CN110117245B - Synthetic method of JAK inhibitor intermediate - Google Patents
Synthetic method of JAK inhibitor intermediate Download PDFInfo
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- CN110117245B CN110117245B CN201910541733.9A CN201910541733A CN110117245B CN 110117245 B CN110117245 B CN 110117245B CN 201910541733 A CN201910541733 A CN 201910541733A CN 110117245 B CN110117245 B CN 110117245B
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- 229940122245 Janus kinase inhibitor Drugs 0.000 title claims abstract description 23
- 238000010189 synthetic method Methods 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 94
- 238000000034 method Methods 0.000 claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 239000001488 sodium phosphate Substances 0.000 claims abstract description 7
- 229910000162 sodium phosphate Inorganic materials 0.000 claims abstract description 7
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims abstract description 7
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 6
- KUGSJJNCCNSRMM-UHFFFAOYSA-N ethoxyboronic acid Chemical compound CCOB(O)O KUGSJJNCCNSRMM-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- -1 2-methyl-but-2-yl Chemical group 0.000 claims description 44
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 39
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 5
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 3
- 150000008065 acid anhydrides Chemical class 0.000 claims description 3
- 238000001308 synthesis method Methods 0.000 abstract description 7
- 239000003444 phase transfer catalyst Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 70
- 239000000543 intermediate Substances 0.000 description 67
- 238000003786 synthesis reaction Methods 0.000 description 44
- 230000015572 biosynthetic process Effects 0.000 description 43
- 238000005160 1H NMR spectroscopy Methods 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 239000003795 chemical substances by application Substances 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000012043 crude product Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- PAVZHTXVORCEHP-UHFFFAOYSA-N ethylboronic acid Chemical compound CCB(O)O PAVZHTXVORCEHP-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 3
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- XRPVXVRWIDOORM-UHFFFAOYSA-N 2-methylbutanoyl chloride Chemical compound CCC(C)C(Cl)=O XRPVXVRWIDOORM-UHFFFAOYSA-N 0.000 description 2
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- NGFFLHMFSINFGB-UHFFFAOYSA-N [chloro(methoxy)phosphoryl]oxymethane Chemical compound COP(Cl)(=O)OC NGFFLHMFSINFGB-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- SQMRXOOOJGRPOT-UHFFFAOYSA-N ethyl 2,3-dihydro-1h-pyrrole-4-carboxylate Chemical compound CCOC(=O)C1=CNCC1 SQMRXOOOJGRPOT-UHFFFAOYSA-N 0.000 description 2
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Substances OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- AYHWHPDMLFMSLP-BDAKNGLRSA-N (3R,4S)-4-ethyl-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-3-carboxylic acid Chemical compound CC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(O)=O AYHWHPDMLFMSLP-BDAKNGLRSA-N 0.000 description 1
- LKPALAXKZXXURJ-OLZOCXBDSA-N (3r,4s)-4-ethyl-1-phenylmethoxycarbonylpyrrolidine-3-carboxylic acid Chemical compound C1[C@H](C(O)=O)[C@H](CC)CN1C(=O)OCC1=CC=CC=C1 LKPALAXKZXXURJ-OLZOCXBDSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 1
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 1
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 1
- 102000042838 JAK family Human genes 0.000 description 1
- 108091082332 JAK family Proteins 0.000 description 1
- 230000004163 JAK-STAT signaling pathway Effects 0.000 description 1
- 229940116839 Janus kinase 1 inhibitor Drugs 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 1
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 1
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 1
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 1
- 210000000633 nuclear envelope Anatomy 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000035778 pathophysiological process Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical group OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention discloses a synthesis method of a JAK inhibitor intermediate, which comprises the following steps: reacting a compound (2) serving as a raw material with ethyl boric acid in the presence of a catalyst, sodium phosphate and a phase transfer catalyst to obtain a JAK inhibitor intermediate (C); the intermediate (C) is subjected to hydrolysis reaction to obtain a compound (B), and the compound (B) is subjected to chiral catalytic hydrogenation reaction to obtain an intermediate (A); the invention provides a JAK inhibitor intermediate and a synthesis method thereof, by which the JAK inhibitor intermediate can be obtained with high yield and high purity, the reaction condition is mild, the post-treatment is simple, and the method is suitable for industrial mass production.
Description
Technical Field
The invention relates to the technical field of drug synthesis, and relates to a method for synthesizing a JAK inhibitor intermediate by adopting a chiral catalysis method.
Background
JAK (just animal kinase) kinases, a family of non-receptor tyrosine kinases that include JAK1, JAK2, JAK3 and TYK 1. The substrates of JAKs are Signal Transducers and Activators of Transcription (STATs). STAT is phosphorylated by JAK, dimerizes, and then enters nucleus through nuclear membrane to regulate the expression of related genes, and the signal path is called JAK-STAT pathway, so that JAK plays an important role in the pathophysiological process of immune-mediated diseases and can be used for treating some autoimmune diseases such as atopic dermatitis, rheumatoid arthritis, psoriasis, ulcerative colitis and the like.
