WO2014173855A1 - Process for preparing enantiomerically enriched 3-hydroxymethylpiperidine - Google Patents
Process for preparing enantiomerically enriched 3-hydroxymethylpiperidine Download PDFInfo
- Publication number
- WO2014173855A1 WO2014173855A1 PCT/EP2014/058040 EP2014058040W WO2014173855A1 WO 2014173855 A1 WO2014173855 A1 WO 2014173855A1 EP 2014058040 W EP2014058040 W EP 2014058040W WO 2014173855 A1 WO2014173855 A1 WO 2014173855A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydroxymethylpiperidine
- piperidine
- mixture
- carboxylic acid
- enantiomerically enriched
- Prior art date
Links
- VUNPWIPIOOMCPT-UHFFFAOYSA-N piperidin-3-ylmethanol Chemical compound OCC1CCCNC1 VUNPWIPIOOMCPT-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 23
- 239000000203 mixture Substances 0.000 claims description 114
- -1 tetrahydroborate salt Chemical class 0.000 claims description 89
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 78
- XJLSEXAGTJCILF-RXMQYKEDSA-N (R)-nipecotic acid zwitterion Chemical compound OC(=O)[C@@H]1CCCNC1 XJLSEXAGTJCILF-RXMQYKEDSA-N 0.000 claims description 67
- 238000000034 method Methods 0.000 claims description 34
- 239000003638 chemical reducing agent Substances 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 31
- 229910052751 metal Inorganic materials 0.000 claims description 30
- 239000002184 metal Substances 0.000 claims description 30
- 230000009467 reduction Effects 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 229910052796 boron Inorganic materials 0.000 claims description 24
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 20
- 150000002739 metals Chemical class 0.000 claims description 19
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 17
- 239000003960 organic solvent Substances 0.000 claims description 17
- 229910000085 borane Inorganic materials 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- 150000002148 esters Chemical class 0.000 claims description 15
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 14
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- 239000000010 aprotic solvent Substances 0.000 claims description 12
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- 238000010626 work up procedure Methods 0.000 claims description 12
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 10
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 7
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- 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 description 6
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- 230000003287 optical effect Effects 0.000 abstract description 29
- VUNPWIPIOOMCPT-LURJTMIESA-N [(3s)-piperidin-3-yl]methanol Chemical compound OC[C@H]1CCCNC1 VUNPWIPIOOMCPT-LURJTMIESA-N 0.000 abstract description 13
- VUNPWIPIOOMCPT-ZCFIWIBFSA-N [(3r)-piperidin-3-yl]methanol Chemical compound OC[C@@H]1CCCNC1 VUNPWIPIOOMCPT-ZCFIWIBFSA-N 0.000 abstract description 2
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- UXUFTKZYJYGMGO-CMCWBKRRSA-N (2s,3s,4r,5r)-5-[6-amino-2-[2-[4-[3-(2-aminoethylamino)-3-oxopropyl]phenyl]ethylamino]purin-9-yl]-n-ethyl-3,4-dihydroxyoxolane-2-carboxamide Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NCC)O[C@H]1N1C2=NC(NCCC=3C=CC(CCC(=O)NCCN)=CC=3)=NC(N)=C2N=C1 UXUFTKZYJYGMGO-CMCWBKRRSA-N 0.000 description 1
- LRZWUDOLANRDSF-JEDNCBNOSA-N (3s)-piperidine-3-carboxylic acid;hydrochloride Chemical compound Cl.OC(=O)[C@H]1CCCNC1 LRZWUDOLANRDSF-JEDNCBNOSA-N 0.000 description 1
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- LEEANUDEDHYDTG-UHFFFAOYSA-N 1,2-dimethoxypropane Chemical compound COCC(C)OC LEEANUDEDHYDTG-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- NIOYEYDJTAEDFH-UHFFFAOYSA-N 1-(2-hydroxyethoxy)-2-methylpropan-2-ol Chemical compound CC(C)(O)COCCO NIOYEYDJTAEDFH-UHFFFAOYSA-N 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003764 2,4-dimethylpentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N 2-Ethylhexanoic acid Chemical class CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- QNVRIHYSUZMSGM-LURJTMIESA-N 2-Hexanol Natural products CCCC[C@H](C)O QNVRIHYSUZMSGM-LURJTMIESA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- PFNHSEQQEPMLNI-UHFFFAOYSA-N 2-methyl-1-pentanol Chemical compound CCCC(C)CO PFNHSEQQEPMLNI-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000004337 3-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- PCWGTDULNUVNBN-UHFFFAOYSA-N 4-methylpentan-1-ol Chemical compound CC(C)CCCO PCWGTDULNUVNBN-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000000023 Kugelrohr distillation Methods 0.000 description 1
- 239000001358 L(+)-tartaric acid Substances 0.000 description 1
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- VPGGUYWSIDCOID-HKGPVOKGSA-N [(3S)-piperidin-3-yl]methanol Chemical compound N1C[C@H](CCC1)CO.OC[C@@H]1CNCCC1 VPGGUYWSIDCOID-HKGPVOKGSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 150000008378 aryl ethers Chemical class 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- OWBTYPJTUOEWEK-UHFFFAOYSA-N butane-2,3-diol Chemical compound CC(O)C(C)O OWBTYPJTUOEWEK-UHFFFAOYSA-N 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- BTVWZWFKMIUSGS-UHFFFAOYSA-N dimethylethyleneglycol Natural products CC(C)(O)CO BTVWZWFKMIUSGS-UHFFFAOYSA-N 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical class CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- ZTCISUWBWFVAJF-VGMFFHCQSA-N ethyl (3S)-piperidine-3-carboxylate (3S)-1-ethylpiperidine-3-carboxylic acid Chemical compound C(C)N1C[C@@H](C(=O)O)CCC1.N1C[C@H](CCC1)C(=O)OCC ZTCISUWBWFVAJF-VGMFFHCQSA-N 0.000 description 1
- XIWBSOUNZWSFKU-SSDOTTSWSA-N ethyl (3r)-piperidine-3-carboxylate Chemical compound CCOC(=O)[C@@H]1CCCNC1 XIWBSOUNZWSFKU-SSDOTTSWSA-N 0.000 description 1
- ZCEGLOKZSLNARG-FJXQXJEOSA-N ethyl (3s)-piperidine-3-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)[C@H]1CCCNC1 ZCEGLOKZSLNARG-FJXQXJEOSA-N 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- ZTCISUWBWFVAJF-UHFFFAOYSA-N ethyl piperidine-3-carboxylate 1-ethylpiperidine-3-carboxylic acid Chemical compound C(C)N1CC(C(=O)O)CCC1.N1CC(CCC1)C(=O)OCC ZTCISUWBWFVAJF-UHFFFAOYSA-N 0.000 description 1
- 229940093476 ethylene glycol Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- AUONNNVJUCSETH-UHFFFAOYSA-N icosanoyl icosanoate Chemical compound CCCCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCCCC AUONNNVJUCSETH-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000005309 metal halides Chemical class 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002763 monocarboxylic acids Chemical class 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QQZOPKMRPOGIEB-UHFFFAOYSA-N n-butyl methyl ketone Natural products CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- VPGGUYWSIDCOID-UHFFFAOYSA-N piperidin-3-ylmethanol Chemical compound N1CC(CCC1)CO.N1CC(CCC1)CO VPGGUYWSIDCOID-UHFFFAOYSA-N 0.000 description 1
- ZGCRGXBESNSBAJ-JEDNCBNOSA-N piperidine-3-carboxylic acid (3S)-piperidine-3-carboxylic acid Chemical compound OC(=O)C1CCCNC1.OC(=O)[C@H]1CCCNC1 ZGCRGXBESNSBAJ-JEDNCBNOSA-N 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 150000003899 tartaric acid esters Chemical class 0.000 description 1
- OJCLHERKFHHUTB-VIFPVBQESA-N tert-butyl (3s)-3-(hydroxymethyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H](CO)C1 OJCLHERKFHHUTB-VIFPVBQESA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YTZKOQUCBOVLHL-UHFFFAOYSA-N tert-butylbenzene Chemical compound CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
Definitions
- the present invention relates to a process for preparing enantiomerically enriched 3- hydroxymethylpiperidine and in particular the S-enantiomer of (S)-3-hydroxymethyl- piperidine in high chemical and optical purity.
- the invention also relates to extremely pure (S)-3-hydroxymethylpiperidine and (R)-3-hydroxymethylpiperidine.
- Both (R)- and in particular (S)-3-hydroxymethylpiperidine are valuable building blocks for the preparation of bioactive compounds, such as antagonistic ligands of receptors in the central nervous system, thrombin inhibitors (see EP 468231 ), thrombin inhibitors (see WO 99/67215), farnesyltransferase inhibitors (see US 2003/0134846) and vinblastine like antitumor agent desacetyldihydronavelbine (see e.g. Magnus et al., J. Org. Chem., 56 (1991 ) 1 166-1 170).
- bioactive compounds such as antagonistic ligands of receptors in the central nervous system, thrombin inhibitors (see EP 468231 ), thrombin inhibitors (see WO 99/67215), farnesyltransferase inhibitors (see US 2003/0134846) and vinblastine like antitumor agent desacetyldihydronavelbine (see e.g.
- the process should allow the preparation of enantiomerically enriched PPM with high enantiomeric enrichment of preferably at least 98 % ee, in particular at least 99 % ee and at the same time high chemical purity, of preferably at least 98 %, in particular at least 99 % (determined by gas chromatography). Moreover, the process should provide enantiomerically enriched PPM with high yields at low costs.
- certain boron containing reducing agents namely BH3, complexes of BH3, such as BH3-ether or thioether complexes, mixtures of tetrahydroborate salt with a metal salt of group 2, 4 or 12 metals and tetrahydroborates of group 2, 4 or 12 metals or lanthanide metals, and mixtures thereof, result in a reduction of enantiomerically enriched piperidine-3-carboxylic acid as well as of esters of enantiomerically enriched piperidine-3-carboxylic acid with high yields and high conservation of stereochemistry without significant formation of organic by-products and, after aqueous work-up, allow for the preparation of enantiomerically enriched PPM with high enantiomeric excess of frequently at least 98 % ee, in particular at least 99 % ee and at the same time high chemical purity, of preferably at least 98 %, in particular at least 99 %.
- boron containing reducing agent is selected from the group consisting of BH3, complexes of BH3, mixtures of a tetrahydroborate salt with a metal salt of group 2, 4 or 12 metals and tetrahydroborates of group 2, 4 or 12 metals, and mixtures thereof.
- the present invention relates to non-racemic 3- hydroxymethylpiperidine, which has an enantiomeric excess with regard to one of the enantiomers of 3-hydroxymethylpiperidine of at least 98 % ee, in particular at least 99 % ee and a chemical purity of at least 98 %, in particular at least 99 % and especially at least 99.5 %, as determined by gas chromatography.
- the present invention relates to a method of extracting 3- hydroxymethylpipendine from an aqueous alkaline solution, which comprises treatment of an alkaline solution of 3-hydroxymethylpiperidine with an extractant, which is an organic solvent or solvent mixture, where the pH of the aqueous alkaline solution is at least pH 10, in particular at least pH 12.
- an extractant which is an organic solvent or solvent mixture
- the prefix C n -C m indicates the possible carbon numbers a radical may have.
- halogen as used herein includes e.g. fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.
- Ci-Cs-alkyl examples include the aforementioned Ci-C4-alkyl radicals and n-pentyl, 2-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 2-hexyl, 2-methylpentyl, 3-methylpentyl, 2-ethylbutyl, 2,3- dimethylbutyl, n-heptyl, 2-heptyl, 2-methylhexyl, 3-methylhexyl, 2-ethylpentyl, 3- ethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, n-octyl, 2-octyl, 2-ethylhexyl, etc.
- alkoxyalkyl relates to an alkoxy radical as defined above, which is bound to an alkyi radical, where the alkoxy radical preferably has 1 to 4 carbon atoms and the alkyi part preferably has also 1 to 4 carbon atoms.
- alkoxyalkyl include 2- methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-butoxyethyl, 2-methoxypropyl, 2- ethoxypropyl, 2-propoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4- metoxybutyl, 3-methoxybutyl, 2-methoxy-2,2-dimethylethyl etc.
- aryl relates to an aromatic or at least partially aromatic mono- or bicyclic hydrocarbon radical, such as phenyl, naphthyl, indanyl, indenyl and tetrahydronaphthyl, which is unsubstituted or may carry 1 , 2 or 3 radicals selected from halogen, C1-C4- alkyl and Ci-C4-alkoxy.
- Aryl is in particular phenyl, which is unsubstituted or may carry 1 , 2 or 3 radicals selected from halogen, Ci-C4-alkyl and Ci-C4-alkoxy.
- arylalkyl relates to an aryl radical as defined above, in particular to substituted or unsubstituted phenyl, which is bound to an alkyl radical, in particular to a Ci-C4-alkyl radical.
