester) by HF, followed by aqueous work up
All equipments (flask, tube, cooler, bubbler, etc.) were made in PTFE. The bis-TFA-ester (290 g ; 0.58 mol) was placed in a 500 ml three-neck PTFE round bottom flask equipped with cooler (-100C), a constant nitrogen flow and tube to introduce the HF. The system was cooled at -300C before the addition of HF. 116 g of HF (5.8 mol ; 7.6 eq.) were added in 25 minutes. The cool bath was removed and the temperature increased slowly to 25°C. It was stirred overnight at room temperature. Afterwards 149 g of water (8.3 mol) were added slowly at 00C and an organic phase separated. The organic phase was washed once with water and once with a solution of NaHCO3. 114 g of organic were obtained, having a content of ethyl 4,4-difluorocyclohexanoate of 85 %. The organic phase was distilled and 70.3 g ethyl 4,4-difluorocyclohexanoate with a purity of 98.7 % were obtained.
Example 6 : Fluorination of ethyl 4,4-bis(trifluoroacetoxy)cyclohexanoate (bis-TFA ester) by HF
All equipments (flask, tube, cooler, bubbler, etc.) were made in PTFE. The system was flushed with nitrogen before running the reaction.
The bis-TFA-ester was placed in a 500 ml three-neck PTFE round bottom flask equipped with a cooler (-100C) and tube to introduce the HF.
The system was cooled to 00C and HF was added in 30 minutes. The cool bath was removed and the temperature increased slowly to 25°C. Samples were taken by time and analyzed via GC. The quantity of bis-TFA-ester and HF, and the results are summarized in the following table 1.
Example 7 : One -pot process
The synthesis was carried out in a Hastelloy C276 reactor of a volume of 250 cc, equipped with a gas turbine, a pressure sensor, a temperature probe, a
dipping tube and a rupture disc to 25 b. The reaction temperature was kept at ambient temperature via a water bath. Ethyl 4-oxocyclohexanoate (17.3 g, 0.10 mol) and TFAH (52.9 g, 0.25 mol) were first introduced in the reactor, followed by HF (30.5 g, 1.53 mol) after cooling down the reactor in dry ice and vacuum. Conversions of 50 and 86 % were measured after respectively 18 and 88 h of reaction time. The selectivity to ethyl 4,4-difluorocyclohexanoate reached 90 %. Example 8 : One -pot process
The synthesis was carried out in the apparatus described in the previous example by introducing consecutively ethyl 4-oxocyclohexanoate (18.6 g, 0.11 mol), the HF (25.0 g, 1.25 mol) and trifluoroacetic chloride (31.0 g, 0.23 mol) after cooling down the reactor and evacuation. The conversion of the ketone was estimated to be 75 % after 16 h of stirring at ambient temperature. The selectivity to ethyl 4,4-difluorocyclohexanoate was 50 %. The main by- products were chlorinated compounds.
Example 9 : Acid-catalyzed hydrolysis of ethyl 4,4-difluorocyclohexanoate
A suspension of ethyl 4,4-difluorocyclohexanoate (41.7 g ; 0.22 mol) and concentrated aqueous HCl solution (107.5 g ; 1.9 mol ; 8.8 eq.) was placed into a round bottom flask equipped with a cooler (2°C). The mixture was heated under stirring to 400C for 6 h. Afterwards the solution was extracted 5 times with ethyl ether and the combined fractions were washed once with saturated aqueous NaCl solution. The solvent was removed and a solid was obtained which was recrystallised two times from hot chloroform. 19.2 g were isolated with a purity determined by NMR of 99.5 % and no olefmic compound was detectable via NMR. The yield was 55 %.