The ipatinib is an oral JAK1 inhibitor and is used for treating diseases such as rheumatoid arthritis, psoriasis, arthritis and the like. The ipatinib is a chiral molecule, and the existing synthesis method of the chiral intermediate pyrrolidine carboxylic acid part mainly comprises a chemical resolution method and a chiral catalytic synthesis method. The synthesis of the racemate is reported in the patent literature (WO2015/061665Al), which reports very low yields and the enantiomers are obtained by resolution on chiral preparative columns. Another patent document (US2013/0072470Al) reports the synthesis of its racemate by chemical resolution to obtain the desired enantiomer, but the resolution is very poor, with a yield of 13% and an enantiomeric purity of 96% ee. The patent literature (WO2017066775) reports a synthesis method of asymmetric hydrogenation of intermediates, and the literature reports that when the method is used for synthesizing chiral precursor olefin C, only high-activity triflate can be used under the action of a noble metal Pd catalyst, and the high-activity triflate is easily hydrolyzed under high temperature and alkaline conditions, so that most of triflate is decomposed into raw material 1, and the yield of the step is only about 22%, which is far lower than the crude yield of 91% described in the literature.
Disclosure of Invention
The invention provides a synthesis method of a JAK inhibitor intermediate, aiming at providing a high-efficiency synthesis method of the JAK inhibitor intermediate aiming at the defects of the prior art.
The invention also provides a JAK inhibitor intermediate, and other JAK inhibitor intermediates can be quickly synthesized with high yield by using the intermediate.
A method of synthesizing a JAK inhibitor intermediate comprising: reacting a compound (2) serving as a raw material with ethyl boric acid in the presence of a catalyst, sodium phosphate and a phase transfer catalyst to obtain a JAK inhibitor intermediate (C);
the compound (2) is one or more of the compounds shown in the following formula:
R1is selected from C1-C5Alkyl or benzyl; r2Is selected from C1-C5An alkyl group;
L1selected from-C (═ O) -, -SO2-、
R3Is selected from C1～C5Alkyl, phenyl, trifluoromethyl, p-tolyl or
The intermediate (C) is one or more compounds shown in the following formula:
in the present invention, C1～C5The alkyl group mainly comprises methyl, ethyl, n-propyl, isopropyl, butyl and n-butylAn alkyl group, an isobutyl group, a tert-butyl group, three n-pentyl groups (1-position, 2-position, 3-position) at different substitution positions, an isopentyl group (1-position, 2-position, 3-position, 4-position) at 4-position at different substitution positions, and the like.
Preferably, the compound (2) contains
Molar amount of (a): the molar ratio of the compound (2) to the ethyl boric acid is 1 (1-5); further preferably 1 (1-2); further 1 (1-1.6); the molar ratio of the compound (2) to the sodium phosphate is 1: (1-5); further preferably 1 (1-4); further 1 (1-3); when 1mol of the compound (2) reacts, the amount of the phase transfer catalyst is 0.5-500 g; more preferably 0.5 to 200 g.
Preferably, the catalyst is (PCy)3-NiCl2The molar amount of the compound (2) added is 0.5 to 10%, and more preferably 0.8 to 2%; the reaction temperature is 40 to 120 ℃, and more preferably 60 to 100 ℃.
Preferably, the reaction solvent is selected from one or more of THF, methyl tert-butyl ether, toluene, and the like.
After the reaction is finished, methyl tert-butyl ether, toluene and the like can be used for extraction, the crude product obtained by extraction can be refined by column chromatography or refining methods such as recrystallization, and when column chromatography is adopted, ethyl acetate and petroleum ether can be used as eluent for column chromatography refining.
Preferably, the compound (2) is one or more compounds represented by the following formula:
preferably, R is1Selected from tert-butyl or benzyl; r2Selected from methyl, ethyl; r3Selected from methyl, ethyl, isopropyl, tert-butyl, 2-methyl-but-2-yl, phenyl, trifluoromethyl, p-tolyl.
Preferably, R in the formula (D)3Is selected from C1-C5Alkyl, trifluoromethyl, phenyl; wherein C is1-C5The alkyl group is preferably a methyl group, an ethyl group, an isopropyl group, a tert-butyl group or an isopentyl group. R in the formula (E)3Selected from methyl, phenyl, trifluoromethyl, p-tolyl; r in the formula (I)3Selected from C1-C4 alkyl groups, more preferably methyl, ethyl, etc.; r in the formula (J)3Selected from C1-C2 alkyl, phenyl, and the like.
Preferably, the intermediate (C) is subjected to hydrolysis reaction to obtain a compound (B), and the compound (B) is subjected to chiral catalytic hydrogenation reaction to obtain an intermediate (A);
the compound (B) is one or more of the compounds shown in the following formula:
the intermediate (A) is one or more of the compounds shown in the following formula:
the hydrolysis reaction can be carried out under acidic condition or alkaline condition; alternatively, the hydrolysis reaction may be carried out in an aqueous solution of sodium hydroxide or potassium hydroxide, the molar ratio of the intermediate (C) to sodium hydroxide or potassium hydroxide being 1: (1-10), more preferably 1: (1-2). The reaction can be easily water or an alcohol solvent containing about 40 to 99% of water, for example, a methanol, ethanol or isopropanol solvent containing water. The reaction temperature is preferably 20 to 70 ℃, and more preferably 30 to 70 ℃. After the reaction is finished, the target product compound (B) can be obtained by acidification and extraction.