- arylalkyl include benzyl, 1 -phenylethyl and 2- phenylethyl, where the phenyl ring in the aforementioned groups is unsubstituted or may carry 1 , 2 or 3 radicals selected from halogen, Ci-C4-alkyl and Ci-C4-alkoxy.
- group 2, 4 or 12 metals refers to the metals of groups 2, 4 or 12 of the periodic table according to lUPAC and includes in particular the following metals: Mg, Ca, Zr and Zn.
- step a) of the invention enantiomerically enriched piperidine-3-carboxylic acid or in particular an enantiomerically enriched ester of piperidine-3-carboxylic acid is provided.
- Suitable esters of piperidine-3-carboxylic acid include e.g. the alkyl esters of piperidine- 3-carboxylic acid, in particular the Ci-C6-alkyl esters of piperidine-3-carboxylic acid, the alkoxyalkyl esters of piperidine-3-carboxylic acid, e.g. the Ci-C4-alkoxy-Ci-C4-alkyl esters of piperidine-3-carboxylic acid, in particular the Ci-C4-alkoxyethyl esters of piperidine-3-carboxylic acid, arylalkyl esters of piperidine-3-carboxylic acid, e.g.
- aryl-Ci- C4-alkyl esters of piperidine-3-carboxylic acid in particular phenyl-Ci-C4-alkyl esters of piperidine-3-carboxylic acid such as benzyl or phenethyl esters of piperidine-3- carboxylic acid and aryl esters of piperidine-3-carboxylic acid, e.g. the phenyl ester of piperidine-3-carboxylic acid.
- esters of piperidine- 3-carboxylic acid in particular the Ci-C6-alkyl esters and benzyl esters of piperidine-3- carboxylic acid, more particularly the Ci-C3-alkyl esters of piperidine-3-carboxylic acid and especially the ethyl ester of piperidine-3-carboxylic acid are preferred.
- the enantiomerically enriched piperidine-3-carboxylic acid as well as the enantio- merically enriched ester of piperidine-3-carboxylic acid which is provided in step a) and reacted in step b) preferably has an enantiomeric excess of at least 80 % ee, in particular at least 90 % ee.
- an enantiomerically enriched piperidine-3-carboxylic acid or an enantiomerically enriched ester of piperidine-3- carboxylic is used in step b) which has an enantiomeric excess of at least 98 % ee, especially at least 99 % ee.
- Enantiomerically enriched piperidine-3-carboxylic acid as well as enantiomerically enriched esters of piperidine-3-carboxylic acid (the esters are hereinafter termed AEPC), such as the enantiomerically enriched Ci-C6-alkylester or benzylesters, in particular a Ci-C3-alkylester and especially the methyl or ethyl ester of piperidine-3- carboxylic acid are known and can be provided by any method known in the art for this or a similar purpose, for example by asymmetric synthesis, by synthesis starting from a chiral precursor, such as enantiomerically enriched piperidine-3-carboxylic acid, or by enantiomeric enrichment of a mixture of the enantiomers of piperidine-3-carboxylic acid or of the enantiomers of the respective piperidine-3-carboxylic acid esters.
- AEPC enantiomerically enriched Ci-C6-
- Enantiomeric enrichment of piperidine-3-carboxylic acid or of AEPCs can be accomplished by customary methods, e.g. by chiral chromatography or by separation of diastereomers that can be generated by derivatization or salt formation of piperidine- 3-carboxylic acid or AEPCs with a chiral resolving agent.
- Preferred chiral resolving agents in this context are chiral acids capable of forming diastereomeric acid addition salts that can be enriched regarding one enantiomer of the piperidine-3-carboxylic acid or the AEPC, for example by fractional crystallization.
- step a) of process A comprises subjecting racemic AEPC, in particular a racemic Ci-C4-alkylester of piperidine-3- carboxylic acid, especially the racemic ethyl ester of piperidine-3-carboxylic acid, to enantiomeric enrichment by fractional crystallization of an acid addition salt of AEPC with a chiral acid.
- racemic AEPC in particular a racemic Ci-C4-alkylester of piperidine-3- carboxylic acid, especially the racemic ethyl ester of piperidine-3-carboxylic acid
- AEPC enantiomers in this manner.
- This enantiomeric enrichment can be used to enrich the R-enantiomer or the S-enantiomer of the AEPC, and is preferably used to enrich the S-enantiomer.
- Preferred chiral acids in this respect are those known in the art, such as tartaric acid, as described for example in US 5220016 and in WO 00/56730, or mandelic acid or dibenzoyl tartaric acid as described in EP1341762, or ethers of 2- hydroxy-propionic acid as described in US6340762.
- Enantiomeric enrichment of the R- enantiomer of AEPC is preferably achieved by crystallization of the acid addition salt of AEPC with one of the following acids: L(+) tartaric acid or D-mandelic acid.
- Enantiomeric enrichment of the S-enantiomer of AEPC, in particular the ethyl ester of S-piperidine-3-carboxylic acid is preferably achieved by crystallization of the acid addition salt of AEPC with one of the following acids: D(-) tartaric acid or L-mandelic acid.
- the fractional crystallization of piperidine-3-carboxylic acid or AEPC, respectively, with a chiral acid results in crystals of acid addition salts of piperidine-3- carboxylic acid or AEPC which are enantiomerically enriched with regard to (R)- or (S)- enantiomer.
- the mother liquor obtained in said crystallizations is depleted with regard to this respective enantiomer and therefore contains an excess of the opposite enantiomer of piperidine-3-carboxylic acid or AEPC.
- the mother liquor obtained from the crystallization of (R)-enantiomer acid addition salts is enriched with regard to (S)-enantiomer.
- the piperidine-3-carboxylic acid or APEC, respectively, contained in said mother liquor may be subjected to a racemization.
- an additional amount of the desired enantiomer can be prepared by means of enantiomeric enrichment, for example according to the methods involving fractional crystallization mentioned above.
- Racemization of non-racemic AEPC is usually accomplished by treating AEPC with a base according to known procedures that are described for example in WO 02/068391. Suitable methods include e.g. treatment with catalytic amounts of sodium ethoxylate as base.
- the acid addition salts of piperidine-3-carboxylic acid or AEPC with a chiral acid obtained by the methods for enantiomeric enrichment of the preceding embodiment can be transformed into the free base, i.e. free piperidine-3-carboxylic acid or free AEPC, according to well-known techniques.
- the acid addition salt of the AEPC is treated either with a diluted aqueous base, such as an aqueous solution of an alkali metal carbonate, alkali metal hydrogen carbonate or alkali metal hydroxide such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodium hydroxide, calcium hydroxide or potassium hydroxide, or with a basic ion exchange resin.
- the free base may be extracted from the thus obtained mixture by a suitable method, such as extraction with an organic solvent.
- the addition of base is preferably conducted under cooling. It is further preferred to use a concentrated aqueous solution of a base.
- a solution of its acid addition salt is treated with a basic ion-exchange resin or the acid, which has been used as a chiral auxiliary is
- the free base of piperidine-3-carboxylic acid can be prepared by hydrolysis of an AEPC according to well known methods.
- step b) of the inventive process the enantiomerically enriched piperidine-3- carboxylic acid or enantiomerically enriched AEPC is subjected to a reduction with a boron containing reducing agent.
- the boron containing reducing agent is selected from the group consisting of the following groups a) to d) and mixtures thereof such as mixtures of the :
- BH3-complexes such as BH3-ether or thioether complexes, e.g. BH3- tetrahydrofurane, BH3-diethylether or BH3-dimethyl sulphide adducts, c) mixtures of a tetrahydroborate salt with a metal salt of group 2, 4 or 12 metals, and
- tetrahydroborates of group 2, 4 or 12 metals, such as zinc tetrahydroborate The enantiomerically enriched piperidine-3-carboxylic acid or AEPC is typically employed in step b) as is, i.e. as the free base, but it may also be used as its acid addition salt, in particular as its monohydrochloride.
- the enantiomerically enriched AEPC is preferably employed as the free base.
- the reducing agent is BH3, in particular in-situ generated BH3. In-situ generation of BH3 can be achieved by well no known techniques such as described by Abiko et al. Tetrahedron Letters (1992), 33(38), 5517- 5518; McKennon et al. J. Org. Chem. (1993), 58, 3568-2571 ; and Prasad et al.
- in-situ generation of BH3 can be achieved by using mixtures of a
- tetrahydroborate salt in particular an alkalimetal tetrahydroborate, especially lithium, sodium or potassium tetrahydroborate
- a strong Broenstedt acid such as an organosulfonic acid, e.g. methane sulfonic acid, trifluoromethane sulfonic acid or toluene sulfonic acid or a mineral acid such as H2SO4, H3PO4 or HCI, or with a Lewis acid such as trimethylsilyl halides, boron halides such as BF3 or BF3-etherate.
- In-situ generation of BH3 can also be achieved by using mixtures of tetrahydroborate salt, in particular an alkalimetal tetrahydroborate, especially lithium, sodium or potassium tetrahydroborate, with an electrophile such as iodine.
- the relative molar amount of the activating agent (acid or electrophile such as iodine) to the tetrahydroborate may vary and is preferably in the range from 0.05 to 2 mol, in particular from 0.1 to 1.2 mol and especially 0.2 to 1.1 mol per mol of tetrahydroborate.
- the reducing agent is selected from mixtures of a tetrahydroborate salt with a metal salt of group 2, 4 or 12 metals.
- suitable metal salts include the halides, in particular the chlorides, the sulfates, phosphates, oxides, hydroxides, carbonates, Ci-Cio-carboxylates and Ci-Cs- alcoholates of these metals.
- particularly suitable alcoholates are the alcoholates which are derived from alkanols having 1 to 8 carbon atoms, in particular 1 to 6 or 1 to 4 carbon atoms, such as the methanolates, ethanolates and
- carboxylates are the carboxylates which are derived from aliphatic or aromatic carboxylic acids, in particular mono- or dicarboxylic acids having 1 to 10 carbon atoms, e.g. the formiates, acetates, propionates, butyrates, hexanoates, 2-ethylhexanoates and benzoates.
- Preferred salts are the halides and especially the chlorides of these metals.
- suitable tetrahydroborate salts are alkalimetal tetrahydroborates, in particular sodium or potassium tetrahydroborate, and tetra-Ci-C4-alkylammonium tetrahydroborate such as commercially available tetrabutylammonium tetrahydroborate and also lithium tetrahydroborate.
- Particularly suitable metal salts of group 2, 4 or 12 metals are the salts of the following metals: calcium, magnesium, zirconium and zinc, with most preference given to zinc.
- Particularly preferred salts of the aforementioned metals are the halides, in particular the chlorides.
- an alkalimetal tetrahydroborate or a tetra-Ci-C4-alkylammonium tetrahydroborate in particular sodium or potassium tetrahydroborate or lithium tetrahydroborate
- metal halides especially metal chlorides, or metal oxides of group 2, 4, 10 or 12 metals
- zinc chloride, magnesium chloride or calcium chloride which are preferably in their anhydrous form, such as ZnC , MgC , CaC , ZrCU, with particular preference given to zinc halides, especially ZnC .
- tetrahydroborate salt may vary and is preferably in the range from 0.05 to 2 mol, in particular from 0.1 to 1 .2 mol and especially 0.4 to 0.6 mol of metal salt per mol of tetrahydroborate.
- the amount of reducing agent will depend on the type of reducing agent in a known manner or can be determined by routine experiments. If an AEPC is used in embodiment c), the amount of reducing agent will generally be in the range from at least 2 moles of boron bound hydrogen atoms in the boron compound of the reducing agent per mole of enantiomerically enriched AEPC, preferably from 3 to 10 moles, especially from 3 to 8 moles of boron bound hydrogen atoms per mole of enantiomerically enriched AEPC.
- the amount of reducing agent will be in the range from at least 0.75 moles of boron compound of the reducing agent per mole of enantiomerically enriched AEPC, preferably from 0.75 to 2.5 moles, especially from 0.75 to 2 moles of boron compound per mole of
- the amount of reducing agent will generally be in the range from at least 2 moles of boron bound hydrogen atoms in the boron compound of the reducing agent per mole of enantiomerically enriched piperidine-3-carboxylic acid, e.g. from 3 to 10 moles, especially from 3 to 8 moles of boron bound hydrogen atoms per mole of enantiomerically enriched piperidine-3- carboxylic acid.
- the amount of reducing agent will be in the range from at least 0.75 moles of boron compound of the reducing agent per mole of enantiomerically enriched AEPC, e.g. from 0.75 to 2.5 moles, especially from 0.75 to 2 moles moles of boron compound per mole of enantiomerically enriched piperidine-3-carboxylic acid.
- the amount of reducing agent will generally be in the range from at least 4 moles of boron bound hydrogen atoms in the boron compound of the reducing agent per mole of enantiomerically enriched AEPC or piperidine-3-carboxylic acid, e.g. from 4 to 16 moles, especially from 8 to 14 moles of boron bound hydrogen atoms per mole of enantiomerically enriched AEPC or piperidine-3-carboxylic acid.
