CN107759623A - Intermediate of JAK inhibitor and preparation method thereof - Google Patents
Intermediate of JAK inhibitor and preparation method thereof Download PDFInfo
- Publication number
- CN107759623A CN107759623A CN201610707558.2A CN201610707558A CN107759623A CN 107759623 A CN107759623 A CN 107759623A CN 201610707558 A CN201610707558 A CN 201610707558A CN 107759623 A CN107759623 A CN 107759623A
- Authority
- CN
- China
- Prior art keywords
- pyrazol
- yls
- bromo
- preparation
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 56
- 229940122245 Janus kinase inhibitor Drugs 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 85
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims abstract description 41
- -1 boric acid 1H pyrazoles Chemical class 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000002994 raw material Substances 0.000 claims abstract description 17
- 239000004327 boric acid Substances 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 45
- 239000007787 solid Substances 0.000 claims description 38
- 239000002585 base Substances 0.000 claims description 34
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 20
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 18
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 13
- 238000000926 separation method Methods 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 11
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 10
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 9
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 claims description 9
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 claims description 9
- 229960000948 quinine Drugs 0.000 claims description 9
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims description 8
- LOPKSXMQWBYUOI-BDAKNGLRSA-N (1s,2r)-1-amino-2,3-dihydro-1h-inden-2-ol Chemical compound C1=CC=C2[C@H](N)[C@H](O)CC2=C1 LOPKSXMQWBYUOI-BDAKNGLRSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 229940080818 propionamide Drugs 0.000 claims description 7
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 7
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 238000010792 warming Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- BRTFVKHPEHKBQF-UHFFFAOYSA-N bromocyclopentane Chemical compound BrC1CCCC1 BRTFVKHPEHKBQF-UHFFFAOYSA-N 0.000 claims description 5
- 229940125898 compound 5 Drugs 0.000 claims description 5
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 5
- GEJJWYZZKKKSEV-UONOGXRCSA-N (1r,2s)-2-amino-1,2-diphenylethanol Chemical compound C1([C@@H](O)[C@@H](N)C=2C=CC=CC=2)=CC=CC=C1 GEJJWYZZKKKSEV-UONOGXRCSA-N 0.000 claims description 4
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- YFHNDHXQDJQEEE-UHFFFAOYSA-N acetic acid;hydrazine Chemical compound NN.CC(O)=O YFHNDHXQDJQEEE-UHFFFAOYSA-N 0.000 claims description 4
- RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims description 4
- 239000012024 dehydrating agents Substances 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 229960002179 ephedrine Drugs 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 150000004702 methyl esters Chemical class 0.000 claims description 4
- 229960005181 morphine Drugs 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- XFSCVCVPECOHBL-NSHDSACASA-N (2r)-2-phenyl-2-(propan-2-ylamino)ethanol Chemical class CC(C)N[C@@H](CO)C1=CC=CC=C1 XFSCVCVPECOHBL-NSHDSACASA-N 0.000 claims description 3
- VWLBJWIPYIYRBM-FIMIILAWSA-N (4ar,5as,8ar,13as,15as,15br)-10,11-dimethoxy-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2h-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinoline-14-one;dihydrate Chemical compound O.O.O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 VWLBJWIPYIYRBM-FIMIILAWSA-N 0.000 claims description 3
- GOOCRIHPADOQAS-ZNUXJMJHSA-N (4ar,5as,8ar,13as,15as,15br)-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2h-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinoline-14-one;sulfuric acid Chemical compound OS(O)(=O)=O.O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1.O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 GOOCRIHPADOQAS-ZNUXJMJHSA-N 0.000 claims description 3
- HVBCJKTZKQWQAU-UHFFFAOYSA-N 1-bromopyrrole Chemical class BrN1C=CC=C1 HVBCJKTZKQWQAU-UHFFFAOYSA-N 0.000 claims description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 3
- QMXOFBXZEKTJIK-UHFFFAOYSA-N Glycinol Natural products C1=C(O)C=C2OCC3(O)C4=CC=C(O)C=C4OC3C2=C1 QMXOFBXZEKTJIK-UHFFFAOYSA-N 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical group O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 3
- 229960000412 strychnine sulfate Drugs 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 claims description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 2
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 claims description 2
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 claims description 2
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 claims description 2
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- OGTLYUDOIVBATN-UHFFFAOYSA-N 1-bromopyrazole Chemical class BrN1C=CC=N1 OGTLYUDOIVBATN-UHFFFAOYSA-N 0.000 claims 1
- KIOOPXXIFXEVLQ-UHFFFAOYSA-N Cl[P]Cl Chemical compound Cl[P]Cl KIOOPXXIFXEVLQ-UHFFFAOYSA-N 0.000 claims 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 claims 1
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- 235000009508 confectionery Nutrition 0.000 claims 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims 1
- 150000003948 formamides Chemical class 0.000 claims 1
- 229940017219 methyl propionate Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 239000003054 catalyst Substances 0.000 abstract description 5
- 238000012805 post-processing Methods 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 4
- 238000004440 column chromatography Methods 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 description 76
- 239000012043 crude product Substances 0.000 description 35
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 21
- 238000005406 washing Methods 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- XJRBAMWJDBPFIM-UHFFFAOYSA-N methyl vinyl ether Chemical class COC=C XJRBAMWJDBPFIM-UHFFFAOYSA-N 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000001035 drying Methods 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000001914 filtration Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 239000007832 Na2SO4 Substances 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229910052736 halogen Inorganic materials 0.000 description 9
- 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 238000010583 slow cooling Methods 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 4
- 238000006845 Michael addition reaction Methods 0.000 description 4
- 230000003321 amplification Effects 0.000 description 4
- 229940125773 compound 10 Drugs 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 4
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical group [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 4
- 206010028537 myelofibrosis Diseases 0.000 description 4
- 238000003199 nucleic acid amplification method Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 150000003217 pyrazoles Chemical class 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 description 3
- 229960000215 ruxolitinib Drugs 0.000 description 3
- DUFGYCAXVIUXIP-UHFFFAOYSA-N 4,6-dihydroxypyrimidine Chemical class OC1=CC(O)=NC=N1 DUFGYCAXVIUXIP-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IEQIQSYQNXYJEC-UHFFFAOYSA-N C=O.ClC1=NC=NC(=C1C(=O)O)Cl Chemical compound C=O.ClC1=NC=NC(=C1C(=O)O)Cl IEQIQSYQNXYJEC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- STNJBCKSHOAVAJ-UHFFFAOYSA-N Methacrolein Chemical compound CC(=C)C=O STNJBCKSHOAVAJ-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- NDTCXABJQNJPCF-UHFFFAOYSA-N chlorocyclopentane Chemical compound ClC1CCCC1 NDTCXABJQNJPCF-UHFFFAOYSA-N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- BPMFZUMJYQTVII-UHFFFAOYSA-N guanidinoacetic acid Chemical compound NC(=N)NCC(O)=O BPMFZUMJYQTVII-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000003863 metallic catalyst Substances 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 241001614291 Anoplistes Species 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 101100011509 Drosophila melanogaster Baldspot gene Proteins 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 208000032027 Essential Thrombocythemia 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 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
- GGZGOFOXIDRBFY-UHFFFAOYSA-N [P].C(CC)#N Chemical compound [P].C(CC)#N GGZGOFOXIDRBFY-UHFFFAOYSA-N 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- COQOYMRZIFLJII-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].CC(C)(O)C(C)(C)O COQOYMRZIFLJII-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- HHSARRMUXPDGJD-UHFFFAOYSA-N butyl(dimethyl)silicon Chemical compound CCCC[Si](C)C HHSARRMUXPDGJD-UHFFFAOYSA-N 0.000 description 1
- 150000001721 carbon Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- YYDZNOUMWKJXMG-UHFFFAOYSA-N chloro(phenyl)phosphane Chemical compound ClPC1=CC=CC=C1 YYDZNOUMWKJXMG-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- GCUVBACNBHGZRS-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-2,4-dien-1-yl(diphenyl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.c1cc[c-](c1)P(c1ccccc1)c1ccccc1 GCUVBACNBHGZRS-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- HTHVSMTZYMMWKO-UHFFFAOYSA-N formamide Chemical compound NC=O.NC=O HTHVSMTZYMMWKO-UHFFFAOYSA-N 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229940045773 jakafi Drugs 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- CUUYGSBOZFZTQY-UHFFFAOYSA-M methoxy(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(OC)C1=CC=CC=C1 CUUYGSBOZFZTQY-UHFFFAOYSA-M 0.000 description 1
- DKBNVGOWHNOALZ-UHFFFAOYSA-N methyl 3-cyclopentylprop-2-enoate Chemical class COC(=O)C=CC1CCCC1 DKBNVGOWHNOALZ-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 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
- 150000007530 organic bases Chemical class 0.000 description 1
- CKMXAIVXVKGGFM-UHFFFAOYSA-N p-cumic acid Chemical compound CC(C)C1=CC=C(C(O)=O)C=C1 CKMXAIVXVKGGFM-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N pentanal Chemical compound CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- YFSSNCSFDCFTCP-UHFFFAOYSA-N phosphoric acid;propanenitrile Chemical compound CCC#N.OP(O)(O)=O YFSSNCSFDCFTCP-UHFFFAOYSA-N 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000006340 racemization Effects 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
- JFMWPOCYMYGEDM-XFULWGLBSA-N ruxolitinib phosphate Chemical compound OP(O)(O)=O.C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 JFMWPOCYMYGEDM-XFULWGLBSA-N 0.000 description 1
- 239000003579 shift reagent Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of JAK inhibitor Luso profit for new key intermediate of Buddhist nun and preparation method thereof, the propionitrile of the intermediated chemistry entitled (R) 3 (base of 4 boric acid 1H pyrazoles 1) 3 ring penta.The present invention provides new route to prepare Luso profit for Buddhist nun, and each step reaction of the route is respectively provided with higher yields, and overall yield of reaction is high, and products obtained therefrom purity is good, and the post processing of reaction is simple, without column chromatography；And the route is used, the material such as required raw material or the catalyst used all becomes more readily available, and compared with the prior art, the inventive method is more economical, is more suitable for industrialized production.
