CN112430235A - Preparation method of PF-06651600 intermediate - Google Patents
Preparation method of PF-06651600 intermediate Download PDFInfo
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- CN112430235A CN112430235A CN201910792050.0A CN201910792050A CN112430235A CN 112430235 A CN112430235 A CN 112430235A CN 201910792050 A CN201910792050 A CN 201910792050A CN 112430235 A CN112430235 A CN 112430235A
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- alkali
- potassium
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- 238000002360 preparation method Methods 0.000 title abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 125
- 238000006243 chemical reaction Methods 0.000 claims abstract description 73
- 238000000034 method Methods 0.000 claims abstract description 39
- 238000004519 manufacturing process Methods 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 23
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 14
- 239000007810 chemical reaction solvent Substances 0.000 claims description 14
- -1 p-toluenesulfonyl Chemical group 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 9
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 235000011181 potassium carbonates Nutrition 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- BTOJSYRZQZOMOK-UHFFFAOYSA-N 4-chloro-7-(4-methylphenyl)sulfonylpyrrolo[2,3-d]pyrimidine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=NC(Cl)=C2C=C1 BTOJSYRZQZOMOK-UHFFFAOYSA-N 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 229940125898 compound 5 Drugs 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 14
- 239000002994 raw material Substances 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 6
- 238000006467 substitution reaction Methods 0.000 abstract description 3
- JKSBJAIJUUQUJS-GLGOKHISSA-N (3R)-1-benzyl-6-methylpiperidin-3-amine Chemical compound CC1N(C[C@@H](CC1)N)CC1=CC=CC=C1 JKSBJAIJUUQUJS-GLGOKHISSA-N 0.000 abstract description 2
- 238000006264 debenzylation reaction Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000007787 solid Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 238000001816 cooling Methods 0.000 description 12
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 208000004631 alopecia areata Diseases 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000009987 spinning Methods 0.000 description 3
- WIMATVURUXUQLZ-YGPZHTELSA-N tert-butyl N-[(2R)-1,5-dihydroxyhexan-2-yl]carbamate Chemical compound C(=O)(OC(C)(C)C)N[C@@H](CO)CCC(C)O WIMATVURUXUQLZ-YGPZHTELSA-N 0.000 description 3
- MIEJVQLUIIUQIQ-BZSJEYESSA-N tert-butyl N-[(3R)-1-benzyl-6-methylpiperidin-3-yl]carbamate Chemical compound C(=O)(OC(C)(C)C)N[C@@H]1CCC(N(C1)CC1=CC=CC=C1)C MIEJVQLUIIUQIQ-BZSJEYESSA-N 0.000 description 3
- FZVQRSWZWHKIDC-LLVKDONJSA-N C(C)OC([C@@H](CCC(C)=C=O)NC(=O)OC(C)(C)C)=O Chemical compound C(C)OC([C@@H](CCC(C)=C=O)NC(=O)OC(C)(C)C)=O FZVQRSWZWHKIDC-LLVKDONJSA-N 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 229910019020 PtO2 Inorganic materials 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical group O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- YWWWGFSJHCFVOW-MRVPVSSYSA-N 1-o-tert-butyl 2-o-ethyl (2r)-5-oxopyrrolidine-1,2-dicarboxylate Chemical compound CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C YWWWGFSJHCFVOW-MRVPVSSYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- JXUWZXFVCBODAN-UHFFFAOYSA-N 5-methylpyridin-3-amine Chemical compound CC1=CN=CC(N)=C1 JXUWZXFVCBODAN-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 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
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a preparation method of a PF-06651600 intermediate, belonging to the field of pharmaceutical chemistry. According to the method, (5R) -2-methyl-5-amino-1-benzylpiperidine or salts thereof is used as a raw material, a target compound (2S,5R) -5- ((7H-pyrrole) amino) -2-methylpiperidine (compound 09) is obtained through substitution reaction, resolution, protection of dets and debenzylation, and the compound 09 is amidated to obtain PF-06651600. The preparation method has the advantages of low cost, low production cost, mild reaction conditions, high product purity, high yield and safe operation, and can be used for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of a PF-06651600 intermediate.
Background
Alopecia areata is an autoimmune disease, which is mainly characterized by gross hair loss of the head, face and body. The symptoms are caused by the attack of the patient's immune cells on the autologous hair follicles, which are initially round alopecia areata. Alopecia areata has an average age between 25 and 35 years of age, but can also affect children and adolescents, and can occur in both men and women and in all races.