- the amount of reducing agent will be in the range from at least 2 moles of boron compound of the reducing agent per mole of enantiomerically enriched AEPC or piperidine-3-carboxylic acid, e.g. from 1 to 4 moles, especially from 2 to 3,5 moles of boron compound per mole of enantiomerically enriched AEPC or piperidine-3-carboxylic acid.
- the reaction of step b) is usually performed in an organic solvent, in particular an aprotic organic solvent or a solvent mixture containing predominantly an aprotic solvent.
- Suitable solvents include, but are not limited to ethers, in particular di-Ci-C 4 alkyl ethers such as diethyl ether, di-n-propyl ethers, diisopropyl ethers, methyl-tert- butyl ether, ethyl-tert. -butyl ether, mono-, di- and tri-C2-C 4 -alkylylene glycol di-Ci-C 4 alkyl ethers such as dimethyl ethyleneglycol, dimethyl diethyleneglycol,
- triethyleneglycol dimethyl ether propyleneglycol dimethyl ether, alicyclic ethers such as tetrahydrofurane, dioxane and methyltetrahydrofurane, aromatic ethers such as anisol and hydrocarbons, e.g.
- alkanes such as pentane, hexanes, heptanes, cycloalkanes such as cyclopentane, cyclohexane, methylcyclohexane and cycloheptane and aromatic hydrocarbons, in particular mono- and di-Ci-C 4 -alkylbenzenes such as toluene, xylenes, isopropylbenzene, tert.-butylbenzene, cumene and mixtures thereof.
- Suitable solvents may also include alcohols, such as d-Cs-alkanols, e.g.
- the amount of alcohols does generally not exceed 30 Vol.-%, in particular 20 Vol.-%, based on the total amount of organic solvent.
- the reaction is performed essentially in the absence of larger amounts of water, i.e. the amount of water does not exceed 5 Vol.-%, based on the total amount of organic solvent.
- step b) is performed in an aprotic solvent including pure aprotic solvents and mixtures of aprotic solvents.
- the aprotic solvent comprises an ether, in particular a cyclic ether, or a mono-, di- and tri-C2-C4-alkylylene glycol di-Ci-C 4 alkyl ether or a mixture of an ether solvent with a hydrocarbon solvent.
- the total amount of solvent used in step b) is usually in the range from 100 to 1000 g, preferably in the range from 250 to 800 g and in particular in the range from 350 to 700 g, based on 1 mol of piperidine-3-carboxylic acid or AEPC, respectively.
- reaction temperature necessary in step b) may vary and depend on the type of reducing agent. Usually temperatures in the range of 10 to 100°C will be suitable for carrying out step b), however even lower or higher temperatures may be applied without loss of yield or loss of optical purity.
- Step b) yields a reaction mixture which contains enantiomerically enriched 3-hydroxy- methylpiperidine.
- a reaction mixture obtained in step b) at least a part of the enantiomerically enriched 3-hydroxy- methylpiperidine is present as a boron containing derivative, e.g. a complex with a boron compound, which must be hydrolysed during aqueous workup to allow isolation of the desired product, namely the enantiomerically enriched 3-hydroxymethyl- piperidine.
- Aqueous workup of the reaction mixture obtained in step b) in accordance with step c) of the claimed process can principally be performed by mixing the reaction mixture with water, which may contain an acid or a base, followed by isolation of the desired product, e.g. by liquid or solid phase extraction of the desired product from the thus obtained mixture or by crystallization of a suitable salt of the enantiomerically enriched 3-hydroxymethylpiperidine therefrom.
- water which may contain an acid or a base
- isolation of the desired product e.g. by liquid or solid phase extraction of the desired product from the thus obtained mixture or by crystallization of a suitable salt of the enantiomerically enriched 3-hydroxymethylpiperidine therefrom.
- any boron containing organic compounds will be hydrolysed into boric acid or boric acid esters which can be removed prior to isolation of the desired product but which is not necessarily removed. It has been found beneficial to perform step c) in a manner that pH of the aqueous phase is at most pH 6, e.g.
- step c) comprises a hydrolysis of the boron containing reducing agent and optionally present boron containing derivatives of 3-hydroxymethylpiperidine at a pH of at most pH 6, e.g. in the range from pH 0 to pH 6, in particular from pH 0 to pH 3 at least during the initial phase of the workup.
- aqueous workup also includes an extraction step for isolation of the enantiomerically enriched 3-hydroxymethylpiperidine.
- an extraction step for isolation of the enantiomerically enriched 3-hydroxymethylpiperidine.
- a particular embodiment comprises treatment of an alkaline solution of 3-hydroxymethylpiperidine with an extractant, which is an organic solvent or solvent mixture, where the pH of the aqueous alkaline solution is at least pH 10, in particular at least pH 12, e.g. at a pH in the range from pH 10 to 14, in particular from pH 12 to 14.
- the removal is preferably performed at a pH of at least pH 6, e.g. in the range from pH 6 to pH 12.
- Removal of the hydrolysis products can be performed by any conventional steps of solid liquid separation, e.g. by filtration or centrifugation.
- the enantiomerically enriched 3-hydroxymethylpiperidine is extracted from the aqueous phase by using an organic solvent or solvent mixture as an extractant, which comprises at least one organic solvent having limited water miscibility.
- Suitable organic solvents having limited water miscibility include but are not limited to aprotic solvents from the group of ethers, in particular the aforementioned di-Ci-C 4 - alkyl ethers, such as diethyl ether, diisopropyl ether, methyl tert.
- butyl ether and ethyl tert.butyl ether, and alkyl substituted cyclic ethers such as methyltetrahydrofurane, hydrocarbons, in particular aromatic hydrocarbons such as toluene and xylenes, C1-C6- alkylesters of Ci-C6-alkanoic acids, in particular the Ci-C6-alkylesters of acetic acid or propionic acid such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and ethyl propionate, chlorinated hydrocarbons such as dichloromethane and dichloroethane.
- Preferred aprotic solvents are selected from alkylaromatic solvents, methyltetrahydrofurane and Ci-C6-alkylesters of Ci-C6-alkanoic acids.
- Suitable organic solvents having limited water miscibility also include n-butanol, 2- butanol, isobutanol, Cs-Cs-alkanols and Cs-Cs-cycloalkanols.
- suitable as an extractant are tetrahydrofurane or tetrahydrofurane containing mixtures of organic solvents, as tetrahydrofurane is usually not completely miscible with the reaction mixture which is subjected to extraction.
- organic solvents are preferred which have a boiling point at normal pressure in the range from 30 to 1 10°C.
- the extractant comprises at least one organic solvent selected from the group of d-Cs-alkanols, especially d-Cs-alkanols, and C4-C8- cycloalkanols.
- Suitable Ci-Cs-alkanols include methanol, ethanol, n-propanol, isopropanol, 1 -butanol, 2-butanol, 2-methylpropanol, 1 ,1 -dimethylethanol (tert.butanol), n-pentanol, 3-methylbutan-1 -ol (isoamyl alcohol), n-hexanol, 2-hexanol, 3-hexanol, 2- methylpentanol, isohexanol, n-heptanol, 2-ethylhexanol and n-octanol.
- Suitable Cs-Cs- cycloalkanols include in particular cyclopentanol and cyclohexanol.
- the organic solvent or solvent mixture, which is used as an extractant will usually comprise at least one organic solvent having limited water solubility.
- the extractant contains a Ci-C3-alkanol or tert.butanol, it will also contain at least one organic solvent having limited water solubility, in particular at least one aprotic solvent.
- the extractant is preferably a mixture of at least one alcohol selected from the group of Ci-Cs-alkanols, especially Ci-Cs-alkanols, and C4-C8-cycloalkanols and at least one aprotic solvent having limited water-solubility, in particular a mixture of at least one alcohol selected from the group of Ci-Cs-alkanols, especially C1-C5- alkanols, and C4-C8-cycloalkanols and at least one aprotic organic solvent selected from the group consisting of alkylaromatic solvents, methyltetrahydrofurane and C1-C6- alkylesters of Ci-C6-alkanoic acids.
- the relative amount on a volume base of alcohol to aprotic solvent in these mixtures is from 1 :20 to 5:1 v/v in particular from 1 :10 to 2:1 v/v.
- the enantiomerically enriched 3-hydroxymethylpiperidine can be isolated from the extractant by removing the solvent, preferably under reduced pressure, to obtain a solid residue, which may be subjected to further purification, such as distillation, sublimation or recrystallization.
- Suitable solvents for recrystallization include e.g.
- methyltetrahydrofurane and tert.-butylmethyl ether may be removed from an anhydrous solution of 3-hydroxymethylpiperidine by filtration prior to the further purification step.
- the aqueous mixture from which the enantiomerically enriched 3-hydroxymethylpiperidine is extracted by means of an ion exchange resin has a pH of at most pH 8, e.g. in the range from pH 4 to pH 8, in particular from pH 5 to pH 8.
- the enantiomerically enriched 3-hydroxymethylpiperidine is conducted through a bed of the ion exchange resin. Thereby the enantiomerically enriched 3-hydroxymethylpiperidine will be adsorbed by ion-exchange resin, while impurities remain in the aqueous phase.
- the 3-hydroxymethylpiperidine can be eluted from the ion-exchange resin by treatment of the ion exchange resin with a diluted solution of a suitable organic or inorganic acid, in particular by treatment with diluted hydrochloric acid or diluted aqueous sulphuric acid, whereby an aqueous solution of the corresponding salt of 3-hydroxymethylpiperidine followed by adjusting the pH to alkaline pH, e.g.
- 3-hydroxymethylpiperidine may also be eluted from the ion-exchange resin by treatment of the ion exchange resin with a diluted aqueous solution of a suitable amine, such as ammonium hydroxide or diethylamine.
- a suitable amine such as ammonium hydroxide or diethylamine.
- optical purity is at least 97 % ee, especially at least 98 % ee as determined by chiral HPLC, provided that the optical purity of the chiral AEPC or piperidine-3-carboxylic acid, respectively, is not lower.
- Chemical purity is generally at least 90 %, especially at least 95 %, as determined by gas chromatography.
- the thus obtained enantiomerically enriched 3-hydroxymethylpiperidine can be further purified to yield an enantiomerically enriched 3-hydroxymethylpiperidine which has an enantiomeric excess with regard to one of the enantiomers of 3-hydroxymethyl- piperidine of at least 98 % ee, in particular at least 99 % ee and a chemical purity of at least 98 %, in particular at least 99 % and especially at least 99.5 %, as determined by gas chromatography.
- the enantiomerically enriched 3-hydroxymethylpiperidine obtained by the process of the invention can be further purified to increase optical and chemical purity. Further purification may be achieved by recrystallization or distillation of the 3-hydroxymethylpiperidine obtained from work-up c).
- Suitable solvents for recrystallization include e.g. methyltetrahydrofurane and tert.-butylmethyl ether. The following examples shall illustrate the invention.
- NPA 3-piperidinecarboxylic acid (nipecotic acid)
- the enatiomeric ratio S/R was measured via chiral HPLC after derivatisation with mosher's acid chloride on a Chiralpak AD 250/ 4.6/10 column with hexane/isopropanol 90 : 10 as eluent.
- the detection wavelength was 210 nm.
- EXAMPLE 2 Preparation of (S)-ethyl 3-piperidinecarboxylate hydrochloride To a mixture of (S)-ENP (393 g of a 40 % solution in toluene; 1 mol ENP, with an optical purity of 99.4 : 0.6 er) was added water (120 g) and concentrated hydrochloric acid (120 g) under cooling. The mixture was stirred at 60°C overnight. The mixture was concentrated at 80 °C under reduced pressure until a thick slurry was obtained. To this mixture was added acetone (200 mL) and the mixture was stirred at room temperature for 1 h. The solid was collected by filtration. From the mother liquor a second crop was obtained by concentration and subsequent addition of acetone.
- the mixture was extracted 3 times at 50°C with a mixture of isobutanol/toluene (1 :1 ; in total 5 L). After drying over MgS0 4 , the solvent was removed under reduced pressure to yield crude (S)-PPM as a colorless oil which had a chemical purity greater than 98% and an optical purity 99.4:0.6 er.
- the obtained crude (S)-PPM was purified by recrystallization from TBME (2 g per g of crude (S)-PPM).
- (S)-PPM was obtained in a yield greater than 80%, and had a chemical purity greater than 99% and an optical purity of 99.9:0.1 er.
- the mixture was extracted 3 times at 50°C with a mixture of isobutanol/toluene (1 :1 ; 3 x 60 mL). After drying over MgS0 4 , the solvent was removed under reduced pressure to yield an oil (2.55 g with an S-PPM content of 43 %).
- the mixture was extracted 3 times at 50°C with a mixture of isobutanol/toluene (1 :1 ; 3 x 60 mL). After drying over MgS0 4 , the solvent was removed under reduced pressure to yield an oil (7.8 g with an S-PPM content of 34 %).
- EXAMPLE 15 Reduction with the reaction product of a tetrahydroborate salt with iodine
- a suspension of NaBH 4 (4.73 g; 125 mmol) in THF (50 mL) was added (S)-ENP (99.4:0.6 er; 7.86 g; 50 mmol) and the mixture was cooled to 0°C.
