EP1926709A1 - Procédé de synthèse d'un composé chiral de type 3-hydroxypyrrolidine et de dérivés dudit composé de pureté optique élevée - Google Patents
Procédé de synthèse d'un composé chiral de type 3-hydroxypyrrolidine et de dérivés dudit composé de pureté optique élevéeInfo
- Publication number
- EP1926709A1 EP1926709A1 EP06783728A EP06783728A EP1926709A1 EP 1926709 A1 EP1926709 A1 EP 1926709A1 EP 06783728 A EP06783728 A EP 06783728A EP 06783728 A EP06783728 A EP 06783728A EP 1926709 A1 EP1926709 A1 EP 1926709A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- hydroxy
- chiral
- group
- compound
- set forth
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- -1 3-hydroxy pyrrolidine compound Chemical class 0.000 title claims abstract description 58
- 238000000034 method Methods 0.000 title claims abstract description 57
- 230000008569 process Effects 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 230000003287 optical effect Effects 0.000 title description 8
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000005984 hydrogenation reaction Methods 0.000 claims description 42
- 150000001875 compounds Chemical class 0.000 claims description 41
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 36
- 239000003054 catalyst Substances 0.000 claims description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
- RDXMEUDCEWSFDP-UHFFFAOYSA-N 3-chloro-2-hydroxypropanenitrile Chemical compound ClCC(O)C#N RDXMEUDCEWSFDP-UHFFFAOYSA-N 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 229910052751 metal Inorganic materials 0.000 claims description 15
- 239000002184 metal Substances 0.000 claims description 15
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 14
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 230000000269 nucleophilic effect Effects 0.000 claims description 9
- 239000000758 substrate Substances 0.000 claims description 9
- 150000001336 alkenes Chemical class 0.000 claims description 8
- 150000001345 alkine derivatives Chemical class 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000012298 atmosphere Substances 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- 229910052697 platinum Inorganic materials 0.000 claims description 5
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- 150000001299 aldehydes Chemical class 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 4
- 150000003346 selenoethers Chemical class 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 150000003568 thioethers Chemical class 0.000 claims description 4
- 150000002466 imines Chemical class 0.000 claims description 3
- 150000001356 alkyl thiols Chemical class 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- SFDJOSRHYKHMOK-UHFFFAOYSA-N nitramide Chemical compound N[N+]([O-])=O SFDJOSRHYKHMOK-UHFFFAOYSA-N 0.000 claims description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 150000003573 thiols Chemical class 0.000 claims description 2
- 239000007858 starting material Substances 0.000 abstract description 15
- 239000006227 byproduct Substances 0.000 abstract description 13
- 230000009467 reduction Effects 0.000 abstract description 13
- 125000002560 nitrile group Chemical group 0.000 abstract description 11
- 238000011065 in-situ storage Methods 0.000 abstract description 8
- 125000006239 protecting group Chemical group 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 2
- LHBPNZDUNCZWFL-UHFFFAOYSA-N 4-chloro-3-hydroxybutanenitrile Chemical compound ClCC(O)CC#N LHBPNZDUNCZWFL-UHFFFAOYSA-N 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 38
- 230000002829 reductive effect Effects 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- 238000010511 deprotection reaction Methods 0.000 description 23
- 238000001212 derivatisation Methods 0.000 description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 20
- 238000004519 manufacturing process Methods 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000000746 purification Methods 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000006722 reduction reaction Methods 0.000 description 14
- 239000000543 intermediate Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000007868 Raney catalyst Substances 0.000 description 12
- 229910000564 Raney nickel Inorganic materials 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 9