PF-06651600 is a potent, selective inhibitor of JAK3, previously approved by FDA breakthrough therapy for the treatment of alopecia areata. Currently, it is subjected to a phase 3 clinical trial for the treatment of moderate to severe alopecia areata, while continuing the trial for the treatment of Rheumatoid Arthritis (RA), Crohn's Disease (CD) and Ulcerative Colitis (UC); the structure of PF-06651600 is shown by the following formula:
in the prior art, 5-methyl-3-aminopyridine is used as a raw material, for example, WO2010048012 discloses that a metal rhodium catalyst is used to reduce a pyridine ring into a piperidine ring; WO2016112298 discloses the use of PtO2As a catalyst to reduce the pyridine ring. However, the metal catalyst is expensive, generally uses hydrogen for reduction, and is heated and hydrogenated under high pressure for a long time, and the reaction conditions are harsh. E.g. using PtO2The generated platinum black is flammable and dangerous to produce. In the prior art, the multi-step reaction needs column chromatography purification and is difficult to be produced in an enlarged way. In the prior art, (R) -N-3, 5-dinitrobenzoyl phenylglycine is used as a resolving agent, which is expensive and is a document (Organic Process Research)&Development (2019), Ahead of Print) records that the resolving agent has a violent exothermic phenomenon when used, and has potential safety hazard when the resolving agent is not well controlled during production.
Therefore, a new intermediate is urgently needed to be found, or a new method for preparing the intermediate of PF-06651600 is researched to obtain a method which is simple and convenient to operate, easy to implement, high in yield, high in purity, low in cost and environment-friendly, so that the compound PF-06651600 can be better prepared.
Disclosure of Invention
The invention provides a preparation method of a PF-06651600 intermediate, which comprises the steps of taking (5R) -2-methyl-5-amino-1-benzylpiperidine or salts thereof as raw materials, carrying out substitution reaction, resolution, Ts protection removal and benzyl removal to obtain a target compound (2S,5R) -5- ((7H-pyrrole) amino) -2-methylpiperidine (compound 09), and carrying out amidation on the compound 09 to obtain PF-06651600.
In a first aspect, the present invention provides a process for the preparation of intermediate compound 09. A process for preparing compound 09, which comprises reacting compound 08 in a reaction solvent under the action of a catalyst and hydrogen to obtain compound 09,
wherein the catalyst is palladium hydroxide/carbon, palladium dichloride (PdCl)2) At least one of; the method has mild reaction conditions and easy operation, and the prepared compound 09 has high purity and high yield, and is suitable for industrial production.
In some embodiments, the mass ratio of compound 08 to catalyst is from 1:0.05 to 1: 0.2; or the mass ratio is 1:0.1-1: 0.5; or the mass ratio is 1:0.2-1: 0.4. The catalyst with the proportion can better catalyze the reaction to prepare the compound 09.
In some embodiments, the reaction solvent is at least one of isopropanol, n-propanol, methanol, ethanol. The reaction condition is mild, the reagent is easy to obtain, and the method is suitable for industrial production.
In some embodiments, the reaction temperature of the reaction is from 30 ℃ to 100 ℃; or the reaction temperature is 50-80 ℃.
In a second aspect, the present invention provides a process for preparing intermediate compound 08, which comprises reacting compound 07 with a base to obtain compound 08,
the method can obtain a compound 08 with a novel structure, and can better prepare a target compound.
In some embodiments, the base is at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, sodium carbonate, potassium carbonate;
in some embodiments, the molar ratio of compound 07 to base is from 1:1.0 to 1: 2.0; or the molar ratio is 1:1.2-1: 1.5.
In some embodiments, the reaction solvent of the reaction is at least one of tetrahydrofuran, 2-methyltetrahydrofuran, DMF.
In some embodiments, the reaction temperature of the reaction is from 30 ℃ to 100 ℃; or the reaction temperature is 50-80 ℃.
In some embodiments, the compound 07 can be obtained by resolution of compound 06,
in some embodiments, the compound 06 is resolved with a resolving agent, L-DBTA, using methanol or acetone as a solvent.
In some embodiments, the compound 06 is resolved with a resolving agent, L-DTTA, using methanol or acetone as a solvent.
In some embodiments, the reaction temperature for the resolution is from 40 ℃ to 80 ℃; or the reaction temperature is 50-70 ℃.
In some embodiments, the resolving agent equivalent weight is from 0.5eq to 1.0 eq.
In a third aspect, the present invention provides a process for preparing intermediate compound 06, which comprises reacting compound 05 with 4-chloro-7-tosyl-7H-pyrrolo [2,3-D ] pyrimidine in the presence of a base to obtain compound 06,
the method can obtain the compound 06 with a novel structure, and can better prepare a target compound.
In some embodiments, in the method of preparing intermediate compound 06, the base is at least one of sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate;
in some embodiments, in the process for preparing intermediate compound 06, the reaction solvent for the reaction is water;
in some embodiments, in the method of preparing intermediate compound 06, the reaction temperature of the reaction is between 50 ℃ and 180 ℃; or the reaction temperature is 80-150 ℃; or the reaction temperature is 100-130 ℃.
In some embodiments, in the process for preparing intermediate compound 06, a salt of compound 05 is reacted with the base to produce compound 5.
In a fourth aspect, the present invention provides a compound of the formula,
the compound has a novel structure, and can be used for better preparing a target compound and obtaining PF-06651600.
