CN107604020A - The method that living things catalysis prepares the amino piperidine of (S) 1 N benzene methoxycarbonyl group 3 - Google Patents
The method that living things catalysis prepares the amino piperidine of (S) 1 N benzene methoxycarbonyl group 3 Download PDFInfo
- Publication number
- CN107604020A CN107604020A CN201710885707.9A CN201710885707A CN107604020A CN 107604020 A CN107604020 A CN 107604020A CN 201710885707 A CN201710885707 A CN 201710885707A CN 107604020 A CN107604020 A CN 107604020A
- Authority
- CN
- China
- Prior art keywords
- ala
- gly
- leu
- pro
- thr
- 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.)
- Pending
Links
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims description 29
- 238000006555 catalytic reaction Methods 0.000 title claims description 5
- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical compound NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 18
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 241000607291 Vibrio fluvialis Species 0.000 claims description 16
- 102000004190 Enzymes Human genes 0.000 claims description 10
- 108090000790 Enzymes Proteins 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 8
- 241000588724 Escherichia coli Species 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 230000006798 recombination Effects 0.000 claims description 5
- 241000607598 Vibrio Species 0.000 claims description 4
- 206010047400 Vibrio infections Diseases 0.000 claims description 4
- -1 (S)-N- Cbz-3- amino piperazines Chemical class 0.000 claims description 3
- 241000193830 Bacillus <bacterium> Species 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- 108010065394 aminopherase Proteins 0.000 claims description 3
- 238000004176 ammonification Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 15
- 230000000903 blocking effect Effects 0.000 abstract description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 3
- 230000002378 acidificating effect Effects 0.000 abstract description 2
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 abstract 1
- 239000007788 liquid Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 108090000340 Transaminases Proteins 0.000 description 11
- 102000003929 Transaminases Human genes 0.000 description 11
- 239000000243 solution Substances 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 8
- PBFBPDLWODIXHK-LBPRGKRZSA-N benzyl (3s)-3-aminopiperidine-1-carboxylate Chemical class C1[C@@H](N)CCCN1C(=O)OCC1=CC=CC=C1 PBFBPDLWODIXHK-LBPRGKRZSA-N 0.000 description 8
- 108010061238 threonyl-glycine Proteins 0.000 description 8
- 238000000605 extraction Methods 0.000 description 7
- UGVQELHRNUDMAA-BYPYZUCNSA-N Gly-Ala-Gly Chemical compound [NH3+]CC(=O)N[C@@H](C)C(=O)NCC([O-])=O UGVQELHRNUDMAA-BYPYZUCNSA-N 0.000 description 6
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 6
- CLNJSLSHKJECME-BQBZGAKWSA-N Pro-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H]1CCCN1 CLNJSLSHKJECME-BQBZGAKWSA-N 0.000 description 6
- 108010047495 alanylglycine Proteins 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 6
- 108010051307 glycyl-glycyl-proline Proteins 0.000 description 6
- 108010050848 glycylleucine Proteins 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 239000007853 buffer solution Substances 0.000 description 5
- PEUGKEHLRUVPAN-RXMQYKEDSA-N (3r)-piperidin-3-amine Chemical class N[C@@H]1CCCNC1 PEUGKEHLRUVPAN-RXMQYKEDSA-N 0.000 description 4
- RLMISHABBKUNFO-WHFBIAKZSA-N Ala-Ala-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O RLMISHABBKUNFO-WHFBIAKZSA-N 0.000 description 4
- JBVSSSZFNTXJDX-YTLHQDLWSA-N Ala-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](C)N JBVSSSZFNTXJDX-YTLHQDLWSA-N 0.000 description 4
- VGPWRRFOPXVGOH-BYPYZUCNSA-N Ala-Gly-Gly Chemical compound C[C@H](N)C(=O)NCC(=O)NCC(O)=O VGPWRRFOPXVGOH-BYPYZUCNSA-N 0.000 description 4
- DVJSJDDYCYSMFR-ZKWXMUAHSA-N Ala-Ile-Gly Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O DVJSJDDYCYSMFR-ZKWXMUAHSA-N 0.000 description 4
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 4
- BMWFDYIYBAFROD-WPRPVWTQSA-N Gly-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)CN BMWFDYIYBAFROD-WPRPVWTQSA-N 0.000 description 4
- HYMLKESRWLZDBR-WEDXCCLWSA-N Leu-Gly-Thr Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HYMLKESRWLZDBR-WEDXCCLWSA-N 0.000 description 4
- UCBPDSYUVAAHCD-UWVGGRQHSA-N Leu-Pro-Gly Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O UCBPDSYUVAAHCD-UWVGGRQHSA-N 0.000 description 4
- ZJZNLRVCZWUONM-JXUBOQSCSA-N Leu-Thr-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O ZJZNLRVCZWUONM-JXUBOQSCSA-N 0.000 description 4
- 101710164401 Omega-aminotransferase Proteins 0.000 description 4
- HZUKSQHMCTUZJL-UHFFFAOYSA-N P(=O)(O)(O)OCC=1C(=C(C(=NC1)C)O)C=O.P(=O)(O)(O)OC=1C(=NC=C(C1C=O)CO)C Chemical class P(=O)(O)(O)OCC=1C(=C(C(=NC1)C)O)C=O.P(=O)(O)(O)OC=1C(=NC=C(C1C=O)CO)C HZUKSQHMCTUZJL-UHFFFAOYSA-N 0.000 description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 4
- KDBHVPXBQADZKY-GUBZILKMSA-N Pro-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 KDBHVPXBQADZKY-GUBZILKMSA-N 0.000 description 4
- SBVPYBFMIGDIDX-SRVKXCTJSA-N Pro-Pro-Pro Chemical compound OC(=O)[C@@H]1CCCN1C(=O)[C@H]1N(C(=O)[C@H]2NCCC2)CCC1 SBVPYBFMIGDIDX-SRVKXCTJSA-N 0.000 description 4
- SLUWOCTZVGMURC-BFHQHQDPSA-N Thr-Gly-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O SLUWOCTZVGMURC-BFHQHQDPSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 4
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 4
- 108010087924 alanylproline Proteins 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 238000005352 clarification Methods 0.000 description 4
- 108010060199 cysteinylproline Proteins 0.000 description 4
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 4
- 238000000855 fermentation Methods 0.000 description 4
- 230000004151 fermentation Effects 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 4
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 4
- 108010077515 glycylproline Proteins 0.000 description 4
- 229910052698 phosphorus Inorganic materials 0.000 description 4
- 239000011574 phosphorus Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 108010093296 prolyl-prolyl-alanine Proteins 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- ALXLNFWWLXCXSK-UHFFFAOYSA-N benzyl 3-oxopiperidine-1-carboxylate Chemical class C1CCC(=O)CN1C(=O)OCC1=CC=CC=C1 ALXLNFWWLXCXSK-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 210000002429 large intestine Anatomy 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 2
- ZVFVBBGVOILKPO-WHFBIAKZSA-N Ala-Gly-Ala Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O ZVFVBBGVOILKPO-WHFBIAKZSA-N 0.000 description 2
- MQIGTEQXYCRLGK-BQBZGAKWSA-N Ala-Gly-Pro Chemical compound C[C@H](N)C(=O)NCC(=O)N1CCC[C@H]1C(O)=O MQIGTEQXYCRLGK-BQBZGAKWSA-N 0.000 description 2
- OBVSBEYOMDWLRJ-BFHQHQDPSA-N Ala-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N OBVSBEYOMDWLRJ-BFHQHQDPSA-N 0.000 description 2
- SMCGQGDVTPFXKB-XPUUQOCRSA-N Ala-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N SMCGQGDVTPFXKB-XPUUQOCRSA-N 0.000 description 2
- KMGOBAQSCKTBGD-DLOVCJGASA-N Ala-His-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CC1=CN=CN1 KMGOBAQSCKTBGD-DLOVCJGASA-N 0.000 description 2
- OKIKVSXTXVVFDV-MMWGEVLESA-N Ala-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C)N OKIKVSXTXVVFDV-MMWGEVLESA-N 0.000 description 2
- WUHJHHGYVVJMQE-BJDJZHNGSA-N Ala-Leu-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WUHJHHGYVVJMQE-BJDJZHNGSA-N 0.000 description 2