- a solution of iodine (12.7 g; 50 mmol) in THF (20 mL) was added dropwise. The mixture was heated at 50°C overnight. To this mixture was added 1 eq.
- EXAMPLE 17 Reduction of (S)-NPA ⁇ HCI with NaBH 4 + ZnCI 2 in THF
- sodium borohydride (7.6 g; 200 mmol) in THF (20 mL)
- ZnC (13.6 g; 100 mmol) in THF (50 mL)
- the mixture was cooled to 40°C and (S)-NPA hydrochloride (16.6 g; 100 mmol, from EXAMPLE 2) was slowly added.
- the mixture was heated to reflux for 2 h.
- the mixture was cooled to room temperature and carefully poured onto 32 g of water and 32 g of concentrated hydrochloric acid.
- TIC quantitative (tic); PPM was not detected on tic in the remaining water phase and in the organic phase of the 5 th extraction.
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Abstract
The present invention relates to a process for preparing enantiomerically enriched 3-hydroxymethylpiperidine and in particular of the S-enantiomer of (S)-3-hydroxymethyl- piperidine in high chemical and optical purity. The invention also relates to extremely pure (S)-3-hydroxymethylpiperidine and (R)-3-hydroxymethylpiperidine.
Description
Process for preparing enantiomerically enriched 3-hydroxymethylpiperidine Description The present invention relates to a process for preparing enantiomerically enriched 3- hydroxymethylpiperidine and in particular the S-enantiomer of (S)-3-hydroxymethyl- piperidine in high chemical and optical purity. The invention also relates to extremely pure (S)-3-hydroxymethylpiperidine and (R)-3-hydroxymethylpiperidine. BACKGROUND OF THE I NVENTION
Both (R)- and in particular (S)-3-hydroxymethylpiperidine are valuable building blocks for the preparation of bioactive compounds, such as antagonistic ligands of receptors in the central nervous system, thrombin inhibitors (see EP 468231 ), thrombin inhibitors (see WO 99/67215), farnesyltransferase inhibitors (see US 2003/0134846) and vinblastine like antitumor agent desacetyldihydronavelbine (see e.g. Magnus et al., J. Org. Chem., 56 (1991 ) 1 166-1 170). As (R)- and (S)-3-hydroxymethylpiperidine are often used at a very early stage in the synthesis of the bioactive compounds, there is need for high amounts of these compounds having high optical and chemical purity.
Several approaches for the preparation of enantiomerically enriched (R)- and (S)-3- hydroxymethylpiperidine have been described in the art. Hereinafter 3-hydroxymethylpiperidine is termed PPM, while the R- and S-enantiomers thereof are termed (R)-PPM and (S)-PPM, respectively.
For example, Wirz et al., Tetrahedron: Asymmetry (1992), 3(8), 1049-1054 describe resolution of racemic PPM comprising enantioselective hydrolysis with a lipase of the butyryl ester of racemic N-boc protected PPM, yielding N-boc protected (S)-PPM. Deprotection with trifluoroacetic acid followed by extraction with an anion exchange resin, followed by elution with 0.1 NaOH and, extraction with dichloromethane and Kugelrohr distillation of the extract yielded (S)-PPM with an optical purity of 91 % ee.
Danieli et al., Tetrahedron: Asymmetry (1996), 7(2), 345-8 describe reduction of S- enantiomer of methyl N-benzyl nipecotate or methyl N-carboxybenzyl nipecotate with lithium tetrahydroborate in tetrahydrofurane followed by removal of the protecting group, however without giving much details on the reaction conditions.
Bettoni et al., Gazzetta Chimica Italiana (1972), 102(3), 189-95 describe the reduction of (S)-N-benzyl nipecotic acid ethyl ester with lithium aluminium hydride in
tetrahydrofurane followed by debenzylation to yield (S)-PPM. They also describe direct reduction of (R)-ethyl nipecotate with lithium aluminium hydride in tetrahydrofurane to yield (R)-PPM. Magnus et al., J. Org. Chem., 56 (1991 ) 1 166-1 170 describe a similar reaction to obtain (R)-PPM as a yellow oil. The purity of the obtained product is low and during reduction with lithium aluminium hydride a certain loss of the desired
enantiomeric excess occurs.
The additional steps for introducing and removing an N-protecting group that are required in the aforementioned 3-hydroxymethylpiperidine synthetic routes are particularly disadvantageous for the preparation of enantiomerically enriched 3- hydroxymethyl piperidine at an industrial scale.
Goswami et al., Organic Progress Research & Development 5 (2001 ) 415-420 describe fractional crystallisation of the salt of racemic (S)-PPM with L-(-)-dibenzoyl tartaric acid to yield the corresponding salt of (S)-PPM, which was converted directly to (S)-N-(tert- butoxycarbonyl)-3-hydroxymethylpiperidine by hydrolysis and acylation in situ. (S)-3- hydroxymethyl piperidine was not isolated.
The reduction of (R)-nipecotic acid with lithium aluminium hydride (LAH) has been described in WO 2010/027500. Yields of (R)-PPM, however, are low and purity is only moderate. Furthermore, LAH is quite expensive and causes serious safety issues, in particular if it is used at an industrial scale.
Investigations of the inventors of the present invention revealed that the prior art processes do not allow for the preparation of enantiomerically enriched PPM with both high enantiomeric enrichment of at least 98 % ee, in particular at least 99 % ee and at the same time high chemical purity of at least 98 %, in particular at least 99 %
(determined by gas chromatography). Therefore, there is still a strong need for providing a process for preparing
enantiomerically enriched PPM, that overcomes the disadvantages of the prior art. The process should allow the preparation of enantiomerically enriched PPM with high enantiomeric enrichment of preferably at least 98 % ee, in particular at least 99 % ee and at the same time high chemical purity, of preferably at least 98 %, in particular at least 99 % (determined by gas chromatography). Moreover, the process should provide enantiomerically enriched PPM with high yields at low costs.
SUMMARY OF THE INVENTION
Surprisingly, it has been found that certain boron containing reducing agents, namely BH3, complexes of BH3, such as BH3-ether or thioether complexes, mixtures of tetrahydroborate salt with a metal salt of group 2, 4 or 12 metals and tetrahydroborates of group 2, 4 or 12 metals or lanthanide metals, and mixtures thereof, result in a reduction of enantiomerically enriched piperidine-3-carboxylic acid as well as of esters of enantiomerically enriched piperidine-3-carboxylic acid with high yields and high conservation of stereochemistry without significant formation of organic by-products and, after aqueous work-up, allow for the preparation of enantiomerically enriched PPM with high enantiomeric excess of frequently at least 98 % ee, in particular at least 99 % ee and at the same time high chemical purity, of preferably at least 98 %, in particular at least 99 %. Therefore, according to a first aspect the present invention relates to a process for preparing enantiomerically enriched 3-hydroxymethylpiperidine which comprises the following steps:
a) providing enantiomerically enriched piperidine-3-carboxylic acid or an
enantiomerically enriched ester of piperidine-3-carboxylic acid,
b) reduction of the enantiomerically enriched piperidine-3-carboxylic acid or its ester with a boron containing reducing agent to yield a reaction mixture containing enantiomerically enriched 3-hydroxymethylpiperidine; and
c) aqueous work-up of the reaction mixture;
where the boron containing reducing agent is selected from the group consisting of BH3, complexes of BH3, mixtures of a tetrahydroborate salt with a metal salt of group 2, 4 or 12 metals and tetrahydroborates of group 2, 4 or 12 metals, and mixtures thereof.
According to a second aspect the present invention relates to non-racemic 3- hydroxymethylpiperidine, which has an enantiomeric excess with regard to one of the enantiomers of 3-hydroxymethylpiperidine of at least 98 % ee, in particular at least 99 % ee and a chemical purity of at least 98 %, in particular at least 99 % and especially at least 99.5 %, as determined by gas chromatography.
According to a third aspect the present invention relates to a method of extracting 3- hydroxymethylpipendine from an aqueous alkaline solution, which comprises treatment of an alkaline solution of 3-hydroxymethylpiperidine with an extractant, which is an organic solvent or solvent mixture, where the pH of the aqueous alkaline solution is at least pH 10, in particular at least pH 12.
DETAILED DESCRIPTION OF THE I NVENTION
In the context of the present invention, the terms used generically are defined as follows:
The prefix Cn-Cm indicates the possible carbon numbers a radical may have.
The term "halogen" as used herein includes e.g. fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.
The term alkyi relates to a linear or branched alkyi groups having preferably from 1 to 8 carbon atoms (= Ci-Cs-alkyl), in particular 1 to 6 carbon atoms (= Ci-C6-alkyl), 1 or 4 carbon atoms (= Ci-C4-alkyl). Examples of Ci-C4-alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and 1 ,1 -dimethylethyl (= tert. -butyl). Examples of Ci-Cs-alkyl include the aforementioned Ci-C4-alkyl radicals and n-pentyl, 2-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 2-hexyl, 2-methylpentyl, 3-methylpentyl, 2-ethylbutyl, 2,3- dimethylbutyl, n-heptyl, 2-heptyl, 2-methylhexyl, 3-methylhexyl, 2-ethylpentyl, 3- ethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, n-octyl, 2-octyl, 2-ethylhexyl, etc. The term "alkoxy" relates to an oxygen bound alkyi radical as defined above having preferably from 1 to 8 carbon atoms (= d-Cs-alkoxy), in particular 1 to 6 carbon atoms (= Ci-C6-alkoxy), 1 or 4 carbon atoms (= Ci-C4-alkoxy). Examples of alkoxy include in particular methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and 1 ,1 - dimethylethoxy (= tert.-butoxy).
The term "alkoxyalkyl" relates to an alkoxy radical as defined above, which is bound to an alkyi radical, where the alkoxy radical preferably has 1 to 4 carbon atoms and the alkyi part preferably has also 1 to 4 carbon atoms. Examples of alkoxyalkyl include 2- methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-butoxyethyl, 2-methoxypropyl, 2- ethoxypropyl, 2-propoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4- metoxybutyl, 3-methoxybutyl, 2-methoxy-2,2-dimethylethyl etc.
The term "aryl" relates to an aromatic or at least partially aromatic mono- or bicyclic hydrocarbon radical, such as phenyl, naphthyl, indanyl, indenyl and tetrahydronaphthyl, which is unsubstituted or may carry 1 , 2 or 3 radicals selected from halogen, C1-C4- alkyl and Ci-C4-alkoxy. Aryl is in particular phenyl, which is unsubstituted or may carry 1 , 2 or 3 radicals selected from halogen, Ci-C4-alkyl and Ci-C4-alkoxy.
The term "arylalkyl" relates to an aryl radical as defined above, in particular to substituted or unsubstituted phenyl, which is bound to an alkyl radical, in particular to a Ci-C4-alkyl radical. Examples of arylalkyl include benzyl, 1 -phenylethyl and 2- phenylethyl, where the phenyl ring in the aforementioned groups is unsubstituted or may carry 1 , 2 or 3 radicals selected from halogen, Ci-C4-alkyl and Ci-C4-alkoxy.
The term "group 2, 4 or 12 metals" refers to the metals of groups 2, 4 or 12 of the periodic table according to lUPAC and includes in particular the following metals: Mg, Ca, Zr and Zn.
In step a) of the invention, enantiomerically enriched piperidine-3-carboxylic acid or in particular an enantiomerically enriched ester of piperidine-3-carboxylic acid is provided.
Suitable esters of piperidine-3-carboxylic acid include e.g. the alkyl esters of piperidine- 3-carboxylic acid, in particular the Ci-C6-alkyl esters of piperidine-3-carboxylic acid, the alkoxyalkyl esters of piperidine-3-carboxylic acid, e.g. the Ci-C4-alkoxy-Ci-C4-alkyl esters of piperidine-3-carboxylic acid, in particular the Ci-C4-alkoxyethyl esters of piperidine-3-carboxylic acid, arylalkyl esters of piperidine-3-carboxylic acid, e.g. aryl-Ci- C4-alkyl esters of piperidine-3-carboxylic acid, in particular phenyl-Ci-C4-alkyl esters of piperidine-3-carboxylic acid such as benzyl or phenethyl esters of piperidine-3- carboxylic acid and aryl esters of piperidine-3-carboxylic acid, e.g. the phenyl ester of piperidine-3-carboxylic acid.
For the purpose of the present invention enantiomerically enriched esters of piperidine- 3-carboxylic acid, in particular the Ci-C6-alkyl esters and benzyl esters of piperidine-3- carboxylic acid, more particularly the Ci-C3-alkyl esters of piperidine-3-carboxylic acid and especially the ethyl ester of piperidine-3-carboxylic acid are preferred.
The enantiomerically enriched piperidine-3-carboxylic acid as well as the enantio- merically enriched ester of piperidine-3-carboxylic acid which is provided in step a) and reacted in step b) preferably has an enantiomeric excess of at least 80 % ee, in particular at least 90 % ee. In particular embodiments, an enantiomerically enriched piperidine-3-carboxylic acid or an enantiomerically enriched ester of piperidine-3- carboxylic is used in step b) which has an enantiomeric excess of at least 98 % ee, especially at least 99 % ee.