A fifth aspect. The invention provides a method for preparing a compound PF-06651600, which comprises the steps of reacting a compound 09 with acryloyl chloride or acrylate in a reaction solvent in the presence of alkali to obtain a compound PF-06651600,
wherein the reaction solvent can be at least one of water and tetrahydrofuran,
in some embodiments, the base may be at least one of sodium bicarbonate, potassium phosphate, potassium hydrogen phosphate, sodium carbonate,
in some embodiments, the reaction may be at a reaction temperature of-10 ℃ to 50 ℃, or at a reaction temperature of 0 ℃ to 30 ℃, or at a reaction temperature of 10 ℃ to 20 ℃.
The compound PF-06651600 obtained by the method has high yield, high purity and mild reaction conditions, and is suitable for industrial production.
In some embodiments, a method for preparing a PF-06651600 intermediate is provided by the following reaction scheme:
the resolving agent used in the preparation method is low in price, expensive reagents are avoided, the resolving safety is high, the reaction is mild, the reagents are easy to obtain, the product purity is high, the yield is high, the operation is safe, the column chromatography purification is avoided, and the industrial production is facilitated.
In a sixth aspect, the present invention provides a process for preparing compound 05, which comprises reacting compound 04 with an acid to prepare compound 05 or a salt thereof,
wherein the acid is hydrochloric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid or sulfuric acid. The method is beneficial to further preparing the compound 04 to obtain the compound 05 with a novel structure, so that PF-06651600 is easier to obtain, and the method has the advantages of mild reaction conditions, safe operation and low production cost.
In some embodiments, the compound 04 to acid molar ratio is from 1:1 to 1: 6; or the molar ratio is 1:2-1: 5.
In a seventh aspect, the present invention provides a process for preparing intermediate compound 04. A process for preparing compound 04 includes reaction between compound 03 and phenylmethylamine in reaction solvent, post-treating to obtain compound 04,
wherein R is a leaving group which may be methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl. The method is beneficial to obtaining the intermediate compound 04 with a novel structure, and has the advantages of mild reaction conditions, safe operation and low production cost.
In some embodiments, in the method of making compound 04, the reaction solvent is at least one of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dichloromethane, dichloroethane, ethylene glycol dimethyl ether. The method has the advantages of mild reaction conditions, safe operation, easily obtained reagents and low production cost.
In some embodiments, the molar ratio of compound 03 to benzylamine is from 1:1 to 1: 20; or the molar ratio is 1:5-1: 15; or mole of
The ratio was 1: 10.
In some embodiments, in the method of making compound 04, the reaction temperature of the reaction is between 20 ℃ and 80 ℃.
In some embodiments, in the method of making compound 04, the reaction time of the reaction is 4 hours to 48 hours; or the reaction time is 12 to 40 hours; or the reaction time is 24 hours to 30 hours.
In an eighth aspect, the present invention provides a process for preparing compound 03, which comprises reacting compound 02 with R-Cl in the presence of a base to obtain compound 03,
wherein R is a leaving group which may be methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl. The method is beneficial to obtaining the intermediate compound 03 with a novel structure, and has the advantages of mild reaction conditions, safe operation and low production cost.
In some embodiments, in the method of preparing compound 03, the base is at least one of triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate.
In some embodiments, the molar ratio of compound 02 to base is from 1:2 to 1: 3. The method is favorable for better enabling the compound 02 to react completely and obtaining the target compound with high yield.
In some embodiments, in a method of making compound 03, the reaction temperature of the reaction is-10 ℃ to 10 ℃; or the reaction temperature is 0-10 ℃.
In a ninth aspect, the present invention provides a process for preparing compound 02, which comprises reacting compound 01 with a reducing agent in a solvent to obtain compound 02,
wherein the reducing agent is sodium borohydride, potassium borohydride, red aluminum, lithium aluminum hydride (LiAlH)4). The method is beneficial to obtaining the intermediate compound 02 with a novel structure, ensures the raw material of the compound 03 to be obtained, and has the advantages of mild reaction conditions, safe operation and low production cost.
In some embodiments, the molar ratio of compound 01 to reducing agent is from 1:3 to 1: 8; or the molar ratio is 1:4-1: 5.
In some embodiments, in the method of making compound 02, the solvent is at least one of ethanol, methanol, tetrahydrofuran, 2-methyltetrahydrofuran.
In some embodiments, in the method of making compound 02, the reaction temperature of the reaction is between-10 ℃ and 10 ℃.
In a tenth aspect, the present invention provides a compound selected from the group consisting of the compounds of the formula,
wherein R is methylsulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl. The compound has a novel structure, is favorable for better preparing a target compound and is favorable for preparing PF-06651600.
In some embodiments, a method for preparing a PF-06651600 intermediate is provided by the following reaction scheme:
wherein R is a leaving group which is methylsulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl.
