CN112645866A - 1-苄基-4-甲基-5-烷氧基-1,2,3,6-四氢吡啶衍生物的合成及应用 - Google Patents
1-苄基-4-甲基-5-烷氧基-1,2,3,6-四氢吡啶衍生物的合成及应用 Download PDFInfo
- Publication number
- CN112645866A CN112645866A CN202011526908.8A CN202011526908A CN112645866A CN 112645866 A CN112645866 A CN 112645866A CN 202011526908 A CN202011526908 A CN 202011526908A CN 112645866 A CN112645866 A CN 112645866A
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- Prior art keywords
- compound
- acid
- benzyl
- reaction
- sodium
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- 230000015572 biosynthetic process Effects 0.000 title abstract description 8
- 238000003786 synthesis reaction Methods 0.000 title abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 78
- 238000006243 chemical reaction Methods 0.000 claims description 69
- 150000001875 compounds Chemical class 0.000 claims description 48
- -1 methylcyclohexyl Chemical group 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 22
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 20
- 239000003638 chemical reducing agent Substances 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 16
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- 230000002829 reductive effect Effects 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 11
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 10
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 239000011591 potassium Chemical group 0.000 claims description 10
- 229910052700 potassium Inorganic materials 0.000 claims description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 9
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 8
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 8
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical group 0.000 claims description 8
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 8
- 229910052744 lithium Inorganic materials 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- 239000011734 sodium Chemical group 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 238000011065 in-situ storage Methods 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 5
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 5
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 5
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229910001431 copper ion Inorganic materials 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 238000006268 reductive amination reaction Methods 0.000 claims description 5
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000007818 Grignard reagent Substances 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
- 229910000085 borane Inorganic materials 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 150000004795 grignard reagents Chemical class 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000003586 protic polar solvent Substances 0.000 claims description 4
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical group [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical group [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 3