- SOBIAADAMRHGKH-CIUDSAMLSA-N Ala-Leu-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O SOBIAADAMRHGKH-CIUDSAMLSA-N 0.000 description 2
- MEFILNJXAVSUTO-JXUBOQSCSA-N Ala-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MEFILNJXAVSUTO-JXUBOQSCSA-N 0.000 description 2
- DRARURMRLANNLS-GUBZILKMSA-N Ala-Met-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(O)=O DRARURMRLANNLS-GUBZILKMSA-N 0.000 description 2
- ADSGHMXEAZJJNF-DCAQKATOSA-N Ala-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N ADSGHMXEAZJJNF-DCAQKATOSA-N 0.000 description 2
- FFZJHQODAYHGPO-KZVJFYERSA-N Ala-Pro-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N FFZJHQODAYHGPO-KZVJFYERSA-N 0.000 description 2
- ARHJJAAWNWOACN-FXQIFTODSA-N Ala-Ser-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O ARHJJAAWNWOACN-FXQIFTODSA-N 0.000 description 2
- 241000186063 Arthrobacter Species 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- FNXOZWPPOJRBRE-XGEHTFHBSA-N Cys-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CS)N)O FNXOZWPPOJRBRE-XGEHTFHBSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VSVZIEVNUYDAFR-YUMQZZPRSA-N Gly-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN VSVZIEVNUYDAFR-YUMQZZPRSA-N 0.000 description 2
- JRDYDYXZKFNNRQ-XPUUQOCRSA-N Gly-Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN JRDYDYXZKFNNRQ-XPUUQOCRSA-N 0.000 description 2
- QPCVIQJVRGXUSA-LURJTMIESA-N Gly-Gly-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)CNC(=O)CN QPCVIQJVRGXUSA-LURJTMIESA-N 0.000 description 2
- BUEFQXUHTUZXHR-LURJTMIESA-N Gly-Gly-Pro zwitterion Chemical compound NCC(=O)NCC(=O)N1CCC[C@H]1C(O)=O BUEFQXUHTUZXHR-LURJTMIESA-N 0.000 description 2
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 2
- HMHRTKOWRUPPNU-RCOVLWMOSA-N Gly-Ile-Gly Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O HMHRTKOWRUPPNU-RCOVLWMOSA-N 0.000 description 2
- LRQXRHGQEVWGPV-NHCYSSNCSA-N Gly-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)CN LRQXRHGQEVWGPV-NHCYSSNCSA-N 0.000 description 2
- LHYJCVCQPWRMKZ-WEDXCCLWSA-N Gly-Leu-Thr Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LHYJCVCQPWRMKZ-WEDXCCLWSA-N 0.000 description 2
- NSVOVKWEKGEOQB-LURJTMIESA-N Gly-Pro-Gly Chemical compound NCC(=O)N1CCC[C@H]1C(=O)NCC(O)=O NSVOVKWEKGEOQB-LURJTMIESA-N 0.000 description 2
- OOCFXNOVSLSHAB-IUCAKERBSA-N Gly-Pro-Pro Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 OOCFXNOVSLSHAB-IUCAKERBSA-N 0.000 description 2
- GLACUWHUYFBSPJ-FJXKBIBVSA-N Gly-Pro-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)CN GLACUWHUYFBSPJ-FJXKBIBVSA-N 0.000 description 2
- ZLCLYFGMKFCDCN-XPUUQOCRSA-N Gly-Ser-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CO)NC(=O)CN)C(O)=O ZLCLYFGMKFCDCN-XPUUQOCRSA-N 0.000 description 2
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 2
- CUVBTVWFVIIDOC-YEPSODPASA-N Gly-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)CN CUVBTVWFVIIDOC-YEPSODPASA-N 0.000 description 2
- ZVXMEWXHFBYJPI-LSJOCFKGSA-N Gly-Val-Ile Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZVXMEWXHFBYJPI-LSJOCFKGSA-N 0.000 description 2
- HTZKFIYQMHJWSQ-INTQDDNPSA-N His-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CN=CN2)N HTZKFIYQMHJWSQ-INTQDDNPSA-N 0.000 description 2
- FDQYIRHBVVUTJF-ZETCQYMHSA-N His-Gly-Gly Chemical compound [O-]C(=O)CNC(=O)CNC(=O)[C@@H]([NH3+])CC1=CN=CN1 FDQYIRHBVVUTJF-ZETCQYMHSA-N 0.000 description 2
- ZUPVLBAXUUGKKN-VHSXEESVSA-N His-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CC2=CN=CN2)N)C(=O)O ZUPVLBAXUUGKKN-VHSXEESVSA-N 0.000 description 2
- NKVZTQVGUNLLQW-JBDRJPRFSA-N Ile-Ala-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)O)N NKVZTQVGUNLLQW-JBDRJPRFSA-N 0.000 description 2
- AQCUAZTZSPQJFF-ZKWXMUAHSA-N Ile-Ala-Gly Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O AQCUAZTZSPQJFF-ZKWXMUAHSA-N 0.000 description 2
- PFTFEWHJSAXGED-ZKWXMUAHSA-N Ile-Cys-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)NCC(=O)O)N PFTFEWHJSAXGED-ZKWXMUAHSA-N 0.000 description 2
- PFPUFNLHBXKPHY-HTFCKZLJSA-N Ile-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)O)N PFPUFNLHBXKPHY-HTFCKZLJSA-N 0.000 description 2
- PHRWFSFCNJPWRO-PPCPHDFISA-N Ile-Leu-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N PHRWFSFCNJPWRO-PPCPHDFISA-N 0.000 description 2
- YJRSIJZUIUANHO-NAKRPEOUSA-N Ile-Val-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)O)N YJRSIJZUIUANHO-NAKRPEOUSA-N 0.000 description 2
- UGTHTQWIQKEDEH-BQBZGAKWSA-N L-alanyl-L-prolylglycine zwitterion Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O UGTHTQWIQKEDEH-BQBZGAKWSA-N 0.000 description 2
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 description 2
- 241000880493 Leptailurus serval Species 0.000 description 2
- WNGVUZWBXZKQES-YUMQZZPRSA-N Leu-Ala-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O WNGVUZWBXZKQES-YUMQZZPRSA-N 0.000 description 2
- BQSLGJHIAGOZCD-CIUDSAMLSA-N Leu-Ala-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O BQSLGJHIAGOZCD-CIUDSAMLSA-N 0.000 description 2
- PBGDOSARRIJMEV-DLOVCJGASA-N Leu-His-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(O)=O PBGDOSARRIJMEV-DLOVCJGASA-N 0.000 description 2
- CFZZDVMBRYFFNU-QWRGUYRKSA-N Leu-His-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)NCC(O)=O CFZZDVMBRYFFNU-QWRGUYRKSA-N 0.000 description 2
- XQXGNBFMAXWIGI-MXAVVETBSA-N Leu-His-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)CC1=CN=CN1 XQXGNBFMAXWIGI-MXAVVETBSA-N 0.000 description 2
- ORWTWZXGDBYVCP-BJDJZHNGSA-N Leu-Ile-Cys Chemical compound SC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC(C)C ORWTWZXGDBYVCP-BJDJZHNGSA-N 0.000 description 2
- YUTNOGOMBNYPFH-XUXIUFHCSA-N Leu-Pro-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(O)=O YUTNOGOMBNYPFH-XUXIUFHCSA-N 0.000 description 2
- PWPBLZXWFXJFHE-RHYQMDGZSA-N Leu-Pro-Thr Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O PWPBLZXWFXJFHE-RHYQMDGZSA-N 0.000 description 2
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 2
- LINKCQUOMUDLKN-KATARQTJSA-N Leu-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(C)C)N)O LINKCQUOMUDLKN-KATARQTJSA-N 0.000 description 2
- VDIARPPNADFEAV-WEDXCCLWSA-N Leu-Thr-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O VDIARPPNADFEAV-WEDXCCLWSA-N 0.000 description 2
- KLSUAWUZBMAZCL-RHYQMDGZSA-N Leu-Thr-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(O)=O KLSUAWUZBMAZCL-RHYQMDGZSA-N 0.000 description 2
- AAKRWBIIGKPOKQ-ONGXEEELSA-N Leu-Val-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O AAKRWBIIGKPOKQ-ONGXEEELSA-N 0.000 description 2
- WXHHTBVYQOSYSL-FXQIFTODSA-N Met-Ala-Ser Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O WXHHTBVYQOSYSL-FXQIFTODSA-N 0.000 description 2
- IUYCGMNKIZDRQI-BQBZGAKWSA-N Met-Gly-Ala Chemical compound CSCC[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O IUYCGMNKIZDRQI-BQBZGAKWSA-N 0.000 description 2
- DBXMFHGGHMXYHY-DCAQKATOSA-N Met-Leu-Ser Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O DBXMFHGGHMXYHY-DCAQKATOSA-N 0.000 description 2
- NHXXGBXJTLRGJI-GUBZILKMSA-N Met-Pro-Ser Chemical compound [H]N[C@@H](CCSC)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O NHXXGBXJTLRGJI-GUBZILKMSA-N 0.000 description 2
- CIDICGYKRUTYLE-FXQIFTODSA-N Met-Ser-Ala Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O CIDICGYKRUTYLE-FXQIFTODSA-N 0.000 description 2
- CIIJWIAORKTXAH-FJXKBIBVSA-N Met-Thr-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O CIIJWIAORKTXAH-FJXKBIBVSA-N 0.000 description 2
- 108010079364 N-glycylalanine Proteins 0.000 description 2