- 239000010410 layer Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 125000004430 oxygen atom Chemical group O* 0.000 description 5
- 238000007086 side reaction Methods 0.000 description 5
- 150000003512 tertiary amines Chemical class 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 230000002860 competitive effect Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 150000008282 halocarbons Chemical class 0.000 description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000005270 trialkylamine group Chemical group 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- PMIQCQKMLHVMAJ-QMMMGPOBSA-N (2r)-2-[tert-butyl(dimethyl)silyl]oxy-3-chloropropanenitrile Chemical compound CC(C)(C)[Si](C)(C)O[C@@H](CCl)C#N PMIQCQKMLHVMAJ-QMMMGPOBSA-N 0.000 description 3
- JLWWWRQNGBALHW-LLVKDONJSA-N (3r)-4-chloro-3-phenylmethoxybutanenitrile Chemical compound N#CC[C@H](CCl)OCC1=CC=CC=C1 JLWWWRQNGBALHW-LLVKDONJSA-N 0.000 description 3
- JHHZLHWJQPUNKB-SCSAIBSYSA-N (3r)-pyrrolidin-3-ol Chemical compound O[C@@H]1CCNC1 JHHZLHWJQPUNKB-SCSAIBSYSA-N 0.000 description 3
- YQMXOIAIYXXXEE-UHFFFAOYSA-N 1-benzylpyrrolidin-3-ol Chemical compound C1C(O)CCN1CC1=CC=CC=C1 YQMXOIAIYXXXEE-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 238000004508 fractional distillation Methods 0.000 description 3
- 238000010575 fractional recrystallization Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 150000003335 secondary amines Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- RQAOTXDPBZSBLM-COBSHVIPSA-N (2r)-3-chloro-2-trimethylsilyloxybutanenitrile Chemical compound CC(Cl)[C@@H](C#N)O[Si](C)(C)C RQAOTXDPBZSBLM-COBSHVIPSA-N 0.000 description 2
- YQMXOIAIYXXXEE-LLVKDONJSA-N (3r)-1-benzylpyrrolidin-3-ol Chemical compound C1[C@H](O)CCN1CC1=CC=CC=C1 YQMXOIAIYXXXEE-LLVKDONJSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- FRKGSNOMLIYPSH-UHFFFAOYSA-N 3-hydroxypyrrolidin-2-one Chemical compound OC1CCNC1=O FRKGSNOMLIYPSH-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 239000002635 aromatic organic solvent Substances 0.000 description 2
- 239000011942 biocatalyst Substances 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 2
- 229910017052 cobalt Inorganic materials 0.000 description 2
- 239000010941 cobalt Substances 0.000 description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- MDAHZTTVEIHCTO-YGPZHTELSA-N (2r)-2-[tert-butyl(dimethyl)silyl]oxy-3-chlorobutanenitrile Chemical compound CC(Cl)[C@@H](C#N)O[Si](C)(C)C(C)(C)C MDAHZTTVEIHCTO-YGPZHTELSA-N 0.000 description 1
- RDXMEUDCEWSFDP-VKHMYHEASA-N (2r)-3-chloro-2-hydroxypropanenitrile Chemical compound ClC[C@H](O)C#N RDXMEUDCEWSFDP-VKHMYHEASA-N 0.000 description 1
- QTTWIBGBCFLWDM-ZGTCLIOFSA-N (2r)-3-chloro-2-tri(propan-2-yl)silyloxybutanenitrile Chemical compound CC(C)[Si](C(C)C)(C(C)C)O[C@H](C#N)C(C)Cl QTTWIBGBCFLWDM-ZGTCLIOFSA-N 0.000 description 1
- JVFWWCFBUWAOTG-QVDQXJPCSA-N (2r)-3-chloro-2-triethylsilyloxybutanenitrile Chemical compound CC[Si](CC)(CC)O[C@H](C#N)C(C)Cl JVFWWCFBUWAOTG-QVDQXJPCSA-N 0.000 description 1
- PMIQCQKMLHVMAJ-MRVPVSSYSA-N (2s)-2-[tert-butyl(dimethyl)silyl]oxy-3-chloropropanenitrile Chemical compound CC(C)(C)[Si](C)(C)O[C@H](CCl)C#N PMIQCQKMLHVMAJ-MRVPVSSYSA-N 0.000 description 1
- CWBMYKUPMLRKQK-LLVKDONJSA-N (3r)-3-phenylmethoxypyrrolidine Chemical compound C=1C=CC=CC=1CO[C@@H]1CCNC1 CWBMYKUPMLRKQK-LLVKDONJSA-N 0.000 description 1
- YQMXOIAIYXXXEE-NSHDSACASA-N (3s)-1-benzylpyrrolidin-3-ol Chemical compound C1[C@@H](O)CCN1CC1=CC=CC=C1 YQMXOIAIYXXXEE-NSHDSACASA-N 0.000 description 1
- JHHZLHWJQPUNKB-BYPYZUCNSA-N (3s)-pyrrolidin-3-ol Chemical compound O[C@H]1CCNC1 JHHZLHWJQPUNKB-BYPYZUCNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-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
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-butanol Substances CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- BYJAJQGCMSBKPB-UHFFFAOYSA-N 3-hydroxybutanenitrile Chemical compound CC(O)CC#N BYJAJQGCMSBKPB-UHFFFAOYSA-N 0.000 description 1
- IVUOMFWNDGNLBJ-UHFFFAOYSA-N 4-azaniumyl-2-hydroxybutanoate Chemical compound NCCC(O)C(O)=O IVUOMFWNDGNLBJ-UHFFFAOYSA-N 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 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 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229910008326 Si-Y Inorganic materials 0.000 description 1