Description
Technical field
The present invention relates to JAK inhibitor Luso profit to replace Buddhist nun's preparing technical field, and in particular to new Luso profit is among Buddhist nun
Body, its preparation method and Luso profit replace the preparation method of Buddhist nun.
Background technology
A kind of selective JAK1/JAK2 kinase inhibitor of the Luso profit for Buddhist nun (Ruxolitinib) for Orally-administrable, it is
It is first be approved by the fda in the United States for treating intermediate or high-risk myelofibrosis (2011, trade name：Jakafi), it is including primary
Property myelofibrosis, myelofibrosis after myelofibrosis and primary thrombocytosis after polycythemia vera
(2014).At present, Luso profit has obtained global more than 50 individual state approvals, including European Union, Canada and some Asias for Buddhist nun Jakavi
Continent, Latin America and south American countries.At the same time, external report medicine can be used for treating bald spot, this respect in the recent period
During research is further carried out, therefore, the research of the medicine has great importance.
Luso profit is as follows for the chemical structural formula of Buddhist nun：
At present, in terms of synthesis, prepare Luso profit mainly has following several routes for Buddhist nun (Ruxolitinib)：
1., patent WO2007070514 (compound patent) report route：
The route is that Luso profit replaces Buddhist nun's compound patent, and the disadvantage of the route is that (Sem is protected key intermediate 2
Luso profit replace Buddhist nun) need to be prepared with chiral preparatory column, efficiency is low, and cost is too high, and actual application value is relatively low.
2. patent WO2010083283A2 (syntheti c route patent) reports route 1：
The route is reacted using ring valeral as initiation material elder generation witting prepares 3- cyclopenta methacrylaldehyde, in chiral catalyst
Under the conditions of with 4- bromine pyrazoles asymmetry michael addition reactions obtain (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- rings penta the third
Aldehyde, then the propionitrile (ee values 85%) of (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- rings penta is made with ammoniacal liquor and the step of Iod R three, together
Connection boron pinacol ester be coupled to obtain the propionitrile of (R) -3- (4- pinacol borate -1H- pyrazol-1-yls) -3- rings penta, then again with 4-
Chlorine pyrazolopyrimidine coupled product obtains Luso profit and replaces Buddhist nun.The route disadvantage is that chiral shift reagent molecular weight is big, system
Standby condition is harsh, prepares cost height, and the method choice of asymmetric michael additions is not high, is not suitable for amplification production.
3. patent WO2010083283A2 (syntheti c route patent) reports route 2,3：
Above-mentioned two lines are mainly by alkynes intermediate michael additions, the asymmetric hydrogen under the conditions of chiral catalyst
Change and obtain the chiral intermediate ee values 97% of correlation, this two lines disadvantage is that the intermediate feed of two alkynes is not easy
Prepare, cost is high；Hydrogenate the chiral catalyst used and prepare difficult, costs rather expensive, unsuitable industrialized production.
4. patent WO2010083283A2 (syntheti c route patent) reports route 4：
The route obtains (4- pinacol borate -1H- pyrazol-1-yls) -3- rings penta the third of racemization by michael additions
Nitrile, then purify to obtain (R) -3- (4- pinacol borate -1H- pyrazol-1-yls) -3- rings penta the third by chiral column preparative separation
Nitrile, the route are not suitable for amplification production, and efficiency is low, and production cost is high.
5. document Angew.Chem.Int.Ed.2015,54,7149-7153, Alexander M.Haydl et al. reports road
Line：
The route using cyclopenta join alkene as raw material in metal rhodium with being obtained under chiral ligand catalytic condition with 4- bromine pyrazoles additions
To the chiral intermediate of ee values 91%, this route raw material is not easy to obtain, and chiral purity is not high, and purification of intermediate is difficult, and cost is high, uncomfortable
Close amplification production.
To overcome the shortcomings of the existing technology, we look for another way, existing patent limitation is broken through, it is easy to have developed a raw material
, simple to operate, cost is relatively low, reaction can amplification it is strong, the variation route suitable for industrialized production.
The content of the invention
The technical problems to be solved by the invention are to break through the synthetic method that existing Luso profit replaces Buddhist nun, there is provided suitable for industrialization
The Luso profit of production is for Buddhist nun and its new synthesis route and new intermediate of salt.
To solve above technical problem, a kind of technical scheme that the present invention takes is as follows：
A kind of Luso profit for Buddhist nun's (compound 12) and its synthetic method of salt, its use (R) -3- (4- boric acid -1H- pyrazoles -
1- yls) and -3- rings penta propionitrile (compound 9) and 6- halogens -5- (2- methoxy-ethylenes base) pyrimidine-4-yl amine (in the compound, amine
The amine substituted for amino protecting group, such as compound 10) it is raw material, first make the two that Suzuki coupling reactions generation (3R)-ring occur
Amyl group -3- [4- (5- (2- methoxy-ethylenes base) pyrimidine-4-yl amine) pyrazol-1-yl] propionitrile (such as compound 11), then makes
(3R)-cyclopenta -3- [4- (5- (2- methoxy-ethylenes base) pyrimidine-4-yl amine) pyrazol-1-yl] propionitrile (such as compound 11) is sent out
Raw Deprotection and ring-closure reaction generation Luso profit replace Buddhist nun's (compound 12).It is as follows according to this method reaction equation：
In above-claimed cpd 10, Cl substituents can be that other halogens such as Br, I etc. are replaced；As amino protecting group
Boc bases (tertbutyloxycarbonyl) can be other amino protecting groups such as TMS (trimethyl silicon substrate), Tr (trityl), TBS (uncles
Butyldimethyl silicon substrate) etc. replace.
According to the present invention, 6- halogens -5- (2- methoxy-ethylenes base) pyrimidine-4-yl amine can synthesize according to following route
(by taking compound 10 as an example)：
Wherein：In step (1), make 4,6- dihydroxy-pyrimidines and formamide or substitution formamide (such as DMF), three halogen oxygen phosphorus
Reaction generation 4,6- dihalo-pyrimidine -5- carboxylic formaldehyde, further, first in such as less than 8 DEG C of a lower temperature to three halogen oxygen phosphorus
Middle dropwise addition formamide or substitution formamide, add, stir 0.5~2h, then add 4,6- dihydroxy-pyrimidines, and stirring 0.5~
1.5h, backflow is warming up to, is reacted.In step (2), make 4,6- dihalo-pyrimidines -5- carboxylics formaldehyde and NH3/ MeOH reaction generations
4- amino -6- halogen pyrimidine -5- carboxylic formaldehyde.In step (3), make 4- amino -6- chlorine pyrimidine -5- carboxylics formaldehyde and (methoxy) three
Phenyl-phosphonium chloride reacts generation 6- halogen -5- (2- methoxy-ethylenes base) pyrimidine-4-yl amine in a solvent；In step (4), to 6-
The reaction that halogen -5- (2- methoxy-ethylenes base) pyrimidine-4-yl amine carries out amino protecting group obtains 6- halogens -5- (2- methoxyl groups
Vinyl) pyrimidine-4-yl amine.The specific implementation of above step (1)~(4) can refer to conventional implementation well known in the art
And condition.