Enantiomerically enriched piperidine-3-carboxylic acid as well as enantiomerically enriched esters of piperidine-3-carboxylic acid (the esters are hereinafter termed AEPC), such as the enantiomerically enriched Ci-C6-alkylester or benzylesters, in
particular a Ci-C3-alkylester and especially the methyl or ethyl ester of piperidine-3- carboxylic acid are known and can be provided by any method known in the art for this or a similar purpose, for example by asymmetric synthesis, by synthesis starting from a chiral precursor, such as enantiomerically enriched piperidine-3-carboxylic acid, or by enantiomeric enrichment of a mixture of the enantiomers of piperidine-3-carboxylic acid or of the enantiomers of the respective piperidine-3-carboxylic acid esters.
Enantiomeric enrichment of piperidine-3-carboxylic acid or of AEPCs can be accomplished by customary methods, e.g. by chiral chromatography or by separation of diastereomers that can be generated by derivatization or salt formation of piperidine- 3-carboxylic acid or AEPCs with a chiral resolving agent. Preferred chiral resolving agents in this context are chiral acids capable of forming diastereomeric acid addition salts that can be enriched regarding one enantiomer of the piperidine-3-carboxylic acid or the AEPC, for example by fractional crystallization.
According to a preferred embodiment of the invention step a) of process A comprises subjecting racemic AEPC, in particular a racemic Ci-C4-alkylester of piperidine-3- carboxylic acid, especially the racemic ethyl ester of piperidine-3-carboxylic acid, to enantiomeric enrichment by fractional crystallization of an acid addition salt of AEPC with a chiral acid. However, it is also possible to enrich non-racemic mixtures of the
AEPC enantiomers in this manner. This enantiomeric enrichment can be used to enrich the R-enantiomer or the S-enantiomer of the AEPC, and is preferably used to enrich the S-enantiomer. Preferred chiral acids in this respect are those known in the art, such as tartaric acid, as described for example in US 5220016 and in WO 00/56730, or mandelic acid or dibenzoyl tartaric acid as described in EP1341762, or ethers of 2- hydroxy-propionic acid as described in US6340762. Enantiomeric enrichment of the R- enantiomer of AEPC, in particular of the ethyl ester of R-piperidine-3-carboxylic acid, is preferably achieved by crystallization of the acid addition salt of AEPC with one of the following acids: L(+) tartaric acid or D-mandelic acid. Enantiomeric enrichment of the S-enantiomer of AEPC, in particular the ethyl ester of S-piperidine-3-carboxylic acid, is preferably achieved by crystallization of the acid addition salt of AEPC with one of the following acids: D(-) tartaric acid or L-mandelic acid.
As outlined above, the fractional crystallization of piperidine-3-carboxylic acid or AEPC, respectively, with a chiral acid results in crystals of acid addition salts of piperidine-3- carboxylic acid or AEPC which are enantiomerically enriched with regard to (R)- or (S)- enantiomer. Thus, the mother liquor obtained in said crystallizations is depleted with regard to this respective enantiomer and therefore contains an excess of the opposite enantiomer of piperidine-3-carboxylic acid or AEPC. For example, the mother liquor
obtained from the crystallization of (R)-enantiomer acid addition salts is enriched with regard to (S)-enantiomer. In order to avoid loss of yield the piperidine-3-carboxylic acid or APEC, respectively, contained in said mother liquor may be subjected to a racemization. In this way, subsequent to the racemization, an additional amount of the desired enantiomer can be prepared by means of enantiomeric enrichment, for example according to the methods involving fractional crystallization mentioned above. Racemization of non-racemic AEPC is usually accomplished by treating AEPC with a base according to known procedures that are described for example in WO 02/068391. Suitable methods include e.g. treatment with catalytic amounts of sodium ethoxylate as base.
The acid addition salts of piperidine-3-carboxylic acid or AEPC with a chiral acid obtained by the methods for enantiomeric enrichment of the preceding embodiment can be transformed into the free base, i.e. free piperidine-3-carboxylic acid or free AEPC, according to well-known techniques. Typically, for preparing the free base of an AEPC the acid addition salt of the AEPC is treated either with a diluted aqueous base, such as an aqueous solution of an alkali metal carbonate, alkali metal hydrogen carbonate or alkali metal hydroxide such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodium hydroxide, calcium hydroxide or potassium hydroxide, or with a basic ion exchange resin. The free base may be extracted from the thus obtained mixture by a suitable method, such as extraction with an organic solvent. The addition of base is preferably conducted under cooling. It is further preferred to use a concentrated aqueous solution of a base. Typically, for preparing the free base of piperidine-3-carboxylic acid, a solution of its acid addition salt is treated with a basic ion-exchange resin or the acid, which has been used as a chiral auxiliary is
precipitated. Furthermore, the free base of piperidine-3-carboxylic acid can be prepared by hydrolysis of an AEPC according to well known methods.
In step b) of the inventive process, the enantiomerically enriched piperidine-3- carboxylic acid or enantiomerically enriched AEPC is subjected to a reduction with a boron containing reducing agent.
According to the present invention, the boron containing reducing agent is selected from the group consisting of the following groups a) to d) and mixtures thereof such as mixtures of the :
a) BH3, including in situ generated BH3;
b) BH3-complexes, such as BH3-ether or thioether complexes, e.g. BH3- tetrahydrofurane, BH3-diethylether or BH3-dimethyl sulphide adducts,
c) mixtures of a tetrahydroborate salt with a metal salt of group 2, 4 or 12 metals, and
d) tetrahydroborates of group 2, 4 or 12 metals, such as zinc tetrahydroborate. The enantiomerically enriched piperidine-3-carboxylic acid or AEPC is typically employed in step b) as is, i.e. as the free base, but it may also be used as its acid addition salt, in particular as its monohydrochloride. The enantiomerically enriched AEPC is preferably employed as the free base. According to another preferred embodiment a) the reducing agent is BH3, in particular in-situ generated BH3. In-situ generation of BH3 can be achieved by well no known techniques such as described by Abiko et al. Tetrahedron Letters (1992), 33(38), 5517- 5518; McKennon et al. J. Org. Chem. (1993), 58, 3568-2571 ; and Prasad et al.
Tetrahedron (1992), 48(22), 4623-4628.
Generally, in-situ generation of BH3 can be achieved by using mixtures of a
tetrahydroborate salt, in particular an alkalimetal tetrahydroborate, especially lithium, sodium or potassium tetrahydroborate, with a strong Broenstedt acid such as an organosulfonic acid, e.g. methane sulfonic acid, trifluoromethane sulfonic acid or toluene sulfonic acid or a mineral acid such as H2SO4, H3PO4 or HCI, or with a Lewis acid such as trimethylsilyl halides, boron halides such as BF3 or BF3-etherate. In-situ generation of BH3 can also be achieved by using mixtures of tetrahydroborate salt, in particular an alkalimetal tetrahydroborate, especially lithium, sodium or potassium tetrahydroborate, with an electrophile such as iodine. In this embodiment a), the relative molar amount of the activating agent (acid or electrophile such as iodine) to the tetrahydroborate may vary and is preferably in the range from 0.05 to 2 mol, in particular from 0.1 to 1.2 mol and especially 0.2 to 1.1 mol per mol of tetrahydroborate.
According to another preferred embodiment c) the reducing agent is selected from mixtures of a tetrahydroborate salt with a metal salt of group 2, 4 or 12 metals. In this context suitable metal salts include the halides, in particular the chlorides, the sulfates, phosphates, oxides, hydroxides, carbonates, Ci-Cio-carboxylates and Ci-Cs- alcoholates of these metals. In this context, particularly suitable alcoholates are the alcoholates which are derived from alkanols having 1 to 8 carbon atoms, in particular 1 to 6 or 1 to 4 carbon atoms, such as the methanolates, ethanolates and
insopropanolates. In this context, particularly suitable carboxylates are the carboxylates which are derived from aliphatic or aromatic carboxylic acids, in particular mono- or dicarboxylic acids having 1 to 10 carbon atoms, e.g. the formiates, acetates, propionates, butyrates, hexanoates, 2-ethylhexanoates and benzoates.
Preferred salts are the halides and especially the chlorides of these metals.
In embodiment c), suitable tetrahydroborate salts are alkalimetal tetrahydroborates, in particular sodium or potassium tetrahydroborate, and tetra-Ci-C4-alkylammonium tetrahydroborate such as commercially available tetrabutylammonium tetrahydroborate and also lithium tetrahydroborate.
Particularly suitable metal salts of group 2, 4 or 12 metals are the salts of the following metals: calcium, magnesium, zirconium and zinc, with most preference given to zinc. Particularly preferred salts of the aforementioned metals are the halides, in particular the chlorides.
Particular preference is given to the mixtures of an alkalimetal tetrahydroborate or a tetra-Ci-C4-alkylammonium tetrahydroborate, in particular sodium or potassium tetrahydroborate or lithium tetrahydroborate, with metal halides, especially metal chlorides, or metal oxides of group 2, 4, 10 or 12 metals, in particular to the mixtures of the zinc chloride, magnesium chloride or calcium chloride, which are preferably in their anhydrous form, such as ZnC , MgC , CaC , ZrCU, with particular preference given to zinc halides, especially ZnC .
In this embodiment c), the relative molar amount of the metal salt to the
tetrahydroborate salt may vary and is preferably in the range from 0.05 to 2 mol, in particular from 0.1 to 1 .2 mol and especially 0.4 to 0.6 mol of metal salt per mol of tetrahydroborate.
The amount of reducing agent will depend on the type of reducing agent in a known manner or can be determined by routine experiments. If an AEPC is used in embodiment c), the amount of reducing agent will generally be in the range from at least 2 moles of boron bound hydrogen atoms in the boron compound of the reducing agent per mole of enantiomerically enriched AEPC, preferably from 3 to 10 moles, especially from 3 to 8 moles of boron bound hydrogen atoms per mole of enantiomerically enriched AEPC. In particular the amount of reducing agent will be in the range from at least 0.75 moles of boron compound of the reducing agent per mole of enantiomerically enriched AEPC, preferably from 0.75 to 2.5 moles, especially from 0.75 to 2 moles of boron compound per mole of
enantiomerically enriched AEPC.
If piperidine-3-carboxylic acid is used in embodiment c), the amount of reducing agent will generally be in the range from at least 2 moles of boron bound hydrogen atoms in the boron compound of the reducing agent per mole of enantiomerically enriched piperidine-3-carboxylic acid, e.g. from 3 to 10 moles, especially from 3 to 8 moles of boron bound hydrogen atoms per mole of enantiomerically enriched piperidine-3- carboxylic acid. In particular the amount of reducing agent will be in the range from at least 0.75 moles of boron compound of the reducing agent per mole of enantiomerically enriched AEPC, e.g. from 0.75 to 2.5 moles, especially from 0.75 to 2 moles moles of boron compound per mole of enantiomerically enriched piperidine-3-carboxylic acid.
If in-situ borane is used as reducing agent, the amount of reducing agent will generally be in the range from at least 4 moles of boron bound hydrogen atoms in the boron compound of the reducing agent per mole of enantiomerically enriched AEPC or piperidine-3-carboxylic acid, e.g. from 4 to 16 moles, especially from 8 to 14 moles of boron bound hydrogen atoms per mole of enantiomerically enriched AEPC or piperidine-3-carboxylic acid. In particular the amount of reducing agent will be in the range from at least 2 moles of boron compound of the reducing agent per mole of enantiomerically enriched AEPC or piperidine-3-carboxylic acid, e.g. from 1 to 4 moles, especially from 2 to 3,5 moles of boron compound per mole of enantiomerically enriched AEPC or piperidine-3-carboxylic acid.
The reaction of step b) is usually performed in an organic solvent, in particular an aprotic organic solvent or a solvent mixture containing predominantly an aprotic solvent. Suitable solvents include, but are not limited to ethers, in particular di-Ci-C4 alkyl ethers such as diethyl ether, di-n-propyl ethers, diisopropyl ethers, methyl-tert- butyl ether, ethyl-tert. -butyl ether, mono-, di- and tri-C2-C4-alkylylene glycol di-Ci-C4 alkyl ethers such as dimethyl ethyleneglycol, dimethyl diethyleneglycol,
triethyleneglycol dimethyl ether, propyleneglycol dimethyl ether, alicyclic ethers such as tetrahydrofurane, dioxane and methyltetrahydrofurane, aromatic ethers such as anisol and hydrocarbons, e.g. alkanes such as pentane, hexanes, heptanes, cycloalkanes such as cyclopentane, cyclohexane, methylcyclohexane and cycloheptane and aromatic hydrocarbons, in particular mono- and di-Ci-C4-alkylbenzenes such as toluene, xylenes, isopropylbenzene, tert.-butylbenzene, cumene and mixtures thereof. Suitable solvents may also include alcohols, such as d-Cs-alkanols, e.g. methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert.-butanol or n-pentanol, mono-, di- and tri-C2-C4-alkylylene glycols and their mono-Ci-C4-alkyl ethers, such as ethylene glycol, propylene glycol, ethylendiglycol or ethylenglycolmonomethylether. The amount of alcohols does generally not exceed 30 Vol.-%, in particular 20 Vol.-%, based on the total amount of organic solvent. Preferably, the reaction is performed
essentially in the absence of larger amounts of water, i.e. the amount of water does not exceed 5 Vol.-%, based on the total amount of organic solvent.