Example 10 : Base-catalyzed hydrolysis of ethyl 4,4-difluorocyclohexanoate
A suspension of 1.2 g ethyl 4,4-difluorocyclohexanoate (6.3 mmol), 0.6 g KOH (10.6 mmol) 1.7 ml water and 2.4 g ethanol (52 mmol) was placed into a flask equipped with a cooler (2°C). The mixture was heated to 400C for 4h. The largest part of ethanol was removed in vacuum. The residual solid was dissolved in the minimum amount of water. HCl 6M was added until pH=l was reached. The solution was extracted 3 times with ether. The solvent was removed and 0.5 g of wet solid were obtained. The purity measured by GC, was 100 %. Example 11 : Enzyme-catalyzed hydrolysis of ethyl 4,4-difluorocyclohexanoate A suspension of 15.7 g ethyl 4,4-difluorocyclohexanoate (6.3 mmol), 2.1 g
Candida antarctica lipase B from Novozyme (NOVO SP 435) and 375 g of
buffer (Na2HPO4ZNaH2PO4 pH = 7.5, concentration : 50 mM) were placed in a flask. The mixture was stirred at 25°C for 2:30 h. The lipase was filtered off and the solution was acidified until pH = 2 by addition of 35g of HCl 6M. A solid was formed and directly filtered. The aqueous phase was 3 times extracted with CH2Cl2. The solvent was removed using a rotavapor and 3.5 g of additional solid were obtained. The combined solids were dried. Yield : 74.5 %. The purity determined by NMR was 100 %. Example 12 : Reaction at elevated temperature in batch :
In a 500 ml autoclave, 181.5 g of bis-TFA-ester and 75 g of HF (9 mol eq.) were introduced at room temperature. The autoclave was then heated under stirring to 900C. After 1 h a sample was taken and analyzed by GC. The conversion to 4,4-difluorocyclohexanoate derivatives was quantitative after that time. Example 13 : Reaction at elevated temperature in continuous mode : In a 500 ml autoclave, 25O g of bis-TFA-ester and 60 g of HF were introduced at RT. The autoclave was then stirred over night. The next day the temperature was increased to 900C and it was stirred for additional 3h. After that time a sample was taken and analyzed by GC. The conversion of that sample was complete. By doing so a start solution for the continuous process was prepared.
Afterwards the substrate introduction was started. HF and bis-TFA-ester were introduced continuously via pumps into the reactor. Product was also taken out continuously via a diving tube from the liquid phase. The in and out flows were controlled by balances. The adjusted bis-TFA-ester flow was : 70 g/h. The adjusted HF flow was :
18 g/h. That corresponds to an HF quantity of 4.5 eq. The adjusted outlet flow was 88 g/h.
After running this continuous process for 2:45 h a sample of the outlet flow was taken and analyzed by GC. A conversion to 4,4-difluorocyclohexanoate derivatives of 90 % was observed.
Comparative example 1 : Preparation of ethyl 4,4-dichlorocyclohexanoate
Solid PCI5 (109.1 g) was introduced in a three-necked flask provided with a mechanical stirrer and a CaCl2 cartridge. The flask was cooled down with an ice/water mixture bath and ethyl 4-oxocyclohexanoate (71.6 g) was added slowly. During that time the mixture became homogenous. After stirring overnight, 20Og of ice were slowly added. The crude was extracted trice by
200 ml of petroleum ether (60-800C). The organic layer was washed by means of a saturated solution of NaHCOs and dried on MgSO4. The solvent was evaporated in a rotavapor. 63.7 g were isolated and analyzed by GC. The composition of the mixture was the following : 24.6 % of ethyl 4,4-dichlorocyclohexanoate, 72.4 % of 4-chlorocyclohexene ethyl carboxylate. Three other chlorinated species were also identified. Comparative example 2 : Fluorination
The obtained mixture (63.7 g) of comparative example 1 was used for the fluorination using HF (157.6 g) in a PTFE flask. HF was then introduced at dry ice temperature. The mixture was stirred at room temperature overnight.
Afterwards water was added and the occurring phases were separated. The crude was washed three times with 100 ml of water. 20.4 g were obtained and analyzed via GC. The reaction yield of ethyl 4,4-difluorocyclohexanoate was 25 %. The above examples and comparative examples demonstrate inter alia that the process according to the present invention affords the desired product with higher yields than the prior art processes.