Further, described Suzuki coupling reactions are carried out in the presence of alkali and organo-metallic catalyst in solvent.Its
In, alkali can be inorganic base or organic base, specifically such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide；
Solvent can be dioxane, toluene, THF etc.；Organo-metallic catalyst can be tetrakis triphenylphosphine palladium (Pd (PPh3)4)、
[double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride etc..When using these conditions, the conversion ratio of step reaction can reach
To more than 95%, and after reaction terminates, after simple post processing obtains crude product, it can direct plunge into and react in next step.
Further, prepare Luso profit and be divided into two processes for the reaction of Buddhist nun：(3R)-cyclopenta -3- [4- (5- (2- before this
Methoxy-ethylene base) pyrimidine-4-yl amine) pyrazol-1-yl] propionitrile removing amino protecting group, ring closure reaction generation then occurs again
Luso profit replaces Buddhist nun.This two processes can successively be carried out in a system.According to a preferred aspect of the present invention, Luso is prepared
Profit is as follows for the method for Buddhist nun：Make (3R)-cyclopenta -3- [4- (5- (2- methoxy-ethylenes base) pyrimidine-4-yl amine) pyrazol-1-yl]
Propionitrile sloughs amino protecting group in a solvent, under acid condition, then heats to 50~100 DEG C, carries out ring closure reaction, wherein institute
It can be such as tetrahydrofuran, acetonitrile, DMF, methanol, ethanol to state solvent, and acid condition can be formed by adding the acid such as hydrochloric acid,
The step reaction conversion ratio can reach more than 90%.
The present invention also provides the preparation method that a kind of Luso profit replaces Buddhist nun's phosphate (compound 13), and it passes through the present invention first
The above method is made Luso profit and replaces Buddhist nun, then makes itself and phosphatase reaction, and reaction scheme is as follows：
Further, after preparing Luso profit and terminating for the reaction of Buddhist nun, crude product is obtained through simple post processing, crude product is directly thrown
Enter and carry out salt-forming reaction in next step.According to one of the present invention specific and preferred aspect, the crude product of Buddhist nun is replaced to be dissolved in Luso profit molten
During agent is such as isopropanol, ethanol, organic solvent (isopropanol) solution of phosphoric acid is then added dropwise thereto, stirs at room temperature, by
White solid is gradually separated out, is cooled down, filtering, Luso profit is drying to obtain and replaces Buddhist nun's phosphate, purity is higher than 99%.
The present invention also provides a kind of key intermediate of JAK inhibitor, and its chemical name is (R) -3- (4- boric acid -1H- pyrroles
Azoles -1- bases) penta propionitrile of -3- rings, structure is as shown in following formula 9：
Preferably, the JAK inhibitor is that Luso profit replaces Buddhist nun.
The present invention also provides the preparation of the propionitrile (compound 9) of one kind (R) -3- (4- boric acid -1H- pyrazol-1-yls) -3- rings penta
Method, it includes making the propionitrile (compound 8) of (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- rings penta and RMgBr and borate
The step of reaction generation (R) -3- (4- boric acid -1H- pyrazol-1-yls) penta propionitrile (compound 9) of -3- rings, the step reaction equation
It is as follows：
Further, it is described generation compound 9 the step of in, used RMgBr can be isopropylmagnesium chloride,
Tert-butyl group magnesium chloride, ethylmagnesium chloride etc., borate is such as triisopropyl borate ester, trimethylborate, triethyl borate, reaction
Generally carry out in a solvent, suitable solvent is such as tetrahydrofuran, toluene herein.
When implementing reaction, first compound 8 is dissolved in solvent, nitrogen protection, be cooled to such as -10 DEG C of a cryogenic temperature with
Under, RMgBr is added dropwise, after adding, is warming up at such as -5~5 DEG C of a suitable temperature, stirring reaction for a period of time such as 0.5
~2h, then control below -5 DEG C of temperature, dry borate is added dropwise, after dripping off, -5~5 DEG C of reaction a period of times such as 1~
2h, terminate reaction.Wherein reaction can be quenched by adding saturated ammonium chloride solution.
Further, the preparation method of the compound 9 also includes making (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- rings
Penta propionamide (compound 7) is in organic solvent, dehydrating agent effect is lower reacts the step of generating compound 8, the dehydrating agent example
Such as phosphorus pentoxide, trichloro-acetic chloride/triethylamine, zinc chloride, dichloro etherophosphoric acid/DBU, the reaction is preferably in temperature 60
Carried out at~70 DEG C, reaction equation is as follows：
Further, the preparation method of the compound 9 also includes making (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- rings
Penta propionic acid (compound 6) and the ammonia reaction generation propionamide (compound 7) of (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- rings penta
Step.Step reaction can be implemented using the conventional method in this area.In terms of one as the present invention is specific and preferable,
Compound 6 is first reacted in a solvent with carbonyl dimidazoles (CDI), then pass to ammonia and reacted, wherein solvent can be
Such as tetrahydrofuran etc., reaction are preferably carried out at room temperature.The step reaction equation is as follows：
Further, the preparation method of compound 9 also using Chiral Amine split 3- (the bromo- 1H- pyrazol-1-yls of 4-)-
3- cyclopentyl propionic acids (compound 5) obtain the step of (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids (compound 6).
The preparation process can be with equation schematically as follows：
Herein, any Chiral Amine available for chiral resolution can be used.In certain embodiments, Chiral Amine selects following amine
Optical active forms：S- phenyl ethylamines, D- benzene glycinol, (1R, 2S) -2- amino -1,2- diphenyl ethanol, (R) -2- isopropyl ammonia
Base -2- phenylethanols, (1S, 2R) -1- amino -2- indanols, (S) -1- (2- naphthyls) ethamine, quinine, cinchonidine, cinchonine,
Quinine, brucine dihydrate, the hydrate of strychnine sulfate five, ephedrine, morphine, leucyl amine, tyrosine
Hydrazine acetate etc..Preferably, the Chiral Amine is (1S, 2R) -1- amino -2- indanols.
Three implementation Process of the step point：Make the different optical isomers of compound 5 react with Chiral Amine respectively first to give birth to
Into the product of different solubility, secondly, two kinds of products are separated using the difference of two kinds of product solubility；Finally, to by (R)-
The product that the reaction generation of 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids is formed carries out acidolysis, and producing (R) -3-, (4- is bromo-
1H- pyrazol-1-yls) -3- cyclopentyl propionic acids (compound 6)., should when the Chiral Amine used is (1S, 2R) -1- amino -2- indanol
The yield of compound 6 is walked up to more than 30%, and the optical purity of gained compound 6 is higher than 99%.
Further, the preparation method of the compound 9 also includes making 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- rings penta the third
Sour methyl esters (compound 4) reacts the generation compound 5 in the presence of alkali, and the step reaction equation is as follows：
Specifically, step reaction is carried out in solvent such as THF, methanol, ethanol, described alkali can be lithium hydroxide one
Hydrate, potassium hydroxide, sodium hydroxide etc., reaction can be in 20~30 DEG C or so progress of room temperature.
Further, the preparation method of the compound 9 also includes making 3- cyclopentylpropenoic acids methyl esters (compound 3) and 4-
Bromine pyrazoles reacts the generation compound 4 in the presence of base, and the step reaction equation is as follows：
Wherein：The alkali is preferably the carbon -7- alkene (DBU) of 1,8- diazabicylos 11, can also be potassium carbonate, cesium carbonate
Deng.
Further, the preparation method of the compound 9 also includes making cyclopenta formaldehyde (compound 2), phosphinylidyne guanidine-acetic acid
The step of trimethyl and alkali reaction prepare 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acid methyl esters, the step reaction equation is such as
Under：
Further, the preparation method of the compound 9 is also included with Cyclopentane halide and formamide or N- substitution formyl
Amine is the step of raw material prepares cyclopenta formaldehyde (compound 2).Preferably, Cyclopentane halide is first made to be prepared into grignard with reactive magnesium
Reagent, then substitute formamide with formamide or N-.
In the reaction, Cyclopentane halide can be iodo pentamethylene, bromocyclopentane, chlorocyclopentane.When halo ring penta
When alkane is bromocyclopentane or chlorocyclopentane, further preferably using iodine initiation reaction.N- substitutes the optional dimethyl of formamide
Formamide (DMF), diethylformamide (DEF) etc..
According to one of the present invention specific and preferred aspect, the method for preparing cyclopenta formaldehyde (compound 2) is：Make bromo
Pentamethylene (compound 1), with reactive magnesium, then controls and DMF is added dropwise below 10 DEG C of temperature, be added dropwise, room temperature is stirred in the presence of iodine
Reaction is mixed, equation is as follows：
According to a specific aspect of the invention, the preparation of compound 9 uses following synthetic route：
The implementation of each step reaction and condition are referred to noted earlier in the route.