Preferably step b) is performed in an aprotic solvent including pure aprotic solvents and mixtures of aprotic solvents. In particular the aprotic solvent comprises an ether, in particular a cyclic ether, or a mono-, di- and tri-C2-C4-alkylylene glycol di-Ci-C4 alkyl ether or a mixture of an ether solvent with a hydrocarbon solvent.
The total amount of solvent used in step b) is usually in the range from 100 to 1000 g, preferably in the range from 250 to 800 g and in particular in the range from 350 to 700 g, based on 1 mol of piperidine-3-carboxylic acid or AEPC, respectively.
The reaction temperature necessary in step b) may vary and depend on the type of reducing agent. Usually temperatures in the range of 10 to 100°C will be suitable for carrying out step b), however even lower or higher temperatures may be applied without loss of yield or loss of optical purity.
Step b) yields a reaction mixture which contains enantiomerically enriched 3-hydroxy- methylpiperidine. Without being bound to theory it is believed that in the reaction mixture obtained in step b) at least a part of the enantiomerically enriched 3-hydroxy- methylpiperidine is present as a boron containing derivative, e.g. a complex with a boron compound, which must be hydrolysed during aqueous workup to allow isolation of the desired product, namely the enantiomerically enriched 3-hydroxymethyl- piperidine.
Aqueous workup of the reaction mixture obtained in step b) in accordance with step c) of the claimed process can principally be performed by mixing the reaction mixture with water, which may contain an acid or a base, followed by isolation of the desired product, e.g. by liquid or solid phase extraction of the desired product from the thus obtained mixture or by crystallization of a suitable salt of the enantiomerically enriched 3-hydroxymethylpiperidine therefrom. During aqueous workup any boron containing organic compounds will be hydrolysed into boric acid or boric acid esters which can be removed prior to isolation of the desired product but which is not necessarily removed. It has been found beneficial to perform step c) in a manner that pH of the aqueous phase is at most pH 6, e.g. from pH 0 to pH 6, in particular from pH 0 to pH 3 at least during the initial phase of the workup, in order to achieve hydrolysis of the boron containing reducing agent and optionally present boron containing derivatives of 3- hydroxymethylpiperidine. Therefore a particular embodiment of step c) comprises a
hydrolysis of the boron containing reducing agent and optionally present boron containing derivatives of 3-hydroxymethylpiperidine at a pH of at most pH 6, e.g. in the range from pH 0 to pH 6, in particular from pH 0 to pH 3 at least during the initial phase of the workup.
Preferably, aqueous workup also includes an extraction step for isolation of the enantiomerically enriched 3-hydroxymethylpiperidine. It has been found beneficial to extract 3-hydroxymethylpiperidine from an aqueous alkaline solution having a pH of at least pH 10, in particular at a pH of at least pH 12, e.g. at a pH in the range from pH 10 to 14, in particular from pH 12 to 14. Therefore, a particular embodiment comprises treatment of an alkaline solution of 3-hydroxymethylpiperidine with an extractant, which is an organic solvent or solvent mixture, where the pH of the aqueous alkaline solution is at least pH 10, in particular at least pH 12, e.g. at a pH in the range from pH 10 to 14, in particular from pH 12 to 14.
If the hydrolysis products are removed prior to extraction, the removal is preferably performed at a pH of at least pH 6, e.g. in the range from pH 6 to pH 12. Removal of the hydrolysis products can be performed by any conventional steps of solid liquid separation, e.g. by filtration or centrifugation.
In a particular embodiment, the enantiomerically enriched 3-hydroxymethylpiperidine is extracted from the aqueous phase by using an organic solvent or solvent mixture as an extractant, which comprises at least one organic solvent having limited water miscibility. Limited water miscibility in terms of solvents means that the solubility in water at 25°C and 1016 mbar (deinonized water at pH 7) is at most 30 g/100 ml (= 300 g/l). Suitable organic solvents having limited water miscibility include but are not limited to aprotic solvents from the group of ethers, in particular the aforementioned di-Ci-C4- alkyl ethers, such as diethyl ether, diisopropyl ether, methyl tert. butyl ether and ethyl tert.butyl ether, and alkyl substituted cyclic ethers such as methyltetrahydrofurane, hydrocarbons, in particular aromatic hydrocarbons such as toluene and xylenes, C1-C6- alkylesters of Ci-C6-alkanoic acids, in particular the Ci-C6-alkylesters of acetic acid or propionic acid such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and ethyl propionate, chlorinated hydrocarbons such as dichloromethane and dichloroethane. Preferred aprotic solvents are selected from alkylaromatic solvents, methyltetrahydrofurane and Ci-C6-alkylesters of Ci-C6-alkanoic acids.
Suitable organic solvents having limited water miscibility also include n-butanol, 2- butanol, isobutanol, Cs-Cs-alkanols and Cs-Cs-cycloalkanols.
Likewise suitable as an extractant are tetrahydrofurane or tetrahydrofurane containing mixtures of organic solvents, as tetrahydrofurane is usually not completely miscible with the reaction mixture which is subjected to extraction. For extraction those organic solvents are preferred which have a boiling point at normal pressure in the range from 30 to 1 10°C.
It has been found beneficial, if the extractant comprises at least one organic solvent selected from the group of d-Cs-alkanols, especially d-Cs-alkanols, and C4-C8- cycloalkanols. Suitable Ci-Cs-alkanols include methanol, ethanol, n-propanol, isopropanol, 1 -butanol, 2-butanol, 2-methylpropanol, 1 ,1 -dimethylethanol (tert.butanol), n-pentanol, 3-methylbutan-1 -ol (isoamyl alcohol), n-hexanol, 2-hexanol, 3-hexanol, 2- methylpentanol, isohexanol, n-heptanol, 2-ethylhexanol and n-octanol. Suitable Cs-Cs- cycloalkanols include in particular cyclopentanol and cyclohexanol. A skilled person will readily understand that the organic solvent or solvent mixture, which is used as an extractant will usually comprise at least one organic solvent having limited water solubility. Thus, if the extractant contains a Ci-C3-alkanol or tert.butanol, it will also contain at least one organic solvent having limited water solubility, in particular at least one aprotic solvent.
Apart from that, the extractant is preferably a mixture of at least one alcohol selected from the group of Ci-Cs-alkanols, especially Ci-Cs-alkanols, and C4-C8-cycloalkanols and at least one aprotic solvent having limited water-solubility, in particular a mixture of at least one alcohol selected from the group of Ci-Cs-alkanols, especially C1-C5- alkanols, and C4-C8-cycloalkanols and at least one aprotic organic solvent selected from the group consisting of alkylaromatic solvents, methyltetrahydrofurane and C1-C6- alkylesters of Ci-C6-alkanoic acids. Preferably the relative amount on a volume base of alcohol to aprotic solvent in these mixtures is from 1 :20 to 5:1 v/v in particular from 1 :10 to 2:1 v/v.
The enantiomerically enriched 3-hydroxymethylpiperidine can be isolated from the extractant by removing the solvent, preferably under reduced pressure, to obtain a solid residue, which may be subjected to further purification, such as distillation, sublimation or recrystallization. Suitable solvents for recrystallization include e.g.
methyltetrahydrofurane and tert.-butylmethyl ether. Optionally present inorganic salts may be removed from an anhydrous solution of 3-hydroxymethylpiperidine by filtration prior to the further purification step.
It may also be possible to extract the enantiomerically enriched 3-hydroxymethylpiperidine by means of an ion exchange resin, in particular a cationic ion-exchange resin in its H+ form. Preferably, the aqueous mixture from which the enantiomerically enriched 3-hydroxymethylpiperidine is extracted by means of an ion exchange resin has a pH of at most pH 8, e.g. in the range from pH 4 to pH 8, in particular from pH 5 to pH 8. Preferably, the aqueous phase of the initial workup containing the
enantiomerically enriched 3-hydroxymethylpiperidine is conducted through a bed of the ion exchange resin. Thereby the enantiomerically enriched 3-hydroxymethylpiperidine will be adsorbed by ion-exchange resin, while impurities remain in the aqueous phase. The 3-hydroxymethylpiperidine can be eluted from the ion-exchange resin by treatment of the ion exchange resin with a diluted solution of a suitable organic or inorganic acid, in particular by treatment with diluted hydrochloric acid or diluted aqueous sulphuric acid, whereby an aqueous solution of the corresponding salt of 3-hydroxymethylpiperidine followed by adjusting the pH to alkaline pH, e.g. to pH of at least pH 10, in particular at least pH 1 1 and subsequent isolation of the 3-hydroxymethylpiperidine from the aqueous solution by extraction. 3-hydroxymethylpiperidine may also be eluted from the ion-exchange resin by treatment of the ion exchange resin with a diluted aqueous solution of a suitable amine, such as ammonium hydroxide or diethylamine. By the workup of step c) an enantiomerically enriched 3-hydroxymethylpiperidine is obtained, which has both high optical and chemical purity. In particular optical purity is at least 97 % ee, especially at least 98 % ee as determined by chiral HPLC, provided that the optical purity of the chiral AEPC or piperidine-3-carboxylic acid, respectively, is not lower. Chemical purity is generally at least 90 %, especially at least 95 %, as determined by gas chromatography.
The thus obtained enantiomerically enriched 3-hydroxymethylpiperidine can be further purified to yield an enantiomerically enriched 3-hydroxymethylpiperidine which has an enantiomeric excess with regard to one of the enantiomers of 3-hydroxymethyl- piperidine of at least 98 % ee, in particular at least 99 % ee and a chemical purity of at least 98 %, in particular at least 99 % and especially at least 99.5 %, as determined by gas chromatography. So far, it has not been possible to produce enantiomerically enriched 3-hydroxymethylpiperidine, in particular the S-enantiomer having these high chemical and optical purities, even if the enantiomerically enriched 3-hydroxymethyl- piperidine obtained by the prior methods is further purified by conventional purification techniques such distillation or crystallization.
In contrast to prior art the enantiomerically enriched 3-hydroxymethylpiperidine obtained by the process of the invention can be further purified to increase optical and
chemical purity. Further purification may be achieved by recrystallization or distillation of the 3-hydroxymethylpiperidine obtained from work-up c). Suitable solvents for recrystallization include e.g. methyltetrahydrofurane and tert.-butylmethyl ether. The following examples shall illustrate the invention.
Examples
As used herein, the following terms are used as defined below unless otherwise indicated:
ee enantiomeric excess
eq equivalent
er enantiomeric ratio
rt room temperature
ENP ethyl 3-piperidinecarboxylate (ethyl nipecotate)
(S)-ENP (S)-ethyl 3-piperidinecarboxylate ((S)-ethyl nipecotate)
NPA 3-piperidinecarboxylic acid (nipecotic acid)
(S)-NPA (S)-3-piperidinecarboxylic acid (nipecotic acid)
(S)-NPA * HCI (S)-nipecotic acid hydrochloride
GC gas chromatography
MeOH methanol
Me-THF 2-methyltetrahydrofuran
LAH lithium aluminum hydride
PPM 3-hydroxymethylpiperidine (3-piperidylmethanol)
(S)-PPM (S)-3-hydroxymethylpiperidine ((S)-3-piperidylmethanol)
TBME methyl tert-butyl ether
THF tetrahydrofuran
TLC thin layer chromatography The chemical purity was measured via GC on a Shimadzu GC 2010 / GC 14B equipped with a Perkin Elmer PE 624 column (30 m x 0.53 mm, hydrogen as carrier, 0.5 bar) and a FID detector. The injection temperature was 250 °C, the detector temperature was 300 °C, and the temperature gradient was 50 °C (2 min), 10 °C/min, 240 °C (3 min). The sample concentration was 10 mg/mL methanol; the injection volume was 2.0 μΙ_. The retention time is Rt(PPM) = 1 1 min.
The enatiomeric ratio S/R was measured via chiral HPLC after derivatisation with mosher's acid chloride on a Chiralpak AD 250/ 4.6/10 column with hexane/isopropanol
90 : 10 as eluent. The detection wavelength was 210 nm. The retention times were: Rt(R-PPM) = 9 min and Rt(S-PPM) = 10 min, respectively.
I Preparation of starting materials
EXAMPLE 1 : Preparation of (S)-ENP
1 .1 Resolution of ENP with D-tartaric acid To a solution of (S)-ENP (75:25 er; 170 kg) in ethanol/water (94:6; 950 kg) was added 160 kg of D-tartaric acid at 30°C. The mixture was cooled to 20°C and stirred at 20°C for 7 h. A solid precipitated out that was collected by centrifugation and washed with ethanol to yield 262 kg of (S)-ENP · D-tartaric acid (98:2 er). (S)-ENP · D-tartaric acid was recrystallized twice from aqueous ethanol to yield 217 kg of (S)-ENP · D-tartaric acid (99% ee).