Preferably, the catalyst adopted in the chiral catalytic hydrogenation reaction is S-BINAP-Ru (OAc)2A complex, which is added in a molar amount of 0.001 to 0.1 equivalent, more preferably 0.001 to 0.08 equivalent, based on the molar amount of the intermediate (C); the hydrogen pressure is 20 to 60atm, and more preferably30-50 atm; the temperature is 40 to 120 ℃, and more preferably 60 to 90 ℃. The reaction solvent may be methanol, ethanol, etc. The reaction time is preferably 2 to 10 hours. After completion of the reaction, the solvent is removed, and recrystallization is carried out using ethyl acetate or the like to obtain the intermediate (a).
During the reaction of the chiral catalytic hydrogenation, triethylamine and the like can be added, and the molar weight of the added triethylamine is 1-3 times of that of the intermediate (C).
Preferably, the compound (2) is obtained by reacting one or more compounds shown in the compound (1) with corresponding acyl chloride or anhydride;
the compound (1) is one or more of the compounds described by the following formulas:
in this step, an acid-binding agent (e.g., triethylamine) may be added as needed in a molar ratio of the compound (1) to the acid chloride or acid anhydride to the acid-binding agent 1 (0.3 to 3) to (0.6 to 6), and more preferably 1:1 to 1.5:1 to 3. In the step, the reaction temperature is-20 to 50 ℃, and the preferable temperature is-20 to 30 ℃. The reaction solvent may be one or more of dichloromethane, THF, diethyl ether, methyl tert-butyl ether, ethyl acetate, and the like.
In a preferred embodiment, compound (1) is used as a starting material, and reacted with an acid chloride or an acid anhydride to obtain compound (2) or compounds (D) to (J), compound (2) or compounds (D) to (J) is further reacted with ethylboronic acid to obtain compound (C), compound (C) is hydrolyzed to obtain compound (B), and compound (B) is subjected to a final chiral hydrogenation reaction to obtain compound (a).
In the compound (1) and the compounds (C) to (A), R1Preferably benzyl, tert-butyl; the R is2Methyl and ethyl are preferred.
The compound (2) is preferably one or more of the following compounds:
a JAK inhibitor intermediate having the structure:
R1is selected from C1-C5Alkyl or benzyl; r2Is selected from C1-C5An alkyl group; l is1Selected from-C (═ O) -, -SO2-, -C (═ O) - (i.e., as
)；
R3Is selected from C1～C5Alkyl, phenyl, trifluoromethyl, p-tolyl or
And do not satisfy simultaneously: r1When is Bn, R2Is ethyl, L1is-SO2-，R3Is trifluoromethyl.
Preferably, a JAK inhibitor intermediate having the structure:
compared with the prior art, the invention has the beneficial effects that:
the invention provides a JAK inhibitor intermediate and a synthesis method thereof, by which the JAK inhibitor intermediate can be obtained with high yield and high purity, the reaction condition is mild, the post-treatment is simple, and the method is suitable for industrial mass production.
Detailed Description
The present invention will be further specifically described with reference to the following examples, but the present invention is not limited to these examples.
Example 1: general synthetic methods for intermediates D, E, F, G, H, I and J
Adding 10mmol of compound (1) (R)1Tert-butyl or benzyl) and 20mmol triethylamine are added into 20mL dichloromethane, 11mmol of acyl chloride or anhydride is added after a reactor is cooled to 0 ℃, after stirring is carried out for 1-10 h, water is slowly added to stop the reaction, the reaction mixture is separated, the water layer is extracted for 2 times by dichloromethane, the combined dichloromethane is dried, dichloromethane is recovered to obtain a crude product, and the crude product is extracted by ethyl acetate: and (3) carrying out column chromatography on the petroleum ether (10: 1-10: 3) mixed solvent to obtain the product.
Example 2: synthesis of intermediate 1-benzyloxycarbonyl-4-acetoxy dihydropyrrole-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is benzyl, R2The ethyl is used as an acylating agent, and the reaction is carried out for 6 h. The yield was 93%.1H-NMR(400MHz，CDCl3)：1.20-1.23(t,3H),2.22(s,3H),4.15-4.16(m,2H),4.30-4.31(m,4H),5.18(s,2H),7.39-7.40(m,5H)。MS(ESI):334.4。
Example 3: synthesis of intermediate 1-benzyloxycarbonyl-4-acetoxy dihydropyrrole-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is benzyl, R2Ethyl, using acetic acid chloride as acylating agent, and reacting for 2 h. The yield was 96%.