- DZZCICYRSZASNF-FXQIFTODSA-N Pro-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 DZZCICYRSZASNF-FXQIFTODSA-N 0.000 description 2
- KIZQGKLMXKGDIV-BQBZGAKWSA-N Pro-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 KIZQGKLMXKGDIV-BQBZGAKWSA-N 0.000 description 2
- FZHBZMDRDASUHN-NAKRPEOUSA-N Pro-Ala-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1)C(O)=O FZHBZMDRDASUHN-NAKRPEOUSA-N 0.000 description 2
- XQLBWXHVZVBNJM-FXQIFTODSA-N Pro-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 XQLBWXHVZVBNJM-FXQIFTODSA-N 0.000 description 2
- FKLSMYYLJHYPHH-UWVGGRQHSA-N Pro-Gly-Leu Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O FKLSMYYLJHYPHH-UWVGGRQHSA-N 0.000 description 2
- BODDREDDDRZUCF-QTKMDUPCSA-N Pro-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@@H]2CCCN2)O BODDREDDDRZUCF-QTKMDUPCSA-N 0.000 description 2
- MCWHYUWXVNRXFV-RWMBFGLXSA-N Pro-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 MCWHYUWXVNRXFV-RWMBFGLXSA-N 0.000 description 2
- QGLFRQCECIWXFA-RCWTZXSCSA-N Pro-Met-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@@H]1CCCN1)O QGLFRQCECIWXFA-RCWTZXSCSA-N 0.000 description 2
- LEIKGVHQTKHOLM-IUCAKERBSA-N Pro-Pro-Gly Chemical compound OC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 LEIKGVHQTKHOLM-IUCAKERBSA-N 0.000 description 2
- KIDXAAQVMNLJFQ-KZVJFYERSA-N Pro-Thr-Ala Chemical compound C[C@@H](O)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](C)C(O)=O KIDXAAQVMNLJFQ-KZVJFYERSA-N 0.000 description 2
- GZNYIXWOIUFLGO-ZJDVBMNYSA-N Pro-Thr-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GZNYIXWOIUFLGO-ZJDVBMNYSA-N 0.000 description 2
- FUMGHWDRRFCKEP-CIUDSAMLSA-N Ser-Leu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O FUMGHWDRRFCKEP-CIUDSAMLSA-N 0.000 description 2
- UGGWCAFQPKANMW-FXQIFTODSA-N Ser-Met-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(O)=O UGGWCAFQPKANMW-FXQIFTODSA-N 0.000 description 2
- RXSWQCATLWVDLI-XGEHTFHBSA-N Ser-Met-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O RXSWQCATLWVDLI-XGEHTFHBSA-N 0.000 description 2
- PURRNJBBXDDWLX-ZDLURKLDSA-N Ser-Thr-Gly Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CO)N)O PURRNJBBXDDWLX-ZDLURKLDSA-N 0.000 description 2
- IGROJMCBGRFRGI-YTLHQDLWSA-N Thr-Ala-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O IGROJMCBGRFRGI-YTLHQDLWSA-N 0.000 description 2
- CAJFZCICSVBOJK-SHGPDSBTSA-N Thr-Ala-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAJFZCICSVBOJK-SHGPDSBTSA-N 0.000 description 2
- UZJDBCHMIQXLOQ-HEIBUPTGSA-N Thr-Cys-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O UZJDBCHMIQXLOQ-HEIBUPTGSA-N 0.000 description 2
- FDALPRWYVKJCLL-PMVVWTBXSA-N Thr-His-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)NCC(O)=O FDALPRWYVKJCLL-PMVVWTBXSA-N 0.000 description 2
- UQCNIMDPYICBTR-KYNKHSRBSA-N Thr-Thr-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O UQCNIMDPYICBTR-KYNKHSRBSA-N 0.000 description 2
- ZMYCLHFLHRVOEA-HEIBUPTGSA-N Thr-Thr-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ZMYCLHFLHRVOEA-HEIBUPTGSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- ASQFIHTXXMFENG-XPUUQOCRSA-N Val-Ala-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O ASQFIHTXXMFENG-XPUUQOCRSA-N 0.000 description 2
- FTKXYXACXYOHND-XUXIUFHCSA-N Val-Ile-Leu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O FTKXYXACXYOHND-XUXIUFHCSA-N 0.000 description 2
- OVBMCNDKCWAXMZ-NAKRPEOUSA-N Val-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](C(C)C)N OVBMCNDKCWAXMZ-NAKRPEOUSA-N 0.000 description 2
- BMOFUVHDBROBSE-DCAQKATOSA-N Val-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C(C)C)N BMOFUVHDBROBSE-DCAQKATOSA-N 0.000 description 2
- DEGUERSKQBRZMZ-FXQIFTODSA-N Val-Ser-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O DEGUERSKQBRZMZ-FXQIFTODSA-N 0.000 description 2
- UGFMVXRXULGLNO-XPUUQOCRSA-N Val-Ser-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O UGFMVXRXULGLNO-XPUUQOCRSA-N 0.000 description 2
- GBIUHAYJGWVNLN-AEJSXWLSSA-N Val-Ser-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N GBIUHAYJGWVNLN-AEJSXWLSSA-N 0.000 description 2
- GBIUHAYJGWVNLN-UHFFFAOYSA-N Val-Ser-Pro Natural products CC(C)C(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O GBIUHAYJGWVNLN-UHFFFAOYSA-N 0.000 description 2
- CEKSLIVSNNGOKH-KZVJFYERSA-N Val-Thr-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](C(C)C)N)O CEKSLIVSNNGOKH-KZVJFYERSA-N 0.000 description 2
- JVGDAEKKZKKZFO-RCWTZXSCSA-N Val-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N)O JVGDAEKKZKKZFO-RCWTZXSCSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 108010024078 alanyl-glycyl-serine Proteins 0.000 description 2
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 108010090037 glycyl-alanyl-isoleucine Proteins 0.000 description 2
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 2
- 108010078326 glycyl-glycyl-valine Proteins 0.000 description 2
- 108010037850 glycylvaline Proteins 0.000 description 2
- 108010031424 isoleucyl-prolyl-proline Proteins 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 2
- 108010057821 leucylproline Proteins 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 108010016686 methionyl-alanyl-serine Proteins 0.000 description 2
- 108010005942 methionylglycine Proteins 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- MXHCPCSDRGLRER-UHFFFAOYSA-N pentaglycine Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)NCC(O)=O MXHCPCSDRGLRER-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- PEUGKEHLRUVPAN-UHFFFAOYSA-N piperidin-3-amine Chemical class NC1CCCNC1 PEUGKEHLRUVPAN-UHFFFAOYSA-N 0.000 description 2
- USISRUCGEISZIB-UHFFFAOYSA-N piperidin-3-one Chemical class O=C1CCCNC1 USISRUCGEISZIB-UHFFFAOYSA-N 0.000 description 2
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 description 2
- 108010020432 prolyl-prolylisoleucine Proteins 0.000 description 2
- 108010053725 prolylvaline Proteins 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- RIFXIGDBUBXKEI-UHFFFAOYSA-N tert-butyl 3-oxopiperidine-1-carboxylate Chemical class CC(C)(C)OC(=O)N1CCCC(=O)C1 RIFXIGDBUBXKEI-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 241000185996 Arthrobacter citreus Species 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000001559 benzoic acids Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 239000012044 organic layer Substances 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
- 235000021317 phosphate Nutrition 0.000 description 1
- FNIQKHXZAHAFCZ-UHFFFAOYSA-N phosphoric acid;1h-pyrrole Chemical class C=1C=CNC=1.OP(O)(O)=O FNIQKHXZAHAFCZ-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The present invention relates to it is a kind of (S)‑1‑NThe amino piperidine of benzene methoxycarbonyl group 3（Hereinafter referred to as (S)‑NThe amino piperidines of Cbz 3）Preparation method.Mainly solve technical problem of the existing preparation method using tertbutyloxycarbonyl as blocking group less stable under mildly acidic conditions.Technical scheme：A kind of (S)‑NThe preparation method of the amino piperidines of Cbz 3, under conditions of using isopropylamine as nitrogen source, 1 is converted by enzymaticNThe direct formula II of the piperidones of benzene methoxycarbonyl group 3 (S)‑NThe amino piperidines of Cbz 3；Reaction equation is as follows：。
Description
Technical field
The present invention relates to a kind of enantiomer-pure (S)-1-N- benzene methoxycarbonyl group -3- amino piperidines（Referred to as (S)-N-Cbz-
3- amino piperidines）Biocatalysis preparation method.