1 .2 Isolation of (S)-ENP from its tartaric acid salt To a well stirred suspension of 153.6 g of (S)-ENP · D-tartaric acid having an optical purity of 99.4 : 0.6 er in 157 g of xylene (technical mixture) was added dropwise a solution of 69.3 g of technical potassium hydroxide in 78 g of water under cooling. The organic phase was separated; the water phase was extracted successively with 50 g and then 40 g of xylene. The combined organic phase was dried over 10 g of sodium sulfate. Sodium sulfate was filtered off and xylene was removed under reduced pressure to yield the (S)-ENP as a clear liquid having an optical purity of 99.4 : 0.6 er.
EXAMPLE 2: Preparation of (S)-ethyl 3-piperidinecarboxylate hydrochloride To a mixture of (S)-ENP (393 g of a 40 % solution in toluene; 1 mol ENP, with an optical purity of 99.4 : 0.6 er) was added water (120 g) and concentrated hydrochloric acid (120 g) under cooling. The mixture was stirred at 60°C overnight. The mixture was concentrated at 80 °C under reduced pressure until a thick slurry was obtained. To this mixture was added acetone (200 mL) and the mixture was stirred at room temperature for 1 h. The solid was collected by filtration. From the mother liquor a second crop was obtained by concentration and subsequent addition of acetone.
Yield: 157 g (95%)
II Preparation of (S)-3-hydroxymethylpiperidine by reduction of (S)-ENP with a mixtures of a tetrahydroborate salt and ZnC
EXAMPLE 3: Reduction with NaBH4 + ZnC in THF (0.5 mol ZnC per 1 mol sodium tetrahydroborate)
A mixture of NaBH4 (1 13 g; 3 mol), ZnC (anhydrous, 204 g; 1.5 mol) and THF (900 g) was stirred under argon at 66°C for 15 min. The greyish mixture was cooled down to 50°C and (S)-ENP (99.4:0.6 er; 314 g; 2 mol) was added slowly over 4 h. After complete addition, the mixture was stirred at 50°C for further 15 min. The mixture was cooled to 20°C, quenched by adding slowly 500 mL of 37% aqueous hydrochloric acid while cooling and then stirred overnight until no further gas was evolved. TLC
(MeOH/NH4OH 3 : 1 ; ninhydrin) showed complete conversion to 3- hydroxymethylpiperidine.
The reaction mixture was adjusted to pH = 14 by adding a 40% aqueous solution of sodium hydroxide. The mixture was extracted 3 times at 50°C with a mixture of isobutanol/toluene (1 :1 ; in total 5 L). After drying over MgS04, the solvent was removed under reduced pressure to yield crude (S)-PPM as a colorless oil which had a chemical purity greater than 98% and an optical purity 99.4:0.6 er.
The obtained crude (S)-PPM was purified by recrystallization from TBME (2 g per g of crude (S)-PPM). (S)-PPM was obtained in a yield greater than 80%, and had a chemical purity greater than 99% and an optical purity of 99.9:0.1 er.
EXAMPLE 4: Reduction with NaBH4 + ZnC in THF (0.5 mol ZnC per 1 mol sodium tetrahydroborate))
A mixture of NaBH4 (2.08 g; 55 mmol), ZnC (anhydrous, 3.75 g; 27.5 mmol) and THF (70 mL) was stirred under argon for 15 min at 66°C. The mixture was cooled down to 50°C and (S)-ENP (99.4:0.6 er; 7.86 g; 50 mmol) was slowly added. After complete addition the mixture was stirred at 50°C for further 30 min. The mixture was cooled to 20°C. The reaction was quenched at 20°C by adding slowly 1 1 mL of 37 % aqueous hydrochloric acid under cooling. After complete addition the mixture was stirred overnight until no further evolution of gas was observed. TLC showed complete reduction to 3-hydroxymethylpiperidine. The mixture was basified by the addition of a 40 % aqueous solution of sodium hydroxide to a pH of 14. The mixture was extracted with isobutanol/toluene (1 :1 ; 3 x 60 mL). The organic phase was dried over MgS04 and
concentrated under reduced pressure to yield crude (S)-PPM as a solid (5.96 g) which had an optical purity of 99.4:0.6 er and a chemical purity greater than 98%.
EXAMPLE 5: Reduction with NaBH4 + ZnC in THF (0.09 mol ZnC per 1 mol of sodium tetrahydroborate)
A mixture of NaBH4 (4.5 g; 120 mmol), ZnC (anhydrous 1.5 g; 1 1 mmol) and THF (75 mL) was stirred under argon for 2 h at 45°C. A solution of (S)-ENP (17.3 g; 1 10 mmol) in THF (60 mL) was added slowly. After complete addition the mixture was stirred overnight at rt. The mixture was heated again to reflux for 5 h. The reaction was quenched at 20°C by adding slowly methanol under cooling. TLC (MeOH/NH4OH 3 : 1 ; ninhydrin) showed complete conversion to 3-hydroxymethylpiperidine.
EXAMPLE 6: Reduction with KBH4 + ZnC in THF (0.5 mol ZnC per 1 mol of potassium tetrahydroborate
A mixture of KBH4 (4.05 g; 75 mmol), ZnC (anhydrous 5.2 g; 38 mmol) and THF (70 mL) was stirred under argon for 10 min at 66°C. The mixture was cooled down to 50°C and (S)-ENP (99.4:0.6 er; 7.9 g; 50 mmol) was slowly added. After complete addition the mixture was stirred for further 30 min at 50°C. The mixture was cooled to 20°C. The reaction was quenched at 20°C by adding slowly 13 mL of 37% aqueous hydrochloric acid under cooling. After complete addition the mixture was stirred until no further evolution of gas was observed. TLC (MeOH/NH4OH 3 : 1 ; ninhydrin) showed complete conversion to PPM. The pH was adjusted to pH =14 by the addition of a 40% aqueous solution of sodium hydroxide. The mixture was extracted 3 times with a mixture of isobutanol/toluene (1 :1 ; in total 180 mL). After drying over MgS04, the solvent was removed under reduced pressure to yield (S)-PPM as a colorless solid having a chemical purity greater than 98% and an optical purity of 99.4:0.6 er. EXAMPLE 7: Reduction with NaBH4 + ZnC in dimethoxyethane
A mixture of NaBH4 (7.57 g; 200 mmol), ZnC (anhydrous, 13.6 g; 100 mmol) and dimethoxyethane (150 mL) was stirred under argon for 5 min at room temperature and then for 15 min at 50-60°C. (S)-ENP (99.4:0.6 er, 31.4 g; 200 mmol) was added slowly at 60°C. After complete addition the mixture was stirred for 1 h at 60°C. The mixture was cooled to room temperature and quenched by the adding slowly 60 g of cone, hydrochloric acid under cooling. TLC (MeOH/NH4OH 3 : 1 ; ninhydrin) showed complete conversion to PPM.
III Preparation of (S)-3-hydroxymethylpiperidine by reduction of (S)-ENP with a mixtures of a tetrahydroborate salt and various metal chlorides
EXAMPLE 8: Reduction with KBH4 + MgC in THF:
To 9.52 g (100 mmol) MgC (anhydrous) and KBH4 (5.39 g; 100 mmol) in THF was added (S)-ENP (7.86 g; 50 mmol, optical purity 99.6 : 0.4 er) and the mixture was heated to reflux. After complete reaction the mixture was quenched by dropwise addition of 4 M aqueous hydrochloric acid (80 mL). The mixture was basified with sodium hydroxide to pH =14. The mixture was filtered over celite and the resulting filtrate was extracted 3 times with n-butanol/toluene (9:1 1 ; 50 mL). Concentration under reduced pressured yielded (S)-PPM as a clear oil (yield 64 %) which had an optical purity of 97 ee. EXAMPLE 9: Reduction with NaBH4 + CaCI2 in THF
A mixture of NaBH4 (2.84 g; 75 mmol), CaC (anhydrous, 4.22 g; 38 mmol) and THF (70 mL) was stirred under argon at 66°C for 15 min. The mixture was cooled down to 50°C and (S)-ENP (99.4:0.6 er; 7.86 g; 50 mmol) was added over 10 min. After complete addition, the mixture was stirred at 60°C for further 10 h. The mixture was cooled to 20°C, quenched by adding slowly 13 mL of 37% aqueous hydrochloric acid while cooling and then stirred overnight.
The reaction mixture was adjusted to pH = 14 by adding a 40% aqueous solution of sodium hydroxide. The mixture was extracted 3 times at 50°C with a mixture of isobutanol/toluene (1 :1 ; 3 x 60 mL). After drying over MgS04, the solvent was removed under reduced pressure to yield an oil (2.55 g with an S-PPM content of 43 %).
Yield: approx. 19 %
Optical yield: 94 : 6 er;
EXAMPLE 10: Reduction with NaBH4 + ZrCI4 in THF
A mixture of NaBH4 (3.87 g; 100 mmol), ZrC (anhydrous, 5.83 g; 25 mmol) and THF (50 mL) was stirred under argon at 66°C for 15 min. The mixture was cooled down to 50°C and (S)-ENP (8.54 g of a 92% ENP/ 8% toluene solution; 50 mmol; 99.4:0.6 er) was added over 10 min. After complete addition, the mixture was stirred at reflux for further 2 h. The mixture was cooled to 20°C, quenched by adding slowly a mixture of 18 mL of 37% aqueous hydrochloric acid and 18 mL of water while cooling and then stirred overnight.
The reaction mixture was adjusted to pH = 14 by adding a 40% aqueous solution of sodium hydroxide. The mixture was extracted 3 times at 50°C with a mixture of
isobutanol/toluene (1 :1 ; 3 x 60 mL). After drying over MgS04, the solvent was removed under reduced pressure to yield an oil (7.8 g with an S-PPM content of 34 %).
Yield: approx. 46 %
Optical yield: 96.5 : 3.5 er;
IV Preparation of (S)-3-hydroxymethylpiperidine by various reductions (comparative examples)
EXAMPLE 1 1 (comparative example): Reduction with LAH
A mixture of LiAIH4 (3.8 g; 100 mmol) and THF (75 mL) was stirred at 50°C for 30 min. The suspension was cooled to 20°C and a solution of (S)-ENP (98.8:1 .2 er; 15.7 g, 100 mmol) in toluene was added slowly (30 min). The mixture was heated to 80°C for 2 h. The mixture was cooled to 0°C and 7.6 g of water was slowly added under stirring. Then, a saturated aqueous solution of K2CO3 (1 1.4 mL) was slowly added over 30 min. After stirring for 30 min, Celite (10 g) was added. The mixture was filtered over Celite, washed with THF and concentrated under reduced pressure to yield (S)-PPM as a yellow oil (1 1 g). The oil was distilled (approx. 1 mbar, up to 220°C bath temperature) to yield 6.2 g (54 %) of (S)-PPM as colorless oil, which solidified during cooling.
Chemical purity: 88 %; optical purity: 92.9 : 7.1 er
EXAMPLE 12 (comparative example): Reduction with LiBH4
To a suspension of LiCI (10.6 g; 250 mmol) in THF (100 mL) was added KBH4 (13.5 g; 250 mmol) and the mixture was stirred for 1 h at room temperature. (S)-ENP (17.1 g of a 92% ENP/ 8% toluene solution; 100 mmol; 99.4:0.6 er) was added and the mixture was stirred in the presence of Ceramic beads (SiLibeads® Type ZY) for 3 d at room temperature. The mixture was acidified by the addition of 20 mL of cone, hydrochloric acid and 120 mL of water to pH <1. The zirconium balls were removed by filtration and the THF was removed from the clear filtrate under reduced pressure. The residue was basified by the addition of a 40% aqueous solution of potassium hydroxide. The mixture was filtered and the filtrate was extracted with isobutanol/toluene (1 :1 ; 3 x 50 mL). The organic phase was concentrated under reduced pressure to yield PPM as a clear oil (9.6 g; yield: 69 %; PPM content 83 %). Optical purity: 58:42 er.