- 229910006773 Si—Y Inorganic materials 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000003855 acyl compounds Chemical class 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- HUZCTWYDQIQZPM-UHFFFAOYSA-N benzyl 2,2,2-trichloroethanimidate Chemical compound ClC(Cl)(Cl)C(=N)OCC1=CC=CC=C1 HUZCTWYDQIQZPM-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000005587 carbonate group Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical compound O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000012351 deprotecting agent Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a process for the preparation of a chiral
- the present invention relates to an efficient process for the preparation of optically pure chiral 3-hydroxypyrrolidine compound and derivatives thereof, comprised of introducing a suitable protecting group to the starting material 3-chloro-2-hydroxypropionitrile in order to prevent formation of side products during reduction of the nitrile group of the starting material and in-situ intramolecular cyclization at a hydrogenation reaction.
- Chiral 3-hydroxypyrrolidine and derivatives thereof are essential intermediates of a variety of chiral medicines, including antibiotics, analgesics, thrombolytic drugs, antipsychotics, etc.
- Various drugs derived from 3-hydroxypyrrolidine and derivatives thereof are commercially available.
- Several compounds are also reported to be clinically tested. Therefore, it is expected that the demand on chiral 3-hydroxypyrrolidine and its derivatives increases more and more. For these reasons, researches on the inexpensive and efficient production of chiral 3-hydroxypyrrolidine and derivatives thereof take an important role in the field of medicine industry.
- chiral 3-hydroxypyrrolidine derivative was also prepared from decarbonation of chiral 4-hydroxy-2-pyrrolidinecarboxylic acid through combinational treatment with 2-cyclohexen-l-one and cyclohexanol [WO 91/09013; U.S. Patent No. 5,233,053; Chem. Lett., 1986, 893].
- this process is complicated and exhibits a low yield, making it inappropriate for industrial- scale production.
- the method according to the present invention is a safe process and applicable to mass production of the optically pure chiral 3-hydroxypyrrolidine compound.
- 3-hydroxypyrrolidine compound represented by formula 1 is prepared from the following reactions: protection of the hydroxy group of the chiral 3-chloro-2-hydroxypropionitrile represented by formula 2, hydrogenation of the obtained product, optional N-derivatization, and deprotection.
- the protection of the hydroxyl group of the chiral 3-chloro-2-hydroxypropionitrile can minimize side reactions during the hydrogenation and increases the total yield.
- the targeted compound is prepared in high optical purity. Further, the protection of the hydroxyl group effectively prevents the competitive derivatization by the oxygen atom of the hydroxyl group.
- the intermediate compounds from the chiral 3-chloro-2-hydroxypropionitrile can be subject as a crude product, without any particular purification, to the subsequent reactions such as hydroxy protection, hydrogenation, optional derivatization and deprotection, This simplifies the reaction process and improves the production yield. Accordingly, the process of the present invention makes it possible to produce the 3-hydroxypyrrolidine compound represented by formula 1, which is an essential intermediate for a variety of chiral medicines, in an effective manner and in an industrial scale. Best Mode for Carrying Out the Invention
- the present invention relates to an effective process for the preparation of a chiral
- the process in accordance with the present invention comprises the steps of (a) protecting a hydroxy group of chiral 3-chloro-2-hydroxypropionitrile with a hydroxy-protecting group, (b) subjecting the obtained hydroxy-protected compound to a hydrogenation reaction to obtain a corresponding hydroxy-protected pyrrolidine compound or hydrochloride salt thereof and (c) if necessary, deprotecting the hydroxy-protected pyrrolidine compound, or N - derivatizing the hydroxy-protected pyrrolidine compound by reacting the hydroxy- protected pyrrolidine compound with a substrate susceptible to a nucleophilic attack and then deprotecting the obtained N-derivatized pyrrolidine compound.