Background technology
(S)-N- Cbz-3- amino piperidines（Such as formula（II）It is shown）
（II）
It is a kind of important chiral medicinal intermediate.A large amount of natural and non-native bioactive molecules have one or more piperidines
Ring, also many active pharmaceutical ingredients（API）Also the part is contained.SType 3- amino piperidines are to produce Egelieting, Lin Gelieting
Important intermediate, while nitrogen protection amino piperidine can also be used for synthesizing benzoic acids Egelieting.
At present, it is numerous prepare (S)-NThe method of-Cbz-3- amino piperidines（Including conventional chemical methods and catalyzed by biological enzyme）
In, catalyzed by biological enzyme is because with reaction efficiency is high, stereoselectivity is good, reaction condition is gentle, low energy consumption, environment-friendly etc.
Advantage, by more and more extensive concern and increasingly in-depth study.At present prepared by the biology on chiral 3- amino piperidines
Method be concentrated mainly on research (R)- 3- amino piperidines.
Disclosed in patent CN104178536B a kind of biology prepare (R)The method of -3- amino piperidines, withN- tertiary butyloxycarbonyl
Base -3- piperidones is substrate, using isopropylamine or D-alanine as amino group donor, from Cd stress to arthrobacterium
(Arthrobacter. sp.) D- transaminases in the presence of, 3- piperidones is converted into (R) -3- amino piperidines.The invention turns
Rate has important industrial application value up to more than 97%.
One kind is disclosed in patent CN103865964A using transaminase as catalyst, withN- tertbutyloxycarbonyl -3- piperidones
For substrate, in the presence of amino group donor and transaminase, by the 3- piperidones that nitrogen is protected be converted into nitrogen protection (R) -3- amino
Piperidines.Can slough afterwards blocking group obtain (R) -3- amino piperidines or its salt.
Specific synthetic route is as follows：
Wherein PG is protection group, and C can be selected1-4Alkoxy carbonyl group, benzyloxycarbonyl group or benzyl.The amino group donor chosen in the invention is
Isopropylamine, the transaminase of selection from Cd stress to arthrobacterium (Arthrobacter. sp.), obtain table by genetic recombination
Up to the recombination bacillus coli of ω-transaminase.The ee values of product are finally given typically 99% or so, should suitable for large-scale promotion
With.
Pertinent literature（Org. Process Res. Dev. 2016, 20(3), 602-608）Report, ω-transaminase can
Turn ammonia product be effectively catalyzed that achiral ketone obtains enantiomer-pure, specific route is as follows：
Using 1- tertbutyloxycarbonyl -3- piperidones as raw material in document, isopropylamine is chosen as amino group donor, in transaminase (source
In the Ars-TA or the ATA-47 that is bought from German c-LEcta GmbH companies of Arthrobacter citreus) in the presence of, obtain mapping
Body is pure（S）- 1- tertbutyloxycarbonyl -3- amino piperidines, conversion ratio is up to 89%.Specific synthetic route is as follows：
At present document reported by the use of enzymatic method prepare single configuration amino piperidine using tertbutyloxycarbonyl as
Blocking group.At present on (S)-NThe biological preparation method of-Cbz-3- amino piperidines is reported still without Patents.
The content of the invention
It is an object of the invention to provide a kind of high yield and it is efficient (S)-NThe preparation side of-Cbz-3- amino piperidines
Method, mainly solve skill of the existing preparation method using tertbutyloxycarbonyl as blocking group less stable under mildly acidic conditions
Art problem.It is intended to, by a kind of new enzyme technology, realizeNThe ammonification of-Cbz-3- piperidones, so as to realize extensive preparation
Enantiomer-pure (S)-NThe purpose of-Cbz-3- amino piperidines.
Particularly from vibrio fluvialis JS17 or from the ammonia by the genetic recombination of the strain in Escherichia coli
Based transferase has extraordinary activity to this aminating reaction.
Technical scheme：A kind of (S)-N-Cbz-3- amino piperidines preparation method, nitrogen is being used as using isopropylamine
Under conditions of source, by enzymatic convert N-Cbz-3- piperidones direct formula II (S)-N-Cbz-3- amino piperidines；Instead
Answer formula as follows：
In the preparation process in accordance with the present invention, the enzyme is aminopherase（Abbreviation transaminase）.The source of transaminase is included but not
It is limited to vibrios, arthrobacterium and color bacillus.Wherein preferable transaminase derives from vibrio fluvialis JS17（Vibrio Fluvialis
JS17）Or from by the genetic recombination of the strain in Escherichia coli.
In the preparation process in accordance with the present invention, in addition in conventional manner product formula is isolated（II）Described enantiomer.Often
Rule separation method is extracted including organic solvent, ion exchange or chromatography etc..Wherein, preferably using Solvent Extraction Separation not
The formula of reaction（II）Enantiomer.
In the preparation process in accordance with the present invention, the reaction is in organic solvent and the mixture of water, or is carried out in pure water.Make
In the case of with the mixture of organic solvent and water, the organic solvent is miscible with water.Its role is to further increase
Add the dissolubility of substrate simultaneously.Preferably the organic solvent miscible with water isN,N- dimethylformamide.
In the preparation process in accordance with the present invention, the reaction is carried out under conditions of being 7 ~ 9 in pH scopes.Preferable reaction
PH is between 7 ~ 8, wherein the optimal pH chosen is 7.5.PH controls are carried out by adding buffer solution into reaction dissolvent.Often
Buffer solution includes but is not limited to KH2PO4-K2HPO4Or NaH2PO4-Na2HPO4Buffer solution.
In the preparation process in accordance with the present invention, the reaction is carried out under conditions of being 15 ~ 60 DEG C in temperature.When temperature is less than
At 15 DEG C, reaction speed is slower.But when temperature is higher than 60 DEG C, enzyme can irreversible inactivation.For guarantee stable reaction, efficiently enter
Capable purpose, preferable reaction temperature are 25 DEG C.
In the preparation process in accordance with the present invention, in addition to isolate amino product (S)-NThe step of-Cbz-3- amino piperidines.