EXAMPLE 13 (comparative example): Reduction with NaBH4 (5 eq) in ethanol under reflux
To a stirred suspension of NaBhU (9.5 g; 250 mmol) in absolute ethanol (50 g) was added (S)-ENP (8.54 g of a 92% ENP/ 8% toluene solution; 50 mmol; 99.4:0.6 er) and the mixture was stirred at 70°C for 6 h. During this stirring period, further absolute EtOH (60 mL) was added to facilitate stirring. The reaction was quenched by the addition of aqueous hydrochloric acid (300 mmol in 60 g of water). The mixture was stirred for further 3 days at room temperature. Most of the solvent was removed under reduced pressure. The residue was basified by the addition of a 40% aqueous solution of potassium hydroxide under cooling. The mixture was extracted with isobutanol/Me- THF(1 :1 ; 3 x 30 mL). The organic phase was concentrated under reduced pressure to yield PPM as a clear oil (6.5 g; PPM content 51 %; yield: 60%). Optical purity: 68:32 er. Example 14 (comparative example): Reduction with NaBhU (4 eq) in THF under reflux with slowly addition of methanol
To a stirred suspension of NaBhU (9.5 g; 250 mmol) in THF (50 mL) was added (S)- ENP (8.54 g of a 92% ENP/ 8% toluene solution; 50 mmol; 99.4:0.6 er) and the mixture was heated to 70°C. MeOH (50 mL) was added dropwise during 15 min. After 1 h, the reaction cooled to RT and was quenched by the addition of aqueous sat. KHSC solution (50 mL) and cone, hydrochloric acid (5 mL). THF was removed under reduced pressure and the solution was basified by the addition of a 40% aqueous solution of potassium hydroxide. The precipitated K2SO4 was filtered off, and the mixture was extracted at 50°C with isobutanol/Me-THF(1 :1 ; 5 x 20 mL). The organic phase was dried (MgSC ), filtered off and concentrated under reduced pressure to yield PPM as a clear oil (3.9 g; yield: 68%). Optical purity: 78:22 er.
V Preparation of (S)-3-hydroxymethylpiperidine by reduction of (S)-ENP with in situ generated BH3
EXAMPLE 15: Reduction with the reaction product of a tetrahydroborate salt with iodine To a suspension of NaBH4 (4.73 g; 125 mmol) in THF (50 mL) was added (S)-ENP (99.4:0.6 er; 7.86 g; 50 mmol) and the mixture was cooled to 0°C. Then a solution of iodine (12.7 g; 50 mmol) in THF (20 mL) was added dropwise. The mixture was heated at 50°C overnight.
To this mixture was added 1 eq. of NaBH4 (1 .89 g; 50 mmol) and iodine (5.1 g; 20 mmol) and the mixture was stirred at 50°C for 2 h. The mixture was cooled to 20°C and cone, hydrochloric acid (15 g) was slowly added. The mixture was stirred overnight at room temperature. The residue was basified by the addition of a 40% aqueous solution of sodium hydroxide to a pH of 13. The mixture was extracted with isobutanol/toluene (1 :1 ; 3 x 60 mL). The organic phase was dried over MgS04 and concentrated under reduced pressure to yield (S)-PPM as a solid (6.7 g) which had an optical purity of 97 : 3 er and a chemical purity of approx. 75%. EXAMPLE 16: Reduction with the reaction product of a tetrahydroborate salt with Broenstedt acid
To a suspension of NaBhU (4.73 g; 125 mmol) in THF (50 mL) was added (S)-ENP (99.4:0.6 er; 7.86 g; 50 mmol) and the mixture was cooled to 0°C. Then a solution of cone. H2SO4 (6.4 g; 62.5 mmol) in THF (20 mL) was added dropwise. The mixture was heated to 40°C for 2 h. To this mixture was added 1 eq. of NaBH4 (1 .89 g; 50 mmol) and cone. H2SO4 (2.6 g; 25 mmol) and the mixture was stirred at 50°C for 2 h. The mixture was cooled to 20°C and cone, hydrochloric acid (6.4 g) was slowly added. The mixture was stirred overnight at room temperature. The residue was basified by the addition of a 40% aqueous solution of sodium hydroxide to a pH of 13. The mixture was extracted with isobutanol/toluene (1 :1 ; 3 x 60 mL). The organic phase was dried over MgS04 and concentrated under reduced pressure to yield (S)-PPM as a solid (4.5 g) which had an optical purity of 99.4:0.6 er; and a chemical purity greater than 95%) VI Preparation of (S)-3-hydroxymethylpiperidine starting from the acid addition salt of (S)-NPA
EXAMPLE 17: Reduction of (S)-NPA · HCI with NaBH4 + ZnCI2 in THF To a suspension of sodium borohydride (7.6 g; 200 mmol) in THF (20 mL) was added a solution of ZnC (13.6 g; 100 mmol) in THF (50 mL) and the resulting mixture was heated to 66°C for 30 min. The mixture was cooled to 40°C and (S)-NPA hydrochloride (16.6 g; 100 mmol, from EXAMPLE 2) was slowly added. The mixture was heated to reflux for 2 h. The mixture was cooled to room temperature and carefully poured onto 32 g of water and 32 g of concentrated hydrochloric acid. The mixture was stirred overnight, basified with sodium hydroxide (40% solution in water) to pH >13, filtered and extracted three times with iso-butanol/toluene (9:1 1 ; 50 mL). Concentration under reduced pressured yielded (S)-PPM as a solid (yield: 40%) which had a chemical purity of 97.9% and an optical purity of 99.85 : 0.15.
EXAMPLE 18: Reduction of (S)-NPA · HCI with NaBH4 + H2S04 in THF
A suspension of sodium borohydride (7.6 g; 200 mmol) and (S)-NPA hydrochloride (16.6 g; 100 mmol, from EXAMPLE 2) in THF (100 mL) was heated for 2 h at 70°C, till the gas evolution ceased. The temperature was lowered to 50°C and a solution of concentrated sulfuric acid (10.0 g; 100 mmol) in 40 mL of THF was added during 30 min. The suspension was heated to 70°C for 1 h, then cooled to room temperature and carefully poured onto 20 g of cracked ice and 20 g of concentrated hydrochloric acid. The mixture was stirred overnight, basified with sodium hydroxide (40% solution in water) to pH >12, filtered and extracted three times with iso-butanol/toluene (9:1 1 ; 50 mL). Concentration under reduced pressured yielded (S)-PPM as a solid (47% yield), which had a chemical purity of 96% and an optical purity of 99.64 : 0.36. Example 19: Extraction of PPM from an aqueous alkaline solution
A solution of PPM (5.0 g) in a saturated, aqueous NaCI-solution (20 g) was adjusted to a pH equal or greater than 13 by the addition of an aqueous solution of sodium hydroxide (1 to 2 drops). The conditions for the extraction as well as the yield of PPM after extraction are indicated in Table 1 below.
Table 1 :
Solvents (ratio) T Extraction yield
(solvent amount)
isobutanol/toluene (1 :1 ) 50°C 5 * 2 mL/g PPM quantitative isobutanol/metyhl-THF (1 :1 ) 50°C 5 * 2 mL/g PPM quantitative isobutanol/metyhl-THF (1 :1 ) 20°C 5 * 2 mL/g PPM Approx. 80% isobutanol/isopropyl acetate (1 :1 ) 50°C 5 * 2 mL/g PPM quantitative n-butanol/isopropyl acetate (1 :1 ) 50°C 5 * 2 mL/g PPM quantitative n-octanol 50°C 5 * 2 mL/g PPM > 80% (tic) n-octanol/ Me-THF(1 :1 ) 50°C 5 * 2 mL/g PPM > 80% (tic) isoamylalcohol/ Me-THF(1 :1 ) 50°C 5 * 2 mL/g PPM > 80% (tic) cyclohexanol/Me-THF(1 :1 ) 50°C 5 * 2 mL/g PPM > 80% (tic) isopropanol/ isopropyl acetate (1 :3) 50°C 5 * 2 mL/g PPM > 80% (tic) ethanol/ toluene (1 :4) 50°C 5 * 2 mL/g PPM > 80% (tic) methanol/ Me-THF(1 :9) 50°C 5 * 2 mL/g PPM quantitative (tic)
THF 50°C 5 * 2 mL/g PPM > 80% (tic) isobutanol 50°C 5 * 2 mL/g PPM approx 50% (tic)
Me-THF 50°C 5 * 2 mL/g PPM Approx. 60%
TIC: > 80% (tic); only traces of PPM are detected on tic in the remaining water phase and in the organic phase of the 5th extraction.
TIC: quantitative (tic); PPM was not detected on tic in the remaining water phase and in the organic phase of the 5th extraction.
Claims
1 . A process for preparing enantiomerically enriched 3-hydroxymethylpiperidine, which comprises the following steps:
a) providing enantiomerically enriched piperidine-3-carboxylic acid or an
enantiomerically enriched ester of piperidine-3-carboxylic acid, b) reduction of the enantiomerically enriched piperidine-3-carboxylic acid or its ester with a boron containing reducing agent to yield a reaction mixture containing enantiomerically enriched 3-hydroxymethylpiperidine; and c) aqueous work-up of the reaction mixture;
where the boron containing reducing agent is selected from the group consisting of BH3, complexes of BH3, mixtures of a tetrahydroborate salt with a metal salt of group 2, 4 or 12 metals and tetrahydroborates of group 2, 4 or 12 metals, and mixtures thereof.
2. The process of claim 1 , where an ester of piperidine-3-carboxylic acid, in
particular the Ci-C6-alkyl ester, especially ethyl ester of piperidine-3-carboxylic acid is used.
3. The process of any of the preceding claims, where the reducing agent is in-situ generated borane.
4. The process of any of claims 1 or 2, where the reducing agent is selected from the group consisting of mixtures of an alkalimetal tetrahydroborate or a tetra-Ci- C4-alkylammonium tetrahydroborate, in particular lithium, sodium or potassium tetrahydroborate, with a metal salt of group 2, 4 or 12 metals.
5. The process of claim 1 or 2, where the reducing agent is selected from the group consisting of mixtures of an alkalimetal tetrahydroborate or a tetra-Ci-C4- alkylammonium tetrahydroborate, in particular lithium-, sodium or potassium tetrahydroborate, with a zinc salt, in particular a zinc halide, and zinc
tetrahydroborate.
6. The process of any of the preceding claims, where step b) is performed in an organic aprotic solvent.
7. The process of claim 6, where the aprotic solvent comprises an ether, in
particular a cyclic ether, a di-Ci-C3-alkoxy-C2-C4-alkane or a mixture thereof.
The process of any of the preceding claims, where step a) comprises subjecting piperidine-3-carboxylic acid or an ester thereof to enantiomeric enrichment with regard to the S-enantiomer by fractional crystallization of an acid addition salt of piperidine-3-carboxylic acid or an ester thereof with a chiral acid.
The process of claim 8, where step a) comprises subjecting the ethyl ester of piperidine-3-carboxylic acid with tartaric acid or mandelic acid, in particular D- tartaric acid or L-mandelic acid.
The process of any of the preceding claims, where step c) comprises a hydrolysis of the boron containing reducing agent and optionally present boron containing derivatives of 3-hydroxymethylpiperidine at a pH of at most pH 6.
The process of any of the preceding claims, where step c) comprises a first step where the boron containing reducing agent and optionally present boron containing derivatives of 3-hydroxymethylpiperidine are hydrolysed at a pH of at most pH 6 which is followed by a second step where the enantiomerically enriched 3-hydroxymethylpiperidine is extracted from the aqueous phase at a pH of at least pH 10.
The process of claim 1 1 , where the enantiomerically enriched 3-hydroxymethylpiperidine is extracted from the aqueous phase by using an extractant, which is an organic solvent or solvent mixture where the organic solvent or solvent mixture comprises at least one organic solvent having a solubility in water of at most 30 g/100 ml (25°C and 1016 mbar) and/or tetrahydrofurane.
Non-racemic 3-hydroxymethylpiperidine, which has an enantiomeric excess with regard to one of the enantiomers of 3-hydroxymethylpiperidine of at least 98 % ee, in particular at least 99 % ee and a chemical purity of at least 98 %, in particular at least 99 % and especially at least 99.5 %, as determined by gas chromatography.
A method of extracting 3-hydroxymethylpiperidine from an aqueous alkaline solution, which comprises treatment of an alkaline solution of 3- hydroxymethylpiperidine with an extractant, which is an organic solvent or solvent mixture, where the pH of the aqueous alkaline solution is at least pH 10, in particular at least pH 12.
15. The method of claim 14, where the extractant comprises at least one organic solvent having a solubility in water of at most 30 g/100 ml (25°C and 1016 mbar) and/or tetrahydrofurane.
16. The method of claim 15, where at least one solvent of the extractant is a Ci-Cs- alkanol, especially a d-Cs-alkanol, or a C4-C8-cycloalkanol.
17. The method of claim 15, where the extractant further comprises at least one aprotic organic solvent that is selected from alkylaromatic solvents,
methyltetrahydrofurane and Ci-C6-alkylesters of Ci-C6-alkanoic acids.
Priority Applications (2)
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US14/785,278 US20160068486A1 (en) | 2013-04-22 | 2014-04-22 | Process for preparing enantiomerically enriched 3-hydroxymethylpiperidine |
EP14719286.8A EP2989080A1 (en) | 2013-04-22 | 2014-04-22 | Process for preparing enantiomerically enriched 3-hydroxymethylpiperidine |
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EP13164782 | 2013-04-22 | ||
EP13164782.8 | 2013-04-22 |
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PCT/EP2014/058040 WO2014173855A1 (en) | 2013-04-22 | 2014-04-22 | Process for preparing enantiomerically enriched 3-hydroxymethylpiperidine |
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US (1) | US20160068486A1 (en) |
EP (1) | EP2989080A1 (en) |
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US20160068486A1 (en) | 2016-03-10 |
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