- the process in accordance with the present invention is summarized in the following scheme 1 :
- the chiral 3-chloro-2-hydroxypropionitrile represented by formula 2 is used as starting material in the present invention.
- the starting material is easily obtainable from nucleophilic ring opening of chiral epichlorohydrin.
- Korean Patent No. 491809 and references cited therein please refer to Korean Patent No. 491809 and references cited therein.
- the chiral 3-chloro-2-hydroxypropionitrile can be effectively prepared from the reaction of commercially available chiral epichlorohydrin with sodium cyanide in a presence of citric acid.
- the targeted chiral 3-hydroxypyrrolidine compound can be prepared in high yield and with high optical purity, through subsequent reactions: protection of the hydroxy group; reduction of the nitrile group and in situ intramolecular cyclization by hydrogenation; optional JV-derivatization and/or de- protection of the hydroxyl protecting group.
- the reduction of the nitrile group is one of effective organic synthesis techniques to prepare a primary amine and is a commercially available process [The Chemistry of the Cyano Group, John Wiley and Sons, 1970, Chapter 7; U.S. Patent No. 5,237,088; U.S. Patent No. 5,801,286; U.S. Patent No. 5,777,166].
- the reduction of the nitrile group were carried out in a presence of various reducing agents, for example, metal hydrides such as lithium aluminum hydride or sodium borohydride, optionally in combination with an additive [Chem. Soc.
- the primary amine compound can be prepared by reducing the nitrile group through hydrogenation in a presence of a metal catalyst such as palladium, platinum, Raney nickel, Raney cobalt, etc. This process is advantageous in that the product can be easily obtained by filtering out the catalyst and removing the solvent.
- a metal catalyst such as palladium, platinum, Raney nickel, Raney cobalt, etc.
- 3-hydroxypyrrolidine could not be obtainable in high yield and with high purity from direct hydrogenation of the chiral 3-chloro-2-hydroxypropionitrile of formula 2 due to the formation of various side products. Moreover, since the side reactions were reinforced in a large-scale preparation, new solution to avoid the problems should be investigated.
- the starting material chiral S-chloro ⁇ -hydroxypropionitrile
- a hydroxy-protecting group it is crucial that the hydroxy-protecting group should not be decomposed during the subsequent hydrogenation.
- the present inventors tried to protect the hydroxy group of the compound of formula 2 with acyl compounds such as acetyl or benzoyl compound, prior to the hydrogenation.
- these hydroxy-protecting groups were found to be insufficient because they were deprotected under high pressure condition of the hydrogenation.
- the production yield of hydrogenation and subsequent deprotection in a situation that an alkyl group such as methyl or tetrahydropyran was introduced, as a protecting group, to protect the hydroxy group of the compound the formula 2, was found to be as low as 30 %.
- hydroxy-protecting group is a silyl group.
- the chiral 3-chloro-2-hydroxypropionitrile having formula 2 is firstly reacted with a silylizing agent to accomplish the protection of the hydroxy group of the chiral 3-chloro-2-hydroxypropionitrile with a silyl group.
- a silylizing agent is firstly reacted with a silylizing agent to accomplish the protection of the hydroxy group of the chiral 3-chloro-2-hydroxypropionitrile with a silyl group.
- R', R" and R'" represent substituents.
- R', R" and R'" are, each independently, C -C alkyl, C -C cycloalkyl, C -C alkene, C -C alkyne, C -C alkoxy, C -C aryl or (CH ) -R (wherein R is C -C cycloalkyl, C -C alkene, C -C alkyne, C
- the silyl group, introduced as a hydroxyl protecting group, is very stable under various chemical reaction conditions, excluding an acidic condition.
- the introduction and deprotection of the silyl group can be easily carried out [Protecting Groups, Thieme Medical Publishers Inc,. New York, 1994; Protective Groups in Organic Synthesis, John Wiley and Sons, Inc, 1991].
- the protection of the hydroxy group with the silyl group can be easily achieved by reacting a chiral 3-chloro-2-hydroxypropionitrile compound of formula 2 with a silylizing agent in a presence of a base.
- the silylizing agent that can be represented by R'R"R'"Si-Y (wherein, R', R" and R'" are the same as defined in the above and Y represents a leaving group such as halide or sulfonate) is added in an amount of 0.8 - 5 equivalents, preferably in an amount of 1.0 - 2 equivalents, based on the chiral 3-chloro-2-hydroxypropionitrile of formula 2.