- 239000011575 calcium Chemical group 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 229910052742 iron Chemical group 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 239000011777 magnesium Chemical group 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- 239000011701 zinc Chemical group 0.000 claims description 3
- VMKAFJQFKBASMU-KRWDZBQOSA-N (3as)-1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborole Chemical compound C([C@H]12)CCN1B(C)OC2(C=1C=CC=CC=1)C1=CC=CC=C1 VMKAFJQFKBASMU-KRWDZBQOSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- 229930045534 Me ester-Cyclohexaneundecanoic acid Natural products 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 229910004679 ONO2 Inorganic materials 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- CDKFWIMBZAUBRS-UHFFFAOYSA-M [I-].CC[Mg+] Chemical compound [I-].CC[Mg+] CDKFWIMBZAUBRS-UHFFFAOYSA-M 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 150000004792 aryl magnesium halides Chemical class 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 238000007796 conventional method Methods 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 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 claims description 2
- 229940071870 hydroiodic acid Drugs 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- LWLPYZUDBNFNAH-UHFFFAOYSA-M magnesium;butane;bromide Chemical compound [Mg+2].[Br-].CCC[CH2-] LWLPYZUDBNFNAH-UHFFFAOYSA-M 0.000 claims description 2
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 2
- UGVPKMAWLOMPRS-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].CC[CH2-] UGVPKMAWLOMPRS-UHFFFAOYSA-M 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 claims description 2
- 239000003880 polar aprotic solvent Substances 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 18
- 239000004012 Tofacitinib Substances 0.000 abstract description 7
- 229960001350 tofacitinib Drugs 0.000 abstract description 7
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 3
- 230000003356 anti-rheumatic effect Effects 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- BSBVJNUGGBQEPO-UHFFFAOYSA-N 1-benzyl-4-methylpiperidin-3-one Chemical compound C1C(=O)C(C)CCN1CC1=CC=CC=C1 BSBVJNUGGBQEPO-UHFFFAOYSA-N 0.000 description 5
- GSQZOLXWFQQJHJ-UHFFFAOYSA-N 3-bromo-4-methylpyridine Chemical compound CC1=CC=NC=C1Br GSQZOLXWFQQJHJ-UHFFFAOYSA-N 0.000 description 5
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 5
- 229940073608 benzyl chloride Drugs 0.000 description 5
- 238000002390 rotary evaporation Methods 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- NBQIZABGVLUJMB-UHFFFAOYSA-N CC(CCN(CC1=CC=CC=C1)C1)=C1OC Chemical compound CC(CCN(CC1=CC=CC=C1)C1)=C1OC NBQIZABGVLUJMB-UHFFFAOYSA-N 0.000 description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000005902 aminomethylation reaction Methods 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical group [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 4