The reaction route takes D-Boc-pyroglutamic acid ethyl ester as a raw material, and PF-06651600 is obtained through format ring opening, reduction reaction, hydroxyl sulfonylation, cyclization, deprotection and/or salification, substitution reaction, resolution, Ts removal protection, debenzylation and amidation. The preparation method has the advantages of low cost and production cost reduction, and the chiral center is introduced into the raw material, so that the pressure of subsequent compounds to be resolved is reduced. The preparation method has the advantages of mild reaction conditions, easily obtained reagents, high product purity, high yield and safe operation, and can be used for industrial production.
In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
In the description herein, references to the description of the terms "some embodiments," "examples," "specific examples," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
In the present invention, the expression "compound 01" and "compound represented by formula (01)" means the same compound.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mmol means mmol, h means hour, g means g, ml means ml, eq means equivalent, M means mol/L, THF means tetrahydrofuran, 2Me-THF means 2-methyltetrahydrofuran, MeOH means methanol, EtOH means ethanol, CH means3CN represents acetonitrile, DCM represents dichloromethane, DMF represents N, N-dimethylformamide, EA represents ethyl acetate, Boc2O represents di-tert-butyl dicarbonate, TLC represents thin-layer chromatography, NaBH4Represents sodium borohydride, NaOH represents sodium hydroxide, Ms represents methylsulfonyl, Ts or Tos represents p-toluenesulfonyl, L-DBTA represents L- (-) -dibenzoyltartaric acid monohydrate, L-DTTA represents di-p-methylbenzyltartaric acid, NaBH4Denotes sodium borohydride, NH4Cl represents ammonium chloride, NaHCO3Denotes sodium bicarbonate, Na2CO3Representing sodium carbonate, DME glycol dimethyl ether, palladium hydroxide/C palladium hydroxide/carbon and TEA triethylamine.
EXAMPLE 1 preparation of (R) -2- (N-Boc-amino) -5-carbonyl-hexanoic acid ethyl ester (Compound 01)
Under the protection of nitrogen, 60g (1.0eq, 233.2mmol) of Boc-D-pyroglutamic acid ethyl ester and 500ml of THF are sequentially added into a 1000ml three-neck flask, stirred at room temperature, dissolved and cleared, cooled to-40 ℃, slowly added with 110ml (1.4eq, 330mmol) of MeMgBr format reagent, slowly heated to-20 ℃ after finishing dropping, and subjected to TLC central control. After the reaction of the raw materials is finished, 300ml of saturated NH is added dropwise4And (3) quenching the Cl solution, separating liquid, extracting an aqueous phase by 300ml of ethyl acetate, combining organic phases, washing the organic phases by 500ml of water once, performing decompression spin-drying, adding 300ml of N-heptane, cooling, crystallizing, stirring, filtering and drying to obtain 63.7g of (2R) -2- (N-Boc-amino) -5-carbonyl-ethyl hexanoate as an off-white solid with the yield of 93%. GC-MS: M/z:274.1(M +),1H NMR(400MHz,CDCl3)δ5.16(d,J＝6.5Hz,1H),4.15(q,J＝7.1Hz,3H),2.61–2.41(m,2H),2.16–2.02(m,4H),1.84(td,J＝14.4,8.0Hz,1H),1.40(s,9H),1.24(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ207.32,172.27,155.42,79.76,61.33,52.92,39.29,29.85,28.22,26.46,14.07。
EXAMPLE 2 preparation of (R) -2- (N-Boc-amino) -1, 5-hexanediol (Compound 02)
Adding 0160 g (1.0eq, 219.5mmol) of compound and a mixture of 240ml of absolute ethanol and 240ml of THF into a 1000ml four-mouth bottle at room temperature, stirring for dissolving, cooling to-5 ℃, and adding 33.2g (4.0eq, 878mmol) of NaBH in batches4Stirring for 2h under the condition of heat preservation, slowly heating to room temperature for reaction, controlling by TLC until the raw materials completely react, cooling to-10 ℃, slowly dropwise adding 300ml of saturated ammonium chloride solution to quench the reaction, separating out a large amount of solids, filtering, extracting the filtrate with 300ml of EA, spin-drying, adding 200ml of dissolved solution, adding 200ml of DCM for extraction twice, spin-drying under reduced pressure, adding N-heptane for low-temperature crystallization, carrying out suction filtration, and carrying out vacuum pumping on the solids to obtain 46.1g of (2R) -2- (N-Boc-amino) -1, 5-hexanediol white solids with the yield of 90%. GC content is 100%. LC-MS, M/z (ESI), 256.3(M + Na)+)+，1H NMR(400MHz,CDCl3)δ5.07(s,1H),3.81(dd,J＝11.1,5.0Hz,1H),3.70(dd,J＝13.9,7.0Hz,1H),3.59(s,2H),3.18(d,J＝27.1Hz,1H),2.70(s,1H),1.77–1.46(m,4H),1.44(s,9H),1.19(d,J＝6.1Hz,3H)。
EXAMPLE 3 preparation of (R) -1, 5-dimethylsulfonic acid-2- (N-Boc-amino) hexane (Compound 03-Ms)
Under the protection of nitrogen, 0245 g (1.0eq, 192.9mmol) of the compound and 250ml of DCM are added into a 1000ml four-opening bottle, the mixture is stirred and dissolved at room temperature, the temperature is reduced to 0 ℃, 48.8g (2.5eq, 482.2mmol) of TEA is added, the mixture is stirred for 0.5h, the reaction temperature is controlled to be lower than 0 ℃, a DCM solution of 48.6g (2.2eq, 424.4mmol) of MsCl is added dropwise, the mixture is kept warm after the dropwise addition, TLC is monitored until the raw materials are completely reacted, 250ml of water is added for quenching, liquid separation is carried out, the DCM layer is washed once by using 250ml of saturated NaHCO3 and aqueous solution respectively, and the mixture is reduced in pressure and rotary evaporated to dryness at room temperature to obtain 72.8g of (R) -1, 5-dimethyl sulfonic acid-2- (N-Boc-amino) hexane. LC-MS, M/z (ESI), 412.0(M + Na)+)+，1H NMR(400MHz,CDCl3)δ4.82(d,J＝8.8Hz,2H),4.20(dd,J＝14.4,10.6Hz,2H),3.86(d,J＝28.2Hz,1H),3.02(d,J＝10.6Hz,6H),1.70(dd,J＝23.5,14.0Hz,4H),1.50–1.36(m,12H).