Claims
(1 )
wherein COORi designates an ester group
with an activated fluorocarboxylic acid derivative to produce a compound of formula (2),
(2)
wherein COORi is as defined above and R2 is a fluorocarbon substituent
and b) reacting said compound of formula (2) with a fluorinating agent to produce a difluorocyclohexanoic acid ester of formula (3),
(3)
wherein COORi is as defined above.
2 - Process according to claim 1 , wherein said oxocyclohexanoic acid ester is a 4-oxocyclohexanoic acid ester.
3 - Process according to claim 1 or 2, wherein step a) is catalyzed by a nucleophilic catalyst.
4 - Process according to claim 3, wherein step a) is catalyzed by an amine.
5 - Process according to claim 4, wherein said amine is pyridine.
6 - Process according to claims 4 or 5, wherein said amine is present in an amount from 0.005 to 0.05 moles per mole of the oxocyclohexanoic acid ester of formula (1).
7 - Process according to anyone of claims 1 to 6, wherein said activated fluorocarboxylic acid derivative is selected from activated derivatives of trifluoroacetic acid, trifluoropropionic acid and trifluorobutyric acid.
8 - Process according to claim 7, wherein said activated fluorocarboxylic acid derivative is trifluoroacetic anhydride.
9 - Process according to anyone of claims 1 to 8, wherein said fluorinating agent is hydrogen fluoride
10 - Process according to anyone of claims 1 to 9 wherein step (b) is carried out continuously.
11 - Process according to anyone of claims 1 to 10, wherein the difluorocyclohexanoic acid derivative is recovered by an isolation procedure comprising treating at least a fraction of the reaction mixture from step (b) with an aqueous solution, preferably water and subsequently extracting an aqueous fraction obtained from the treatment with the aqueous solution with an organic solvent.
12 - Process according to anyone of claims 1 to 10, wherein the difluorocyclohexanoic acid derivative is recovered by a treatment comprising treating at least a fraction of the reaction mixture from step (b) under reduced pressure to reduce the HF content of said fraction.
13 - Process according to anyone of claims 1 to 12, wherein the molar ratio between said fluorocarboxylic acid derivative and said oxocyclohexanoic acid ester (1) is from 20: 1 to 2:1.
14 - Process according to claim 9, wherein the molar ratio between hydrogen fluoride and said oxocyclohexanoic acid ester of general formula (1) is from 2:1 to 20:1.
15 - Process according to anyone of claims 1 to 14, wherein steps a) and b) are carried out in one -pot.
16 - Process according to anyone of claims 1 to 15, which further comprises c) hydro lysing the difluorocyclohexanoic acid ester to produce the difluorocyclohexanoic acid.
17 - Process according to claim 16, wherein said hydrolysis is enzyme catalysed.
18 - Process according to claim 17, wherein immobilized enzymes are used.
19 - Process according to claim 18, wherein difluorocyclohexanoic acid is recovered from the reaction mixture of step (c) by filtration, preferably after acidification, followed by heat-drying.
20 - Compounds of formula (2) :
(2) wherein COORi is an ester group and R2 is a fluorocarbon substituent.
21 - Compounds according to claim 20, wherein R2 is a trifluoromethyl substituent.
22 - Compounds according to claim 20 or 21, wherein Ri is an ethyl substituent.
23 - Process for hydrolysing a difluorocyclohexanoic acid ester by using enzymatic catalysis.
24 - Process according to claim 23, wherein said catalysis is carried out by means of immobilized enzymes.
25 - Process for the manufacture of UK-427,857 (Maraviroc) which comprises a step wherein enantiopure (S)-3-amino-3-phenylpropan-l-ol is manufactured from a mixture of its enantiomers by crystallizing or precipitating from a solution containing the mixture of enantiomers of 3-amino-3- phenylpropan-1-ol, an enantiopure resolving agent and a solvent, a diastereomeric salt or complex of 3-amino-3-phenylpropan-l-ol with the resolving agent, said salt or complex being enriched in the (S)-enantiomer of 3-amino-3-phenylpropan- 1 -ol.
26 - Process according to Claim 25, wherein the resolving agent is
(S)-N-tosylpyroglutamic acid and the solvent comprises ethyl acetate and isopropanol or acetonitrile.
