CN112430235B - PF-06651600 middle Process for the preparation of a body - Google Patents
PF-06651600 middle Process for the preparation of a body Download PDFInfo
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- CN112430235B CN112430235B CN201910792050.0A CN201910792050A CN112430235B CN 112430235 B CN112430235 B CN 112430235B CN 201910792050 A CN201910792050 A CN 201910792050A CN 112430235 B CN112430235 B CN 112430235B
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- 238000000034 method Methods 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 135
- 238000006243 chemical reaction Methods 0.000 claims abstract description 77
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 25
- 239000002585 base Substances 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 239000007810 chemical reaction solvent Substances 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 13
- -1 p-toluenesulfonyl Chemical group 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 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
- 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
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 7
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 6
- 239000003513 alkali 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
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- 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
- 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
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 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
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 14
- 239000002994 raw material Substances 0.000 abstract description 10
- 230000008901 benefit Effects 0.000 abstract description 8
- 238000009776 industrial production Methods 0.000 abstract description 6
- 238000006467 substitution reaction Methods 0.000 abstract description 4
- 230000009435 amidation Effects 0.000 abstract description 3
- 238000007112 amidation reaction Methods 0.000 abstract description 3
- 238000006264 debenzylation 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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000007787 solid Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 230000001276 controlling effect Effects 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 230000002349 favourable effect Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 208000004631 alopecia areata Diseases 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000001914 filtration 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
- 230000001105 regulatory effect Effects 0.000 description 4
- 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 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-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 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 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
- 201000004384 Alopecia Diseases 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
- 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
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000003676 hair loss Effects 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000012280 lithium aluminium hydride 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
- 239000012044 organic layer Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 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 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 238000005406 washing Methods 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
- 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 description 1
- JXUWZXFVCBODAN-UHFFFAOYSA-N 5-methylpyridin-3-amine Chemical compound CC1=CN=CC(N)=C1 JXUWZXFVCBODAN-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 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
- 125000005396 acrylic acid ester group Chemical group 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
- 125000001309 chloro group Chemical group Cl* 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
- 230000007613 environmental effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007788 liquid 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
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 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
- 238000005086 pumping Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000006722 reduction reaction 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
- 239000007858 starting material Substances 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 PF-06651600 a preparation method of the intermediate, which comprises the following steps, belonging to the field of pharmaceutical chemistry. The method takes (5R) -2-methyl-5-amino-1-benzyl piperidine or salt thereof as a raw material, the target compound (2S, 5R) -5- ((7H-pyrrole) amino) -2-methylpiperidine (compound 09) is obtained through substitution reaction, resolution, ts removal protection and debenzylation, and PF-06651600 can be obtained through amidation of the compound 09. 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 that is primarily characterized by the loss of hair throughout the head, face, and body. The symptoms are caused by the attack of the patient's immune cells on the autologous hair follicles, primarily circular local hair loss. Alopecia areata has an average age of between 25 and 35 years, but can also affect children and adolescents and can occur in both men and women and all ethnicities.
PF-06651600 is a potent, selective inhibitor of JAK3 and has previously been identified as a breakthrough therapy in the FDA 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 in the following formula:
in the prior art, 5-methyl-3-aminopyridine is used as a raw material, and as disclosed in WO2010048012, a rhodium metal catalyst is used for reducing a pyridine ring into a piperidine ring; WO2016112298 discloses the use of PtO 2 The pyridine ring is reduced as a catalyst. However, metal catalysts are expensive, generally reduced with hydrogen, heated and hydrogenated at high pressure for a long period of time, and the reaction conditions are severe. For example, ptO is used 2 The platinum black produced is flammable and dangerous to produce. In the prior art, the multi-step reaction needs column chromatography purification, and is difficult to realize large-scale production. In the prior art, (R) -N-3, 5-dinitrobenzoyl phenylglycine is used as a resolving agent, which is expensive, and the document (Organic Process Research)&Development (2019), ahead of Print) describes that a violent exothermic phenomenon exists when a resolving agent is used, and potential safety hazards still exist when the resolving agent is not well controlled during production.
Therefore, there is an urgent need to find a new intermediate, or to research a new method for preparing an intermediate of PF-06651600, so as to obtain a method with simple operation, easy implementation, high yield, high purity, low cost, and environmental friendliness, thereby better preparing the obtained compound PF-06651600.