EXAMPLE 4 preparation of (5R) -5- (N-Boc-amino) -2-methyl-1-benzylpiperidine (Compound 04)
Under the protection of nitrogen, 198mL (10eq,1797mmol) of benzylamine is added into a 1000mL three-necked bottle, the temperature is raised to 45 ℃ under the protection of nitrogen, 70g of compound 03-Ms (1.0eq,179.8mmol) are dissolved in 140mL of 2-MeTHF, the 2-MeTHF is slowly dripped into the system of the benzylamine, the temperature is raised to 60 ℃ after the dripping is finished, the reaction is carried out for 24-48h, the TLC is controlled to be finished, the solvent is removed by reduced pressure distillation, 200mL of DCM is added, the temperature is reduced to 0 ℃, glacial acetic acid is dripped to adjust the system to be neutral, 200mL of water is used for washing three times, the DCM is dried by reduced pressure rotation, and (5R) -5- (N-Boc-amino) -2-methyl-1-benzylpiperidine brown yellow oily46.5g, yield 85%. The oil was used directly in the next reaction. LC-MS M/z (ESI) 305.3(M + H)+，1H NMR(400MHz,CDCl3)δ7.41–7.30(m,5H),5.48(d,J＝5.7Hz,1H),4.52(s,1H),4.06(d,J＝13.5Hz,1H),3.76(s,1H),3.32(d,J＝13.5Hz,1H),2.71(d,J＝11.2Hz,1H),2.41(dd,J＝12.3,6.1Hz,1H),2.25(d,J＝10.4Hz,1H),1.76(d,J＝11.7Hz,1H),1.60(dd,J＝10.4,6.5Hz,2H),1.44(s,9H),1.24(d,J＝5.8Hz,3H).
EXAMPLE 5 preparation of (5R) -2-methyl-5-amino-1-benzylpiperidine hydrochloride (Compound 05 hydrochloride)
At room temperature, adding EA140mL into a 500mL single-neck bottle containing 0446.5 g of 1.0eq, 152.7mmol) of the compound to dissolve, dropwise adding 230mL (4.5eq,690mmol) of 3M HCl solution of EA, stirring at room temperature for removing Boc salt, monitoring by HPLC until the reaction is complete, transferring the reaction solution into a 1000mL four-neck bottle, adding 370mL of water, stirring, separating, washing the aqueous phase once with 370mL of EA to obtain a pale yellow (5R) -2-methyl-5-amino-1-benzylpiperidine hydrochloride aqueous solution, wherein the yield is 100% of theoretical yield, and directly using the solution in the next reaction. LC-MS M/z (ESI) 205.2(M + H)+，1H NMR(400MHz,MeOD)δ7.35(dt,J＝14.8,7.2Hz,4H),7.25(t,J＝7.0Hz,1H),4.03(d,J＝13.2Hz,1H),3.28(s,1H),2.73(dd,J＝12.4,5.2Hz,1H),2.59(s,1H),2.39(dd,J＝12.4,2.6Hz,1H),1.87–1.69(m,3H),1.62(dt,J＝21.9,8.0Hz,1H),1.34(dd,J＝19.9,7.4Hz,2H),1.24(d,J＝6.3Hz,3H)。
EXAMPLE 6 preparation of (5R) -5- ((7-tosyl-7H-pyrrolo [2,3] pyrimidine) amino) -2-methyl-1-benzylpiperidine (Compound 06)
To a 1000ml four-necked flask containing an aqueous solution of Compound 05-HCl at room temperature, Na was added2CO3Adjusting pH to neutral, adding Na2CO325.9g(1.6eq,244.4mmol), dissolved with stirring for 0.5H, and added with 4-chloro-7-tosyl-7H-pyrrole [2,3-D ]]46g (0.98eq, 149mmol) of pyrimidine, stirring at room temperature for 0.5H, heating to 120 ℃, stirring overnight, controlling the reaction in HPLC to be complete, cooling to 60 ℃, dropwise adding 370ml of EA, continuing to stir and cool to room temperature after dropwise adding, separating liquid, extracting the aqueous phase once with 200ml of EA, combining EA layers, washing the organic phase twice with 300ml of water, and performing reduced pressure spin-drying to obtain (5R) -5- ((7-tosyl-7H-pyrrole [2,3]]Pyrimidine) amino) -2-methyl-1-benzylpiperidine foamy solid 57.8g, yield 80%, purity 95%. LC-MS M/z (ESI) 476.2(M + H)+，1H NMR(400MHz,DMSO)δ8.13(d,J＝5.3Hz,1H),7.93(t,J＝8.2Hz,2H),7.50(dt,J＝20.7,8.4Hz,2H),7.44–7.34(m,2H),7.26(t,J＝4.7Hz,3H),7.15(dt,J＝22.7,7.0Hz,2H),6.88(d,J＝32.2Hz,1H),4.14(d,J＝29.3Hz,1H),3.94(d,J＝13.8Hz,0.5H),3.19(d,J＝13.8Hz,0.5H),2.93–2.71(m,1H),2.44(d,J＝7.7Hz,1H),2.33(s,3H),1.82(dd,J＝25.6,14.9Hz,1H),1.76–1.49(m,3H),1.40–1.25(m,1H),1.08(dd,J＝47.6,6.2Hz,3H)。