- a base imidazole, 2,6-lutidine, N,N - dimethylaminopyridine and salts thereof, tertiary amine and hydrates thereof can be mentioned.
- Preferable is trialkylamine.
- trialkylamine examples include trimethylamine, triethylamine and diisopropylethylamine.
- the base is added in an amount of 0.8 - 10 equivalents, preferably in an amount of 1.0 - 3.0 equivalents, based on the chiral 3-chloro-2-hydroxypropionitrile of formula 2.
- An organic solvent that can be used in the protection reaction is not particularly limited, and any one that is common in the art can be used. Examples of the organic solvent include N, N - dimethylformamide, aliphatic or aromatic hydrocarbon, halogenated hydrocarbon and ethers.
- aromatic organic solvents such as toluene and benzene, halogenated alkane such as dichloromethane and chloroform and ethers such as ethyl ether, tetrahydrofuran and dioxane may be used.
- Reaction temperature is preferably in the range of 0 to 100 0 C, more preferably of 10 to 4O 0 C.
- Another preferable hydroxy-protecting group is a benzyl group.
- the benzyl group is known to be deproteced during the hydrogenation reaction. Nonetheless, the benzyl group, introduced as a hydroxy-protecting group of the chiral 3-chloro-2-hydroxypropionitrile, is stable under the hydrogenation using Raney nickel and provides satisfactory results.
- a metal catalyst such as palladium and platinum, the benzyl group was deprotected during the hydrogenation and showed very low yield.
- * represents a chiral center and Z means a hydroxy-protecting group, preferably a silyl group.
- the nitrile group of the hydroxy-protected compound of formula 3 is firstly reduced through the hydrogenation, providing a primary amine compound.
- the resultant intermediate represented by the formula 5 undergoes in situ intramolecular cyclization.
- a hydroxy-protected pyrrolidine compound or hydrochloride salt thereof, which is represented by formula 4 is obtained.
- the ratio of the free hydroxy-protected pyrrolidine (free base) to the hydrochloride salt thereof depends upon the metal catalyst used in the hydrogenation and pH of the reaction. In any case, the hydroxy-protected pyrrolidine compound can be obtained as a free base by treating with 0.5 - 1 equivalent of a base.
- the hydrogenation is performed in a presence of a metal catalyst and under hydrogen atmosphere.
- the metal catalyst that can be used in the hydrogenation is not particularly limited and may be any one generally known in the art. Preferable is palladium (Pd), platinum (Pt), Raney nickel (Raney-Ni) and Raney cobalt (Raney-Co). In a case that the benzyl group is used as the hydroxy-protecting group, Raney nickel (Raney-Ni) is preferable.
- the metal catalyst is added in an amount of 5 - 80 wt%, preferably in an amount of 5 - 25 wt%.
- the hydrogen gas is supplied in a pressure of 1 - 50 bar, preferably 2-10 bar.
- the reaction is performed at a temperature of 25 - 200 0 C, preferably 50 - 15O 0 C under stirring for 1 - 30 hours, preferably 2 - 5 hours. After all the reactants were consumed, typical filtration and distillation under reduced pressure gave a hydroxy-protected pyrrolidine compound or hydrochloride salt thereof, which is represented by formula 4.
- the solvent to be used is not particularly limited and may be any one commonly used in the art. Specifically, JV,./V-dimethylformamide, dimethyl sulfoxide, aliphatic or aromatic hydrocarbon, halogenated hydrocarbon, ether or alcohol may be used.
- the alcohol include C 1 -C 4 alcohol, such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and ?-butanol.
- C 1 -C 4 alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and ?-butanol.
- the meal catalyst is filtered out and the volatile solvent is removed by distillation under reduced pressure to give the hydroxy-protected pyrrolidine represented by the formula 4 or its hydrochloride salt.
- the obtained crude product can be then directly subject to the next derivatization or deprotection without any further special purification. Since the hydroxy-protected pyrrolidine compound of formula 4 or its hydrochloride salt is prepared in a high purity, the purification process is simplified and the production yield is improved.
- the hydrochloride salt of the hydroxy-protected pyrrolidine was treated with an inorganic base (e.g., NaOH) to obtain a free base.
- an inorganic base e.g., NaOH
- the compound represented by the formula 4 can be directly applicable to the deprotection or the N-derivatization in the form of hydrochloride salt, because deprotection is not affected by the presence of HCl.