Disclosure of Invention
The invention provides a preparation method of a PF-06651600 intermediate, which takes (5R) -2-methyl-5-amino-1-benzyl piperidine or salt thereof as a raw material, and obtains a target compound (2S, 5R) -5- ((7H-pyrrole) amino) -2-methyl piperidine (compound 09) through substitution reaction, resolution, ts protection and debenzylation, and the compound 09 can obtain PF-06651600 through amidation.
In a first aspect, the present invention provides a process for preparing intermediate compound 09. A process for preparing compound 09, which comprises, in a reaction solvent, reacting compound 08 with a catalyst and hydrogen to obtain compound 09,
wherein the catalyst is palladium hydroxide/carbon, palladium dichloride (PdCl) 2 ) At least one of (a) and (b); 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 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, comprising reacting compound 07 with a base to produce compound 08,
the method can obtain the compound 08 with novel structure, and can prepare the target compound better.
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 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, or both.
In some embodiments, the reaction temperature of the reaction is from 30 ℃ to 100 ℃; or the reaction temperature is 50-80 ℃.
In some embodiments, compound 07 may be resolved from 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 of the resolution is from 40 ℃ to 80 ℃; or the reaction temperature is 50-70 ℃.
In some embodiments, the resolving agent equivalent is from 0.5eq to 1.0eq.
In a third aspect, the present invention provides a process for preparing intermediate compound 06 comprising reacting compound 05 with 4-chloro-7-tosyl-7H-pyrrolo [2,3-D ] pyrimidine in the presence of a base to produce compound 06,
the method can obtain the compound 06 with novel structure, and can prepare the target compound better.
In some embodiments, in the process for 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 of the reaction is water;
in some embodiments, in the process for preparing intermediate compound 06, the reaction temperature of the reaction is from 50 ℃ to 180 ℃; or the reaction temperature is 80-150 ℃; or the reaction temperature is 100-130 ℃.
In some embodiments, in a 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 novel structure, and can better prepare and obtain the target compound and 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 acrylic acid ester in a reaction solvent in the presence of alkali to prepare 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 temperature of the reaction may be-10 ℃ to 50 ℃, or the reaction temperature is 0 ℃ to 30 ℃, or the reaction temperature is 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 process for preparing a PF-06651600 intermediate is provided in the following reaction scheme:
the preparation method has the advantages of low cost of the resolving agent, avoidance of expensive reagents, high resolving safety, mild reaction, easy reagent acquisition, high product purity, high yield, safe operation, avoidance of column chromatography purification and contribution to industrial production.
In a sixth aspect, the present invention provides a process for preparing compound 05, comprising 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 favorable for 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 molar ratio of compound 04 to acid is 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 producing compound 04, which comprises reacting compound 03 with benzylamine in a reaction solvent, subjecting to post-treatment to produce compound 04,
wherein R is a leaving group which may be methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl. The method is favorable for obtaining the intermediate compound 04 with novel structure, and has mild reaction conditions, safe operation and low production cost.
In some embodiments, in the method of preparing 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 benzyl amine is 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 process for preparing compound 04, the reaction temperature of the reaction is from 20 ℃ to 80 ℃.
In some embodiments, in the method of preparing compound 04, the reaction time of the reaction is from 4 hours to 48 hours; or the reaction time is 12 hours 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, comprising 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 favorable for 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 leading the compound 02 to react completely and obtaining the target compound with high yield.
In some embodiments, in the method of preparing compound 03, the reaction temperature of the reaction is from-10 ℃ to 10 ℃; or the reaction temperature is 0-10 ℃.
In a ninth aspect, the present invention provides a process for preparing compound 02, comprising 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 favorable for obtaining the intermediate compound 02 with a novel structure, ensures that the raw materials of the compound 03 are obtained, has mild reaction conditions, is safe to operate and has low production cost.
In some embodiments, the molar ratio of compound 01 to reducing agent is from 1:3 to 1:8; or a molar ratio of 1:4 to 1:5.
In some embodiments, in the method of preparing compound 02, the solvent is at least one of ethanol, methanol, tetrahydrofuran, 2-methyltetrahydrofuran.
In some embodiments, in the method of preparing compound 02, the reaction temperature of the reaction is from-10 ℃ to 10 ℃.