Preferably, by simply post-processing after obtaining crude product after back reaction terminates, direct plunge into and react in next step.
The present invention is also provided one kind and is split as 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids using resolution reagent
(R) method of -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids, wherein resolution reagent is Chiral Amine.
Further, the resolution reagent is S- phenyl ethylamines, D- benzene glycinol, (1R, 2S) -2- amino -1,2- diphenyl
Ethanol, (R) -2- isopropylamino -2- phenylethanols, (1S, 2R) -1- amino -2- indanols, (S) -1- (2- naphthyls) ethamine, quinine,
Cinchonidine, cinchonine, quinine, brucine dihydrate, the hydrate of strychnine sulfate five, ephedrine, morphine,
One or more combinations in leucyl amine, tyrosine hydrazine acetate.Preferably, resolution reagent is (1S, 2R) -1- amino -2-
Indanol.
Further, 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids are first made to be reacted with resolution reagent, then to production
Objects system carries out crystallization and separation solid crystal, and acidolysis is finally carried out to solid crystal and obtains (R) -3- (bromo- 1H- pyrroles of 4-
Azoles -1- bases) -3- cyclopentyl propionic acids.
Due to the implementation of above technical scheme, the present invention has the following advantages that compared with prior art：
The present invention provides new route to prepare Luso profit for Buddhist nun, and each step reaction of the route is respectively provided with higher yields,
Overall yield of reaction is high, and products obtained therefrom purity is good, and the post processing of reaction is simple, without column chromatography；And the route is used, it is required
The material such as raw material or the catalyst used all becomes more readily available, and compared with the prior art, the inventive method is more economical, is more suitable for work
Industry metaplasia is produced.
Brief description of the drawings
Fig. 1 is the nuclear magnetic spectrogram of the products therefrom of embodiment 8.
Embodiment
Below in conjunction with specific embodiment, the present invention will be further described in detail, but the invention is not restricted to following implementation
Example.Unreceipted condition is normal condition in embodiment.
Embodiment 1：The preparation of cyclopenta formaldehyde (compound 2)
It is some to weigh bromocyclopentane, is dissolved on a small quantity in 5 times of anhydrous THF of volume, adds magnesium chips (1eq), catalytic amount iodine list
Matter, nitrogen protection, 40 DEG C or so initiation reactions are warming up to, 30~40 DEG C of dropwise addition bromocyclopentanes of temperature control, are dripped off, insulated and stirred 1
~2h, DMF (1.05eq) is added dropwise below 10 DEG C of temperature control, after dripping off, 30 DEG C of stirring 1h of room temperature, 3 times of volumes is added into feed liquid
MTBE, less than 0 DEG C is added dropwise 3N watery hydrochloric acid and adjusts pH 3~4, liquid separation, and water layer is extracted twice (every time with 3 times of volumes) with MTBE, extremely produced
Thing proposes substantially, merges organic phase, and saturated brine washes twice, anhydrous Na2SO4Dry, filtering, be concentrated under reduced pressure into dry, obtain crude product
Cyclopenta formaldehyde, yield 90%~95%, it is directly used in and reacts in next step.
Embodiment 2：The preparation of 3- cyclopentylpropenoic acids methyl esters (compound 3)
Potassium tert-butoxide (1.05eq) is weighed, is dissolved in the anhydrous THF of 10 times of volumes, nitrogen protection, 0 DEG C or so, to feed liquid
Middle dropwise addition phosphoryl 3-acetic acid methyl ester (1.1eq), drips off, and 0 DEG C or so, 2~3h of stirring reaction is incubated, if weighing cyclopenta formaldehyde
It is dry, 2 times of volume anhydrous THF solutions are configured to, 0 DEG C or so is added drop-wise in above-mentioned feed liquid, after dripping off, is warmed to room temperature 30 DEG C or so and stirs
12~15h of reaction is mixed, has been reacted.5 times of volume MTBE dilutions are added in feed liquid, 10 times of volume of water, liquid separation, water layer is respectively with 3 times
Twice, saturated brine washes twice, anhydrous Na for the MTBE back extraction of volume2SO4Dry, filtering, be concentrated under reduced pressure to obtain crude product 3- cyclopenta
Methyl acrylate, yield 85%~90%, it is directly used in and reacts in next step.
Embodiment 3：The preparation of 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids methyl esters (compound 4)
It is some to weigh 3- cyclopentylpropenoic acid methyl esters, is dissolved in the acetonitrile of 5 times of volumes, feed liquid adds 4- bromine pyrazoles
(1.1eq), DBU (1.5eq), is added, 30 DEG C of stirring reaction about 12~16h of feed liquid room temperature, and raw material reaction is complete.It is concentrated under reduced pressure small
Volume, 5 times of volume MTBE dilutions, washing being added in feed liquid, 1N watery hydrochloric acid adjusts pH 3~4 to wash, washing, saturated brine washing,
Anhydrous Na2SO4Dry, filtering, be concentrated under reduced pressure to obtain crude product 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acid methyl esters, yield 90
~95%, it is directly used in next one-step hydrolysis.
Embodiment 4：The preparation of 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids (compound 5)
It is some to weigh 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acid methyl esters, is dissolved in the THF of 6 times of volumes, feed liquid
Lithium hydroxide monohydrate (1.2eq) 3 times of v aqueous solutions are added, are added, 30 DEG C of 1~2h of stirring reaction of feed liquid room temperature, raw material
Reaction is complete.Feed liquid adds the MTBE dilutions of 5 times of volumes, and feed liquid adds 1N watery hydrochloric acid and adjusts pH3~4, liquid separation, 3 times of bodies of water layer
Long-pending MTBE back extraction twice, merges organic phase, water washing, the washing of saturation NaCl liquid, anhydrous Na2SO4Dry, filtering, be concentrated under reduced pressure
Crude product 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids are obtained, yield 85%~90%, is directly used in and splits in next step.
Embodiment 5：(R) preparation of -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids (compound 6)
It is some to weigh 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids, is dissolved in the isopropanol of 5 times of volumes, then to
3 times of volume isopropanol solution of (1S, 2R) -1- amino -2- indanols (0.9eq) are added in the feed liquid, 12- is stirred at room temperature in feed liquid
15h, cross filter solid.Solid crude product is recrystallized with 5 times of volume isopropanols, feed liquid Slow cooling crystallization, crosses filter solid, solid crude product
Recrystallized with 5 times of volume isopropanols, feed liquid Slow cooling crystallization, cross filter solid, drying detection optical purity is higher than 99%, chemistry
Purity is higher than 99%, yield 30~35%.
Weigh that above-mentioned drying solid is some, add the MTBE of 4 times of volumes, add and first adjust the left sides of PH to 3~4 with 1N watery hydrochloric acid
The right side, liquid separation, water layer are stripped with 3 times of volume MTBE.Merge organic phase, water washing, saturated brine washing, anhydrous Na2SO4Dry, mistake
Filter, be concentrated under reduced pressure to obtain crude product (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids, yield 90%~95%, HPLC purity
Higher than 99%.
The step product nuclear magnetic data is as follows：1HNMR(CDCl3,400MHz)δ:1.03~1.12 (1H, m), 1.16~1.27
(1H, m), 1.33~1.40 (1H, m), 1.41~1.70 (4H, m), 1.83~1.90 (1H, m), 2.33~2.44 (1H, m),
2.87 (1H, dd, J=16.0,4.0Hz), 3.13 (1H, dd, J=16.0,12.0Hz), 4.21~4.26 (1H, m), 7.44
(1H,s),7.48(1H,s).
Embodiment 6：(R) preparation of -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids (compound 6)
It is some to weigh 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids, is dissolved in the isopropanol of 5 times of volumes, then to
3 times of volume isopropanol solution of S- phenyl ethylamines (0.9eq) are added in the feed liquid, 12-15h is stirred at room temperature in feed liquid, crosses filter solid.Gu
Body crude product is recrystallized with 5 times of volume isopropanols, feed liquid Slow cooling crystallization, crosses filter solid, 5 times of volume isopropanols of solid crude product
Recrystallization, feed liquid Slow cooling crystallization, filter solid is crossed, drying detection optical purity is higher than 99%, and chemical purity is higher than 99%, receives
Rate 10~15%.
Weigh that above-mentioned drying solid is some, add the MTBE of 4 times of volumes, add and first adjust the left sides of pH to 3~4 with 1N watery hydrochloric acid
The right side, liquid separation, water layer are stripped with 3 times of volume MTBE.Merge organic phase, water washing, saturated brine washing, anhydrous Na2SO4Dry, mistake
Filter, be concentrated under reduced pressure to obtain crude product (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids, yield 90%~95%, HPLC purity
Higher than 99%.