Example 4: synthesis of intermediate 1-benzyloxycarbonyl-4-trifluoroacetyloxydihydropyrrole-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is benzyl, R2The ethyl is reacted for 3h by using trifluoroacetic anhydride as an acylating agent. The yield was 87%.1H-NMR(400MHz，CDCl3)：
1.21-1.24(t,3H),4.24-4.26(m,2H),4.40-4.44(m,4H),5.19(s,2H),7.38-7.40(m,5H)。MS(ESI):388.4。
Example 5: synthesis of intermediate 1-benzyloxycarbonyl-4-isobutyryloxydihydropyrrole-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is benzyl, R2For ethyl, isobutyric anhydride was used as acylating agent for 10 h. The yield was 94%.1H-NMR(400MHz，CDCl3)：1.20-1.34(m,9H),2.57-2.60(m,1H),4.15-4.18(m,2H),4.24-4.26(m,4H),5.19(s,2H),7.29-7.40(m,5H)。MS(ESI):362.6。
Example 6: synthesis of intermediate 1-benzyloxycarbonyl-4-isobutyryloxydihydropyrrole-3-carboxylic acid ethyl ester
According to example 1Process, Compound (1), R1Is benzyl, R2Is ethyl, and is reacted for 2h by using isobutyryl chloride as an acylating agent. The yield was 96%.
Example 7: synthesis of intermediate 1-benzyloxycarbonyl-4-pivaloyloxydihydropyrrole-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is benzyl, R2Is ethyl, pivaloyl chloride is used as an acylating agent, and the reaction is carried out for 3 hours. The yield was 99%.1H-NMR(400MHz，CDCl3)：1.28-1.30(m,12H),4.21-4.23(m,2H),4.40-4.43(m,4H),5.19(s,2H),7.39-7.40(m,5H)。MS(ESI):376.5。
Example 8: synthesis of intermediate 1-benzyloxycarbonyl-4- (2, 2-methylbutyryloxy) dihydropyrrole-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is benzyl, R2For ethyl, 2-methylbutyryl chloride is used as an acylating agent and reacted for 3 h.
The yield was 98%.1H-NMR(400MHz，CDCl3)：1.00-1.03(t,3H),1.12(s,3H),1.13(s,3H),1.16-1.19(m,2H),1.24-1.26(m,3H)4.22-4.23(m,2H),4.39-4.42(m,4H),5.19(s,2H),7.39-7.40(m,5H)。MS(ESI):390.6。
Example 9: synthesis of intermediate 1-benzyloxycarbonyl-4-methanesulfonyloxy dihydropyrrole-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is benzyl, R2For ethyl, methanesulfonyl chloride is used as an acylating agent, and the reaction is carried out for 2 h. The yield was 83%.1H-NMR(400MHz，CDCl3)：1.25-1.26(t,3H),3.33(s,3H)4.15-4.19(m,6H),5.20(s,2H),7.39-7.44(m,5H)。MS(ESI):370.5。
Example 10: synthesis of intermediate 1-benzyloxycarbonyl-4-methanesulfonyloxy dihydropyrrole-3-carboxylic acid methyl ester
According to the method of example 1, in the compound (1), R1Is benzyl, R2For methyl, p-methanesulfonyl chloride is used as an acylating agent and reacted for 2 h.
The yield was 78%.1H-NMR(400MHz，CDCl3)：3.35(s,3H),3.82(s,3H)4.43-4.48(m,4H),5.19(s,2H),7.39-7.40(m,5H)。MS(ESI):356.6。
Example 11: synthesis of intermediate 1-benzyloxycarbonyl-4-trifluoromethanesulfonyloxy dihydropyrrole-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is benzyl, R2Using trifluoromethanesulfonic anhydride as an acylating agent for reacting for 1 h. The yield was 91%.1H-NMR(400MHz，CDCl3): 1.32-1.33(t,3H),4.15-4.19(m,2H),4.40-4.44(m,4H),5.20(s,2H),7.39-7.44(m, 5H). Known compounds
Example 12: synthesis of intermediate 1-benzyloxycarbonyl-4-p-toluenesulfonyloxy dihydropyrrole-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is benzyl, R2For ethyl, p-toluenesulfonyl chloride is used as an acylating agent and reacted for 4 h. The yield was 73%.1H-NMR(400MHz，CDCl3)：1.24-1.25(t,3H),2.45(s,3H)，4.15-4.17(m,2H),4.40-4.42(m,4H),5.19(s,2H),7.33-7.44(m,9H)。MS(ESI):446.7。
Example 13: synthesis of intermediate 1-benzyloxycarbonyl-4-acetoxycarbonyl-3-pyrrolidylsulfate
According to the method of example 1, in the compound (1), R1Is benzyl, R2For ethyl, the reaction was carried out for 5h using sulfuryl chloride as acylating agent (0.6 mmol). The yield was 67%.1H-NMR(400MHz，CDCl3)：1.22-1.23(t,3H),4.15-4.17(m,2H),4.41-4.43(m,4H),5.18(s,2H),7.35-7.40(m,5H)。MS(ESI):645.9。