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- KJTGXUXBSYLSPL-UHFFFAOYSA-M CC(C=C[N+](CC1=CC=CC=C1)=C1)=C1OC.[Cl-] Chemical compound CC(C=C[N+](CC1=CC=CC=C1)=C1)=C1OC.[Cl-] KJTGXUXBSYLSPL-UHFFFAOYSA-M 0.000 description 3
- ZDBPGVPHZWVDRM-UHFFFAOYSA-N CC(CCN(CC1=CC=CC=C1)C1)=C1OCCO Chemical compound CC(CCN(CC1=CC=CC=C1)C1)=C1OCCO ZDBPGVPHZWVDRM-UHFFFAOYSA-N 0.000 description 3
- BOOYJCVJPIBCJX-UHFFFAOYSA-N CCOC1=C(C)CCN(CC2=CC=CC=C2)C1 Chemical compound CCOC1=C(C)CCN(CC2=CC=CC=C2)C1 BOOYJCVJPIBCJX-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 150000002466 imines Chemical class 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- LUULLPVXDQXQNP-UHFFFAOYSA-N 2-(4-methylpyridin-3-yl)oxyethanol Chemical compound CC1=C(C=NC=C1)OCCO LUULLPVXDQXQNP-UHFFFAOYSA-N 0.000 description 2
- JSPPTLFMCHNHSG-UHFFFAOYSA-N 3-ethoxy-4-methylpyridine Chemical compound CCOC1=CN=CC=C1C JSPPTLFMCHNHSG-UHFFFAOYSA-N 0.000 description 2
- VTZQHJXNUHHEPL-UHFFFAOYSA-N 3-methoxy-4-methylpyridine Chemical compound COC1=CN=CC=C1C VTZQHJXNUHHEPL-UHFFFAOYSA-N 0.000 description 2
- XYGHZCUAGXFIPY-UHFFFAOYSA-N 4-methyl-3-propan-2-yloxypyridine Chemical compound CC(C)OC1=CN=CC=C1C XYGHZCUAGXFIPY-UHFFFAOYSA-N 0.000 description 2
- IBKMZYWDWWIWEL-UHFFFAOYSA-N 4-methylpyridin-3-amine Chemical compound CC1=CC=NC=C1N IBKMZYWDWWIWEL-UHFFFAOYSA-N 0.000 description 2
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 2
- HGZCQBLEXIWQSN-UHFFFAOYSA-M CC(C)OC1=C(C)C=C[N+](CC2=CC=CC=C2)=C1.[Cl-] Chemical compound CC(C)OC1=C(C)C=C[N+](CC2=CC=CC=C2)=C1.[Cl-] HGZCQBLEXIWQSN-UHFFFAOYSA-M 0.000 description 2
- XHLHYRVWQGBYJP-UHFFFAOYSA-N CC(C)OC1=C(C)CCN(CC2=CC=CC=C2)C1 Chemical compound CC(C)OC1=C(C)CCN(CC2=CC=CC=C2)C1 XHLHYRVWQGBYJP-UHFFFAOYSA-N 0.000 description 2
- DOBGMGPFIYYTQM-UHFFFAOYSA-M CC(C=C[N+](CC1=CC=CC=C1)=C1)=C1OCCO.[Cl-] Chemical compound CC(C=C[N+](CC1=CC=CC=C1)=C1)=C1OCCO.[Cl-] DOBGMGPFIYYTQM-UHFFFAOYSA-M 0.000 description 2
- QAMSZYMTYHYSNN-UHFFFAOYSA-M CCOC1=C(C)C=C[N+](CC2=CC=CC=C2)=C1.[Cl-] Chemical compound CCOC1=C(C)C=C[N+](CC2=CC=CC=C2)=C1.[Cl-] QAMSZYMTYHYSNN-UHFFFAOYSA-M 0.000 description 2
- JJLJMEJHUUYSSY-UHFFFAOYSA-L Copper hydroxide Chemical compound [OH-].[OH-].[Cu+2] JJLJMEJHUUYSSY-UHFFFAOYSA-L 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 238000006887 Ullmann reaction Methods 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 2
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 229940076286 cupric acetate Drugs 0.000 description 2
- 229960003280 cupric chloride Drugs 0.000 description 2
- 229940045803 cuprous chloride Drugs 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000006197 hydroboration reaction Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 229960004247 tofacitinib citrate Drugs 0.000 description 2
- SYIKUFDOYJFGBQ-YLAFAASESA-N tofacitinib citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 SYIKUFDOYJFGBQ-YLAFAASESA-N 0.000 description 2