Embodiment 7：(R) preparation of -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids (compound 6)
It is some to weigh 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids, is dissolved in the isopropanol of 5 times of volumes, then to
5 times of volume isopropanol solution of quinine (0.9eq) are added in the feed liquid, 12-15h is stirred at room temperature in feed liquid, crosses filter solid.Solids crude
Product are recrystallized with 10 times of volume isopropanols, feed liquid Slow cooling crystallization, cross filter solid, solid crude product is again with 10 times of volume isopropyls
Alcohol is recrystallized, and crosses filter solid, and solid crude product is recrystallized with 10 times of volume isopropanols again, feed liquid Slow cooling crystallization, and filtering is solid
Body, drying detection optical purity are higher than 99%, and chemical purity is higher than 99%, yield 10~15%.
Weigh that above-mentioned drying solid is some, add the MTBE of 4 times of volumes, add and first adjust the left sides of PH to 3~4 with 1N watery hydrochloric acid
The right side, liquid separation, water layer are stripped with 3 times of volume MTBE.Merge organic phase, water washing, saturated brine washing, anhydrous Na2SO4Dry, mistake
Filter, be concentrated under reduced pressure to obtain crude product (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids, yield 90%~95%, HPLC purity
Higher than 99%.
Embodiment 8：(R) preparation of -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids (compound 6)
It is some to weigh 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids, is dissolved in the isopropanol of 5 times of volumes, then to
5 times of volume isopropanol solution of cinchonidine (0.9eq) are added in the feed liquid, 12-15h is stirred at room temperature in feed liquid, crosses filter solid.Gu
Body crude product is recrystallized with 10 times of volume isopropanols, feed liquid Slow cooling crystallization, crosses filter solid, solid crude product is again with 10 times of volumes
Recrystallisation from isopropanol, filter solid is crossed, solid crude product is recrystallized with 10 times of volume isopropanols again, feed liquid Slow cooling crystallization, mistake
Filter solid, drying detection optical purity are higher than 99%, and chemical purity is higher than 99%, yield 5~10%.
Weigh that above-mentioned drying solid is some, add the MTBE of 4 times of volumes, add and first adjust the left sides of PH to 3~4 with 1N watery hydrochloric acid
The right side, liquid separation, water layer are stripped with 3 times of volume MTBE.Merge organic phase, water washing, saturated brine washing, anhydrous Na2SO4Dry, mistake
Filter, be concentrated under reduced pressure to obtain crude product (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids, yield 90%~95%, HPLC purity
Higher than 99%.
Embodiment 9：(R) preparation of the propionamide (compound 7) of -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- rings penta
It is some to weigh (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids, is dissolved in 4 times of volume dry tetrahydrofurans
In, carbonyl dimidazoles (3eq) are added, nitrogen protection reacts at room temperature 3h, and raw material reaction is complete.Feed liquid leads to ammonia about 30 minutes, material
Liquid adds the MTBE dilutions of 4 times of volumes, and feed liquid adds the moisture liquid of 4 times of volumes, and water layer is stripped with the MTBE of 3 times of volumes, merged
Organic phase, water washing, saturated brine washing, anhydrous Na2SO4Dry, filtering, be concentrated under reduced pressure to obtain crude product (R) -3- (bromo- 1H- pyrroles of 4-
Azoles -1- bases) penta propionamide of -3- rings, 10 times of volume normal heptanes are beaten to obtain white solid, yield 90~95%, HPLC 98% with
On.
Products therefrom nuclear magnetic data is as follows：1HNMR(CDCl3,400MHz)δ:1.03~1.13 (1H, m), 1.20~1.30
(1H, m), 1.33~1.41 (1H, m), 1.43~1.71 (4H, m), 1.79~1.87 (1H, m), 2.31~2.43 (1H, m),
2.68 (1H, dd, J=16.0,4.0Hz), 2.94 (1H, dd, J=16.0,8.0Hz), 4.26~4.32 (1H, m), 5.36 (1H,
brs),5.52(1H,brs),7.43(1H,s),7.74(1H,s)
Embodiment 10：(R) preparation of the propionitrile (compound 8) of -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- rings penta
It is some to weigh (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) penta propionamide of -3- rings, is dissolved in 4 times of volumes and dries tetrahydrochysene furan
In muttering, phosphorus pentoxide (3eq) is added, nitrogen protection, heat up 60~70 DEG C of 1~2h of reaction, and raw material reaction is complete.Feed liquid adds
The MTBE dilutions of 4 times of volumes, the saturated sodium bicarbonate that feed liquid adds 4 times of volumes are quenched, liquid separation, the MTBE of 3 times of volumes of water layer
Back extraction, merge organic phase, water washing, saturated brine washing, anhydrous Na2SO4Dry, filtering, be concentrated under reduced pressure to obtain crude product (R) -3-
The propionitrile of (the bromo- 1H- pyrazol-1-yls of 4-) -3- rings penta, yield 90%~95%, it is directly used in and reacts in next step.
The step product nuclear magnetic data is as follows：1HNMR(CDCl3,400MHz)δ:1.08~1.17 (1H, m), 1.18~1.27
(1H, m), 1.44~1.76 (5H, m), 1.87~194 (1H, m), 2.42~2.52 (1H, m), 2.86 (1H, dd, J=16.0,
4.0Hz), 3.02 (1H, dd, J=16.0,8.0Hz), 4.08~4.14 (1H, m), 7.51 (1H, s), 7.52 (1H, s)
Embodiment 11：(R) preparation of the propionitrile (compound 9) of -3- (4- boric acid -1H- pyrazol-1-yls) -3- rings penta
It is some to weigh (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) penta propionitrile of -3- rings, is dissolved in 4 times of volume dry tetrahydrofurans
In, nitrogen protection, feed liquid cools -15 DEG C, and isopropylmagnesium chloride (1.15eq) is added dropwise into feed liquid, adds, -5 DEG C of feed liquid~5 DEG C
Stirring reaction 1h, control below -5 DEG C of temperature, dry triisopropyl borate ester (1.05eq) is added dropwise, after dripping off, -5~5 DEG C of reactions
1~2h, reaction is complete, and feed liquid adds the MTBE dilutions of 4 times of volumes, and the saturated ammonium chloride that feed liquid adds 4 times of volumes is quenched, point
Liquid, water layer are stripped with the MTBE of 3 times of volumes, merge organic phase, water washing, saturated brine washing, anhydrous Na 2SO4 dryings, mistake
Filter, be concentrated under reduced pressure the propionitrile of crude product (R) -3- (4- boric acid -1H- pyrazol-1-yls) -3- rings penta, 10 times of volume normal heptanes are beaten
White solid, yield 85%~90%, HPLC more than 98%.
The step product nuclear magnetic data is as follows：1HNMR(DMSO-d6,400MHz)δ:1.02~1.12 (1H, m), 1.19~
1.29 (2H, m), 1.36~1.61 (4H, m), 1.72~1.80 (1H, m), 2.26~2.37 (1H, m), 3.02~3.15 (2H,
M), 4.36~4.42 (1H, m), 7.73 (1H, s), 7.76 (2H, brs), 7.92 (1H, s)
Embodiment 12：The chloro- 5- of 6- (2- methoxy-ethylenes base) pyrimidine -4- (double t-butoxycarbonyls) base amine (i.e. compound 10)
Preparation
Synthetic route is as follows：
Comprise the following steps that：
(1) POCl is weighed3(4eq) is added in reaction bulb, under nitrogen protection, is cooled to 0 DEG C or so, is added into feed liquid
DMF (1.85eq), during dropwise addition, temperature control adds in 0~8 DEG C, 0~10 DEG C of feed liquid, stirs 1h, 4,6- dihydroxies are added into feed liquid
Yl pyrimidines, add, feed liquid warms naturally to room temperature, stirs 1h, then heats to backflow, stirs 2h, and feed liquid cooling is stirred
Night.Feed liquid decompression boils off unnecessary POCl3, residue is slowly added in frozen water, with ethyl acetate extraction product (2 times of volume *
3), merge organic phase, wash (2 times of volumes), saturated sodium bicarbonate solution washing (2 times of volumes), anhydrous sodium sulfate drying, mistake
Filter, is concentrated under reduced pressure, obtains crude product 4,6- dichloro pyrimidine -5- carboxylic formaldehyde (yield:70%), it is directly used in and reacts in next step.