Example 14: synthesis of intermediate 1-benzyloxycarbonyl-4-acetoxycarbonyl-3-dihydropyrrole phosphate triester
According to the method of example 1, in the compound (1), R1Is benzyl, R2For ethyl, phosphorus oxychloride was used as acylating agent (0.5mmol) and the reaction was carried out for 5 h. The yield was 71%.1H-NMR(400MHz，CDCl3)：1.22-1.24(t,3H),4.14-4.17(m,2H),4.40-4.43(m,4H),5.19(s,2H),7.32-7.44(m,5H)。MS(ESI):919.1。
Example 15: synthesis of intermediate 1-benzyloxycarbonyl-4-acetoxycarbonyl-3-oxalic acid dihydropyrrole diester
According to the method of example 1, in the compound (1), R1Is benzyl, R2For ethyl, reaction was carried out for 5h using oxalyl chloride as acylating agent (0.6 mmol). The yield was 84%.1H-NMR(400MHz，CDCl3)：1.21-1.22(t,3H),4.15-4.16(m,2H),4.42-4.43(m,4H),5.19(s,2H),7.35-7.39(m,5H)。MS(ESI):637.7。
Example 16: synthesis of intermediate 1-benzyloxycarbonyl-4-dimethy loxy pyrroline-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is benzyl, R2For ethyl, dimethylcarbamoyl chloride was used as acylating agent for 1 h. The yield was 97%.1H-NMR(400MHz，CDCl3)：1.20-1.22(t,3H),3.11(s,3H),3.02(s,3H),4.15-4.16(m,2H),4.41-4.42(m,4H),5.19(s,2H),7.37-7.39(m,5H)。MS(ESI):363.5。
Example 17: synthesis of intermediate 1-benzyloxycarbonyl-4-dimethoxyphosphoryloxy dihydropyrrole-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is benzyl, R2Is ethyl, and dimethoxy phosphoryl chloride is used as an acylating agent to react for 6 h. The yield was 87%.1H-NMR(400MHz，CDCl3)：1.21-1.23(t,3H),3.56(s,6H),4.14-4.16(m,2H),4.30-4.32(m,4H),5.18(s,2H),7.19-7.36(m,10H)，7.39-7.40(m,5H)。MS(ESI):400.5。
Example 18: synthesis of intermediate 1-benzyloxycarbonyl-4-diphenylphosphoryloxydihydropyrrole-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is benzyl, R2The ethyl group is reacted for 10h by using diphenoxy phosphorus chloride as an acylating agent. The yield was 91%.1H-NMR(400MHz，CDCl3)：1.21-1.23(t,3H),4.14-4.16(m,2H),4.30-4.32(m,4H),5.18(s,2H),7.19-7.36(m,10H)，7.39-7.40(m,5H)。MS(ESI):524.7。
Example 19: synthesis of intermediate ethyl 1-tert-butoxycarbonyl-4-acetoxy-dihydropyrrole-3-carboxylate
According to the method of example 1, in the compound (1), R1Is tert-butyl, R2The ethyl is used as an acylating agent, and the reaction is carried out for 5 h. The yield was 95%.1H-NMR(400MHz，CDCl3)：1.29-1.30(t,3H),1.48(s,9H),2.24(s,3H),4.20-4.23(m,2H),4.31-4.34(m,4H)。MS(ESI):300.5。
Example 20: in the compound (1), R1Is tert-butyl, R2Synthesis of intermediate ethyl 1-tert-butoxycarbonyl-4-acetoxy-dihydropyrrole-3-carboxylate for ethyl
The reaction was carried out as in example 1 using acetic acid chloride as acylating agent for 2 h. The yield was 97%.
Example 21: synthesis of intermediate 1-tert-butyloxycarbonyl-4-trifluoroacetyloxydihydropyrrole-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is tert-butyl, R2The ethyl is reacted for 3h by using trifluoroacetic anhydride as an acylating agent. The yield was 93%.1H-NMR(400MHz，CDCl3)：1.28-1.29(t,3H),1.49(s,9H),4.21-4.23(m,2H),4.33-4.35(m,4H)。MS(ESI):354.5。
Example 22: synthesis of intermediate 1-tert-butyloxycarbonyl-4-isobutyryloxydipyrrole-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1)，R1Is tert-butyl, R2For ethyl, isobutyric anhydride was used as acylating agent for 10 h. The yield was 95%.1H-NMR(400MHz，CDCl3)：1.24-1.26(d,6H),1.28-1.30(t,3H),1.48(s,9H),2.67-2.69(m,1H),4.20-4.23(m,2H),4.34-4.35(m,4H)。MS(ESI):328.5。
Example 23: synthesis of intermediate 1-tert-butyloxycarbonyl-4-isobutyryloxydipyrrole-3-carboxylic acid ethyl ester
According to the method of example 11, in the compound (1), R1Is tert-butyl, R2Is ethyl, and is reacted for 2h by using isobutyryl chloride as an acylating agent. The yield was 97%.