- N-derivatization is affected by the presence of HCl, because the ⁇ -derivatization is normally performed in a presence of excess base.
- the pyrrolidine compound of formula 4 can be used in the deprotection and the N-derivatization in a form of the hydrochloride salt.
- the resultant hydroxy-protected pyrrolidine compound or its hydrochloride salt represented by formula 4 is converted to the chiral 3-hydroxypyrrolidine or derivatives thereof through optional N-derivatization and deprotection.
- the targeted chiral 3-hydroxypyrrolidine or N-substituted chiral 3-hydroxypyrrolidine having formula 1 is prepared from the hydroxy-protected pyrrolidine compound of formula 4 or its hydrochloride salt.
- Deprotection under the acidic condition gives chiral 3-hydroxypyrrolidine as an acid additive salt, from which the chiral 3-hydroxypyrrolidine can be easily recovered during a workup process by the treatment with a base (e.g., an inorganic base containing hydroxy, phosphate or carbonate group).
- a base e.g., an inorganic base containing hydroxy, phosphate or carbonate group.
- Deprotection of the benzyl group is accomplishable through hydrogenation in a presence of a metal catalyst such as palladium and platinum.
- a metal catalyst such as palladium and platinum.
- the targeted pyrrolidine compound is a benzyl-protected compound, deprotection would be unnecessary.
- Specific conditions for the de- protection of the silyl group are as follows.
- the hydroxy-protected pyrrolidine compound of formula 4 or its hydrochloride salt is firstly dissolved into an organic solvent and a deprotecting agent is added, under stirring, to the solution in an amount of 0.1 - 10 equivalents (preferably in 0.5 - 2.0 equivalents) at a reaction temperature of 0 - 100 0 C (preferably 10 - 3O 0 C).
- the solvent is not particularly limited and may be anyone commonly used in the art. Specifically, ⁇ f, ⁇ f-dimethylformamide, dimethyl sulfoxide, aliphatic or aromatic hydrocarbon, halogenated hydrocarbon, ether or alcohol may be used.
- the alcohol include C -C alcohol, such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and ?-butanol.
- C -C alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and ?-butanol.
- the hydroxy-protected pyrrolidine compound of formula 4 is sequentially subject to JV-derivatization and deprotection to provide chiral JV-substituted 3-hydroxypyrrolidine compound.
- the JV-derivatization is performed by reacting the hydroxy-protected pyrrolidine compound of formula 4 with a substrate susceptible to a nucleophilic attack. That is, the ./V-derivatization is carried out by nucleophilic attack of the nitrogen atom of the hydroxy-protected pyrrolidine compound of formula 4 to the substrate susceptible to the nucleophilic attack.
- the substrate susceptible to the nucleophilic attack is typically represented by the formula R-Y (wherein R is car- bohydride and Y is a leaving group).
- R is car- bohydride and Y is a leaving group.
- the leaving group include a halogen atom, sulfonate and anhydride.
- the substrate is normally added in an amount of 0.8 - 2 equivalents, preferably in an amount of 1.0 - 2.0 equivalents.
- the N - derivatization is performed in a presence of a base.
- the base include imidazole, 2,6-lutidine, JV,./V-dimethylaminopyridine and salts thereof, tertiary amine and hydrates thereof.
- Preferable is trialkylamine.
- trialkylamine examples include trimethylamine, triethylamine and diisopropylethylamine.
- the base is added in an amount of 0.8 - 10 equivalents, preferably in an amount of 1.0 - 3.0 equivalents, based on the hydroxy-protected pyrrolidine compound of formula 4.
- the organic solvent used in the reaction is not particularly limited and may be anyone commonly used in the art. Examples of the organic solvent include JV,./V-dimethylformamide, aliphatic or aromatic hydrocarbon, halogenated hydrocarbon and ether.
- aromatic organic solvents such as toluene and benzene, halogenated alkanes such as dichloromethane and chloroform or ethers such as ethyl ether, tetrahydrofuran and dioxane may be used.
- Reaction temperature can be suitably adjustable depending on the substrate to be used, which is well known to the person of ordinary skill in the art. Typically, the reaction is carried out at a temperature of 0 - 100 0 C.
- the targeted compound is obtainable in high purity after typical workup process.
- the resulting compound can be applicable to the next deprotection without any further special purification (e.g., fractional distillation and recrystallization). This contributes to the simplification of the process and the improvement of production yield.