(2) it is some to weigh 4,6- dichloro pyrimidine -5- carboxylic formaldehyde, adds toluene dissolving (5 times of volumes), 7M is added into feed liquid
NH3/ MeOH solution (3eq), feed liquid are heated to 60 DEG C, stirring reaction 1h, added into NH3/ MeOH solution (1eq), continues to stir
1h, TLC are detected, and raw material fundamental reaction is complete.Feed liquid is cooled to room temperature, is concentrated under reduced pressure and steams solvent, is added in residue appropriate
H2O (3 times of volumes), stirring, ethyl acetate/n-butanol mixed solvent (V/V=2/1) extraction (4 times of volume * 2), merge organic
Phase, anhydrous sodium sulfate drying, filtering, it is concentrated under reduced pressure dry, obtains crude product 4- amino -6- chlorine pyrimidine -5- carboxylic formaldehyde (yield：
100%), direct plunge into and react in next step.
(3) it is some (1.05eq) to weigh (methoxy) triphenyl-phosphonium chloride, adds THF (30 times of volumes), stirs,
Under nitrogen protection, -5 DEG C are cooled to, t-BuOK (1.05eq) is added thereto, adds, 0 DEG C of feed liquid, stirs 1h.To above-mentioned feed liquid
4- amino -6- chlorine pyrimidine -5- carboxylic formaldehyde is added portionwise, adds, feed liquid warms naturally to room temperature, stirring reaction 30h, TLC detection,
Raw material fundamental reaction is complete.Feed liquid is cooled to 0 DEG C, adds saturated ammonium chloride liquid and reaction is quenched, concentrated hydrochloric acid is added in feed liquid, adjust
PH to 1~2, feed liquid are extracted with ethyl acetate and (2 times of volume * 2, extract the removal of impurity), water layer again with 6N NaOH liquid regulation pH to 8~
9, extracted (10 times of volume * 3) with ethyl acetate, merge organic phase, anhydrous sodium sulfate drying, filtering, be concentrated under reduced pressure to obtain the chloro- 5- of 6-
(2- methoxy-ethylenes base) pyrimidine-4-yl amine crude product (yield:60%), it is directly used in and reacts in next step.
(4) it is some to weigh the chloro- 5- of 6- (2- methoxy-ethylenes base) pyrimidine-4-yl amine, adds ethyl acetate (15 times of volumes),
DMAP (0.2eq), stirring, Boc is added dropwise into the feed liquid2O (2.2eq), is added, and feed liquid is warming up to 45~50 DEG C, and stirring is anti-
2h, TLC is answered to detect, raw material fundamental reaction is complete.Feed liquid is cooled to 0~5 DEG C, and 1N HCl solutions wash (5 times of volumes), saturated carbon
Sour hydrogen sodium liquid washs (5 times of volumes), anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure, obtains the chloro- 5- of 6- (2- methoxy-ethylenes base)
Pyrimidine -4- (double t-butoxycarbonyls) base amine crude product (E/Z=5/1), the crude product recrystallize through ethyl acetate/heptane system, obtain 6-
Chloro- 5- (2- methoxy-ethylenes base) pyrimidine -4- (double t-butoxycarbonyls) base amine (E formulas) is (yield of compound 10:60%), class
White solid.
Embodiment 13：(3R)-cyclopenta -3- [4- (5- (2- methoxy-ethylenes base) pyrimidine-4-yl amine) pyrazol-1-yl] third
The preparation of nitrile (compound 11)
Weigh the propionitrile (1eq) of (R) -3- (4- boric acid -1H- pyrazol-1-yls) -3- rings penta, 6- chloro- 5- (2- methoxy-ethylenes
Base) pyrimidine -4- (double t-butoxycarbonyls) base amine (1.03eq), potassium carbonate (3eq), Pd (PPh3) 4 (3%eq) be some, add anti-
Answer in bottle, THF (10 times of volumes) and H2O (2 times of volumes) is added into bottle, system nitrogen displacement 3~4 times, under nitrogen protection, is expected
Liquid is heated to 50~60 DEG C, reacts 12~15h, and raw material fundamental reaction is complete.Ethyl acetate (10 times of volumes) is added into feed liquid
With H2O (5 times of volumes), stir, stand, liquid separation, organic phase H2O washings (3 times of volumes), anhydrous sodium sulfate drying, (pad is suitable for filtering
Measure silica gel), filtrate decompression concentration is dry, obtains crude product (3R)-cyclopenta -3- [4- (5- (2- methoxy-ethylenes base) pyrimidine-4-yl amine)
Pyrazol-1-yl] propionitrile (yield：96%), it is directly used in and reacts in next step.
Embodiment 14：(3R)-cyclopenta -3- [4- (7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) pyrazol-1-yl] propionitrile
The preparation of (compound 12, i.e. Luso profit replace Buddhist nun)
Weigh step crude product (3R)-cyclopenta -3- [4- (5- (2- methoxy-ethylenes base) pyrimidine-4-yl amine) pyrazoles -1-
Base] propionitrile is some, is dissolved in THF solution (4 times of volumes), adds concentrated hydrochloric acid (2.2eq) thereto, and feed liquid is stirred at room temperature 2~
3h, then backflow is warming up to, stirring reaction 5h, TLC detection, raw material fundamental reaction is complete, and feed liquid is cooled to room temperature, adds saturation
NaHCO3Solution, pH to 8~9 is adjusted, add ethyl acetate extraction (10x), organic phase washed with water (3 times of volumes), anhydrous sulphur
Sour sodium is dried, and filtering, is concentrated under reduced pressure, is obtained (3R)-cyclopenta -3- [4- (7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) pyrazoles -1-
Base] propionitrile crude product (yield：90%).
Embodiment 15：(3R)-cyclopenta -3- [4- (7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) pyrazol-1-yl] propionitrile phosphorus
The preparation of hydrochlorate (i.e. Luso profit replaces Buddhist nun's phosphate)
Weigh according to [4- (7H- pyrrolo-es [2, the 3-d] pyrimidine -4- of (3R)-cyclopenta -3- made from the method for embodiment 10
Base) pyrazol-1-yl] propionitrile crude product is some, and (20 times of volumes) is dissolved in isopropanol, is added dropwise to p isopropylbenzoic acid alcoholic solution thereto
3h is stirred at room temperature in (1.1eq), feed liquid, during which gradually separates out a large amount of white solids, and feed liquid ice bath is cooled to 5~10 DEG C, stirring
0.5h, filter, dry, obtain white solid (3R)-cyclopenta -3- [4- (7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) pyrazoles -1-
Base] propionitrile phosphate (yield：90%), purity is higher than 99%.
The above embodiments merely illustrate the technical concept and features of the present invention, and its object is to allow person skilled in the art
Scholar can understand present disclosure and implement according to this, and it is not intended to limit the scope of the present invention.It is all according to the present invention
The equivalent change or modification that Spirit Essence is made, it should all be included within the scope of the present invention.
Claims (22)
1. a kind of key intermediate of JAK inhibitor, its chemical name is (R) -3- (4- boric acid -1H- pyrazol-1-yls) -3- rings
Penta propionitrile, structure is as shown in following formula 9：
A kind of 2. preparation method of the key intermediate (compound 9) of the JAK inhibitor described in claim 1, it is characterised in that：
It includes making the propionitrile (compound 8) of (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- rings penta give birth to RMgBr and borate reaction
The step of into (R) -3- (4- boric acid -1H- pyrazol-1-yls) penta propionitrile (compound 9) of -3- rings, the step reaction equation is as follows：
3. preparation method according to claim 2, it is characterised in that：Used RMgBr is selected from isopropyl chlorination
One or more combinations in magnesium, tert-butyl group magnesium chloride, ethylmagnesium chloride；The borate be selected from triisopropyl borate ester,
One or more combinations in trimethylborate and triethyl borate.
4. preparation method according to claim 2, it is characterised in that：First by (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3-
The propionitrile of ring penta is dissolved in solvent, nitrogen protection, is cooled to less than -10 DEG C, RMgBr is added dropwise, after adding, is warming up to -5~5
DEG C, 0.5~2h of stirring reaction, then control below -5 DEG C of temperature, dry borate is added dropwise, after dripping off, -5~5 DEG C of reactions 1
~2h, terminate reaction.
5. preparation method according to claim 2, it is characterised in that：Also including making (R) -3-, (4- is bromo- for the preparation method
1H- pyrazol-1-yls) -3- rings penta propionamide (compound 7) in organic solvent, lower reaction generation (R) -3- (4- of dehydrating agent effect
Bromo- 1H- pyrazol-1-yls) penta propionitrile (compound 8) of -3- rings the step of, reaction equation is as follows：
6. preparation method according to claim 5, it is characterised in that：Generation (R) -3- (bromo- 1H- pyrazoles -1- of 4-
Base) -3- rings penta propionitrile reaction in, dehydrating agent is selected from phosphorus pentoxide, trichloro-acetic chloride/triethylamine, zinc chloride and dichloro phosphorus
Acetoacetic ester/DBU, react and carried out at 60~70 DEG C of temperature.