Example 24: synthesis of intermediate ethyl 1-tert-butoxycarbonyl-4-pivaloyloxydihydropyrrole-3-carboxylate
According to the method of example 1, in the compound (1), R1Is tert-butyl, R2Is ethyl, pivaloyl chloride is used as an acylating agent, and the reaction is carried out for 3 hours. The yield was 98%.1H-NMR(400MHz，CDCl3)：1.22-1.24(t,3H),1.29(s,9H),1.45(s,9H),4.17-4.19(m,2H),4.28-4.30(m,4H)。MS(ESI):342.5。
Example 25: synthesis of intermediate ethyl 1-tert-butoxycarbonyl-4- (2, 2-methylbutanoyloxy) dihydropyrrole-3-carboxylate
According to the method of example 1, in the compound (1), R1Is tert-butyl, R2For ethyl, 2-methylbutyryl chloride is used as an acylating agent and reacted for 3 h. The yield was 99%.1H-NMR(400MHz，CDCl3)：1.00-1.02(t,3H),1.12(s,3H),1.13(s,3H),1.16-1.20(m,2H),1.24-1.26(t,3H),1.46(s,9H),4.18-4.19(m,2H),4.39-4.41(m,4H)。MS(ESI):356.6。
Example 26: synthesis of intermediate 1-tert-butyloxycarbonyl-4-methylsulfonyloxydihydropyrrole-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is tert-butyl, R2For ethyl, methanesulfonyl chloride is used as an acylating agent, and the reaction is carried out for 2 h. The yield was 81%.1H-NMR(400MHz，CDCl3)：1.35-1.36(t,3H),1.49(s,9H),3.27(s,3H),4.25-4.26(m,2H),4.35-4.37(m,4H)。MS(ESI):336.5
Example 27: synthesis of intermediate 1-tert-butyloxycarbonyl-4-trifluoromethanesulfonyloxy pyrroline-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is tert-butyl, R2Using trifluoromethanesulfonic anhydride as an acylating agent for reacting for 1 h. The yield was 90%.1H-NMR(400MHz，CDCl3): 1.33-1.34(t,3H),1.50(s,9H),4.31-4.34(m,2H),4.39-4.41(m, 4H). Example 28: synthesis of intermediate 1-tert-butyloxycarbonyl-4-p-toluenesulfonyloxy pyrroline-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is tert-butyl, R2For ethyl, p-toluenesulfonyl chloride is used as an acylating agent and reacted for 4 h. The yield was 81%.1H-NMR(400MHz，CDCl3)：1.28-1.29(t,3H),1.52(s,9H)，2.33(s,3H),4.17-4.19(m,2H),4.41-4.42(m,4H),7.33-7.45(m,4H)。MS(ESI):412.6。
Example 29: synthesis of intermediate 1-tert-butyloxycarbonyl-4-acetoxycarbonyl-3-dihydropyrrole phosphate triester
According to the method of example 1, in the compound (1), R1Is tert-butyl, R2For ethyl, phosphorus oxychloride was used as acylating agent (0.5mmol) and the reaction was carried out for 5 h. The yield was 62%.1H-NMR(400MHz，CDCl3)：1.27-1.29(t,3H),1.46(s,9H)，4.13-4.15(m,2H),4.21-4.24(m,2H),4.54-4.55(m,2H)。MS(ESI):817.0。
Example 30: synthesis of intermediate 1-tert-butyloxycarbonyl-4-acetoxycarbonyl-3-pyrrolidylsulfate
According to the method of example 1, in the compound (1), R1Is tert-butyl, R2For ethyl, the reaction was carried out for 5h using sulfuryl chloride as acylating agent (0.6 mmol). The yield was 66%.1H-NMR(400MHz，CDCl3)：1.24-1.25(t,3H),1.48(s,9H)，4.12-4.14(m,2H),4.40-4.44(m,4H)。MS(ESI):577.8。
Example 31: synthesis of intermediate 1-tert-butyloxycarbonyl-4-acetoxycarbonyl-3-oxalic acid dihydropyrrole diester
According to the method of example 1, in the compound (1), R1Is tert-butyl, R2For ethyl, reaction was carried out for 5h using oxalyl chloride as acylating agent (0.6 mmol). The yield was 78%.1H-NMR(400MHz，CDCl3)：1.29-1.31(t,3H),1.50(s,9H)，4.20-4.22(m,2H),4.38-4.40(m,4H)。MS(ESI):569.8。
Example 32: synthesis of intermediate 1-tert-butyloxycarbonyl-4-dimethy loxy pyrroline-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is tert-butyl, R2For ethyl, dimethylcarbamoyl chloride was used as acylating agent for 1 h. The yield was 97%.1H-NMR(400MHz，CDCl3)：1.26-1.28(t,3H),3.10(s,3H),3.13(s,3H),1.45(s,9H),4.22-4.24(m,2H),4.42-4.43(m,4H)。MS(ESI):329.5。
Example 34: synthesis of intermediate 1-tert-butyloxycarbonyl-4-dimethoxyphosphoryloxy-pyrroline-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is tert-butyl, R2For ethyl, dimethoxy phosphoryl chloride is used as an acylating agent and reacted for 4 h. The yield was 87%.1H-NMR(400MHz，CDCl3)：1.21-1.23(t,3H),1.51(s,9H),3.62(s,6H),4.16-4.18(m,2H),4.31-4.32(m,4H)。MS(ESI):366.5。
Example 34: synthesis of intermediate 1-tert-butyloxycarbonyl-4-diphenylphosphoryloxydihydropyrrole-3-carboxylic acid ethyl ester
According to the method of example 1, in the compound (1), R1Is tert-butyl, R2Is ethyl, and is reacted for 4h by using diphenoxy phosphorus chloride as an acylating agent. The yield was 93%.1H-NMR(400MHz，CDCl3)：1.28-1.30(t,3H),1.51(s,9H),4.21-4.4(m,2H),4.30-4.35(m,4H),7.20-7.36(m,10H)。MS(ESI):490.6。
Example 35: general synthetic method of intermediate 1-tert-butyloxycarbonyl (benzyloxycarbonyl) -4-ethyl dihydropyrrole-3-carboxylic acid ethyl ester
Intermediate 10mmol D, E, F, H, I, G and J (R)1Is tert-butyl or benzyl; r2Is methyl orEthyl), 1.5 equivalents of ethylboronic acid and 3 equivalents of sodium phosphate were added to 20mL of toluene, followed by 0.1mmol of catalyst (PCy)3-NiCl2And 1g of tetrabutylammonium bromide, heating the reactor to 80 ℃, reacting for 10 hours, adding water to stop the reaction, separating the reaction mixture, extracting the water layer with toluene for 2 times, drying the combined solvent, recovering the toluene to obtain a crude product, and performing column chromatography on the crude product with a mixed solvent of ethyl acetate and petroleum ether (10:1) to obtain the product.