Prepare with the inventive method (S)-N- Cbz-3- amino piperidines（II）, enantiomeric excess value be not less than 99%,
Purity is not less than 99%.
The invention has the advantages that using benzene methoxycarbonyl group as amido protecting group, pass through a kind of new enzymatic skill
The efficient production of art realization (S)-N- Cbz-3- amino piperidines are significant.This method is simple and easy, yield is high, selectivity
It is good.
Brief description of the drawings
Fig. 1 isNThe high performance liquid chromatography collection of illustrative plates of the racemate of-Cbz-3- amino piperidines.The peak in left side is S structures
Type, the peak on right side is R configurations.
Fig. 2 is after being converted according to the method for the embodiment of the present invention 3NThe Chiral HPLC of-Cbz-3- amino piperidines
Chromatography collection of illustrative plates.In figure unique peak be target compound (S)-N- Cbz-3- amino piperidines.
Fig. 3 is after being converted according to the method for the embodiment of the present invention 3NThe Chiral HPLC of-Cbz-3- amino piperidines
Combined gas chromatography mass spectrometry collection of illustrative plates.The peak that mass-to-charge ratio m/z is 234.8 in figure be target compound (S)-N- Cbz-3- amino piperidines
Molecular ion peak.
Fig. 4 be according to the embodiment of the present invention 3 method conversion after (S)-NThe hydrogen spectrum nuclear-magnetism of-Cbz-3- amino piperidines
Collection of illustrative plates.1H NMR (400MHz, CDCl3) δ ppm 1.19 - 1.32 (m, 1 H), 1.49 (s, 1 H), 1.71 –
1.78 (m, 1 H), 1.84 – 2.00 (m, 1 H), 2.67 (s, 1 H), 2.80 (s, 1 H), 2.90 (ddd,
J = 13.36, 10.73, 3.26 Hz, 1H), 3.76-4.17 (m, 2 H), 5.12 (d, J = 1.25 Hz, 2
H), 7.27 – 7.40 (m, 5 H)。
Embodiment
Reaction method of the present invention, it is characterised in that comprise the following steps：
(1) transaminase, catalytic ammoniation are utilizedN- Cbz-3- piperidones.Wherein the addition of transaminase is that 0.002 ~ 10g turns ammonia
Enzyme/g substrates.
Reaction temperature is 15 ~ 60 DEG C, preferably 25 DEG C.
Reaction medium used is to add concentration to tremble for 1 ~ 5 mmol/L phosphoric acid pyrroles in 0.5 ~ 2 mol/L isopropylamines and concentration
The pure water of aldehyde or containing phosphate concn in 50 ~ 150 mmol/L（Preferably 90 mmol/L）, pH scopes 7 ~ 9（Preferably
pH = 7.5）KH2PO4-K2HPO4Or NaH2PO4-Na2HPO4Buffer solution or pure water or above-mentioned buffer solution and water are not
Miscible organic solvent（Such as N,N-dimethylformamide or dimethyl sulfoxide）The two-phase system of composition.
(2) after reaction terminates, after reaction solution is passed through nitrogen or negative pressure removing impurity, dichloromethane or methyl- tert fourth are used
Base ether extracts, and after extraction terminates, extraction mixture after layering, takes required organic layer, be thick through centrifuge or filter process
The solution of product.
(3) by the solution of crude product, it can directly be concentrated under reduced pressure dry, finally give shallow under conditions of not higher than 45 DEG C
Yellow, viscous liquid, as enantiomeric excess value are not less than 99%, purity not less than 99% product (S)-N- Cbz-3- ammonia
Phenylpiperidines.
Reagent and raw material used herein are commercially available.
Below according to embodiment, and with reference to accompanying drawing, the present invention is described in detail.In from detailed description below, the present invention
Above-mentioned aspect and other aspects of the present invention will be apparent.The following example is intended merely to illustrate the present invention, and to the present invention
Protection domain does not play any restriction effect.
Embodiment 1
In 50 mL glass jacket reaction bulbs, 20mL water, 0.106 g KH are added2PO4With 0.212 g K2HPO4, stirring
Until solid dissolved clarification；Add 1.7 mL isopropylamine and with phosphorus acid for adjusting pH value to 7；0.05 g is added into reaction solution and turns ammonia
Enzyme freeze-dried powder（From ω-aminotransferase gene from vibrio fluvialis JS17（GenBank: HQ418483.1）It is reconstituted in large intestine bar
The engineering strain fermentation extraction gained of bacterium）With 0.02 g phosphopyridoxal pyridoxal phosphates, 1 g is added after stirringN- Cbz-3- piperidines
Ketone；Adjust and control 25 DEG C of reacting liquid temperature, continuously stir 24 hours；
With 20 mL dichloromethane extractive reaction liquid, lower floor's organic phase is obtained, is filtered after adding a small amount of anhydrous sodium sulfate water removal,
Concentration is evaporated under reduced pressure at 30 DEG C.Gained yellow viscous liquid is weighed to obtain 0.79 g, and thick yield is 78.69%.Gained liquid produces
Product (S)-N- Cbz-3- amino piperidines, through high-efficient liquid phase chromatogram technique analysis, the % of enantiomeric excess value 85.63.Analysis condition：Island
Tianjin LC-20A liquid chromatographs and UV-detector, ChiSapak AS-H（250 × 4.6 mm, 5 μm）Chiral chromatographic column,
Mobile phase：Hexane containing the 0.1% ethylenediamine-ethanol containing 0.1% ethylenediamine（Volume ratio 90: 10）.Under 30 DEG C of 1 mL/min
Balance, the nm of Detection wavelength 254.
Embodiment 2
In 50 mL glass jacket reaction bulbs, 20mL water, 0.106 g KH are added2PO4With 0.212 g K2HPO4, stirring is directly
To solid dissolved clarification；Add 1.7 mL isopropylamine and with phosphorus acid for adjusting pH value to 7；0.05 g is added into reaction solution and turns ammonia
Enzyme freeze-dried powder（From ω-aminotransferase gene from vibrio fluvialis JS17（GenBank: HQ418483.1）It is reconstituted in large intestine bar
The engineering strain fermentation extraction gained of bacterium）With 0.01 g phosphopyridoxal pyridoxal phosphates, 1 g N-Cbz-3- piperidines is added after stirring
Ketone；Adjust and control 37 DEG C of reacting liquid temperature, continuously stir 24 hours；
Post-treatment condition is the same as embodiment 1.Gained yellow viscous liquid is weighed to obtain 0.82 g, and thick yield is 81.67 %.Gained
Liquid be product (S)-N- Cbz-3- amino piperidines, through high-efficient liquid phase chromatogram technique analysis, the % of enantiomeric excess value 83.22.Point
Analysis condition is the same as embodiment 1.
Embodiment 3
In 50 mL glass jacket reaction bulbs, 20mL water, 0.106 g KH are added2PO4With 0.212 g K2HPO4, stirring
Until solid dissolved clarification；Add 1.7 mL isopropylamine and with phosphorus acid for adjusting pH value to 7.5；0.05 g is added into reaction solution to turn
Ammonia enzyme freeze-dried powder（From ω-aminotransferase gene from vibrio fluvialis JS17（GenBank: HQ418483.1）It is reconstituted in large intestine
The engineering strain fermentation extraction gained of bacillus）With 0.01 g phosphopyridoxal pyridoxal phosphates, 1 g is added after stirringN- Cbz-3- piperazines
Pyridine ketone；Adjust and control 25 DEG C of reacting liquid temperature, continuously stir 24 hours；
After reaction terminates, after reaction solution is passed through nitrogen or negative pressure removing impurity, with 20 mL dichloromethane extractive reaction liquid, obtain
Lower floor's organic phase, filtered after adding a small amount of anhydrous sodium sulfate water removal, concentration is evaporated under reduced pressure at 30 DEG C.Gained yellow viscous liquid
Weigh to obtain 0.82 g, and ultimate yield is 81.67 %.Gained liquid be product (S)-N- Cbz-3- amino piperidines, through efficient liquid
GC headspace analysis, enantiomeric excess value is up to 99.48%.Analysis condition is the same as embodiment 1.Product liquid chromatography collection of illustrative plates is shown in
Fig. 2, product liquid chromatography mass combination method collection of illustrative plates are shown in Fig. 3, and the nuclear magnetic spectrum of product is shown in Fig. 4.
Embodiment 4
In 1 L glass jacket reaction bulbs, 400 mL water, 5.3 g KH are added2PO4With 10.6 K2HPO4, stirring is until solid
Body dissolved clarification；Add 8.5 mL isopropylamine and with phosphorus acid for adjusting pH value to 7.5；2.5 g transaminases jelly is added into reaction solution
Dry powder（From ω-aminotransferase gene from vibrio fluvialis JS17（GenBank: HQ418483.1）It is reconstituted in Escherichia coli
Engineering strain fermentation extraction gained）With 0.5 g phosphopyridoxal pyridoxal phosphates, 50 g are added after stirringN- Cbz-3- piperidones；Adjust
It is whole and control 25 DEG C of reacting liquid temperature, continuously stir 24 hours；
After reaction terminates, after reaction solution negative pressure removes impurity, with the extraction of isometric dichloromethane three times, the organic addition of lower floor is obtained
Filtered after entering a small amount of anhydrous sodium sulfate water removal, concentration is evaporated under reduced pressure at 30 DEG C.Gained liquid subtracts under 30 DEG C, nitrogen stream protection
Pressure drying 12 hours, 47.7 g yellow viscous liquids of weighing to obtain, thick yield is 95.02 %.Gained liquid be product (S)-N-
Cbz-3- amino piperidines, through high-efficient liquid phase chromatogram technique analysis, enantiomeric excess value 100%.Analysis condition is the same as embodiment 1.
Those skilled in the art is it should be understood that although for illustrative purposes, this document describes the tool of the present invention
Body embodiment, but various modifications can be carried out to it without departing from the spirit and scope of the present invention.Therefore, it is of the invention specific
Embodiment and embodiment should not be considered as limiting the scope of the invention.The present invention is limited only by the appended claims.This Shen
Please in quote all documents be fully incorporated herein by reference.
Sequence table
<110>Shanghai STA Pharmaceutical R ＆ D Co., Ltd.
Shanghai Syntheall Pharmaceutical Co., Ltd.
Changzhou He Quan pharmaceutcal corporation, Ltds
Close breakthrough drug research and development Co., Ltd in Changzhou
<120>The method that living things catalysis prepares (S) -1-N- benzene methoxycarbonyl group -3- amino piperidines
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 478
<212> PRT
<213>Vibrio fluvialis JS17 (Vibrio fluvialis JS17)
<400> 1
Met Ala Ser Met Thr Gly Gly Gly Gly Met Gly Ala Gly Ser Met Ala
1 5 10 15
Leu Pro Gly Ser Thr Gly Ala Ala Ala Gly Thr Thr Ser Leu Thr Gly
20 25 30
Pro Thr Ala Met Pro Ser Leu His Gly Ala Gly Thr Val Val Val Thr
35 40 45
His Gly Gly Gly Pro Thr Ile Val Ala Val Ala Gly Ala Ala Thr Leu
50 55 60
Ala Ala Ala Ser Gly Leu Thr Ala Met Val Ala Gly Pro Ala His Leu
65 70 75 80
Gly Leu Ile Ala Ala Ala Leu Ala Gly Thr Gly Ala Pro Pro Gly Thr
85 90 95
His Ala Pro Pro Gly Ala Met Ser Ala Gly Thr Val Met Leu Ser Gly
100 105 110
Leu Leu Val Gly Val Ser Pro Pro Ala Ser Gly Ala Val Pro Thr Thr
115 120 125
Ala Ser Gly Ser Gly Ala Ala Ala Thr Met Val Leu Met Leu Thr Pro
130 135 140
Leu His Ala Ala Gly Gly Leu Pro Gly Leu Ala Leu Ile Leu Thr Ala
145 150 155 160
Thr Ala Ala Thr His Gly Val Thr Ala Val Ser Ala Ser Met Thr Gly
165 170 175
Leu Pro Thr Ala Ser Val Pro Gly Leu Pro Leu Pro Gly Pro Val His
180 185 190
Leu Thr Cys Pro His Thr Thr Ala Thr Gly Gly Gly Gly Gly Thr Gly
195 200 205
Gly Gly Pro Val Ala Ala Leu Ala Ala Gly Leu Gly Gly Thr Ile Gly
210 215 220
Ala Gly Gly Ala Ala Thr Ile Ala Gly Pro Pro Ala Gly Pro Val Met
225 230 235 240
Gly Ala Gly Gly Val Ile Pro Pro Ala Leu Gly Thr Pro Gly Ala Ile
245 250 255
Leu Pro Ile Leu Ala Leu Thr Ala Ile Pro Val Ile Ser Ala Gly Val
260 265 270
Ile Cys Gly Pro Gly Ala Thr Gly Ala Thr Thr Gly Cys Val Thr Thr
275 280 285
Ala Pro Thr Pro Ala Ala Ile Ile Ser Ser Leu Ala Leu Thr Ala Gly
290 295 300
Pro Pro Pro Met Gly Ala Val Ile Leu Gly Pro Gly Leu Ser Leu Ala
305 310 315 320
Leu Gly Thr Ala Ile Gly Ala Ile Gly Gly Pro Pro His Gly Pro Thr
325 330 335
Ala Ser Gly His Pro Val Gly Cys Ala Ile Ala Leu Leu Ala Ile Ala
340 345 350
Val Val Met Ala Gly Gly Leu Ala Gly Ala Val Ala Ala Leu Ala Pro
355 360 365
Ala Pro Gly Gly Ala Leu Leu His Ile Ala Gly Ala Pro Ala Ile Gly
370 375 380
Gly Thr Ala Gly Ile Gly Pro Met Thr Ala Leu Gly Ala Val Leu Ala
385 390 395 400
Leu Ala Ser Leu Thr Pro Pro Ala Gly Ala Leu Ser Val Ser Gly Ala
405 410 415
Ile Ala Ala Thr Cys Thr Ala Leu Gly Leu Ile Cys Ala Pro Leu Gly
420 425 430
Gly Ser Val Val Leu Cys Pro Pro Pro Ile Leu Thr Gly Ala Gly Met
435 440 445
Ala Gly Met Pro Ala Leu Leu Gly Leu Ala Leu Ala Leu Val Pro Ala
450 455 460
Gly Val Ala Ala Ala Ala Leu Gly His His His His His His
465 470 475
<210> 2
<211> 1362
<212> DNA
<213>Vibrio fluvialis JS17 (Vibrio fluvialis JS17)
<400> 2
atgaacaaac cgcaaagctg ggaagcccgg gccgagacct attcgctcta tggtttcacc 60
gacatgcctt cgctgcatca gcgcggcacg gtcgtcgtga cccatggcga gggaccctat 120
atcgtcgatg tgaatggccg gcgttatctg gacgccaact cgggcctgtg gaacatggtc 180
gcgggctttg accacaaggg gctgatcgac gccgccaagg cccaatacga gcgttttccc 240
ggttatcacg cctttttcgg ccgcatgtcc gatcagacgg taatgctgtc ggaaaagctg 300
gtcgaggtgt cgccctttga ttcgggccgg gtgttctata caaactcggg gtccgaggcg 360
aatgacacca tggtcaagat gctatggttc ctgcatgcag ccgagggcaa accgcaaaag 420
cgcaagatcc tgacccgctg gaacgcctat cacggcgtga ccgccgtttc ggccagcatg 480
accggcaagc cctataattc ggtctttggc ctgccgctgc cgggctttgt gcatctgacc 540
tgcccgcatt actggcgcta tggcgaagag ggcgaaaccg aagagcagtt cgtcgcccgc 600
ctcgcccgcg agctggagga aacgatccag cgcgagggcg ccgacaccat cgccggtttc 660
tttgccgaac cggtgatggg cgcgggcggc gtgattcccc cggccaaggg gtatttccag 720
gcgatcctgc caatcctgcg caaatatgac atcccggtca tctcggacga ggtgatctgc 780
ggtttcggac gcaccggtaa cacctggggc tgcgtgacct atgactttac acccgatgca 840
atcatctcgt ccaagaatct tacagcgggc tttttcccca tgggggcggt gatccttggc 900
ccggaacttt ccaaacggct ggaaaccgca atcgaggcga tcgaggaatt cccccatggc 960
tttaccgcct cgggccatcc ggtcggctgt gctattgcgc tgaaagcaat cgacgtggtg 1020
atgaatgaag ggctggctga gaacgtccgc cgccttgccc cccgtttcga ggaaaggctg 1080
aaacatatcg ccgagcgccc gaacatcggt gaatatcgcg gcatcggctt catgtgggcg 1140
ctggaggctg tcaaggacaa ggcaagcaag acgccgttcg acggcaacct gtcggtcagc 1200
gagcgtatcg ccaatacctg caccgatctg gggctgattt gccggccgct tggtcagtcc 1260
gtcgtccttt gtccgccctt tatcctgacc gaggcgcaga tggatgagat gttcgataaa 1320
ctcgaaaaag cccttgataa ggtctttgcc gaggttgcct ga 1362
Sequence table
<110>Shanghai STA Pharmaceutical R ＆ D Co., Ltd.