7. preparation method according to claim 5, it is characterised in that：Also including making (R) -3-, (4- is bromo- for the preparation method
1H- pyrazol-1-yls) -3- cyclopentyl propionic acids (compound 6) first reacted in a solvent with carbonyl dimidazoles (CDI), then pass to ammonia
The step of carrying out reaction acquisition (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) penta propionamide (compound 7) of -3- rings, reaction equation
It is as follows：
8. preparation method according to claim 7, it is characterised in that：The preparation method is also split using Chiral Amine
3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids obtain the step of (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids
Suddenly.
9. preparation method according to claim 8, it is characterised in that：The Chiral Amine is selected from S- phenyl ethylamines, the sweet ammonia of D- benzene
Alcohol, (1R, 2S) -2- amino -1,2- diphenyl ethanol, (R) -2- isopropylamino -2- phenylethanols, (1S, 2R) -1- amino -2-
Indanol, (S) -1- (2- naphthyls) ethamine, quinine, cinchonidine, cinchonine, quinine, brucine dihydrate, sulfuric acid horse
The hydrate of money alkali five, ephedrine, morphine, leucyl amine, tyrosine hydrazine acetate.
10. preparation method according to claim 8 or claim 9, it is characterised in that：First make 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3-
Cyclopentyl propionic acid is reacted with Chiral Amine, and crystallization and separation solid crystal are then carried out to product system, finally solid crystal is carried out
Acidolysis obtains (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids.
11. preparation method according to claim 8, it is characterised in that：The preparation method also includes making 3- (the bromo- 1H- of 4-
Pyrazol-1-yl) -3- cyclopentyl propionic acids methyl esters (compound 4) reacted in the presence of alkali generation 3- (the bromo- 1H- pyrazol-1-yls of 4-) -
3- cyclopentyl propionic acids (compound 5), reaction equation is as follows：
12. preparation method according to claim 11, it is characterised in that：Prepare 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- rings
In the reaction of penta propionic acid, described alkali is selected from lithium hydroxide monohydrate, sodium hydroxide, potassium hydroxide, and reacts at room temperature
Carry out.
13. preparation method according to claim 11, it is characterised in that：The preparation method also includes making 3- cyclopenta third
E pioic acid methyl ester (compound 3) reacts generation 3- (the bromo- 1H- pyrazol-1-yls of the 4-) -3- rings in the presence of base with 4- bromines pyrazoles
Penta methyl propionate (compound 4), reaction equation is as follows：
14. preparation method according to claim 13, it is characterised in that：The alkali is selected from 1,8- diazabicylos 11
Carbon -7- alkene, potassium carbonate, cesium carbonate.
15. preparation method according to claim 13, it is characterised in that：The preparation method also includes making cyclopenta formaldehyde
(compound 2), phosphoryl 3-acetic acid methyl ester and alkali reaction prepare 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids methyl esters and (changed
Compound 3) the step of, reaction equation is as follows：
。
16. preparation method according to claim 15, it is characterised in that：The preparation method also includes with Cyclopentane halide
It is the step of raw material prepares cyclopenta formaldehyde (compound 2) with formamide or N- substitution formamides, wherein first making Cyclopentane halide
RMgBr is prepared into reactive magnesium, then substitutes formamide with formamide or N-.
17. preparation method according to claim 16, it is characterised in that：When preparing cyclopenta formaldehyde, make bromocyclopentane
(compound 1), with reactive magnesium, then controls and dimethylformamide (DMF) is added dropwise below 10 DEG C of temperature, drip in the presence of iodine
Finish, reaction is stirred at room temperature, reaction equation is as follows：
18. a kind of Luso profit is for Buddhist nun or the preparation method of its salt, it is characterised in that：Methods described use (R) -3- (4- boric acid -
1H- pyrazol-1-yls) -3- rings penta propionitrile as preparing intermediate.
19. Luso profit according to claim 18 is for Buddhist nun or the preparation method of its salt, it is characterised in that：Methods described includes
Using the method described in any one of claim 2-17 claim come prepare (R) -3- (4- boric acid -1H- pyrazol-1-yls) -
The step of 3- penta propionitrile of ring.
20. 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids using resolution reagent are split as (R) -3- by one kind, (4- is bromo-
1H- pyrazol-1-yls) -3- cyclopentyl propionic acids method, it is characterised in that the resolution reagent is Chiral Amine.
21. according to claim 20 split 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids using resolution reagent
For the method for (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids, it is characterised in that the resolution reagent is S- benzene second
Amine, D- benzene glycinol, (1R, 2S) -2- amino -1,2- diphenyl ethanol, (R) -2- isopropylamino -2- phenylethanols, (1S,
2R) -1- amino -2- indanols, (S) -1- (2- naphthyls) ethamine, quinine, cinchonidine, cinchonine, quinine, brucine two
One or more in hydrate, the hydrate of strychnine sulfate five, ephedrine, morphine, leucyl amine, tyrosine hydrazine acetate
Combination.
22. resolution reagent is used by 3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids according to claim 20 or 21
It is split as the method for (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids, it is characterised in that first make 3- (the bromo- 1H- pyrroles of 4-
Azoles -1- bases) -3- cyclopentyl propionic acids and resolution reagent reacted, and crystallization and separation solid crystal are then carried out to product system, and it is finally right
Solid crystal carries out acidolysis and obtains described (R) -3- (the bromo- 1H- pyrazol-1-yls of 4-) -3- cyclopentyl propionic acids.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610707558.2A CN107759623B (en) | 2016-08-23 | 2016-08-23 | Intermediate of JAK inhibitor and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610707558.2A CN107759623B (en) | 2016-08-23 | 2016-08-23 | Intermediate of JAK inhibitor and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107759623A true CN107759623A (en) | 2018-03-06 |
| CN107759623B CN107759623B (en) | 2020-08-14 |
Family
ID=61264278
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610707558.2A Active CN107759623B (en) | 2016-08-23 | 2016-08-23 | Intermediate of JAK inhibitor and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107759623B (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020163653A1 (en) * | 2019-02-06 | 2020-08-13 | Concert Pharmaceuticals, Inc. | Process for preparing enantiomerically enriched jak inhibitors |
| CN114573489A (en) * | 2022-03-10 | 2022-06-03 | 河北化工医药职业技术学院 | Separation method of carboprost |
| CN114605244A (en) * | 2022-04-19 | 2022-06-10 | 常州沃腾化工科技有限公司 | Preparation method of cyclopentyl formaldehyde |
| WO2023125373A1 (en) * | 2021-12-27 | 2023-07-06 | 江苏威凯尔医药科技有限公司 | Method for preparing ruxolitinib and intermediate thereof |
| US11897889B2 (en) | 2020-08-18 | 2024-02-13 | Incyte Corporation | Process and intermediates for preparing a JAK1 inhibitor |
| US11905292B2 (en) | 2020-08-18 | 2024-02-20 | Incyte Corporation | Process and intermediates for preparing a JAK inhibitor |
| US11919907B2 (en) | 2020-05-21 | 2024-03-05 | Sun Pharmaceutical Industries, Inc. | Deuterated JAK inhibitor and uses thereof |
| US12071439B2 (en) | 2021-07-12 | 2024-08-27 | Incyte Corporation | Process and intermediates for preparing a JAK inhibitor |
| CN118754855A (en) * | 2024-09-06 | 2024-10-11 | 成都凡微析医药科技有限公司 | Purification method of 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentylpropionic acid |
Citations (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1931821A (en) * | 2005-09-16 | 2007-03-21 | 上海医药工业研究院 | Process of resolving optical isomer of 2-hydroxmethyl-3-phenylpropionic acid |