- NVKDDQBZODSEIN-OCCSQVGLSA-N (3r,4r)-1-benzyl-n,4-dimethylpiperidin-3-amine Chemical compound C1C[C@@H](C)[C@@H](NC)CN1CC1=CC=CC=C1 NVKDDQBZODSEIN-OCCSQVGLSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- YKYOIMJLSMZUBA-VAWYXSNFSA-N (e)-n-(2-methylpropyl)undec-2-en-8,10-diynamide Chemical compound CC(C)CNC(=O)\C=C\CCCCC#CC#C YKYOIMJLSMZUBA-VAWYXSNFSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MEOKQEOOBLZWOJ-UHFFFAOYSA-N 1-benzyl-N,4-dimethyl-2H-pyridin-3-amine Chemical compound C(C1=CC=CC=C1)N1CC(=C(C=C1)C)NC MEOKQEOOBLZWOJ-UHFFFAOYSA-N 0.000 description 1
- NVKDDQBZODSEIN-UHFFFAOYSA-N 1-benzyl-n,4-dimethylpiperidin-3-amine Chemical compound C1CC(C)C(NC)CN1CC1=CC=CC=C1 NVKDDQBZODSEIN-UHFFFAOYSA-N 0.000 description 1
- FVRZQLQXDPJADE-UHFFFAOYSA-N 1-benzyl-n,4-dimethylpiperidin-3-amine;hydrochloride Chemical compound Cl.C1CC(C)C(NC)CN1CC1=CC=CC=C1 FVRZQLQXDPJADE-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000004791 alkyl magnesium halides Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- QYJPSWYYEKYVEJ-FDGPNNRMSA-L copper;(z)-4-oxopent-2-en-2-olate Chemical compound [Cu+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O QYJPSWYYEKYVEJ-FDGPNNRMSA-L 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- UESSEMPSSAXQJC-UHFFFAOYSA-N ethanol;methanamine Chemical compound NC.CCO UESSEMPSSAXQJC-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- CUILPNURFADTPE-UHFFFAOYSA-N hypobromous acid Chemical compound BrO CUILPNURFADTPE-UHFFFAOYSA-N 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- XJTQJERLRPWUGL-UHFFFAOYSA-N iodomethylbenzene Chemical compound ICC1=CC=CC=C1 XJTQJERLRPWUGL-UHFFFAOYSA-N 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
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical group [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- XCASJAIZRKXHGU-UHFFFAOYSA-N n-cyclohexyl-1-(4-methoxyphenyl)methanimine Chemical compound C1=CC(OC)=CC=C1C=NC1CCCCC1 XCASJAIZRKXHGU-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical group Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- JBJWASZNUJCEKT-UHFFFAOYSA-M sodium;hydroxide;hydrate Chemical compound O.[OH-].[Na+] JBJWASZNUJCEKT-UHFFFAOYSA-M 0.000 description 1
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical compound O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
本发明涉及药物中间体合成领域,特别是涉及用于制备抗类风湿关节炎药物托法替布的关键中间体合成领域。具体地说,本发明涉及1‑苄基‑4‑甲基‑5‑烷氧基‑1,2,3,6‑四氢吡啶化合物、其合成方法、以及其在制备托法替布的关键中间体顺式1‑苄基‑3‑甲氨基‑4‑甲基哌啶中的应用。
Description
技术领域
本发明涉及药物中间体合成领域,特别是涉及用于制备抗类风湿关节炎药物托法替布的关键中间体合成领域。具体地说,本发明涉及1-苄基-4-甲基-5-烷氧基-1,2,3,6-四氢吡啶化合物、其合成方法、以及其在制备托法替布的关键中间体顺式1-苄基-3-甲氨基-4-甲基哌啶中的应用。
背景技术
枸橼酸托法替布(Tofacitinib citrate)是辉瑞公司研发的首个作用于JAK通路的抑制剂,用于治疗类风湿性关节炎。该产品于2012年11月6日在美国首先批准上市。托法替布的合成通常由关键中间体式VI化合物(3R,4R)-1-苄基-3-甲氨基-4-甲基哌啶经转化得到(流程1)。
中间体式VI化合物的合成方法已有较多报道,文献Org.process.Res.Dev.2003,7,115-120报道了以4-甲基吡啶为原料,经与苄基卤化物反应,还原,硼氢化氧化,并继续氧化成酮,再与甲胺进行还原胺化得到外消旋的中间体,再经拆分得到产物(流程2)。该合成路线较长,硼氢化氧化步骤操作繁琐,后续氧化步骤使用危险和管制的过氧化氢和三氧化硫吡啶试剂,不利于工业化生产。
文献Org.process.Res.Dev.2005,9,51-56报道了以3-氨基-4-甲基吡啶为原料,通过氨基上保护,氢化,还原,苄基化得到1-苄基-3-甲氨基-4-甲基吡啶,最后拆分(流程3)。此路线总收率较低,仅为14.6%,且用到价格昂贵的金属Rh/C催化剂以及危险还原剂氢化铝锂,限制了工业化生产。
文献J.Med.Chem,2008,51,8102-8018报道了合成托法替布一系列衍生物的方法(流程4)。但该方法路线冗长繁琐,使用了昂贵的金属催化剂二氧化铂,且得到的中间体为4种异构体,完全不适合工业化。