Shanghai Syntheall Pharmaceutical Co., Ltd.
Changzhou He Quan pharmaceutcal corporation, Ltds
Close breakthrough drug research and development Co., Ltd in Changzhou
<120>The method that living things catalysis prepares (S) -1-N- benzene methoxycarbonyl group -3- amino piperidines
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 478
<212> PRT
<213>Vibrio fluvialis JS17 (Vibrio fluvialis JS17)
<400> 1
Met Ala Ser Met Thr Gly Gly Gly Gly Met Gly Ala Gly Ser Met Ala
1 5 10 15
Leu Pro Gly Ser Thr Gly Ala Ala Ala Gly Thr Thr Ser Leu Thr Gly
20 25 30
Pro Thr Ala Met Pro Ser Leu His Gly Ala Gly Thr Val Val Val Thr
35 40 45
His Gly Gly Gly Pro Thr Ile Val Ala Val Ala Gly Ala Ala Thr Leu
50 55 60
Ala Ala Ala Ser Gly Leu Thr Ala Met Val Ala Gly Pro Ala His Leu
65 70 75 80
Gly Leu Ile Ala Ala Ala Leu Ala Gly Thr Gly Ala Pro Pro Gly Thr
85 90 95
His Ala Pro Pro Gly Ala Met Ser Ala Gly Thr Val Met Leu Ser Gly
100 105 110
Leu Leu Val Gly Val Ser Pro Pro Ala Ser Gly Ala Val Pro Thr Thr
115 120 125
Ala Ser Gly Ser Gly Ala Ala Ala Thr Met Val Leu Met Leu Thr Pro
130 135 140
Leu His Ala Ala Gly Gly Leu Pro Gly Leu Ala Leu Ile Leu Thr Ala
145 150 155 160
Thr Ala Ala Thr His Gly Val Thr Ala Val Ser Ala Ser Met Thr Gly
165 170 175
Leu Pro Thr Ala Ser Val Pro Gly Leu Pro Leu Pro Gly Pro Val His
180 185 190
Leu Thr Cys Pro His Thr Thr Ala Thr Gly Gly Gly Gly Gly Thr Gly
195 200 205
Gly Gly Pro Val Ala Ala Leu Ala Ala Gly Leu Gly Gly Thr Ile Gly
210 215 220
Ala Gly Gly Ala Ala Thr Ile Ala Gly Pro Pro Ala Gly Pro Val Met
225 230 235 240
Gly Ala Gly Gly Val Ile Pro Pro Ala Leu Gly Thr Pro Gly Ala Ile
245 250 255
Leu Pro Ile Leu Ala Leu Thr Ala Ile Pro Val Ile Ser Ala Gly Val
260 265 270
Ile Cys Gly Pro Gly Ala Thr Gly Ala Thr Thr Gly Cys Val Thr Thr
275 280 285
Ala Pro Thr Pro Ala Ala Ile Ile Ser Ser Leu Ala Leu Thr Ala Gly
290 295 300
Pro Pro Pro Met Gly Ala Val Ile Leu Gly Pro Gly Leu Ser Leu Ala
305 310 315 320
Leu Gly Thr Ala Ile Gly Ala Ile Gly Gly Pro Pro His Gly Pro Thr
325 330 335
Ala Ser Gly His Pro Val Gly Cys Ala Ile Ala Leu Leu Ala Ile Ala
340 345 350
Val Val Met Ala Gly Gly Leu Ala Gly Ala Val Ala Ala Leu Ala Pro
355 360 365
Ala Pro Gly Gly Ala Leu Leu His Ile Ala Gly Ala Pro Ala Ile Gly
370 375 380
Gly Thr Ala Gly Ile Gly Pro Met Thr Ala Leu Gly Ala Val Leu Ala
385 390 395 400
Leu Ala Ser Leu Thr Pro Pro Ala Gly Ala Leu Ser Val Ser Gly Ala
405 410 415
Ile Ala Ala Thr Cys Thr Ala Leu Gly Leu Ile Cys Ala Pro Leu Gly
420 425 430
Gly Ser Val Val Leu Cys Pro Pro Pro Ile Leu Thr Gly Ala Gly Met
435 440 445
Ala Gly Met Pro Ala Leu Leu Gly Leu Ala Leu Ala Leu Val Pro Ala
450 455 460
Gly Val Ala Ala Ala Ala Leu Gly His His His His His His
465 470 475
<210> 2
<211> 1362
<212> DNA
<213>Vibrio fluvialis JS17 (Vibrio fluvialis JS17)
<400> 2
atgaacaaac cgcaaagctg ggaagcccgg gccgagacct attcgctcta tggtttcacc 60
gacatgcctt cgctgcatca gcgcggcacg gtcgtcgtga cccatggcga gggaccctat 120
atcgtcgatg tgaatggccg gcgttatctg gacgccaact cgggcctgtg gaacatggtc 180
gcgggctttg accacaaggg gctgatcgac gccgccaagg cccaatacga gcgttttccc 240
ggttatcacg cctttttcgg ccgcatgtcc gatcagacgg taatgctgtc ggaaaagctg 300
gtcgaggtgt cgccctttga ttcgggccgg gtgttctata caaactcggg gtccgaggcg 360
aatgacacca tggtcaagat gctatggttc ctgcatgcag ccgagggcaa accgcaaaag 420
cgcaagatcc tgacccgctg gaacgcctat cacggcgtga ccgccgtttc ggccagcatg 480
accggcaagc cctataattc ggtctttggc ctgccgctgc cgggctttgt gcatctgacc 540
tgcccgcatt actggcgcta tggcgaagag ggcgaaaccg aagagcagtt cgtcgcccgc 600
ctcgcccgcg agctggagga aacgatccag cgcgagggcg ccgacaccat cgccggtttc 660
tttgccgaac cggtgatggg cgcgggcggc gtgattcccc cggccaaggg gtatttccag 720
gcgatcctgc caatcctgcg caaatatgac atcccggtca tctcggacga ggtgatctgc 780
ggtttcggac gcaccggtaa cacctggggc tgcgtgacct atgactttac acccgatgca 840
atcatctcgt ccaagaatct tacagcgggc tttttcccca tgggggcggt gatccttggc 900
ccggaacttt ccaaacggct ggaaaccgca atcgaggcga tcgaggaatt cccccatggc 960
tttaccgcct cgggccatcc ggtcggctgt gctattgcgc tgaaagcaat cgacgtggtg 1020
atgaatgaag ggctggctga gaacgtccgc cgccttgccc cccgtttcga ggaaaggctg 1080
aaacatatcg ccgagcgccc gaacatcggt gaatatcgcg gcatcggctt catgtgggcg 1140
ctggaggctg tcaaggacaa ggcaagcaag acgccgttcg acggcaacct gtcggtcagc 1200
gagcgtatcg ccaatacctg caccgatctg gggctgattt gccggccgct tggtcagtcc 1260
gtcgtccttt gtccgccctt tatcctgacc gaggcgcaga tggatgagat gttcgataaa 1320
ctcgaaaaag cccttgataa ggtctttgcc gaggttgcct ga 1362
Claims (8)
1. a kind of living things catalysis prepare (S)-1-NThe method of-benzene methoxycarbonyl group -3- amino piperidines, it is characterized in that with isopropylamine
Under conditions of nitrogen source, converted by enzymaticNThe direct formula II of-Cbz-3- piperidones (S)-N- Cbz-3- amino piperazines
Pyridine；Reaction equation is as follows：
。
2. the method as described in claim 1, it is characterized in that also including isolating the ammonification production described in Formula II in conventional manner
Thing.
3. the method as described in claim 1, it is characterized in that wherein described react in organic solvent and the mixture of water, or
Carried out in pure water.
4. the method as described in claim 3, it is characterized in that wherein described organic solvent is miscible with water.
5. the method as described in claim 1, it is characterized in that wherein described reaction is 7 ~ 9 in pH scopes, the reaction
Carried out under conditions of being 15 ~ 60 DEG C in temperature.
6. the method as described in claim 1, it is characterized in that wherein described enzyme is aminopherase.
7. the method as described in claim 6, it is characterized in that wherein described aminopherase from vibrios, arthrobacterium or
One kind in color bacillus.
8. the method as described in claim 7, it is characterized in that the vibrios is from vibrio fluvialis JS17 or by the river
Vibrios JS17 genetic recombination is flowed in Escherichia coli.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710885707.9A CN107604020A (en) | 2017-09-27 | 2017-09-27 | The method that living things catalysis prepares the amino piperidine of (S) 1 N benzene methoxycarbonyl group 3 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710885707.9A CN107604020A (en) | 2017-09-27 | 2017-09-27 | The method that living things catalysis prepares the amino piperidine of (S) 1 N benzene methoxycarbonyl group 3 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107604020A true CN107604020A (en) | 2018-01-19 |
Family
ID=61058807
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710885707.9A Pending CN107604020A (en) | 2017-09-27 | 2017-09-27 | The method that living things catalysis prepares the amino piperidine of (S) 1 N benzene methoxycarbonyl group 3 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107604020A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112824381A (en) * | 2019-11-21 | 2021-05-21 | 广东东阳光药业有限公司 | Preparation method of piperidylamine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008028654A1 (en) * | 2006-09-06 | 2008-03-13 | Lonza Ag | Process for preparation of optically active n-protected 3 -aminopyrrolidine or optically active n-protected 3-aminopiperidine and the corresponding ketones by optical resolution of the racemic amine mixtures employing a bacterial omega-transaminase |
| CN103865964A (en) * | 2014-03-14 | 2014-06-18 | 上海朴颐化学科技有限公司 | Method for synthesizing (R)-3-amino-piperidine by adopting transaminase method |
| CN105734089A (en) * | 2014-12-11 | 2016-07-06 | 南京博优康远生物医药科技有限公司 | An asymmetric synthesis method for (R)-3-amino piperidine derivatives |
-
2017
- 2017-09-27 CN CN201710885707.9A patent/CN107604020A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008028654A1 (en) * | 2006-09-06 | 2008-03-13 | Lonza Ag | Process for preparation of optically active n-protected 3 -aminopyrrolidine or optically active n-protected 3-aminopiperidine and the corresponding ketones by optical resolution of the racemic amine mixtures employing a bacterial omega-transaminase |
| CN103865964A (en) * | 2014-03-14 | 2014-06-18 | 上海朴颐化学科技有限公司 | Method for synthesizing (R)-3-amino-piperidine by adopting transaminase method |
| CN105734089A (en) * | 2014-12-11 | 2016-07-06 | 南京博优康远生物医药科技有限公司 | An asymmetric synthesis method for (R)-3-amino piperidine derivatives |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112824381A (en) * | 2019-11-21 | 2021-05-21 | 广东东阳光药业有限公司 | Preparation method of piperidylamine |
| CN112824381B (en) * | 2019-11-21 | 2024-04-26 | 广东东阳光药业股份有限公司 | Preparation method of piperidine amine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107384885B (en) | Application of imine reductase and mutant thereof in synthesis of (S) -1-aryl-1, 2, 3, 4-tetrahydroisoquinoline | |
| JP7306720B2 (en) | Modified transaminase polypeptides and uses thereof | |
| CN105603015B (en) | A kind of production method of L-glufosinate-ammonium | |
| KR101869432B1 (en) | Omega-transaminase mutants with activity improvements toward ketones and methods for producing optically pure amines | |
| CN116042745A (en) | Method for producing 1, 6-fructose diphosphate by enzymatic method | |
| Petri et al. | Asymmetric synthesis of a high added value chiral amine using immobilized ω-transaminases | |
| Xu et al. | Enzymatic synthesis of optical pure β-nitroalcohols by combining d-aminoacylase-catalyzed nitroaldol reaction and immobilized lipase PS-catalyzed kinetic resolution | |
| CN107604020A (en) | The method that living things catalysis prepares the amino piperidine of (S) 1 N benzene methoxycarbonyl group 3 | |
| CN107574194A (en) | The method that living things catalysis prepares the hydroxy piperidine of (R) 1 N benzene methoxycarbonyl group 3 | |
| CN103966275B (en) | Bioanalysis prepares high-purity S-Leucine | |
| CN112522228B (en) | R-aminotransferase from pseudomonas ammoxidation and synthesis method thereof | |
| CN107604019A (en) | The method that living things catalysis prepares the amino piperidine of (R) 1 N benzene methoxycarbonyl group 3 | |
| CN105018439B (en) | A kind of carbonyl reductase and its application in synthesis of chiral hydroxy compounds | |
| JP2016521565A (en) | Kachin production method | |
| Tudorache et al. | Sequential deracemization of sulfoxides via whole-cell resolution and heterogeneous oxidation | |
| CN104846025B (en) | A kind of method for preparing (2S, 3R) -2- benzoyl aminomethyls -3-hydroxybutyrate methyl esters | |
| CN105087704B (en) | Controllable multi-enzyme cascade reaction for synthesizing optical pure allylic epoxy ketone or alcohol | |
| CN111118076B (en) | Method for biocatalytically reducing nitro compound | |
| EP4116289A1 (en) | Synthesis method for fluorine-containing chiral amine compound | |
| US20030224495A1 (en) | Method for the improved production and isolation of trans-dihydroxycyclohexadiene carboxylic acids and/or derivatives thereof and genetically modified organism suitable therefor | |
| Zhu et al. | Identification of imine reductases for asymmetric synthesis of 1-aryl-tetrahydroisoquinolines | |
| Khan et al. | Imine Reductases | |
| CN107586798A (en) | The method that living things catalysis prepares the hydroxy piperidine of (S) 1 N benzene methoxycarbonyl group 3 | |
| CN106636292B (en) | Preparation method of (1R,4S) - (-) -2-azabicyclo [2.2.1] hept-5-ene-3-ketone | |
| CN117925654A (en) | Pseudomonas putida omega-aminotransferase gene with wide substrate spectrum and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20190109 Address after: Room 602-604, Building No. 1, 288 Fute Middle Road, Waigaoqiao Bonded Zone, Pudong New Area, Shanghai, 2001 Applicant after: Shanghai STA Pharmaceutical R & D Co., Ltd. Applicant after: Shanghai SynTheAll Pharmaceutical Co., Ltd. Applicant after: CHANGZHOU HEQUAN PHARMACEUTICAL CO., LTD. Address before: Room 602,604, Building No. 1, 288 Fute Middle Road, Waigaoqiao Bonded Zone, Pudong New Area, Shanghai, 2001 Applicant before: Shanghai STA Pharmaceutical R & D Co., Ltd. Applicant before: Shanghai SynTheAll Pharmaceutical Co., Ltd. Applicant before: CHANGZHOU HEQUAN PHARMACEUTICAL CO., LTD. Applicant before: Changzhou whole new drug research and Development Co., Ltd. |
|
| TA01 | Transfer of patent application right | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180119 |
|
| WD01 | Invention patent application deemed withdrawn after publication |