EXAMPLE 7 preparation of (2S,5R) -5- ((7-tosyl-7H-pyrrolo [2,3] pyrimidine) amino) -2-methyl-1-benzylpiperidine (Compound 07)
Adding 500mL of methanol and 24.5g (0.65eq, 68mmol) of L-DBTA24 into a 1000mL single-neck bottle filled with 0650g (1.0eq, 105mmol) of the compound at room temperature, stirring and dissolving, heating to 40-80 ℃, reacting for 12-48h, separating out a large amount of solid, cooling to room temperature, crystallizing, stirring for 4-8h, filtering, leaching with methanol, adding DCM300mL and 5% Na into the solid2CO3The solution (300 ml) is stirred and dissolved, separated, washed and the DCM layer is dried by spinning under reduced pressure to obtain (2S,5R) -5- ((7-tosyl-7H-pyrrole [2,3]]Pyrimidine) amino) -2-methyl-1-benzylpiperidine as a white foamy solid 20.5g in 41% yield with 98% purity ee>98.5％。LC-MS:m/z(ESI):476.2(M+H)+，1H NMR(400MHz,DMSO)δ8.13(s,1H),7.93(d,J＝8.2Hz,2H),7.69(d,J＝6.5Hz,1H),7.52(d,J＝3.8Hz,1H),7.41(d,J＝8.1Hz,2H),7.27(d,J＝7.2Hz,2H),7.16(dt,J＝23.7,7.0Hz,3H),7.03(s,1H),4.18(s,1H),2.80(d,J＝6.0Hz,1H),2.46(d,J＝6.5Hz,2H),2.34(s,3H),1.67(t,J＝20.0Hz,2H),1.56(d,J＝9.1Hz,1H),1.22(s,3H),1.02(d,J＝6.4Hz,3H)。
Adding 50mL of acetone and 2.45g (0.65eq, 6.8mmol) of L-DBTA into a 1000mL single-neck flask containing 065 g (1.0eq, 10.5mmol) of the compound at room temperature, stirring for dissolving, heating to 40-80 ℃, reacting for 12-48h, precipitating a large amount of solid, cooling to room temperature, crystallizing, stirring for 4-8h, filtering, leaching with acetone, adding 30mL of DCM and 5% of Na into the solid, stirring for 4-8h, filtering, leaching with acetone, and adding 30mL of DCM and 5% of Na into the solid2CO3The solution (30 ml) is stirred and dissolved, separated, washed and the DCM layer is dried by spinning under reduced pressure to obtain (2S,5R) -5- ((7-tosyl-7H-pyrrole [2,3]]Pyrimidine) amino) -2-methyl-1-benzylpiperidine 1.8g as a white foamy solid in 36% yield and 97% purity ee>98％。LC-MS:m/z(ESI):476.2(M+H)+。
EXAMPLE 8 preparation of (2S,5R) -5- ((7H-pyrrole) amino) -2-methyl-1-benzylpiperidine (Compound 08)
At room temperature, 150mL of 2-MeTHF and 150mL of NaOH2.18g (1.3eq, 54.5mmol) are added into a 500mL single-neck bottle containing 0720 g (1.0eq, 26.4mmol) of the compound, stirred and dissolved, the temperature is raised to 50-90 ℃, the reaction is controlled to be complete in HPLC, the temperature is reduced, the pressure is reduced, the mixture is dried, 100mL of DCM and 100mL of water are added, stirred and extracted, liquid separation is carried out, the organic phase is washed once by 100mL of water, and the pressure is reduced, so that 12.8g of (2S,5R) -5- ((7H-pyrrole) amino) -2-methyl-1-benzylpiperidine is obtained as a light brown solid, the yield is 95%, and the purity is 98%. LC-MS M/z (ESI) 322.25(M + H)+，1H NMR(400MHz,MeOD)δ8.06(d,J＝10.7Hz,1H),7.39(d,J＝7.1Hz,2H),7.29(t,J＝7.2Hz,2H),7.26–7.21(m,1H),7.09(t,J＝6.7Hz,1H),6.59(d,J＝3.0Hz,1H),4.33(s,1H),4.05(t,J＝14.0Hz,1H),3.51(d,J＝12.9Hz,1H),2.83(dd,J＝11.7,6.3Hz,1H),2.77(s,1H),2.62(d,J＝10.9Hz,1H),1.94–1.64(m,4H),1.27(d,J＝6.4Hz,3H).。
Example 9(2S,5R) -5- ((7H-pyrrole) amino) -2-methylpiperidine (compound 09)
At room temperature, 125mL of isopropanol, 10-20% of palladium hydroxide/C (relative to the mass ratio of the compound 08), 2.6g of glacial acetic acid (1.1eq, 43.3mmol) and 12.5mL of water are added into a 250mL single-neck bottle containing 0812.5 g of the compound (1.0eqq, 38.9mmol), hydrogen is replaced, normal pressure hydrogenation is carried out, the mixture is heated to 50-80 ℃ for reaction, HPLC is controlled to be complete in reaction, suction filtration is carried out, a filter cake is leached by isopropanol, and filtrate is obtained to be dried by spinning to obtain 9g of (2S,5R) -5- ((7H-pyrrole) amino) -2-methylpiperidine light brown solid, the yield is 95.0%, and the purity is 98%. LC-MS M/z (ESI) 232.3(M + H)+。
EXAMPLE 10 preparation of (2S,5R) -5- ((7H-pyrrole) amino) -2-methyl-1- (3-acryloyl) piperidine (Compound PF-06651600)
To a 250ml single-neck flask containing 099 g (1.0eq, 38.9mmol) of compound was added saturated NaHCO at room temperature3Cooling 90ml of solution and 90ml of THF (tetrahydrofuran), slowly dropwise adding 4.23g (1.2eq, 46.7mmol) of acryloyl chloride at 0-20 ℃, controlling the reaction temperature to be complete in HPLC (high performance liquid chromatography), transferring to a 500ml reaction bottle, adding 100ml of EA for extraction twice, combining organic layers, cooling, dropwise adding 13ml of 3M (1eq, 39mmol) of EA solution for salification, controlling in TLC (thin layer chromatography), adding 100ml of water for extraction twice, combining water phase and saturated NaHCO, and performing liquid-liquid separation3Adjusting the pH value to be neutral, cooling, crystallizing, filtering, and drying to obtain 9.4g of (2S,5R) -5- ((7H-pyrrole) amino) -2-methyl-1- (3-acryloyl) piperidine white solid with the yield of 84.7%, the purity of 99% and the ee value of 99%. LC-MS M/z (ESI) 286.3(M + H)+，1H NMR(400MHz,DMSO)δ11.53(s,1H),8.10(d,J＝10.8Hz,1H),7.47–7.25(m,1H),7.08(s,1H),6.80(dd,J＝30.9,17.3Hz,1H),6.58(s,1H),6.09(dd,J＝16.7,2.0Hz,1H),5.67(dd,J＝10.5,1.9Hz,1H),4.79(s,0.5H),4.54(d,J＝13.2Hz,0.5H),4.37(s,0.5H),4.21–3.94(m,1.5H),3.07–2.89(m,0.5H),2.63(dd,J＝23.2,11.5Hz,0.5H),1.94–1.54(m,4H),1.20(dd,J＝22.4,6.5Hz,3H).
To a 250ml single-neck flask containing 099 g (1.0eq, 38.9mmol) of compound was added saturated NaHCO at room temperature3Cooling 90ml of solution and 90ml of THF (tetrahydrofuran), slowly dropwise adding 4.67g of acryloyl ethyl ester (1.2eq, 46.7mmol) at 0-20 ℃, controlling the reaction in HPLC (high performance liquid chromatography) until the reaction is complete, transferring to a 500ml reaction bottle, adding 100ml of EA for extraction twice, combining organic layers, cooling, dropwise adding 13ml of 3M hydrochloric acid (1eq, 39mmol) EA solution for salification, controlling in TLC (thin layer chromatography), adding 100ml of water for extraction twice, combining water phase and saturated NaHCO, and performing combined extraction3Adjusting the pH value to be neutral, cooling, crystallizing, filtering, and drying to obtain 8.9g of (2S,5R) -5- ((7H-pyrrole) amino) -2-methyl-1- (3-acryloyl) piperidine white solid with the yield of 80.2%, the purity of 95% and the ee value of 98%. LC-MS M/z (ESI) 286.3(M + H)+。
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (14)
1. A method of making compound 09, comprising: in a reaction solvent, reacting the compound 08 under the action of a catalyst and hydrogen to obtain a compound 09,
wherein the catalyst is at least one of palladium hydroxide/carbon, palladium/carbon and palladium dichloride.