In a tenth aspect, the present invention provides a compound selected from the group consisting of compounds of the formula,
wherein R is methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl. The compound has novel structure, is beneficial to better preparing and obtaining the target compound, and is beneficial to preparing and obtaining PF-06651600.
In some embodiments, a process for preparing a PF-06651600 intermediate is provided in the following reaction scheme:
wherein R is a leaving group which is methanesulfonyl, 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, hydroxysulfonylation, ring formation, deprotection and/or salification, substitution reaction, resolution, ts removal protection, debenzylation and amidation. The preparation method has the advantages that the raw materials are obtained, the price is low, the production cost is reduced, a chiral center is introduced into the raw materials, and the pressure for separating the subsequent compounds 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 should 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 a relative importance or number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature. In the description of the present invention, the meaning of "a plurality" is two or more, unless explicitly defined otherwise.
In the description of the present specification, the descriptions of the terms "some implementations," "some embodiments," "examples," "particular 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 present invention. In this specification, schematic representations of the above terms are not necessarily directed 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, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
In the present invention, the expressions "compound 01" and "compound represented by formula (01)" mean the same compound.
Detailed Description
In order to better understand the technical solution of the present invention, the following further discloses some non-limiting examples, which are further described in detail.
The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
In the present invention, mmol means millimoles, h means hours, g means grams, ml means milliliters, eq means equivalent, M means mol/L, THF means tetrahydrofuran, 2Me-THF means 2-methyltetrahydrofuran, meOH means methanol, etOH means ethanol, CH 3 CN represents acetonitrile, DCM represents dichloromethane, DMF represents N, N-dimethylformamide, EA represents ethyl acetate, boc 2 O represents di-tert-butyl dicarbonate, TLC represents thin-layer chromatography, naBH 4 Represents sodium borohydride, naOH represents sodium hydroxide, ms represents methanesulfonyl, ts or Tos represents p-toluenesulfonyl, L-DBTA represents L- (-) -dibenzoyltartaric acid monohydrate, L-DTTA represents di-p-methylbenzyltartaric acid, naBH 4 Represents sodium borohydride, NH 4 Cl represents ammonium chloride, naHCO 3 Represents sodium bicarbonate, na 2 CO 3 Represents sodium carbonate, DME represents ethylene glycol dimethyl ether, palladium hydroxide/C represents palladium hydroxide/carbon, and TEA represents triethylamine.
EXAMPLE 1 preparation of (R) -2- (N-Boc-amino) -5-carbonyl-hexanoic acid ethyl ester (Compound 01)
Under the protection of nitrogen, to60g (1.0 eq,233.2 mmol) of Boc-D-pyroglutamic acid ethyl ester, 500ml of THF, stirring and clearing at room temperature, cooling to-40 ℃, slowly dropwise adding 110ml (1.4 eq,330 mmol) of MeMgBr format reagent, slowly heating to-20 ℃ after dropwise adding, and controlling by TLC. After the reaction of the raw materials, 300ml of saturated NH is added dropwise 4 The Cl solution was quenched, separated, the aqueous phase was extracted with 300ml of ethyl acetate, the combined organic phases were washed once with 500ml of water, dried under reduced pressure, added with 300ml of N-heptane, cooled down, stirred, filtered and dried to give 63.7g of an off-white solid of ethyl (2R) -2- (N-Boc-amino) -5-carbonyl-hexanoate in 93% yield. GC-MS: M/z:274.1 (M+), 1 H NMR(400MHz,CDCl 3 )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). 13 C NMR(101MHz,CDCl 3 )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)