专利CN108610279A报道了以3-氨基-4-甲基吡啶为原料,经还原胺化,成盐,还原三步合成外消旋中间体(流程5)。该路线起始原料价格贵且不易获得,还原和酸化得到的产物后处理比较繁琐。
专利WO2014097150与CN108689915A报道了以3-溴-4-甲基吡啶为起始原料,利用Ullmann反应实现胺甲基化,其区别在于前者先成盐后进行胺甲基化反应,后者先进行胺甲基化后成盐(流程6)。该路线中Ullmann反应存在反应条件较苛刻,产率不高,后处理繁琐等缺点。
综上所述,目前已报道的化合物VI的制备方法关键在于哌啶环构建和氨甲基化两个步骤,但目前已知的每种方法,均存在工艺操作繁琐、使用管制和危险试剂、使用贵金属催化剂、收率不理想、反应条件苛刻等问题。因此,有必要进一步研究适合化合物VI的工业化生产的简洁高效的合成方法。
为了克服现有技术存在的缺点与不足,本发明提供了一种新的化合物VI的合成方法。该方法具有操作便利,原材料廉价易得,产物收率高,中间体和目标产物的纯度好等特点,且易于进行工业化生产。
发明内容
在本发明中,下列术语具有以下所述的含义:
单独或与其他基团组合的术语“烷基”表示由碳和氢原子组成的直链或支链的单价饱和烃基团。“C1-C10烷基”表示具有1至10个碳原子的烷基,优选C1-C6烷基。“C1-C6烷基”表示具有1至6个碳原子的支链或直链烷基,例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、异戊基、正己基。
“卤素”是指氟、氯、溴、碘。
“卤代烷基”表示被一个或多个卤素取代的如上所述的烷基,优选卤代C1-C6烷基,例如三氟甲基。
“环烷基”是指由碳原子和氢原子组成的环状的饱和烷基基团,优选C3-C7环烷基,例如环丙基、环丁基、环戊基、环己基或环庚基。
“芳基”是指由碳原子和氢原子组成的单环或稠合双环的芳香环。“C5-10芳基”是指含有5-10个碳原子的芳基。例如,C5-10芳基可以是苯基或萘基。
“芳烷基”是指被如上所述的芳基取代的如上所述的烷基,例如苄基。
“取代的烷基”、“取代的环烷基”、“取代的芳基”和“取代的芳烷基”分别是指被如上所述的烷基、卤素、卤代烷基、羟基和/或氨基所取代的如上所述的烷基、环烷基、芳基和芳烷基。它们的实例包括但不限于2-羟基-乙基、2-氨基-乙基、3-羟基丙基、4-羟基-丁基、甲基环己基、2-甲基苯基、4-甲基苯基、4-丙基苄基、4-甲基苄基等。
“C1-C4醇”是指具有1-4个碳原子的醇,例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇或叔丁醇。
本发明的目的在于提供一种用于制备托法替布的关键中间体,即顺式-1-苄基-3-甲氨基-4-甲基哌啶的合成方法。该方法优点为路线简短、原料易得、条件温和、提纯方便、收率较高且容易实现规模化生产。
本发明所要解决的技术问题是通过如下技术方案实现的。
第一方面,本发明提供式I化合物,命名为1-苄基-4-甲基-5-烷氧基-1,2,3,6-四氢吡啶,结构如下:
其中R选自:烷基,取代的烷基,环烷基,取代的环烷基,芳基,取代的芳基,芳烷基,或取代的芳烷基。
例如,R选自:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、2-羟基-乙基、2-氨基-乙基、3-羟基丙基、4-羟基-丁基、戊基、环戊基、己基、环己基、甲基环己基、苯基、2-甲基苯基、对甲基苯基、苄基、4-丙基苄基或4-甲基苄基。
在一个优选的实施方案中,R选自:C1-C6烷基、环己基、2-羟基乙基、2-氨基乙基、3-羟基丙基、4-羟基丁基、苄基或苯基。
更优选地,R选自:甲基、乙基、正丙基、异丙基、正丁基、异丁基、环己基、2-羟基乙基、2-氨基乙基、3-羟基丙基或苄基。
第二方面,本发明提供了式I化合物的制备方法,
其中,L为离去基团,R如上文对式I化合物所述,M为金属元素,n选自1、2或3,X为卤素,所述方法包括以下步骤:
步骤(1):化合物IV与ROH或(RO)nM反应生成化合物III,
步骤(2):化合物III与苄基卤化物反应生成化合物II,和
步骤(3):化合物II在还原剂作用下被还原生成化合物I。
在一些优选的实施方案中,具体反应条件如下:
步骤(1):在惰性气体氛围下,在极性溶剂中,化合物IV与ROH或(RO)nM在铜离子或钯催化剂的催化作用下发生取代反应生成化合物III。
所述的铜离子催化剂选自氯化亚铜、氯化铜、溴化亚铜、溴化铜、碘化亚铜、碘化铜、硫酸铜、硝酸铜、乙酸铜、氢氧化铜、或乙酰丙酮铜。
所述的钯离子催化剂选自氯化钯、三苯基膦氯化钯、醋酸钯。
所述化合物IV中,L为卤素,例如F、Cl、Br或I,或者L为-OCOR1、-OR2或-ONO2。
R1为烷基或卤代烷基,例如CF3或CH3。
R2为烷基磺酰基或芳基磺酰基,或取代的烷基磺酰基或芳基磺酰基,例如对甲苯磺酰基,对溴苯磺酰基,硝基苯磺酰基,三氟甲磺酰基,甲磺酰基,5-(二甲氨基)萘-1-磺酰基。
所述的(RO)nM中,M为金属元素,M可以选自锂、钠、钾、钙、镁、铝、锌或铁,n为金属M的化合价,且n选自1、2或3.
在一些具体的实施方案中,当M为锂、钠、钾时,n为1;当M为钙、镁或锌时,n=2;当M为铝或铁时,n=3。
在更优选的实施方案中,L为Cl或Br。
所述的(RO)nM中R取代基如上所述。
优选地,所述的(RO)nM为固体的碱金属盐或其溶液。
例如,碱金属盐为锂盐、钠盐或钾盐,碱金属盐的溶液包括锂盐、钠盐、钾盐在C1-C4醇中的溶液。或者,可通过加入强碱与ROH反应在原位制备所述(RO)nM溶液。
在所述原位制备(RO)nM溶液的方法中,强碱选自金属锂、金属钠、金属钾、氢化钠、氢化钾、氢化钙、叔丁醇钠、叔丁醇钾、氢氧化钠、氢氧化钾或格式试剂中的一种或几种。
所述的格式试剂为烷基卤化镁或芳基卤化镁,例如甲基溴化镁、乙基溴化镁、乙基碘化镁、丙基溴化镁、丁基溴化镁、苯基溴化镁。
化合物IV与ROH的投料比为1.0:1.0-20.0。
化合物IV与(RO)nM的投料比为1.0:(1.0-20.0)/n,n选自1、2或3。
所述铜离子为I价或II价铜离子,包括且不限于氯化亚铜、溴化亚铜、碘化亚铜、氯化铜、溴化铜、碘化铜、硫酸铜、硝酸铜、乙酸铜。
催化剂用量为0.1-20.0mol%,优选为0.5-10.0mol%。
所述反应溶剂为极性非质子溶剂、质子溶剂或其混合物,包括N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、N-甲基吗啉、甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、乙二醇、丙二醇、丁二醇、或它们的任意两种或两种以上的混合物。
所述反应温度为20-150℃,例如60-150℃,优选为100-130℃。
反应时间为1.0-10.0小时。
步骤(2):化合物III与苄基卤化物反应生成化合物II。
所述苄基卤化物可以是氯化苄、溴化苄或碘化苄。化合物III与苄基卤化物的投料比为1:1.0-3.0。
反应温度为0~150℃,优选10~80℃。
反应时间为2~48h。
步骤(3):化合物II在质子溶剂中,经还原剂还原生成式I化合物。
所述质子溶剂可以为甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、乙二醇、丙二醇或其混合物。
所述还原剂可以为本领域常用的还原剂,例如硼氢化锂、硼氢化钠、硼氢化钾、氰基硼氢化钠、三乙基硼氢化锂或硼烷。
反应温度为-5-30℃。
反应时间为0.5-24h。
第三方面,本发明还提供了用于制备托法替布的关键中间体式VI化合物(即,顺式-1-苄基-3-甲氨基-4-甲基哌啶)的合成方法,所述方法包括以下步骤:
步骤(4):式I化合物在酸性条件下水解得到式V化合物,和
步骤(5):化合物V与甲胺在还原剂存在下进行还原胺化,并与盐酸成盐生成式VI化合物。
在一些优选的实施方案中,具体反应条件如下:
步骤(4):式I化合物1-苄基-4-甲基-5-烷氧基-1,2,3,6-四氢吡啶在酸性条件下发生水解反应得到式V化合物1-苄基-4-甲基哌啶-3-酮。
反应所用的酸为无机酸或有机酸。例如,无机酸可包括盐酸、氢溴酸、氢碘酸、硫酸、磷酸、硝酸、次氯酸、次溴酸、次磷酸、次硫酸。有机酸可包括甲酸、乙酸、三氟乙酸、草酸、酒石酸、柠檬酸、对甲苯磺酸、三氟甲磺酸。
反应所用的酸优选为盐酸,例如6M盐酸溶液。
式I化合物与酸的投料比为1:1~1:10。
反应溶剂为质子或非质子有机溶剂,例如甲醇、乙醇、正丙醇、异丙醇、二氯甲烷、四氢呋喃、2-甲基四氢呋喃、1,4-二噁烷、甲苯,反应温度为0-110℃,反应时间为0.5~10小时。
步骤(5):式V化合物与甲胺反应形成希夫碱,然后与还原剂反应得到式VI化合物1-苄基-3-甲氨基-4-甲基哌啶,式VI化合物与盐酸成盐进一步纯化。
所述的甲胺为甲胺的酸加成盐或甲胺的醇溶液。其中甲胺的酸加成盐为甲胺的盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、甲酸盐或乙酸盐。
所述的还原剂为本领域常用的还原剂,例如氰基硼氢化钠、三乙酰氧基硼氢化钠、三乙基硼氢化锂、硼烷、(S)-2-甲基-CBS-噁唑硼烷,或者可按照常规方法在原位制备上述还原剂,例如,三乙酰氧基硼氢化钠制备方法可参考文献Org.process.Res.Dev.2003,7,115-120。
在一个优选的实施方案中,制备式VI化合物的方法包括以下步骤:
步骤(1):化合物IV与ROH或(RO)nM反应生成化合物III,
步骤(2):化合物III与苄基卤化物反应生成化合物II,
步骤(3):化合物II在还原剂作用下被还原生成化合物I,
步骤(4):化合物I在酸性条件下水解得到化合物V,和
步骤(5):化合物V与甲胺在还原剂存在下进行还原胺化,并与盐酸成盐生成式VI化合物,
其中,L为离去基团,R如权利要求1所述,M和n如权利要求3所述,且X为卤素。
在进一步优选的实施方案中,步骤(1)、(2)、(3)、(4)、(5)各自的反应条件如上文所述。
具体实施方式
通过以下实施例对本发明的方法进行进一步的说明。应当理解,提供以下实施例的目的仅仅是为了能够更好的理解本发明,而不是以任何方式限定本发明的范围。
实施例1-4通过以下路线制备1-苄基-5-甲氧基-4-甲基-1,2,3,6-四氢吡啶。
实施例1
3-甲氧基-4-甲基吡啶的制备:
氮气保护下,向250mL三口瓶中加入3-溴-4-甲基吡啶17.2g和DMF 100.0mL溶清后,加入甲醇钠10.8g和CuBr 0.72g,反应液升温至130℃搅拌5小时。TLC(PE:EA=2:1)监测原料反应完全,有白色固体NaBr逐渐生成,反应混合物降至室温,加水40.0mL淬灭反应,混合液加入甲基叔丁基醚60mL×3提取,合并有机层,加入20.0mL饱和NaCl洗涤,旋蒸浓缩得深黄色液体17.50g,粗收率100%,GC纯度91.5%,无需纯化直接用于下一步反应。1H-NMR(400MHz,CDCl3)δ8.16(s,1H),8.12(d,J=4.8Hz,1H),7.06(d,J=4.8Hz,1H),3.91(s,3H),2.23(s,3H)。
实施例2
1-苄基-3-甲氧基-4-甲基吡啶鎓氯化物的制备:
氮气保护下,向250mL反应瓶中加入上述反应产物3-甲氧基-4-甲基吡啶17.5g,溶于乙腈120mL,加入氯化苄13.8mL,加热至80℃回流搅拌7小时,TLC(PE:EA=2:1)显示原料反应完全,颜色逐渐变深。反应混合物降至室温,将反应液旋转蒸发至干,加入石油醚,室温搅拌分散,抽滤除去石油醚,滤饼抽干,得灰白色固体22.6g,粗收率90.4%,产物不经纯化直接用于下一步反应。
实施例3
1-苄基-5-甲氧基-4-甲基-1,2,3,6-四氢吡啶的制备:
向500mL反应瓶中加入上述1-苄基-3-甲氧基-4-甲基吡啶鎓氯化物22.6g,溶于220mL甲醇,控制内温10-25℃,分批加入NaBH4 10.26g,反应剧烈,放气放热。加料完毕后室温继续搅拌2小时,TLC(DCM:MeOH=10:1)监测反应完全。加水80mL淬灭反应,蒸去甲醇,加入EtOAc 100mL×2次,合并有机层,水洗,蒸馏至干,得浅黄色液体17.0g,收率87.0%。1H-NMR(400MHz,CDCl3)δ7.36-7.25(m,5H),3.59(s,2H),3.48(s,3H),2.98-2.96(m,2H),2.50(t,J=5.6Hz,2H),2.07-2.05(m,2H),1.63(s,3H);13C-NMR(100MHz,CDCl3)δ145.8,137.9,129.2,128.2,127.1,113.3,62.6,57.4,51.7,49.8,30.0,14.9ppm.;MS(EI):217.2,(C14H19NO[M]+)。
实施例4
1-苄基-5-甲氧基-4-甲基-1,2,3,6-四氢吡啶的制备:
向50mL反应瓶中加入上述1-苄基-3-甲氧基-4-甲基吡啶鎓氯化物2.70g,溶于20mL甲醇,控制内温10-25℃下分批加入NaBH4 1.05g,反应放气放热,加料完毕室温继续搅拌2小时,TLC(v/v DCM:MeOH=10:1)监测反应完全。加水10mL淬灭反应,蒸去甲醇,加入EtOAc 10mL×2提取,合并有机层,水洗,蒸馏至干,得浅黄色液体1.64g,收率82.1%。
实施例5-7通过以下路线合成1-苄基-5-乙氧基-4-甲基-1,2,3,6-四氢吡啶:
实施例5
3-乙氧基-4-甲基吡啶的制备:
氮气保护下,向250mL三口瓶中加入3-溴-4-甲基吡啶17.2g和DMF 100mL溶清后,加入乙醇钠13.6g,加入CuCl2 0.67g,加热至130℃搅拌反应7小时。TLC(v/v PE:EA=2:1)监测原料反应完全,有白色固体NaBr逐渐生成,反应混合物降至室温,加水40mL淬灭反应,加入甲基叔丁基醚60mL×3提取,合并有机层,水洗,浓缩至干得深黄色液体11.20g,粗收率81.8%。1H-NMR(400MHz,CDCl3)δ8.15(s,1H),8.10(d,J=4.0Hz,1H),7.05(d,J=4.4Hz,1H),4.12(q,J=6.8Hz,2H),2.23(s,3H),1.44(t,J=7.2Hz,3H)。
实施例6
1-苄基-3-乙氧基-4-甲基吡啶鎓氯化物的制备:
氮气保护下,向250mL反应瓶中加入上述反应产物3-乙氧基-4-甲基吡啶11.2g(82mmol)和乙腈120mL溶清后,加入氯化苄12.4g,加热至80℃回流搅拌7小时,TLC(v/v PE:EA=2:1)监测原料反应完全,颜色逐渐变深。反应混合物降至室温,将反应液浓缩至干,加入石油醚,室温搅拌分散,抽滤除去石油醚,滤饼抽干,得灰白色固体18.3g,粗收率98.0%。产物不经纯化直接用于下一步反应。
实施例7
1-苄基-5-乙氧基-4-甲基-1,2,3,6-四氢吡啶的制备:
向500mL反应瓶中加入上述1-苄基3-乙氧基-4-甲基吡啶鎓氯化物18.3g和200mL乙醇溶清后,控制内温10-25℃分批加入NaBH4 8.78g,反应缓慢放气放热。加料完毕室温继续搅拌2小时,TLC(DCM:MeOH=10:1)监测反应完全。加水80mL淬灭反应,蒸去乙醇,加入EtOAc 100mL×2提取,合并有机层,水洗,蒸馏至干,得到浅黄色液体产物16.7g,收率90.0%。1H-NMR(400MHz,CDCl3)δ7.35-7.24(m,5H),3.66(q,J=6.8Hz,2H),3.58(s,2H),2.96(s,2H),2.50(t,J=4.2Hz,2H),2.06(m,2H),1.63(s,3H),1.21(t,J=7.2Hz,3H);13C-NMR(100MHz,CDCl3)δ144.8,138.2,129.2,128.2,127.1,113.7,65.1,62.6,52.5,49.9,30.1,15.6,15.2ppm.;MS(EI):231.1,(C15H21NO[M]+)。
实施例8-10通过以下路线合成1-苄基-5-异丙氧基-4-甲基-1,2,3,6-四氢吡啶:
实施例8
3-异丙氧基-4-甲基吡啶的制备:
氮气保护下,向250mL三口瓶中加入异丙醇20mL,控温-5-5℃分批加入NaH 2.0g(60%)制备异丙醇钠,然后依次加入DMF 40mL、反应底物3-溴-4-甲基吡啶4.3g和CuBr180mg,体系变浅蓝色。加热至130℃搅拌反应4小时,TLC(PE:EA=2:1)监测原料基本反应完全。冷却至室温,加20mL水淬灭反应,减压蒸除剩余异丙醇,剩余液加入甲基叔丁基醚20mL×3提取,有絮状物生成,过滤,合并有机相,水洗,浓缩至干,得浅黄色液体2.4g,收率63.6%。产物不经纯化直接用于下一步反应。1H-NMR(400MHz,CDCl3)δ8.18(s,1H),8.09(d,J=4.4Hz,1H),7.06(d,J=4.4Hz,1H),4.63-4.57(m,1H),2.22(s,3H),1.36(d,J=6.0Hz,6H)。
实施例9
1-苄基-3-异丙氧基-4-甲基吡啶鎓氯化物的制备:
氮气保护下,向100mL反应瓶中加入上述反应产物3-异丙氧基-4-甲基吡啶2.4g和乙腈30mL溶清后,加入氯化苄2.43g,加热至80℃回流搅拌5小时,TLC(PE:EA=2:1)监测原料反应完全。降至室温,将反应液浓缩至干,加入石油醚,室温搅拌分散,抽滤除去石油醚,滤饼抽干,得白色固体4.0g,粗收率90.0%。产物不经纯化直接用于下一步反应。
实施例10
1-苄基-5-异丙氧基-4-甲基-1,2,3,6-四氢吡啶的制备
向100mL反应瓶中加入上述1-苄基-3-异丙氧基-4-甲基吡啶鎓氯化物4.0g和甲醇40mL溶清后,控制内温10-25℃,分批加入NaBH4 1.64g,反应放气放热。加料完毕室温继续搅拌1小时,TLC(DCM:MeOH=10:1)监测反应完全。加水20mL淬灭反应,蒸去甲醇,加入EtOAc40mL×2提取,合并有机层,水洗,浓缩至干,得产物为无色液体2.97g,收率84.2%。1H-NMR(400MHz,CDCl3)δ7.34-7.22(m,5H),3.98-3.92(m,1H),3.57(s,2H),2.92(s,2H),2.50(t,J=4.2Hz,2H),2.07(s,2H),1.62(s,3H),1.15(d,J=6.0Hz,6H);13C-NMR(100MHz,CDCl3)δ143.3,138.3,129.1,128.2,127.0,114.2,70.3,62.6,53.2,50.0,30.2,22.7,15.7ppm.;MS(EI):245.2,(C16H23NO[M]+)。
实施例11-13通过以下路线合成1-苄基-5-(2-羟基-乙氧基)-4-甲基-1,2,3,6-四氢吡啶。
实施例11
3-(2-羟基-乙氧基)-4-甲基吡啶的制备:
氮气保护下,向100mL三口瓶中加入乙二醇12.4g、3-溴-4-甲基吡啶3.44g、NaOH1.6g和CuCl2 134mg,混合后,体系变深蓝色。加热到130℃搅拌反应3个小时,TLC(v/v DCM:MeOH=10:1)监测反应基本完全。冷却至室温,减压蒸馏除去乙二醇,加入二氯甲烷40mL×2萃取,合并有机相,水洗,浓缩至干,加入正己烷结晶,过滤得浅黄色固体2.14g产物,收率70.0%。1H-NMR(400MHz,CDCl3)δ8.12(s,1H),8.08(d,J=4.4Hz,1H),7.04(d,J=4.4Hz,1H),4.15-4.13(t,2H),3.99-3.96(t,2H),2.22(s,3H)。
实施例12
1-苄基-3-(2-羟基-乙氧基)-4-甲基吡啶鎓氯化物的制备:
向100mL反应瓶中加入上一步产物3-(2-羟基-乙氧基)-4-甲基吡啶2.14g和乙腈25ml,加入氯化苄2.12g,升温回流搅拌6小时,TLC(DCM:MeOH=10:1)监测原料反应完全。冷却至室温,有固体析出,浓缩乙腈,加入30mL甲基叔丁基醚分散,抽滤,得灰白色固体3.7g,产率94.0%。
实施例13
1-苄基-5-(2-羟基-乙氧基)-4-甲基-1,2,3,6-四氢吡啶的制备
向100mL反应瓶中加入1-苄基-3-(2-羟基-乙氧基)-4-甲基吡啶鎓氯化物3.65g,溶于50mL甲醇,降温至10℃,分批加入NaBH4 1.25g,加毕升至室温搅拌3h,TLC(v/v DCM:MeOH=10:1)监测反应基本完全。加入水10mL淬灭反应,旋蒸除去甲醇,加入乙酸乙酯20mL×2萃取,水洗,浓缩至干,得到2.75g浅黄色液体,产率85%。1H-NMR(400MHz,CDCl3)δ7.42-7.27(m,5H),3.75-3.74(m,6H),3.14(m,2H),2.64-2.66(m,2H),2.16(m,2H),2.16(s,3H);13C-NMR(100MHz,CDCl3)δ143.6,135.7,129.7,128.6,127.9,114.6,71.3,62.0,61.8,51.6,49.3,29.2,15.2ppm;MS(ESI):248.05,(C15H21NO2,[M+1]+)。
实施例14-17举例说明了从式I化合物制备中间体化合物VI的合成方法
实施例14
1-苄基-4-甲基哌啶-3-酮(化合物V)的制备方法一:
向250mL反应瓶中加入17.0g的1-苄基-5-甲氧基-4-甲基-1,2,3,6-四氢吡啶和150mL甲醇,溶清后,加入6M HCl 39mL,将反应液加热至60℃回流2h,TLC(v/v PE:EA=2:1)监测原料完全转化。反应混合物降至室温,减压蒸去甲醇,加入水50mL,加入NaOH固体调pH至大于11,加入乙酸乙酯50mL×2提取,有机层水洗,旋蒸至干得红棕色粗品21.0g,粗收率100%,无需纯化直接用于下一步反应。取少量粗品经柱层析,得浅黄色液体用于结构鉴定。1H-NMR(400MHz,CDCl3)δ7.34-7.26(m,5H),3.58-3.57(m,2H),3.25-3.21(d,J=14.0Hz,1H),2.95-2.92(m,1H),2.80-2.77(d,J=14.0Hz,1H),2.47-2.45(m,1H),2.36-2.33(m,1H),2.06-2.01(m,1H),1.66-1.63(m,1H),1.08(d,J=6.4Hz,3H);13C-NMR(100MHz,CDCl3)δ208.6,137.2,129.2,128.4,127.5,64.1,62.6,51.9,43.0,32.9.,14.2ppm;ESI-MS:204.05,(C13H17NO,[M+1]+)。
实施例15
1-苄基-4-甲基哌啶-3-酮(化合物V)的制备方法二:
向100mL反应瓶中加入2.0g 1-苄基-5-乙氧基-4-甲基-1,2,3,6-四氢吡啶和20mLMeOH溶清后,加入4.8mL 6M HCl,反应液加热至60℃回流2h,TLC(v/v PE:EA=2:1)监测原料完全转化。反应混合物降至室温,减压蒸去甲醇,加入水20mL,加入NaOH固体调pH至大于11,加入乙酸乙酯15mL×2提取,有机层水洗,旋蒸至干得深黄色粗品2.1g,粗收率100%,直接用于下一步反应。
实施例16
1-苄基-4-甲基哌啶-3-酮(化合物V)的制备方法三:
向100mL反应瓶中加入2.66g 1-苄基-5-(2-羟基-乙氧基)-4-甲基-1,2,3,6-四氢吡啶和20mL甲醇溶清后,加入5mL 6M HCl,反应液加热至60度回流2h,TLC(v/v PE:EA=2:1)监测原料完全转化。反应混合物降至室温,减压蒸去甲醇,加入水20mL,加入NaOH固体调pH至大于11,加入乙酸乙酯15mL×2提取,有机层水洗,旋蒸至干得深黄色粗品2.13g,粗收率100%,直接用于下一步反应。
实施例17
1-苄基-3-甲氨基-4-甲基哌啶盐酸盐的制备:
氮气保护下,向250mL反应瓶中加入1-苄基-4-甲基哌啶-3-酮21.0g和甲苯60mL溶清后,控温15℃,滴加30%的甲胺的乙醇溶液50mL,再加入AcOH 4.8mL,加毕后室温搅拌2h制备亚胺中间体,倒入滴液漏斗中。向500mL三口瓶中,加入NaBH4 3.95g,溶于80mL THF,冷却到10度,缓慢滴加乙酸28.3g,剧烈放气放热,滴加完毕于15℃搅拌2h原位制备NaBH(OAc)3。控制内温低于20℃,将上述亚胺反应液滴加入该体系中,滴加完毕体系自然升至室温反应,TLC(v/v PE:EA=2:1)监测反应完全。加入30%NaOH水溶液调节pH至11-12,分层,水层用甲苯50mL×2提取,合并有机层,减压浓缩至干得游离碱粗品。将粗品溶于100mLEtOH,室温下缓慢滴加浓盐酸14mL,滴毕搅拌30min,固体逐渐析出,控制内温为5-10℃继续缓慢搅拌1h,抽滤得粉白色固体,加入EtOAc 80mL室温打浆,过滤,得白色固体17.8g。两步总收率80.4%。游离后分析GC含量100%,dr值:99.2:0.8。1H-NMR(400MHz,CDCl3)δ7.28-7.18(m,5H),3.53(d,J=12.8Hz,1H),3.39(d,J=12.8Hz,1H),2.69-2.62(m,2H),2.40(s,1H),2.29(s,3H),2.12-2.02(m,2H),1.66(s,1H),1.47-1.43(m,3H),0.92(d,J=7.2Hz,3H);13C-NMR(100MHz,CDCl3)δ138.8,128.9,128.1,126.8,63.1,59.1,54.5,52.6,34.5,33.2,29.8,16.3ppm;MS(EI):218.2,(C14H22N2[M]+)。
Claims (16)
2.根据权利要求1所述的化合物,其特征在于R为:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、2-羟基-乙基、2-氨基-乙基、3-羟基丙基、4-羟基-丁基、戊基、环戊基、己基、环己基、甲基环己基、苯基、2-甲基苯基、对甲基苯基、苄基、4-丙基苄基或4-甲基苄基。
4.根据权利要求3的方法,其特征为:
L为卤素,例如F、Cl、Br或I,或者L为-OCOR1、-OR2或-ONO2,
R1为烷基或卤代烷基,例如CF3或CH3,和/或
R2为烷基或芳基磺酰基,或取代的烷基或芳基磺酰基,例如对甲苯磺酰基,对溴苯磺酰基,硝基苯磺酰基,三氟甲磺酰基,甲磺酰基或5-(二甲基氨基)萘-1-磺酰基。
5.根据权利要求3或4任一项所述的方法,其中步骤(1)是在铜离子或钯催化剂的催化下进行。
6.根据权利要求3-5任一项所述的方法,其特征在于(RO)nM中M选自锂、钠、钾、钙、镁、铝、锌或铁。
7.根据权利要求6所述的方法,其特征在于所述的(RO)nM为固体的碱金属盐或其溶液,例如锂盐、钠盐、钾盐或其在C1-C4醇中的溶液,或加入强碱与ROH反应原位制备所述(RO)nM溶液。
8.根据权利要求7所述的方法,其中加入强碱与ROH反应原位制备所述(RO)nM溶液,其特征在于所述的强碱为选自金属锂、金属钠、金属钾、氢化钠、氢化钾、氢化钙、叔丁醇钠、叔丁醇钾、氢氧化钠、氢氧化钾或格式试剂中的一种或几种。
9.根据权利要求8所述的方法,其中所述格式试剂为烷基卤化镁或芳基卤化镁,例如甲基溴化镁、乙基溴化镁、乙基碘化镁、丙基溴化镁、丁基溴化镁或苯基溴化镁。
10.根据权利要求3所述的方法,其特征在于步骤(1)的反应溶剂为极性非质子溶剂、质子溶剂或其混合物,例如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、N-甲基吗啉、甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、乙二醇、丙二醇、丁二醇、或它们的任意两种或两种以上的混合物。
11.根据权利要求3所述的方法,其特征在于步骤(2)中X为氯、溴或碘。
12.根据权利要求3所述的制备方法,其特征在于步骤(3)中还原剂选自硼氢化锂、硼氢化钠、硼氢化钾、氰基硼氢化钠、三乙基硼氢化锂或硼烷。
14.根据权利要求13所述的方法,其中步骤(4)中所用的酸为有机或无机酸,例如盐酸、氢溴酸、氢碘酸、硫酸、磷酸、硝酸、甲酸、乙酸、三氟乙酸、草酸、酒石酸、柠檬酸、对甲苯磺酸或三氟甲磺酸。
15.根据权利要求13或14所述的方法,其中步骤(5)中所用的还原剂为氰基硼氢化钠、三乙酰氧基硼氢化钠、三乙基硼氢化锂、硼烷、(S)-2-甲基-CBS-噁唑硼烷、或者按照常规方法原位制备的上述还原剂。
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