2. The method according to claim 1, wherein the mass ratio of the compound 08 to the catalyst is 1:0.05-1: 0.2; or the mass ratio is 1:0.1-1: 0.5; or the mass ratio is 1:0.2-1: 0.4.
3. The method of claim 1, wherein the reaction solvent is at least one of isopropanol, n-propanol, methanol, and ethanol.
4. The process of claim 1, the reaction temperature of the reaction is from 30 ℃ to 100 ℃; or the reaction temperature is 50-80 ℃.
5. The method of claim 1, comprising: the compound 07 reacts with alkali to produce a compound 08,
the alkali is at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, sodium carbonate and potassium carbonate.
6. The method of claim 5, the molar ratio of compound 07 to base is from 1:1.0 to 1: 2.0; or the molar ratio is 1:1.2-1: 1.5.
7. The method of claim 5, wherein said compound 07 is obtained by the resolution of compound 06 using L-DBTA and/or L-DTTA as the agent
8. The method of claim 5, wherein the reaction solvent for reacting compound 07 with a base is at least one of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, and DMF.
9. The process of claim 5, wherein the reaction temperature of compound 07 with base is 30 ℃ to 100 ℃; or the reaction temperature is 50-80 ℃.
10. The method of claim 7, comprising: in the presence of alkali, the compound 05 reacts with 4-chloro-7-tosyl-7H-pyrrolo [2,3-D ] pyrimidine to prepare a compound 06,
the alkali is at least one of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate,
the reaction solvent of the reaction is water,
the reaction temperature of the reaction is 80-150 ℃, or the reaction temperature is 100-130 ℃.
11. The method of claim 10, comprising: the salt of compound 05 is reacted with the base to produce compound 5.
12. The method of claim 10, comprising: reacting the compound 03 with benzylamine, performing post-treatment to obtain a compound 04, reacting the compound 04 with acid to obtain a compound 05 or a salt thereof,
wherein R is methylsulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl.
13. A compound selected from the group consisting of those of the formula,
14. a method of making compound PF-06651600, comprising: in a reaction solvent, under the condition of alkali existence, the compound 09 reacts with acryloyl chloride or acrylic ester to prepare a compound PF-06651600,
wherein the reaction solvent is at least one of water and tetrahydrofuran,
the alkali is at least one of sodium bicarbonate, potassium hydrogen phosphate, sodium carbonate and potassium carbonate,
the reaction temperature of the reaction is 0-30 ℃; or the reaction temperature is 10-20 ℃.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106061973A (en) * | 2013-12-05 | 2016-10-26 | 辉瑞公司 | Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides |
| WO2016178110A1 (en) * | 2015-05-01 | 2016-11-10 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl, pyrrolo[2,3-b]pyridinyl acrylamides and epoxides thereof |
| CN107793418A (en) * | 2017-10-24 | 2018-03-13 | 扬子江药业集团有限公司 | Industrial production method of tofacitinib citrate |
| CN108484607A (en) * | 2018-03-26 | 2018-09-04 | 山东科兴生物制品有限公司 | Novel preparation method of tofacitinib citrate |
-
2019
- 2019-08-26 CN CN201910792050.0A patent/CN112430235B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106061973A (en) * | 2013-12-05 | 2016-10-26 | 辉瑞公司 | Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides |
| WO2016178110A1 (en) * | 2015-05-01 | 2016-11-10 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl, pyrrolo[2,3-b]pyridinyl acrylamides and epoxides thereof |
| CN107793418A (en) * | 2017-10-24 | 2018-03-13 | 扬子江药业集团有限公司 | Industrial production method of tofacitinib citrate |
| CN108484607A (en) * | 2018-03-26 | 2018-09-04 | 山东科兴生物制品有限公司 | Novel preparation method of tofacitinib citrate |
Non-Patent Citations (1)
| Title |
|---|
| ATLI THORARENSEN等: "Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1‑((2S,5R)‑5-((7H‑Pyrrolo[2,3‑d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans" * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115894338A (en) * | 2021-08-27 | 2023-04-04 | 华南理工大学 | Method for preparing Ritlecetinib intermediate by coupling chemical enzyme and biological enzyme |
| CN115894338B (en) * | 2021-08-27 | 2024-02-13 | 华南理工大学 | Method for preparing Ritlecritinib intermediate by chemical-biological enzyme coupling |
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