A mixture of 01 g (1.0 eq,219.5 mmol) of the compound and 240ml of absolute ethanol and 240ml of THF was added to a 1000ml four-necked flask at room temperature, stirred and dissolved, cooled to-5℃and 33.2g (4.0 eq,878 mmol) of NaBH were added in portions 4 Stirring for 2h at a constant temperature, slowly heating to room temperature for reaction, controlling in TLC until the raw materials are reacted completely, cooling to-10 ℃, slowly dripping 300ml of saturated ammonium chloride solution for quenching reaction, precipitating a large amount of solid, filtering, extracting the filtrate with 300ml of EA, spin-drying, adding 200ml of solution, adding 200ml of DCM for extraction twice, decompressing and spin-drying, adding N-heptane for Wen Xijing, filtering, and vacuum-pumping the solid to obtain 46.1g of (2R) -2- (N-Boc-amino) -1, 5-hexanediol white solid with the yield of 90 percent. GC is 100%. LC-MS: M/z (ESI): 256.3 (M+Na) + ) + ， 1 H NMR(400MHz,CDCl 3 )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-dimethyl-sulfo-2- (N-Boc-amino) hexane (Compound 03-Ms)
To a 1000ml four-necked flask under nitrogen protection were added 02 g (1.0 eq,192.9 mmol) of the compound and 250ml of DCM, dissolved by stirring at room temperature, cooled to 0℃and 48.8g (2.5 eq,482.2 mmol) of TEA were added, stirred for 0.5h, the reaction temperature was controlled to be less than 0℃and 48.6g (2.2 eq,424.4 mmol) of MsCl of DCM solution was added dropwise, after completion of the dropwise addition, the reaction was incubated until the starting material was complete, TLC was monitored, 250ml of water was added, the mixture was separated, the DCM layer was washed once with 250ml of saturated NaHCO3 and aqueous solution, and evaporated to dryness under reduced pressure at room temperature to give 72.8g of (R) -1, 5-dimethyl-sulfo-2- (N-Boc-amino) hexane yellow oil in 97% yield. LC-MS: M/z (ESI): 412.0 (M+Na) + ) + ， 1 H NMR(400MHz,CDCl 3 )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 (10 eq,1797 mmol) of benzylamine is added into a 1000mL three-port bottle, the temperature is raised to 45 ℃ under the protection of nitrogen, 70g of compound 03-Ms (1.0 eq,179.8 mmol) is dissolved in 140mL of 2-MeTHF, the mixture is slowly added into a system of benzylamine in a dropwise manner, the temperature is raised to 60 ℃ after the dropwise manner, the reaction is carried out for 24-48h, the TLC is controlled until the raw materials are reacted completely, the dissolved solvent is removed by distillation under reduced pressure, 200mL of DCM is added, the temperature is reduced to 0 ℃, the glacial acetic acid regulating system is dropwise added to be neutral, the mixture is washed three times with 200mL of water, and the DCM is dried in a rotary manner under reduced pressure to obtain 46.5g of (5R) -5- (N-Boc-amino) -2-methyl-1-benzyl piperidine as brown yellow oil with the yield of 85%. The oil can be directly used for the followingThe reaction is carried out in one step. LC-MS: M/z (ESI): 305.3 (M+H) + ， 1 H NMR(400MHz,CDCl 3 )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)
To a 500mL single-necked flask containing compound 04 46.5g 1.0eq,152.7mmol) was added 140mL of EA for dissolution, 230mL (4.5 eq,690 mmol) of 3M HCl was added dropwise, and the solution was desalted and stirred at room temperature, followed by HPLC monitoring until the reaction was complete, transferring the reaction solution to a 1000mL four-necked flask, adding 370mL of water for stirring, separating the solution, and washing the aqueous phase once with 370mL of EA to obtain a pale yellow (5R) -2-methyl-5-amino-1-benzylpiperidine hydrochloride aqueous solution, the yield was 100% of the theoretical yield, and the solution was directly used for the next reaction. LC-MS: M/z (ESI): 205.2 (M+H) + ， 1 H 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)
Na was added to a 1000ml four-necked flask containing an aqueous solution of Compound 05-HCl at room temperature 2 CO 3 Regulating pH to neutral, and adding Na 2 CO 3 25.9g (1.6 eq,244.4 mmol) were dissolved by stirring for 0.5h, 4-chloro was added-7-tosyl-7H-pyrrole [2,3-D]Pyrimidine 46g (0.98 eq,149 mmol), stirring at room temperature for 0.5H, heating to 120deg.C, stirring overnight, controlling the reaction to complete in HPLC, cooling to 60deg.C, dropwise adding 370ml EA, continuing stirring and cooling to room temperature after completion, separating liquid, extracting water phase with 200ml EA once, mixing EA layers, washing organic phase with 300ml water twice, and spin-drying under reduced pressure to obtain (5R) -5- ((7-tosyl-7H-pyrrole [2, 3)]Pyrimidine) amino) -2-methyl-1-benzylpiperidine as a foamy solid 57.8g in 80% yield, 95% purity. LC-MS: M/z (ESI): 476.2 (M+H) + ， 1 H 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-pyrrole [2,3] pyrimidine) amino) -2-methyl-1-benzylpiperidine (Compound 07)