Example 36: synthesis of intermediate 1-benzyloxycarbonyl-4-ethyl-3-dihydropyrrole carboxylic acid methyl ester
According to the method of example 35, 1-benzyloxycarbonyl-4-methanesulfonyloxy dihydropyrrole-3-carboxylic acid methyl ester was reacted at 80 ℃ for 10 hours in 87% yield.1H-NMR(400MHz，CDCl3)：1.12-1.13(t,3H),2.67-2.69(m,2H),3.78(s,3H),4.35-4.44(m,4H),5.19(s,2H),7.39-7.41(m,5H)。MS(ESI):290.5。
Example 37: synthesis of intermediate 1-benzyloxycarbonyl-4-ethyl-3-dihydropyrrole carboxylic acid ethyl ester
According to the method of example 35, 1-benzyloxycarbonyl-4-trifluoromethanesulfonyloxydihydropyrrole-3-carboxylic acid ethyl ester was reacted at 80 ℃ for 10 hours in 82% yield.1H-NMR(400MHz，CDCl3)：δ1.11-1.13(t,3H),1.30-1.33(t,3H),2.66-2.69(m,2H),4.21-4.24(m,2H),4.36-4.44(m,4H),5.18(s,2H)7.38-7.40(m,5H)。
Example 38 (comparative): literature comparison experiment, synthesis of intermediate 1-carbobenzoxy-4-ethyl-3-pyrroline carboxylic acid ethyl ester
Will 10Adding 1-benzyloxycarbonyl-4-trifluoromethanesulfonyloxy dihydropyrrole-3-carboxylic acid ethyl ester mmol, ethylboric acid 15mmol, potassium carbonate 30mmol and water 1mL into toluene 20mL, and adding DPPF-PdCl as catalyst 0.1mmol2Heating a reactor to 80 ℃ to react for 10 hours, then the raw materials disappear, adding water to stop the reaction, separating the reaction mixture, extracting a water layer for 2 times by using toluene, drying the combined solvent, recovering the toluene to obtain a crude product, carrying out column chromatography on the crude product by using a mixed solvent of ethyl acetate and petroleum ether (10:1) to obtain a product with the yield of 22 percent, and recovering 68 percent of the initial raw material of 1-benzyloxycarbonyl-4-oxa-3-pyrrolidine carboxylic acid ethyl ester,
this indicates that the reactants are preferentially decomposed to the starting materials at this addition.
Example 39: synthesis of intermediate 1-tert-butyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid ethyl ester
10mmol of 1-tert-butoxycarbonyl-4-dimethylyloxydihydropyrrole-3-carboxylic acid ethyl ester, 1.5 equivalents of ethylboronic acid and 3 equivalents of sodium phosphate were added to 20mL of toluene, and 0.1mmol of catalyst P (Cy) was added thereto3-NiCl2And 1g of tetrabutylammonium bromide, heating the reactor to 80 ℃, reacting for 10 hours, adding water to stop the reaction, separating the reaction mixture, extracting the water layer with toluene for 2 times, drying the combined solvent, recovering the toluene to obtain a crude product, and performing column chromatography on the crude product with a mixed solvent of ethyl acetate and petroleum ether (10:1) to obtain the product. The yield was 83%.1H-NMR(400MHz，CDCl3)：1.09-1.13(t,3H),1.30-1.34(m,3H),1.50(s,9H),2.65-2.68(m,2H),4.21-4.25(m,2H),4.27-4.34(m,4H)。MS(ESI):270.5。
Other examples are shown in the following table:
the products of examples 40-52 were:
the products of examples 53-58 were:
example 59: synthesis of intermediate 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid
Dissolving 10mmol of 1-benzyloxycarbonyl-4-ethyl dihydropyrrole-3-carboxylic acid ethyl ester in 5mL of ethanol, adding 6mL of 10% NaOH solution, reacting at room temperature for 6 hours under stirring, acidifying the reaction solution to acidity with 20% hydrochloric acid, removing the solvent under reduced pressure, extracting the residue with dichloromethane for 2 times, drying the combined dichloromethane, removing the dichloromethane to obtain a product, crystallizing with ethyl acetate, with the yield of 91%, and performing nuclear magnetic data on the product:1H-NMR(400MHz，CDCl3)：1.10-1.15(t,3H),2.69-2.71(m,2H),4.39-4.46(m,4H),5.19(s,2H)7.28-7.40(m,5H)。
example 60: synthesis of intermediate 1-tert-butyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid
Dissolving 10mmol of 1-tert-butyloxycarbonyl-4-ethyl dihydropyrrole-3-carboxylic acid ethyl ester in 5mL of ethanol, adding 6mL of 10% NaOH solution, reacting at 50 ℃ for 4h, acidifying the reaction solution to acidity with 20% phosphoric acid, decompressing to remove the solvent, extracting the residue with dichloromethane for 2 times, drying the combined dichloromethane, removing the dichloromethane to obtain a product, crystallizing with ethyl acetate, and obtaining the product with 94% yield.1H-NMR(400MHz，CDCl3)：1.09-1.13(t,3H),1.49(s,9H),2.64-2.68(m,2H),4.27-4.34(m,4H)。MS(ESI):242.4。
Example 61: synthesis of intermediate (3R,4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid
Under the protection of nitrogen, 20mmol of 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, 20mmol of triethylamine and 0.06mmol of S-BINAP-Ru (OAc)2Dissolving a complex in 100mL of deoxidized methanol, placing a reaction bottle in a pressure kettle, introducing hydrogen, replacing nitrogen in the reaction kettle for three times, raising the pressure of the hydrogen to 40atm, heating to 75 ℃, reacting for 7 hours, discharging the hydrogen carefully after different catalyst dosages and different times, opening the reaction kettle, taking out the reaction bottle, removing the methanol, and crystallizing by using ethyl acetate to obtain a product, wherein the yield is 84%, the purity is not less than 99%, and the chiral purity of HPLC is not less than 99%.1H-NMR(400MHz，CD3OD)：1.00-1.03(t,3H),1.39-1.43(m,2H),3.14-3.16(m,1H),3.31-3.35(m,1H),3.57-3.65(m,2H),3.65-3.67(m,1H),3.90-3.92(m,1H),5.13-5.33(m,2H)7.33-7.39(m,5H)。
Example 62: synthesis of intermediate (3R,4S) -1-tert-butyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid
Under the protection of nitrogen, 20mmol of 1-tert-butyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, 20mmol of triethylamine and 0.06mmol of S-BINAP-Ru (OAc)2Dissolving the complex in 100mL of deoxidized methanol, putting a reaction bottle into a pressure kettle, introducing hydrogen, replacing nitrogen in the reaction kettle for three times, raising the pressure of the hydrogen to 40atm, heating to 75 ℃, reacting for 7 hours, carefully releasing the hydrogen, opening the reaction kettle, taking out the reaction bottle, removing the methanol, crystallizing by using ethyl acetate to obtain the product with the yield of 82%. The chiral purity is more than or equal to 99 percent.1H-NMR(400MHz，CDCl3)：0.95-0.98(t,3H),1.48(s,9H),1.29-1.33(m,1H),1.70-1.72(m,1H),2.41-2.42(m,1H),2.76-2.78(m,1H),3.10-3.15(m,1H),3.60-3.82(m,3H)。MS(ESI):244.5。MS(ESI):244.4。
Claims (5)
1. A method of synthesizing a JAK inhibitor intermediate comprising: reacting a compound (2) serving as a raw material with ethylboric acid in the presence of a catalyst, sodium phosphate and tetrabutylammonium bromide to obtain a JAK inhibitor intermediate (C); the catalyst is (PCy)3-NiCl2；
The compound (2) is one of the compounds shown in the following formula:
the intermediate (C) is one of the compounds shown in the following formula:
as contained in the compound (2)
The molar ratio of the compound (2) to the ethylboric acid is 1 (1-5); the molar ratio of the compound (2) to the sodium phosphate is 1: (1-5); when 1mol of the compound (2) reacts, the required amount of tetrabutylammonium bromide is 0.5-500 g;
the molar weight of the added catalyst is 0.5-10% of that of the compound (2), and the reaction temperature is 40-120 ℃;
the R is1Selected from tert-butyl or benzyl; r2Selected from methyl, ethyl;
R3selected from methyl, ethyl, isopropyl, tert-butyl, 2-methyl-but-2-yl, phenyl, trifluoromethyl, p-tolyl.
2. The method of synthesizing a JAK inhibitor intermediate according to claim 1, wherein the intermediate (C) is subjected to hydrolysis reaction to obtain the compound (B), and the compound (B) is subjected to chiral catalytic hydrogenation reaction to obtain the intermediate (a);
the compound (B) is one of the compounds shown in the following formula:
the intermediate (A) is one of the compounds shown in the following formula:
3. the method for synthesizing a JAK inhibitor intermediate according to claim 2, wherein the catalyst used in the chiral catalytic hydrogenation reaction is S-BINAP-Ru (OAc)2The complex is added in a molar amount of 0.001-0.1 equivalent of the molar amount of the intermediate (C), the hydrogen pressure is 20-60 atm, and the temperature is 40-120 ℃.
4. The method for synthesizing a JAK inhibitor intermediate according to claim 1, wherein the compound (2) is obtained by reacting one of the compounds represented by the compound (1) with a corresponding acid chloride or acid anhydride;
the compound (1) is one of the compounds represented by the following formulas:
5. a JAK inhibitor intermediate having the structure:
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