- the deprotection process can be carried out in the same manner as described in the above. After de- protection of the hydroxy-protecting group, the targeted chiral JV-substituted 3-hydroxypyrrolidine compound is finally prepared.
- the chiral 3-hydroxypyrrolidine may directly undergo N - derivatization by the reaction with a substrate susceptible to nucleophilic attack and the obtained compound is used as an intermediate in the synthesis of chiral medicines.
- direct derivatization of the chiral 3-hydroxypyrrolidine compound involves competitive derivatization by the nitrogen atom and the oxygen atom of the chiral 3-hydroxypyrrolidine.
- both the nitrogen atom and the oxygen atom competitively participate in the derivatization reaction.
- the competitive nucleophilic attack by the oxygen atom produces adverse side product, which reduces the production yield of the target compound and makes the purification process complicated.
- 3-hydroxypyrrolidine compound represented by the following formula 1 can be prepared:
- Z represents hydrogen or benzyl and R is hydrogen, C -C alkyl
- C cycloalkyl, C -C cycloalkenyl, heterocycle or polycycle C -C carbonyl, C -C carboxyl, silyl, ether, thioether, selenoether, ketone, aldehyde, ester, phosphoryl, r phos ⁇ phonate, ' X p-hos I p-hine,' sulfony J l or ( y CH 2 ) k -R 3 (wherein R 3 is C 2 -C 10 alkene, C 2 -C 10 alkyne, C -C alkoxy, C -C aryl, C -C cycloalkyl, C -C cycloalkenyl, heterocycle
- Example 4 (66.9 mmol) obtained from Example 4 was dissolved into methanol (40 mL), 25 wt% of Raney-Ni catalyst suspended in methanol (40 mL) was added. The mixture was stirred under 20 bar of hydrogen pressure while varying the reaction temperatures of 3O 0 C to 12O 0 C.
- the target compound (/?)-3-(?-butyldimethylsilyloxy)pyrrolidine was obtained in the same manner as described in the Example 5.
- Example 4 (66.9 mmol) obtained in Example 4 was dissolved into methanol (40 mL), 25 wt% of Raney-Ni catalyst suspended in methanol (40 mL) was added. The mixture was stirred at 5O 0 C, 7O 0 C and 100 0 C, respectively, while varying the hydrogen pressure.
- the target compound (/?)-3-(?-butyldimethylsilyloxy)pyrrolidine was obtained in the same manner as described in the Example 5.
- Example 10 Preparation of (R )- N -benzyl-3-hydroxypyrrolidine [91] To 2 L high-pressure reactor, 100 g of (R)-2-(t - butyldimethylsilyloxy)-3-chloropropionitrile dissolved into methanol (500 mL) and 25 g of Raney-Ni suspended in methanol (500 mL) were added. The mixture was heated to 100 0 C and stirred for 2 hours under 5 bar of hydrogen pressure. The reaction solution was cooled to room temperature and filtered through celite to remove the catalyst. 34.2 g of NaOH and 65.0 g of benzyl chloride were successively added dropwise to the remaining filtrate.
- the obtained filtrate was concentrated under reduced pressure to obtain 98.0 g of the targeted compound (R)-3-(benzyloxy)-4-chlorobutanenitrile (yield: 93 %).
- the obtained product was subject to the subsequent hydrogenation without any further purification.
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Abstract
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KR1020060080184A KR100743617B1 (ko) | 2005-08-25 | 2006-08-24 | 고광학순도를 갖는 키랄 3-히드록시 피롤리딘 및 그유도체를 제조하는 방법 |
PCT/KR2006/003341 WO2007024113A1 (fr) | 2005-08-25 | 2006-08-24 | Procédé de synthèse d'un composé chiral de type 3-hydroxypyrrolidine et de dérivés dudit composé de pureté optique élevée |
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EP0269258A2 (fr) * | 1986-10-27 | 1988-06-01 | A.H. Robins Company, Incorporated | Procédé de préparation d'un composé pyrrolidinol |
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- 2006-08-24 WO PCT/KR2006/003341 patent/WO2007024113A1/fr active Application Filing
- 2006-08-24 EP EP06783728A patent/EP1926709A4/fr not_active Withdrawn
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EP1926709A4 (fr) | 2009-06-24 |
WO2007024113A1 (fr) | 2007-03-01 |
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