To a 1000mL single-port flask containing 0650g (1.0 eq,105 mmol) of the compound, 500mL of methanol and 24.5g (0.65 eq,68 mmol) of L-DBTA24.5g were added at room temperature and stirred for dissolution, the temperature was raised to 40-80 ℃, the reaction was carried out for 12-48 hours, a large amount of solid was precipitated, the temperature was lowered to room temperature, crystallization was carried out for 4-8 hours, filtration, rinsing with methanol was carried out, and 300mL of DCM and 5% Na were added to the solid 2 CO 3 300ml of solution is stirred and dissolved, separated, washed with water and the DCM layer is dried 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, 41% yield, 98% purity, ee>98.5％。LC-MS:m/z(ESI):476.2(M+H) + ， 1 H 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)。
To a 1000mL single-necked flask containing 06.5 g (1.0 eq,10.5 mmol) of the compound at room temperature, 50mL of acetone and 2.45g (0.65 eq,6.8 mmol) of L-DBTA are added and dissolved by stirring, the temperature is raised to 40-80 ℃, the reaction is carried out for 12-48 hours, a large amount of solid is separated out, the temperature is reduced to room temperature, crystallization is carried out for 4-8 hours, filtration and acetone leaching are carried out, 30mL of DCM and 5% Na are added to the solid 2 CO 3 30ml of solution is stirred and dissolved, separated, washed with water and the DCM layer is dried 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 1.8g, 36% yield, 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)
To a 500mL single-necked flask containing 07 g (1.0 eq,26.4 mmol) of the compound was added 150mL of 2-MeTHF and 2.18g (1.3 eq,54.5 mmol) of NaOH under stirring at room temperature, the mixture was dissolved, heated to 50-90℃until the reaction was completed by HPLC, cooled, dried under reduced pressure, extracted by stirring with 100mL of DCM and 100mL of water, separated, and the organic phase was washed once with 100mL of water and dried under reduced pressure to give 12.8g of (2S, 5R) -5- ((7H-pyrrole) amino) -2-methyl-1-benzylpiperidine as a pale brown solid in a yield of 95% and a purity of 98%. LC-MS: M/z (ESI): 322.25 (M+H) + ， 1 H 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)
To a 250mL single-port flask containing 12.5g (1.0 eq,38.9 mmol) of the compound (08) at room temperature was added 125mL of isopropyl alcohol, 10% -20% palladium hydroxide/C (mass ratio relative to the compound (08)), 2.6g (1.1 eq,43.3 mmol) of glacial acetic acid and 12.5mL of water, displaced with hydrogen, hydrogenated at normal pressure, heated to 50-80 ℃ to react, controlled by HPLC until the reaction is complete, suction filtered, and the filter cake rinsed with isopropyl alcohol to give 9g of (2 s, 5R) -5- ((7H-pyrrole) amino) -2-methylpiperidine as a pale brown solid as a filtrate by spin-drying, with a yield of 95.0% and a purity of 98%. LC-MS: M/z (ESI): 232.3 (M+H) + 。
EXAMPLE 10 preparation of (2S, 5R) -5- ((7H-pyrrole) amino) -2-methyl-1- (3-propenoyl) piperidine (Compound PF-06651600)
To a 250ml single-necked flask containing 09 g (1.0 eq,38.9 mmol) of compound, saturated NaHCO, was added at room temperature 3 90ml of solution and 90ml of THF, cooling to 0 ℃, slowly dropwise adding 4.23g (1.2 eq,46.7 mmol) of acryloyl chloride, controlling the reaction temperature to 0-20 ℃, controlling the reaction to be complete in HPLC, transferring to a reaction bottle of 500ml, adding 100ml of EA for extraction twice, combining organic layers, cooling, dropwise adding 13ml of 3M hydrochloric acid (1 eq,39 mmol) EA solution for salifying, controlling the TLC, adding 100ml of water for extraction twice, combining aqueous phase and saturated NaHCO 3 The pH value is regulated to be neutral, the temperature is reduced, crystallization is carried out, suction filtration and drying are carried out, and 9.4g of (2S, 5R) -5- ((7H-pyrrole) amino) -2-methyl-1- (3-acryl) piperidine white solid is obtained, the yield is 84.7%, the purity is 99%, and the ee value is 99%. LC-MS: M/z (ESI): 286.3 (M+H) + ， 1 H 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-necked flask containing 09 g (1.0 eq,38.9 mmol) of compound, saturated NaHCO, was added at room temperature 3 90ml of solution and 90ml of THF, cooling to 0 ℃, slowly dropwise adding 4.67g (1.2 eq,46.7 mmol) of ethyl acrylate, controlling the reaction temperature to 0-20 ℃, controlling the reaction to be complete in HPLC, transferring to a reaction bottle of 500ml, adding 100ml of EA for extraction twice, combining organic layers, cooling, dropwise adding 13ml of 3M hydrochloric acid (1 eq,39 mmol) EA solution for salifying, controlling the TLC, adding 100ml of water for extraction twice, combining aqueous phase and saturated NaHCO 3 The pH value is regulated to be neutral, the temperature is reduced, crystallization is carried out, suction filtration and drying are carried out, 8.9g of (2S, 5R) -5- ((7H-pyrrole) amino) -2-methyl-1- (3-acryloyl) piperidine white solid is obtained, the yield is 80.2%, the purity is 95%, and the ee value is 98%. LC-MS: M/z (ESI): 286.3 (M+H) + 。
While the methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and combinations of the methods and applications described herein can be made and applied within the spirit and scope of the invention. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention.
Claims (17)
1. A method of preparing compound 09, comprising:
(1) Reacting compound 03 with benzylamine, post-treating to obtain compound 04, reacting compound 04 with acid to obtain compound 05 or its salt,
wherein R is methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl,
(2) In the presence of alkali, the compound 05 reacts with 4-chloro-7-toluenesulfonyl-7H-pyrrole [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 ℃,
(3) Resolution of compound 06 gives compound 07, the reagents used for the resolution are L-DBTA and/or L-DTTA,
(4) Compound 07 is reacted with a base to produce compound 08,
the alkali is at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, sodium carbonate and potassium carbonate;
(5) In a reaction solvent, the compound 08 reacts under the action of a catalyst and hydrogen to prepare a compound 09,
wherein the catalyst is at least one of palladium hydroxide/carbon, palladium/carbon and palladium dichloride.
2. The process according to claim 1, wherein the mass ratio of compound 08 to catalyst is from 1:0.05 to 1:0.2.
3. The process according to claim 1, wherein the mass ratio of compound 08 to catalyst is from 1:0.1 to 1:0.5.
4. The process according to claim 1, wherein the mass ratio of compound 08 to catalyst is from 1:0.2 to 1:0.4.
5. The method according to claim 1, wherein the reaction solvent in the step (5) is at least one of isopropanol, n-propanol, methanol and ethanol.
6. The process of claim 1, wherein the reaction temperature of step (5) is from 30 ℃ to 100 ℃.
7. The process of claim 1, wherein the reaction temperature of step (5) is from 50 ℃ to 80 ℃.
8. The process of claim 1, wherein the molar ratio of compound 07 to base in step (4) is from 1:1.0 to 1:2.0.
9. The process of claim 1, wherein the molar ratio of compound 07 to base in step (4) is from 1:1.2 to 1:1.5.
10. The process according to claim 1, wherein the reaction solvent for the reaction of compound 07 with the base in step (4) is at least one of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, DMF.
11. The process of claim 1, wherein the reaction temperature of the compound 07 with the base in step (4) is 30 ℃ to 100 ℃.
12. The process of claim 1, wherein the reaction temperature of the compound 07 with the base in step (4) is 50 ℃ to 80 ℃.
13. The method according to claim 1, comprising: the salt of compound 05 reacts with the base to produce compound 5.
14. The process according to claim 1, wherein the reaction temperature of the reaction to produce compound 06 is from 100 ℃ to 130 ℃.
15. A process for the preparation of compound 05 or a salt thereof comprising: reacting compound 03 with benzylamine, post-treating to obtain compound 04, reacting compound 04 with acid to obtain compound 05 or its salt,
wherein R is methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl.
16. A method of preparing compound PF-06651600 comprising: the process according to any one of claims 1 to 14 for preparing compound 09, then reacting compound 09 with acryloyl chloride or an acrylate in the presence of a base in a reaction solvent to obtain 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 ℃.
17. The process of claim 16, wherein the reaction temperature of the reaction is from 10 ℃ to 20 ℃.
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