EP4352064A1 - Verfahren zur herstellung eines biotinzwischenprodukts - Google Patents
Verfahren zur herstellung eines biotinzwischenproduktsInfo
- Publication number
- EP4352064A1 EP4352064A1 EP21944657.2A EP21944657A EP4352064A1 EP 4352064 A1 EP4352064 A1 EP 4352064A1 EP 21944657 A EP21944657 A EP 21944657A EP 4352064 A1 EP4352064 A1 EP 4352064A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- mol
- trifluoromethanesulfonate
- compound
- otf
- formula
- 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
- 238000000034 method Methods 0.000 title claims abstract description 34
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 title claims abstract description 29
- 235000020958 biotin Nutrition 0.000 title abstract description 6
- 239000011616 biotin Substances 0.000 title abstract description 6
- 229960002685 biotin Drugs 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- 125000003118 aryl group Chemical group 0.000 claims abstract description 11
- 125000001424 substituent group Chemical group 0.000 claims abstract description 11
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 6
- 125000006239 protecting group Chemical group 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 23
- -1 indium halide Chemical class 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 14
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 12
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 11
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 239000010949 copper Substances 0.000 claims description 5
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 239000011701 zinc Substances 0.000 claims description 5
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 claims description 4
- IWAKWOFEHSYKSI-UHFFFAOYSA-N 1-chloro-2-methylbutane Chemical compound CCC(C)CCl IWAKWOFEHSYKSI-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000005140 aralkylsulfonyl group Chemical group 0.000 claims description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000006535 bis-trifluoromethyl methyl group Chemical group 0.000 claims description 3
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 3
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 claims description 3
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 3
- PKDJOGCLKUPILB-UHFFFAOYSA-N 3-trimethylsilylpropanenitrile Chemical compound C[Si](C)(C)CCC#N PKDJOGCLKUPILB-UHFFFAOYSA-N 0.000 claims description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 2
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- HIYUMYXSGIKHHE-UHFFFAOYSA-M bismuth trifluoromethanesulfonate Chemical compound [Bi+3].[O-]S(=O)(=O)C(F)(F)F HIYUMYXSGIKHHE-UHFFFAOYSA-M 0.000 claims description 2
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 claims description 2
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 2
- 150000004292 cyclic ethers Chemical class 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 229910052738 indium Inorganic materials 0.000 claims description 2
- PGJLOGNVZGRMGX-UHFFFAOYSA-L iron(2+);trifluoromethanesulfonate Chemical compound [Fe+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F PGJLOGNVZGRMGX-UHFFFAOYSA-L 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- HSYLTRBDKXZSGS-UHFFFAOYSA-N silver;bis(trifluoromethylsulfonyl)azanide Chemical compound [Ag+].FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F HSYLTRBDKXZSGS-UHFFFAOYSA-N 0.000 claims description 2
- LCHWKMAWSZDQRD-UHFFFAOYSA-N silylformonitrile Chemical compound [SiH3]C#N LCHWKMAWSZDQRD-UHFFFAOYSA-N 0.000 claims description 2
- JKNHZOAONLKYQL-UHFFFAOYSA-K tribromoindigane Chemical compound Br[In](Br)Br JKNHZOAONLKYQL-UHFFFAOYSA-K 0.000 claims description 2
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- RMUKCGUDVKEQPL-UHFFFAOYSA-K triiodoindigane Chemical compound I[In](I)I RMUKCGUDVKEQPL-UHFFFAOYSA-K 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- ZMLPZCGHASSGEA-UHFFFAOYSA-M zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F ZMLPZCGHASSGEA-UHFFFAOYSA-M 0.000 claims description 2
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Substances [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 claims description 2
- KLRHPHDUDFIRKB-UHFFFAOYSA-M indium(i) bromide Chemical compound [Br-].[In+] KLRHPHDUDFIRKB-UHFFFAOYSA-M 0.000 description 6
- 235000000638 D-biotin Nutrition 0.000 description 5
- 239000011665 D-biotin Substances 0.000 description 5
- 229940125782 compound 2 Drugs 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- RDXMSZVVYKUPFN-UHFFFAOYSA-N 2,4-dioxoimidazolidine-1-carbonitrile Chemical compound O=C1CN(C#N)C(=O)N1 RDXMSZVVYKUPFN-UHFFFAOYSA-N 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- OROGUZVNAFJPHA-UHFFFAOYSA-N 3-hydroxy-2,4-dimethyl-2H-thiophen-5-one Chemical class CC1SC(=O)C(C)=C1O OROGUZVNAFJPHA-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000004201 L-cysteine Substances 0.000 description 1
- 235000013878 L-cysteine Nutrition 0.000 description 1
- 229930003756 Vitamin B7 Natural products 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- OCVXZQOKBHXGRU-UHFFFAOYSA-N iodine(1+) Chemical compound [I+] OCVXZQOKBHXGRU-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000005394 methallyl group Chemical group 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- 239000011735 vitamin B7 Substances 0.000 description 1
- 235000011912 vitamin B7 Nutrition 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Definitions
- the present invention is related to a process for producing an important biotin intermediate.
- the D-Biotin also known as Vitamin H, is mainly applied to the fields of medicine and sanitation, nutrition enhancer, feed additive, cosmetics and drinks, etc.
- the molecular structural formula of the D-Biotin is shown as follows:
- a known process for producing the above compound (a) comprises: a) L-cysteine or L-serine is used as raw material to produce an optically active hydantoin which is then converted to an intermediate compound (IX) , b) the intermediate compound (IX) is converted into a bicyclic cyanohydantoin (I) in two steps, and c) the bicyclic cyanohydantoin (I) is finally converted to the compound (a) in additional two steps. (see US 5,095,118 A)
- step b) is critical but it has two steps with using expensive catalysts and reagents. As a result, the process is not good enough for industry.
- the present invention provides an improved process for producing a biotin intermediate compound (I) ,
- R 1 and R 2 are each independently of one another H, lower alkyl, lower cycloalkyl, aryl, or lower aralkyl, optionally substituted by one or more substituents;
- R 3 is H, or a protective group which is suitable for a nitrogen atom
- X and Y are each independently of one another O or S.
- the process of the present application reduces the steps for producing the compound of formula (I) , and reduces cost by avoiding expensive catalysts and provides high yields and/or selectivity.
- lower alkyl refers to C 1 -C 10 alkyl, i.e., branched or unbranched, cyclic or non-cyclic, saturated hydrocarbon comprising 1-10 carbon atoms.
- the “lower alkyl” is C 1 -C 6 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, iso-pentyl, tert-pentyl, cyclopentyl, hexyl, isohexyl, tert-hexyl, cyclohexyl, octyl, isooctyl, tert-octyl, cyclooctyl, nonyl, isononyl, tert-nonyl, cyclononyl, decyl, isodecyl, tert-decyl, cyclodecyl. More preferably, the “lower alkyl” is methyl or ethyl.
- aryl refers to a carbocyclic aromatic system containing one ring, or two or three rings fused together where in the ring atoms are all carbon.
- aryl includes, but is not limited to groups such as phenyl, benzyl, xylyl and naphthalenyl.
- lower cycloalkyl refers to a saturated monocyclic, bicyclic or tricyclic group wherein the ring atoms of the cyclic system are all carbon and wherein each cyclic moiety contains from 3 to 12 carbon atom ring members.
- One group of lower cycloalkyl has from 5 to 7 carbon atoms. Examples of lower cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.
- lower aralkyl refers to an aryl attached to the parent molecular moiety through a lower alkyl, wherein the aryl and the lower alkyl are defined herein.
- lower silyl refers to a structure represented by R 1 R 2 R 3 Si-wherein R 1 , R 2 and R 3 are each independently of one another lower alkyl or aryl as defined herein.
- lower alkoxyl refers to the structure represented by (lower alkyl) -O-, wherein the lower alkyl is as defined herein.
- halo or “halogen” as used refers to a group of elements including fluorine (F) , chlorine (Cl) , bromine (Br) and iodine (I) , preferably refers to Cl or Br.
- halide as used is meant to include iodide, bromide, chloride and fluoride, and preferably bromide or iodide, and more preferably bromide.
- substituteduent or “substituents” as used refers to lower alkyl, lower alkoxyl, hydroxyl, halo, -NH 2 , -NO 2 , cyano and/or isocyano.
- the symbol as used in the compound formulas of the present invention means the connected group is connected to a chiral carbon in S-and/or R-configuration.
- the present invention provides a process for producing a compound of formula (I) , or a stereoisomer thereof, or a stereoisomeric mixture thereof, comprising reacting a compound of formula (II) , or a stereoisomer thereof, or a stereoisomeric mixture thereof, with a cyanide in the presence of a catalyst,
- R 1 and R 2 are each independently of one another H, lower alkyl, lower cycloalkyl, aryl, or lower aralkyl, optionally substituted by one or more substituents;
- R 3 is H, or a protective group which is suitable for a nitrogen atom
- R 4 is H, lower alkyl, lower silyl, acyl, lower alkyl sulfonyl, arylsulfonyl, or lower aralkyl sulfonyl, optionally substituted by one or more substituents;
- X and Y are each independently of one another O or S.
- the cyanide is a cyanosilane such as trimethylsilyl cyanide (TMSCN) and ⁇ -trimethylsilylpropionitrile.
- TMSCN trimethylsilyl cyanide
- ⁇ -trimethylsilylpropionitrile Preferably, the cyanide is TMSCN.
- the catalyst is selected from a group consisting of trifluoromethanesulfonic acid (HOTf) , trifluoromethanesulfonate esters such as trimethylsilyl trifluoromethanesulfonate (TMSOTf) and tert-butyldimethylsilyl trifluoromethanesulfonate (t-BuMe 2 SiOTf) , trifluoromethanesulfonate salts such as zinc trifluoromethanesulfonate (Zn (OTf) 2 ) , iron trifluoromethanesulfonate (Fe (OTf) 3 ) , copper trifluoromethanesulfonate (Cu (OTf) 2 ) , ytterbium trifluoromethanesulfonate (Yb (OTf) 3 ) , scandium trifluoromethanesulfonate (Sc (OTf) 3 ) , silver trifluoromethanesulf
- the catalyst is preferably HOTf, TMSOTf, t-BuMe 2 SiOTf, Zn (OTf) 2 , Fe (OTf) 3 , Cu (OTf) 2 , Yb (OTf) 3 , Sc (OTf) 3 , AgOTf, Bi (OTf) 3 , InBr 3 , InI 3 , AgNTf 2 , or trifluoromethansulfonimide, or mixture thereof. More preferably, the catalyst is HOTf, TMSOTf, Zn (OTf) 2 , Cu (OTf) 2 , AgOTf, InBr 3 or trifluoromethansulfonimide, or mixture thereof. The most preferably, the catalyst is TMSOTf.
- the protective group may be tert-butyl, benzyl, 4-methoxybenzyl, 3, 4-dimethoxybenzyl, 4-methylbenzyl, allyl, methallyl, crotyl, methoxymethyl, trimethylsilyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl.
- R 1 and R 2 are, each independently of one another, preferably H, C 1 -C 6 alkyl, or phenyl or benzyl, optionally substituted by one or more substituents, and more preferably R 1 is H and R 2 is phenyl.
- R 3 is preferably tert-butyl or benzyl, optionally substituted by one or more substituents, more preferably, R 3 is benzyl.
- R 4 is preferably H, methyl, ethyl, trifluoromethyl, bistrifluoromethylmethyl, trimethylsilyl (-TMS) , formyl, acetyl, propionyl, benzoyl, 4-nitrobenzoyl, methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, phenylsulfonyl, toluenesulfonyl or benzylsulfonyl.
- R 4 is H, acetyl, propionyl, benzoyl, toluenesulfonyl, bistrifluoromethylmethyl or trifluoromethanesulfonyl.
- R 4 is H, acetyl or -TMS.
- R 1 is H
- R 2 is phenyl
- R 3 is benzyl
- R 4 is H
- X is S
- Y is O.
- the stereoisomer of the present invention includes enantiomers and diastereomers.
- the compound of the formula (I) has the following stereoisomers:
- R 4 is defined as above.
- the compound of the formula (I) is one of the following stereoisomers:
- the compound of the formula (II) is one of the following stereoisomers:
- the cyanide may be added in an amount of from 1 mol to 20 mol, preferably from 1.5 mol to 15 mol, more preferably from 2 mol to 10 mol, per 1 mole of the compound of formula (II) .
- the catalyst may be added in an amount of from 0.01 mol to 1 mol, preferably from 0.05 mol to 0.8 mol, more preferably from 0.1 mol to 0.5 mol, per 1 mole of the compound of formula (II) .
- the reaction of the process of the present invention may be carried out in a solvent, or mixture thereof.
- suitable solvent include but are not limited to alkane such as cyclohexane, haloalkane such as chloroform, dichloromethane (DCM) , 1, 1, 2, 2-tetrachloroethane and 1-chloro-2-methylbutane, alkanoic acid such as dimethyl carbonate (DMC) , nitriles such as acetonitrile (ACN) and benzonitrile, aromatic alkane such as toluene, and cyclic ether such as tetrahydrofuran (THF) , and mixture thereof.
- alkane such as cyclohexane
- haloalkane such as chloroform, dichloromethane (DCM) , 1, 1, 2, 2-tetrachloroethane and 1-chloro-2-methylbutane
- alkanoic acid such as dimethyl carbonate (DMC)
- the solvent may be used in the reaction in an amount of from 1 mL to 30 mL, preferably from 2 mL to 20 mL, more preferably from 2 mL to 7 mL, per 1 mole of the compound of formula (II) .
- the reaction of the process of the present invention may be carried out at the temperature of from -50°C to 200°C, preferably from 0°C to 100°C, more preferably 10°C to 50°C, the most preferably at room temperature.
- the obtained compound of the formula (I) may be isolated and/or purified by a well-known process in the art and used for the preparation of (+) -biotin. Accordingly, the present invention also provides a process for producing (+) -biotin which comprises the process for producing the compound of formula (I) as described herein.
- the process of the present application simplifies the operation, avoids expensive catalysts and improves yield of the compound of formula (I) compared to the process of prior art.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2021/099884 WO2022257151A1 (en) | 2021-06-11 | 2021-06-11 | Process for producing biotin intermediate |
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| EP4352064A1 true EP4352064A1 (de) | 2024-04-17 |
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| CN116396306A (zh) * | 2023-04-13 | 2023-07-07 | 华东理工大学 | 一种d-生物素关键中间体硫内酯的制备方法 |
| WO2024250224A1 (en) * | 2023-06-08 | 2024-12-12 | Dsm Ip Assets B.V. | A process for producing a biotin intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3776385D1 (de) * | 1986-04-19 | 1992-03-12 | Merck Patent Gmbh | Verfahren zur herstellung von d-(+)-biotin. |
| DE3928263A1 (de) * | 1989-08-26 | 1991-02-28 | Merck Patent Gmbh | Verfahren zur herstellung von 7-cyan-7,7a-dihydro-1h,3h-imidazol(1,5-c) thiazol-5(6h)-onen |
| DE4024692A1 (de) * | 1990-08-03 | 1992-02-06 | Merck Patent Gmbh | Verfahren zur herstellung von cyanhydantoinen |
| DE4116157A1 (de) * | 1991-05-17 | 1992-11-19 | Merck Patent Gmbh | Verfahren zur herstellung von imidazothiazolon-derivaten |
| CN101255171A (zh) * | 2002-12-13 | 2008-09-03 | 明治制果株式会社 | 2-位取代碳青霉烯衍生物的中间体及其制备方法 |
| EP1730145A1 (de) * | 2004-03-22 | 2006-12-13 | Boehringer Ingelheim Pharmaceuticals Inc. | Alpha-trifluormethylalkohole oder -amine als glucocorticoidmimetika |
| KR20140015319A (ko) * | 2011-02-02 | 2014-02-06 | 이데미쓰 고산 가부시키가이샤 | 함질소 헤테로환 유도체, 유기 전기발광 소자용 전자 수송 재료, 및 그것을 이용하여 이루어지는 유기 전기발광 소자 |
| FR2972453B1 (fr) * | 2011-03-09 | 2013-11-29 | Minakem | Nouveau procede de synthese du (1r,2s,5s)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate de methyle ou de l'un de ses sels |
| CN107793434B (zh) * | 2016-09-07 | 2022-05-24 | 帝斯曼知识产权资产管理有限公司 | 用于制备经取代的咪唑并噻唑酮的方法 |
| CN111620903A (zh) * | 2020-06-17 | 2020-09-04 | 安徽贝克联合制药有限公司 | C-核苷类似物以及用于合成瑞德西韦合成的含腈c-核苷类化合物的制备方法及其应用 |
| CN117440956B (zh) * | 2021-06-11 | 2026-03-17 | 帝斯曼知识产权资产管理有限公司 | 用于生产生物素中间体的工艺 |
| CN119101067A (zh) * | 2023-06-08 | 2024-12-10 | 帝斯曼知识产权资产管理有限公司 | 用于生产生物素中间体的方法 |
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- 2021-06-11 WO PCT/CN2021/099884 patent/WO2022257151A1/en not_active Ceased
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| WO2022257151A1 (en) | 2022-12-15 |
| CN117440957A (zh) | 2024-01-23 |
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