27 - Process according claim 25 or 26, wherein crystallization or precipitation is initiated by cooling the solution.
28 - Process according anyone of claims 25 to 27, wherein crystallization or precipitation is initiated by introducing a seed material into the solution.
29 - Process according to anyone of claims 25 to 28, which further comprises recovering enantiopure (S)-3-amino-3-phenylpropan-l-ol from the complex or the salt.
30 - Process according to claim 29, further comprising reacting the
(S)-3-amino-3-phenylpropan-l-ol with an activated 4,4-difluorocyclohexyl carboxylic acid species, preferably with 4,4-difluorocyclohexyl carboxylic acid chloride to produce (S)-4,4-difluorocyclohexyl carboxylic acid (l 'phenyl-3'- hydroxy-propane)amide.
31 - Process according to claim 30 which comprises forming 4,4-difluorocyclohexyl carboxylic acid chloride by reaction of 4,4-difluorocyclohexyl carboxylic acid with a chlorinating agent in an aprotic organic solvent having a boiling point from 35°C to 800C.
32 - Process according to claim 30 or 31 which further comprises producing a 4,4-difluorocyclohexyl carboxylic acid derivative according to the process of anyone of claims 1 to 19.
33 - Process according to anyone of claims 30 to 32, further comprising reacting the (S)-4,4-difluorocyclohexyl carboxylic acid (l 'phenyl-3'-hydroxy- propane)amide with an activating agent to convert the 3 '-hydroxy group into a leaving group.
34 - Process according to claim 33 wherein the activating agent is p-toluenesulphonic acid chloride to produce (S)-4,4-difluorocyclohexyl carboxylic acid (l 'phenyl-3'-p-toluenesulphonyl-propane)amide.
35 - Process according to claim 33 or 34, further comprising substituting the leaving group by 3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl)-exo-8- azabicyclo[3.2.1]octane to produce UK-427,857 (Maraviroc).
36 - A crystallized or precipitated diastereomeric salt or diastereomeric complex of (S)-3-amino-3-phenylpropan-l-ol with an enantiopure resolving agent.
37 - The crystallized or precipitated diastereomeric salt or diastereomeric complex according to claim 36, wherein the resolving agent is enantiopure N-sulphonyl pyroglutamic acid.
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EP07107158.3 | 2007-04-27 | ||
EP07107158A EP1985603A1 (en) | 2007-04-27 | 2007-04-27 | Process for preparing difluorocyclohexanoic acid derivatives |
EP07150337.9 | 2007-12-21 | ||
EP07150337 | 2007-12-21 |
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Citations (5)
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JPS6354331A (en) * | 1986-08-26 | 1988-03-08 | Asahi Chem Ind Co Ltd | Production of 1,1-difluorocyclohexane |
WO2001090106A2 (en) * | 2000-05-26 | 2001-11-29 | Pfizer Limited | Tryasolyl tropane derivatives as ccr5 modulators |
EP1364938A1 (en) * | 2001-01-31 | 2003-11-26 | Asahi Glass Company, Limited | Process for producing fluorine compound |
WO2005014519A1 (en) * | 2003-08-07 | 2005-02-17 | Honeywell Specialty Chemicals Seelze Gmbh | Process for the preparation of geminal difluoroalkanes |
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US3580923A (en) * | 1968-02-14 | 1971-05-25 | Ici Ltd | Resolution process |
JPS6354331A (en) * | 1986-08-26 | 1988-03-08 | Asahi Chem Ind Co Ltd | Production of 1,1-difluorocyclohexane |
WO2001090106A2 (en) * | 2000-05-26 | 2001-11-29 | Pfizer Limited | Tryasolyl tropane derivatives as ccr5 modulators |
EP1364938A1 (en) * | 2001-01-31 | 2003-11-26 | Asahi Glass Company, Limited | Process for producing fluorine compound |
WO2005014519A1 (en) * | 2003-08-07 | 2005-02-17 | Honeywell Specialty Chemicals Seelze Gmbh | Process for the preparation of geminal difluoroalkanes |
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