| CN1931855A (en) * | 2005-09-16 | 2007-03-21 | 上海医药工业研究院 | Compound 2-methylol-3-substituted phenyl propionic acid with optical activity and its resolving process |
| CN102267893A (en) * | 2011-06-15 | 2011-12-07 | 嘉兴学院 | Preparation method of royal jelly acid |
| CN102348693A (en) * | 2009-01-15 | 2012-02-08 | 因西特公司 | Processes for preparing JAK inhibitors and related intermediate compounds |
| CN102952029A (en) * | 2011-09-30 | 2013-03-06 | 北京海步国际医药科技发展有限公司 | Reagent and method for resolving 2-hydroxyl-3-methoxy-3,3-diphenyl propionic acid racemate |
| CN103415515A (en) * | 2010-11-19 | 2013-11-27 | 因塞特公司 | Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors |
| CN104030984A (en) * | 2014-06-06 | 2014-09-10 | 西北师范大学 | Method for preparing pyrazole derivative |
| US20150183805A1 (en) * | 2013-03-06 | 2015-07-02 | Incyte Corporation | Processes and intermediates for making a jak inhibitor |
| CN105061420A (en) * | 2015-06-04 | 2015-11-18 | 南京旗昌医药科技有限公司 | JAK inhibitor crystal forms, preparation methods and applications thereof |
| CN105294657A (en) * | 2015-10-30 | 2016-02-03 | 西华大学 | Preparation method of crizotinib |
| CN105418616A (en) * | 2015-12-26 | 2016-03-23 | 山东大学 | JAK kinase inhibitor containing 4-aminopyrazole structure, preparation method and application thereof |
| CN105452239A (en) * | 2013-05-17 | 2016-03-30 | 因赛特公司 | Bipyrazole derivatives as jak inhibitors |
| CN105541847A (en) * | 2009-10-09 | 2016-05-04 | 因西特控股公司 | Hydroxyl, keto, and glucuronide derivatives of 3-(4-(7h-pyrrolo[2,3-d] pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
| WO2016085939A2 (en) * | 2014-11-24 | 2016-06-02 | Case Western Reserve University | Compounds and methods of treating ocular disorders |
| CN105777756A (en) * | 2014-07-02 | 2016-07-20 | 广东东阳光药业有限公司 | Heteroaryl compound and application thereof in medicines |
-
2016
- 2016-08-23 CN CN201610707558.2A patent/CN107759623B/en active Active
Patent Citations (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1931855A (en) * | 2005-09-16 | 2007-03-21 | 上海医药工业研究院 | Compound 2-methylol-3-substituted phenyl propionic acid with optical activity and its resolving process |
| CN1931821A (en) * | 2005-09-16 | 2007-03-21 | 上海医药工业研究院 | Process of resolving optical isomer of 2-hydroxmethyl-3-phenylpropionic acid |
| CN102348693A (en) * | 2009-01-15 | 2012-02-08 | 因西特公司 | Processes for preparing JAK inhibitors and related intermediate compounds |
| CN105669676A (en) * | 2009-01-15 | 2016-06-15 | 因西特控股公司 | Processes for preparing jak inhibitors and related intermediate compounds |
| CN105541847A (en) * | 2009-10-09 | 2016-05-04 | 因西特控股公司 | Hydroxyl, keto, and glucuronide derivatives of 3-(4-(7h-pyrrolo[2,3-d] pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
| CN103415515A (en) * | 2010-11-19 | 2013-11-27 | 因塞特公司 | Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors |
| CN102267893A (en) * | 2011-06-15 | 2011-12-07 | 嘉兴学院 | Preparation method of royal jelly acid |
| CN102952029A (en) * | 2011-09-30 | 2013-03-06 | 北京海步国际医药科技发展有限公司 | Reagent and method for resolving 2-hydroxyl-3-methoxy-3,3-diphenyl propionic acid racemate |
| US20150183805A1 (en) * | 2013-03-06 | 2015-07-02 | Incyte Corporation | Processes and intermediates for making a jak inhibitor |
| CN105452239A (en) * | 2013-05-17 | 2016-03-30 | 因赛特公司 | Bipyrazole derivatives as jak inhibitors |
| CN104030984A (en) * | 2014-06-06 | 2014-09-10 | 西北师范大学 | Method for preparing pyrazole derivative |
| CN105777756A (en) * | 2014-07-02 | 2016-07-20 | 广东东阳光药业有限公司 | Heteroaryl compound and application thereof in medicines |
| WO2016085939A2 (en) * | 2014-11-24 | 2016-06-02 | Case Western Reserve University | Compounds and methods of treating ocular disorders |
| CN105061420A (en) * | 2015-06-04 | 2015-11-18 | 南京旗昌医药科技有限公司 | JAK inhibitor crystal forms, preparation methods and applications thereof |
| CN105294657A (en) * | 2015-10-30 | 2016-02-03 | 西华大学 | Preparation method of crizotinib |
| CN105418616A (en) * | 2015-12-26 | 2016-03-23 | 山东大学 | JAK kinase inhibitor containing 4-aminopyrazole structure, preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| 刘军: "《有机化学》", 31 August 2014 * |
| 马世昌: "《基础化学反应》", 31 January 2003 * |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020163653A1 (en) * | 2019-02-06 | 2020-08-13 | Concert Pharmaceuticals, Inc. | Process for preparing enantiomerically enriched jak inhibitors |
| CN113906032A (en) * | 2019-02-06 | 2022-01-07 | 康塞特医药品有限公司 | Methods for preparing enantiomerically enriched JAK inhibitors |
| US11919907B2 (en) | 2020-05-21 | 2024-03-05 | Sun Pharmaceutical Industries, Inc. | Deuterated JAK inhibitor and uses thereof |
| US11897889B2 (en) | 2020-08-18 | 2024-02-13 | Incyte Corporation | Process and intermediates for preparing a JAK1 inhibitor |
| US11905292B2 (en) | 2020-08-18 | 2024-02-20 | Incyte Corporation | Process and intermediates for preparing a JAK inhibitor |
| US12071439B2 (en) | 2021-07-12 | 2024-08-27 | Incyte Corporation | Process and intermediates for preparing a JAK inhibitor |
| WO2023125373A1 (en) * | 2021-12-27 | 2023-07-06 | 江苏威凯尔医药科技有限公司 | Method for preparing ruxolitinib and intermediate thereof |
| CN114573489A (en) * | 2022-03-10 | 2022-06-03 | 河北化工医药职业技术学院 | Separation method of carboprost |
| CN114573489B (en) * | 2022-03-10 | 2023-08-22 | 河北化工医药职业技术学院 | Separation method of carboprost |
| CN114605244A (en) * | 2022-04-19 | 2022-06-10 | 常州沃腾化工科技有限公司 | Preparation method of cyclopentyl formaldehyde |
| CN114605244B (en) * | 2022-04-19 | 2023-10-24 | 常州沃腾化工科技有限公司 | Preparation method of cyclopentyl formaldehyde |
| CN118754855A (en) * | 2024-09-06 | 2024-10-11 | 成都凡微析医药科技有限公司 | Purification method of 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentylpropionic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107759623B (en) | 2020-08-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107759623A (en) | Intermediate of JAK inhibitor and preparation method thereof | |
| CN107759601A (en) | A kind of preparation method of JAK inhibitor and its salt | |
| JP6921087B2 (en) | Ruxolitinib synthesis process | |
| CN104487430B (en) | For the method manufacturing hydroxylated cyclopenta pyrimidine compound | |
| CN107176955B (en) | A kind of Ba Rui replaces the preparation method of Buddhist nun | |
| CN107311875A (en) | The synthetic method of aramine | |
| CN110845482B (en) | Process for preparing indole compounds | |
| CN104520263B (en) | The method preparing amino-acid compound | |
| CN103509037B (en) | A kind of clopidogrel and the preparation method of intermediate thereof | |
| CN108218754B (en) | Preparation method of 2- (2,5-difluorophenyl) pyrrolidine | |
| CN104910002B (en) | A kind of preparation method of dezocine key intermediate | |
| ES2749100T3 (en) | Processes for preparing (cyclopentyl [d] pyrimidin-4-yl) piperazine compounds | |
| CN100368402C (en) | Preparation method of ornidazole optical enantiomer | |
| CN108912032A (en) | It is a kind of（3S, 4R）The chemical synthesis process of -4- methylpyrrolidin- 3- base amino methanol t-butyl ester hydrochloride | |
| CN105646447A (en) | Synthesis method of dipeptidyl peptidase inhibitor | |
| CN104193643B (en) | For the synthesis of the intermediate of anti-AIDS drug toughener cobicistat | |
| CN108129430A (en) | A kind of synthetic method of Li Tasite intermediates | |
| CN105503927A (en) | Method for synthesizing 3, 6-dihydro-2H-pyrazine (thiazine) furan-4-boric acid ester | |
| CN103351346A (en) | Preparation method of impurity HP1 in bendamustine hydrochloride | |
| JP4425654B2 (en) | Water-soluble transition metal-diamine complex, method for producing the same, and use thereof | |
| CN107445964A (en) | A kind of synthetic method of Vardenafil hydrochloric acid impurity | |
| CN109020977B (en) | Preparation method of Acaraburtinib | |
| JPWO2017043626A1 (en) | Process for producing optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative | |
| KR20200068678A (en) | Process for manufacturing spiro derivatives | |
| CN109796448B (en) | Preparation process of dasatinib |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |