CN103012395B - Preparation method of heterocyclic benzene compound - Google Patents
Preparation method of heterocyclic benzene compound Download PDFInfo
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- CN103012395B CN103012395B CN201310001003.2A CN201310001003A CN103012395B CN 103012395 B CN103012395 B CN 103012395B CN 201310001003 A CN201310001003 A CN 201310001003A CN 103012395 B CN103012395 B CN 103012395B
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- -1 heterocyclic benzene compound Chemical class 0.000 title claims abstract description 44
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 230000000694 effects Effects 0.000 claims abstract description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 37
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000000741 silica gel Substances 0.000 claims description 21
- 229910002027 silica gel Inorganic materials 0.000 claims description 21
- 229960001866 silicon dioxide Drugs 0.000 claims description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- ZMWAZMYBMAAMAW-UHFFFAOYSA-N 4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)aniline Chemical compound C1CN(C)CCN1CC1=CC=C(N)C=C1C(F)(F)F ZMWAZMYBMAAMAW-UHFFFAOYSA-N 0.000 claims description 11
- 229960000583 acetic acid Drugs 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 11
- 239000012362 glacial acetic acid Substances 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims description 10
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 10
- 238000010828 elution Methods 0.000 claims description 10
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 10
- 239000007858 starting material Substances 0.000 claims description 10
- 239000004305 biphenyl Substances 0.000 claims description 6
- 235000010290 biphenyl Nutrition 0.000 claims description 6
- 125000006267 biphenyl group Chemical group 0.000 claims description 6
- 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 claims description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 5
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000012790 confirmation Methods 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000005859 coupling reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229910052763 palladium Inorganic materials 0.000 description 7
- SKJCWIFHLDWPEO-UHFFFAOYSA-N 3-benzyl-4-phenylbutan-2-one Chemical class C=1C=CC=CC=1CC(C(=O)C)CC1=CC=CC=C1 SKJCWIFHLDWPEO-UHFFFAOYSA-N 0.000 description 4
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical group 0.000 description 4
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 101150003085 Pdcl gene Proteins 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 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 2
- 239000003814 drug Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- RQMTZMWXNZQOPD-UHFFFAOYSA-N (8'-diphenylphosphanyl-4,4,4',4',6,6'-hexamethyl-2,2'-spirobi[3h-chromene]-8-yl)-diphenylphosphane Chemical compound C=12OC3(OC4=C(P(C=5C=CC=CC=5)C=5C=CC=CC=5)C=C(C)C=C4C(C)(C)C3)CC(C)(C)C2=CC(C)=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 RQMTZMWXNZQOPD-UHFFFAOYSA-N 0.000 description 1
- XGCDBGRZEKYHNV-UHFFFAOYSA-N 1,1-bis(diphenylphosphino)methane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CP(C=1C=CC=CC=1)C1=CC=CC=C1 XGCDBGRZEKYHNV-UHFFFAOYSA-N 0.000 description 1
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 1
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 1
- UXKCLTPQRBKROC-UHFFFAOYSA-N C(C)(C)C1=C(C(=CC(=C1)C(C)C)C(C)C)C1=CC=CC=C1.[P] Chemical group C(C)(C)C1=C(C(=CC(=C1)C(C)C)C(C)C)C1=CC=CC=C1.[P] UXKCLTPQRBKROC-UHFFFAOYSA-N 0.000 description 1
- DANMWBNOPFBJSZ-UHFFFAOYSA-N Cc1c(C)c(I)ccc1 Chemical compound Cc1c(C)c(I)ccc1 DANMWBNOPFBJSZ-UHFFFAOYSA-N 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 208000031852 Gastrointestinal stromal cancer Diseases 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-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
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- QKLWAMMQKBOTCD-UHFFFAOYSA-N butane;diphenylphosphane Chemical compound CCCC.C=1C=CC=CC=1PC1=CC=CC=C1 QKLWAMMQKBOTCD-UHFFFAOYSA-N 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- FSRXIRGQJIHEFB-UHFFFAOYSA-N diphenylphosphane;ethane Chemical compound CC.C=1C=CC=CC=1PC1=CC=CC=C1 FSRXIRGQJIHEFB-UHFFFAOYSA-N 0.000 description 1
- TWWJJVNUZQLCPD-UHFFFAOYSA-N diphenylphosphane;methane Chemical compound C.C=1C=CC=CC=1PC1=CC=CC=C1 TWWJJVNUZQLCPD-UHFFFAOYSA-N 0.000 description 1
- ONDPGJBEBGWAKI-UHFFFAOYSA-N diphenylphosphane;propane Chemical compound CCC.C=1C=CC=CC=1PC1=CC=CC=C1 ONDPGJBEBGWAKI-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- SACNIGZYDTUHKB-UHFFFAOYSA-N ditert-butyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C(C)(C)C)C(C)(C)C SACNIGZYDTUHKB-UHFFFAOYSA-N 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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Abstract
The invention relates to a preparation method of a heterocyclic benzene compound. The preparation method comprises the step of carrying out coupled reaction between a compound as shown in formula I and the compound as shown in formula II under the effect of a catalyst A, so as to obtain the compound as shown in formula III; and the reaction is shown as follows, wherein Ar, R1, R2, X and A are identified as the specifications shown. According to the method of synthesizing the heterocyclic benzene compound, described in the technical scheme, the reaction yield is greatly increased; the 'one-pot' method is carried out, so that the reaction process is safe and simple; and the method is very suitable for industrial production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, the preparation method of a kind of heterocyclic benzene compound of specific design.
Background technology
Applicant discloses a class Tyrosylprotein kinase micromolecular inhibitor-heterocyclic benzene compound in patent application 201110440651.9, this compounds can prevent and/or treat lymphoma, lung cancer, gastro-intestinal stromal cancer, carcinoma of the pancreas, mammary cancer, prostate cancer, leukemia, lung cancer, liver cancer, the diseases such as cervical cancer, and the resistance that effectively can overcome that existing medicine imatinib mesylate (Gleevec) brings out.This kind of compou nd synthesis method that applicant also discloses in this patent documentation, wherein condensation reaction catalyzer be palladium and 1,10-phenanthroline, but this step synthetic condensation agent reactions steps yield is very low, and aftertreatment comparatively bothers, be not suitable for suitability for industrialized production, therefore applicant is follow-up has carried out large quantifier elimination to the preparation method of this compounds again.
Summary of the invention
By research, applicant develops a kind of new synthetic method, and namely the present invention comes therefrom.
The invention provides a kind of preparation method of heterocyclic benzene compound, the method for: under the effect of catalyst A, there is linked reaction in the compound shown in the compound shown in formula I and formula II, generate the compound shown in formula III,
Wherein,
Ar is phenyl or substituted-phenyl, R
1for sulphur, oxygen or amino, R
2for hydrogen base, alkyl or substituted alkyl, X is halogen; A is palladium complex and Phosphine ligands catalyzer.Wherein halogen can be fluorine, chlorine, bromine, iodine etc.
Preferably, in aforesaid method, described Ar is the phenyl of phenyl, alkyl and/or halogen substiuted.When wherein Ar is substituted-phenyl, can be monosubstituted, also can be polysubstituted, and substituting group can be alkyl or halogen, such as methyl, chloromethyl, chlorine, fluorine etc.
Preferably, in aforesaid method, described R
2for hydrogen base, methyl or fluoro-alkyl.
Preferably, in aforesaid method, described X is chlorine or bromine.
Further, in the preparation method of above-mentioned heterocyclic benzene compound, palladium part is zeroth order palladium part, divalent palladium part or the mixture of the two.
Preferably, described palladium part is two (bis-Ya Benzyl benzylacetones) palladium [Pd (dba)
2], three (dibenzalacetones) close palladium (0) [Pd
2(dba)
3)], tetrakis triphenylphosphine palladium (0) [Pd (PPh
3)
4] or [two (diphenylphosphino) ferrocene of 1,1'-] palladium chloride [PdCl
2(dppf) one or more].
Preferably, described Phosphine ligands is tri-butyl phosphine, 2, the two diphenyl phosphine-1 of 2'-, 1'-dinaphthalene (BINAP), 1, two (diphenylphosphine) methane (dppm) of 1-, 1, two (diphenylphosphine) ethane (dppe) of 2-, 1, two (diphenylphosphine) propane (dppp) of 3-, 1, two (diphenylphosphine) butane (dppb) of 4-, 1, two (diphenylphosphine) ferrocene (dppf) of 1'-, 8, two (diphenylphosphino)-4 of 8'-, 4, 4', 4', 6, 6'-hexamethyl-2, the two chroman (SPANphos) of 2'-spiral shell, 4, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (Xantphos), 2-dicyclohexyl phosphorus-2, 4, 6-tri isopropyl biphenyl (Xphos) or 2-di-t-butyl phosphine-2 ', 4 ', one or more in 6 '-tri isopropyl biphenyl (Tert-Butyl Xphos).
The preparation method of further described heterocyclic benzene compound for: there is linked reaction in the compound shown in the compound shown in formula Ia and formula IIa, the compound shown in production IIIa under the effect of catalyst A,
Wherein, A is palladium complex and Phosphine ligands catalyzer.
The present invention has mainly selected Buchwald – Hartwig linked reaction to synthesize this heterocyclic benzene compound, and reaction mechanism is as follows, specifically can be see
chinese Journal of Synthetic chemisrty Voll5.2007.No89.
In the technical program, the method for synthesizing heterocyclic pyrimidine benzene-like compounds, significantly improves reaction yield, and adopts the mode of " treating different things alike ", and reaction process safely, simply, is very applicable to suitability for industrialized production.
Accompanying drawing explanation
The crystallogram of the product that Fig. 1 embodiment 1 is obtained
Embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is further elaborated.
embodiment 1
In the flask of 2L, under nitrogen protection, add 35.4g(90mmol) N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides (WO2005/77945), with 27.9g(99mmol) 3-trifluoromethyl-4-[(4-methylpiperazine-1-yl) methyl] aniline (EP1840122), 4.13g(4.5mmol) three (dibenzalacetones) close palladium (0) [Pd
2(dba)
3)], 2 of 4.2g (4.95mmol), the two diphenyl phosphine-1 of 2'-, 1'-dinaphthalene (BINAP), 15.2g(135mmol) potassium tert.-butoxide, with 1 of 1.5L, 4-dioxane, after being heated to 120 DEG C of backflow 6h, HPLC prosecution is when confirming that starting material left is less than 2%, rear stopping heating, heat filtering, filtrate leaves standstill room temperature and again filters rear dropping 3ml glacial acetic acid, after use 200g, 100-200 order silica gel system is husky, cross silicagel column, the elution of AE:PE1:15, obtain white solid, 38g, yield 63%, purity 99%, fusing point 215 DEG C, 1HNMR:(400MHz, DMSO): δ 10.01 (s, 1H), 8.32 (s, 1H), 7.40 (dd, J=1.2, 7.2Hz, 1H), 7.30-7.24 (m, 3H), 6.94 (s, 1H), 6.84 (d, J=2.4Hz, 1H), 6.74 (dd, 1H, J=2.0, 8.4Hz, 1H), 3.38 (s, 2H), 2.58 (S, 3H), 2.47 (m, 8H), 2.14 (s, 3H).
embodiment 2
In the flask of 2L, under nitrogen protection, add 35.5g(90mmol) N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides, with 27.7g(99mmol) 3-trifluoromethyl-4-[(4-methylpiperazine-1-yl) methyl] aniline, 5.1g(4.4mmol) tetrakis triphenylphosphine palladium (0) [Pd (PPh
3)
4], the toluene solution of 5ml (5mmol) tri-butyl phosphine (TTBP), 15.0g(135mmol) potassium tert.-butoxide, with 1 of 1.5L, 4-dioxane, after being heated to 120 DEG C of backflow 6h, HPLC prosecution is when confirming that starting material left is less than 2%, rear stopping heating, heat filtering, filtrate leaves standstill room temperature and again filters rear dropping 3ml glacial acetic acid, after use 200g, 100-200 order silica gel system is husky, cross silicagel column, the elution of AE:PE1:15, obtain white solid, 35g, yield 58%, purity 99%, fusing point 215 DEG C, 1HNMR:(400MHz, DMSO): δ 10.01 (s, 1H), 8.32 (s, 1H), 7.40 (dd, J=1.2, 7.2Hz, 1H), 7.30-7.24 (m, 3H), 6.94 (s, 1H), 6.84 (d, J=2.4Hz, 1H), 6.74 (dd, 1H, J=2.0, 8.4Hz, 1H), 3.38 (s, 2H), 2.58 (S, 3H), 2.47 (m, 8H), 2.14 (s, 3H).
embodiment 3
In the flask of 2L, under nitrogen protection, add 35.2g(90mmol) N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides, with 28.0g(99mmol) 3-trifluoromethyl-4-[(4-methylpiperazine-1-yl) methyl] aniline, 4.20g(4.6mmol) three (dibenzalacetones) close palladium (0) (Pd
2(dba)
3), the toluene solution of 5ml (5mmol) tri-butyl phosphine (TTBP), 15.2g(135mmol) potassium tert.-butoxide, with 1 of 1.5L, 4-dioxane, after being heated to 120 DEG C of backflow 6h, HPLC prosecution is when confirming that starting material left is less than 2%, rear stopping heating, heat filtering, filtrate leaves standstill room temperature and again filters rear dropping 3ml glacial acetic acid, after use 200g, 100-200 order silica gel system is husky, cross silicagel column, the elution of AE:PE1:15, obtain white solid, 41g, yield 68%, purity 99%, fusing point 215 DEG C, 1HNMR:(400MHz, DMSO): δ 10.01 (s, 1H), 8.32 (s, 1H), 7.40 (dd, J=1.2, 7.2Hz, 1H), 7.30-7.24 (m, 3H), 6.94 (s, 1H), 6.84 (d, J=2.4Hz, 1H), 6.74 (dd, 1H, J=2.0, 8.4Hz, 1H), 3.38 (s, 2H), 2.58 (S, 3H), 2.47 (m, 8H), 2.14 (s, 3H).
embodiment 4
In the flask of 2L, under nitrogen protection, add 35.0g(90mmol) N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides, with 27.8g(99mmol) 3-trifluoromethyl-4-[(4-methylpiperazine-1-yl) methyl] aniline, 5.2g(4.6mmol) tetrakis triphenylphosphine palladium (0) [Pd (PPH
3)
4], 2 of 4.4g (5mmol), the two diphenyl phosphine-1 of 2'-, 1'-dinaphthalene (BINAP), 15.3g(135mmol) potassium tert.-butoxide, with 1 of 1.5L, 4-dioxane, after being heated to 120 DEG C of backflow 6h, HPLC prosecution is when confirming that starting material left is less than 2%, rear stopping heating, heat filtering, filtrate leaves standstill room temperature and again filters rear dropping 3ml glacial acetic acid, after use 200g, 100-200 order silica gel system is husky, cross silicagel column, the elution of AE:PE1:15, obtain white solid, 32g, yield 53%, purity 99%, fusing point 215 DEG C, 1HNMR:(400MHz, DMSO): δ 10.01 (s, 1H), 8.32 (s, 1H), 7.40 (dd, J=1.2, 7.2Hz, 1H), 7.30-7.24 (m, 3H), 6.94 (s, 1H), 6.84 (d, J=2.4Hz, 1H), 6.74 (dd, 1H, J=2.0, 8.4Hz, 1H), 3.38 (s, 2H), 2.58 (S, 3H), 2.47 (m, 8H), 2.14 (s, 3H).
embodiment 5
In the flask of 2L, under nitrogen protection, add 35.0g(90mmol) N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides, with 27.8g(99mmol) 3-trifluoromethyl-4-[(4-methylpiperazine-1-yl) methyl] aniline, 2.6g(4.6mmol) two (bis-Ya Benzyl benzylacetones) palladium [Pd (dba)
2], 2 of 4.4g (5mmol), the two diphenyl phosphine-1 of 2'-, 1'-dinaphthalene (BINAP), 15.3g(135mmol) potassium tert.-butoxide, with 1 of 1.5L, 4-dioxane, after being heated to 120 DEG C of backflow 6h, HPLC prosecution is when confirming that starting material left is less than 2%, rear stopping heating, heat filtering, filtrate leaves standstill room temperature and again filters rear dropping 3ml glacial acetic acid, after use 200g, 100-200 order silica gel system is husky, cross silicagel column, the elution of AE:PE1:15, obtain white solid, 35g, yield 58%, purity 99%, fusing point 215 DEG C, 1HNMR:(400MHz, DMSO): δ 10.01 (s, 1H), 8.32 (s, 1H), 7.40 (dd, J=1.2, 7.2Hz, 1H), 7.30-7.24 (m, 3H), 6.94 (s, 1H), 6.84 (d, J=2.4Hz, 1H), 6.74 (dd, 1H, J=2.0, 8.4Hz, 1H), 3.38 (s, 2H), 2.58 (S, 3H), 2.47 (m, 8H), 2.14 (s, 3H).
embodiment 6
In the flask of 2L, under nitrogen protection, add 35.0g(90mmol) N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides, with 27.8g(99mmol) 3-trifluoromethyl-4-[(4-methylpiperazine-1-yl) methyl] aniline, 2.6g(4.6mmol) two (bis-Ya Benzyl benzylacetones) palladium (Pd (dba)
2), the toluene solution of 5ml (5mmol) tri-butyl phosphine (TTBP), 15.3g(135mmol) potassium tert.-butoxide, with 1 of 1.5L, 4-dioxane, after being heated to 120 DEG C of backflow 6h, HPLC prosecution is when confirming that starting material left is less than 2%, rear stopping heating, heat filtering, filtrate leaves standstill room temperature and again filters rear dropping 3ml glacial acetic acid, after use 200g, 100-200 order silica gel system is husky, cross silicagel column, the elution of AE:PE1:15, obtain white solid, 33g, yield 54%, purity 99%, fusing point 215 DEG C, 1HNMR:(400MHz, DMSO): δ 10.01 (s, 1H), 8.32 (s, 1H), 7.40 (dd, J=1.2, 7.2Hz, 1H), 7.30-7.24 (m, 3H), 6.94 (s, 1H), 6.84 (d, J=2.4Hz, 1H), 6.74 (dd, 1H, J=2.0, 8.4Hz, 1H), 3.38 (s, 2H), 2.58 (S, 3H), 2.47 (m, 8H), 2.14 (s, 3H).
embodiment 7
In the flask of 2L, under nitrogen protection, add 35.0g(90mmol) N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides, with 27.8g(99mmol) 3-trifluoromethyl-4-[(4-methylpiperazine-1-yl) methyl] aniline, 2.6g(4.6mmol) two (bis-Ya Benzyl benzylacetones) palladium (Pd (dba)
2), the 2-dicyclohexyl phosphorus-2 of 2.4g (5mmol), 4, 6-tri isopropyl biphenyl (Xphos), 15.3g(135mmol) potassium tert.-butoxide, with 1 of 1.5L, 4-dioxane, after being heated to 120 DEG C of backflow 6h, HPLC prosecution is when confirming that starting material left is less than 2%, rear stopping heating, heat filtering, filtrate leaves standstill room temperature and again filters rear dropping 3ml glacial acetic acid, after use 200g, 100-200 order silica gel system is husky, cross silicagel column, the elution of AE:PE1:15, obtain white solid, 36g, yield 60%, purity 99%, fusing point 215 DEG C, 1HNMR:(400MHz, DMSO): δ 10.01 (s, 1H), 8.32 (s, 1H), 7.40 (dd, J=1.2, 7.2Hz, 1H), 7.30-7.24 (m, 3H), 6.94 (s, 1H), 6.84 (d, J=2.4Hz, 1H), 6.74 (dd, 1H, J=2.0, 8.4Hz, 1H), 3.38 (s, 2H), 2.58 (S, 3H), 2.47 (m, 8H), 2.14 (s, 3H).
embodiment 8
In the flask of 2L, under nitrogen protection, add 35.0g(90mmol) N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides, with 27.8g(99mmol) 3-trifluoromethyl-4-[(4-methylpiperazine-1-yl) methyl] aniline, 5.2g(4.6mmol) tetrakis triphenylphosphine palladium (0) (Pd (PPh
3)
4), the 2-dicyclohexyl phosphorus-2 of 2.4g (5mmol), 4, 6-tri isopropyl biphenyl (Xphos), 15.3g(135mmol) potassium tert.-butoxide, with 1 of 1.5L, 4-dioxane, after being heated to 120 DEG C of backflow 6h, HPLC prosecution is when confirming that starting material left is less than 2%, rear stopping heating, heat filtering, filtrate leaves standstill room temperature and again filters rear dropping 3ml glacial acetic acid, after use 200g, 100-200 order silica gel system is husky, cross silicagel column, the elution of AE:PE1:15, obtain white solid, 32g, yield 53%, purity 99%, fusing point 216 DEG C, 1HNMR:(400MHz, DMSO): δ 10.01 (s, 1H), 8.32 (s, 1H), 7.40 (dd, J=1.2, 7.2Hz, 1H), 7.30-7.24 (m, 3H), 6.94 (s, 1H), 6.84 (d, J=2.4Hz, 1H), 6.74 (dd, 1H, J=2.0, 8.4Hz, 1H), 3.38 (s, 2H), 2.58 (S, 3H), 2.47 (m, 8H), 2.14 (s, 3H).
embodiment 9
In the flask of 2L, under nitrogen protection, add 35.0g(90mmol) N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides, with 27.8g(99mmol) 3-trifluoromethyl-4-[(4-methylpiperazine-1-yl) methyl] aniline, 4.13g(4.5mmol) three (dibenzalacetones) close palladium (0) (Pd
2(dba)
3), the 2-dicyclohexyl phosphorus-2 of 2.4g (5mmol), 4, 6-tri isopropyl biphenyl (Xphos), 15.3g(135mmol) potassium tert.-butoxide, with 1 of 1.5L, 4-dioxane, after being heated to 120 DEG C of backflow 6h, HPLC prosecution is when confirming that starting material left is less than 2%, rear stopping heating, heat filtering, filtrate leaves standstill room temperature and again filters rear dropping 3ml glacial acetic acid, after use 200g, 100-200 order silica gel system is husky, cross silicagel column, the elution of AE:PE1:15, obtain white solid, 32g, yield 53%, purity 99%, fusing point 215 DEG C, 1HNMR:(400MHz, DMSO): δ 10.01 (s, 1H), 8.32 (s, 1H), 7.40 (dd, J=1.2, 7.2Hz, 1H), 7.30-7.24 (m, 3H), 6.94 (s, 1H), 6.84 (d, J=2.4Hz, 1H), 6.74 (dd, 1H, J=2.0, 8.4Hz, 1H), 3.38 (s, 2H), 2.58 (S, 3H), 2.47 (m, 8H), 2.14 (s, 3H).
embodiment 10
Under nitrogen protection, the 1N added, N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) is amino]-5-thiazole carboxamides, with 1.1N, 3-trifluoromethyl-4-[(4-methylpiperazine-1-yl) methyl] aniline, [two (diphenylphosphino) ferrocene of 1,1'-] palladium chloride [PdCl of 5%mol
2(dppf)], 4 of 5.5%mol, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (Xantphos), 1.5Nmol potassium tert.-butoxide, 1, 4-dioxane makees solvent, after being heated to 120 DEG C of backflow 6h, rear stopping heating, heat filtering, filtrate leaves standstill room temperature and again filters rear dropping 3ml glacial acetic acid, system is husky, cross silicagel column, obtain white solid, purity 99%, fusing point 215 DEG C, 1HNMR:(400MHz, DMSO): δ 10.01 (s, 1H), 8.32 (s, 1H), 7.40 (dd, J=1.2, 7.2Hz, 1H), 7.30-7.24 (m, 3H), 6.94 (s, 1H), 6.84 (d, J=2.4Hz, 1H), 6.74 (dd, 1H, J=2.0, 8.4Hz, 1H), 3.38 (s, 2H), 2.58 (S, 3H), 2.47 (m, 8H), 2.14 (s, 3H).
Should be noted that; the foregoing is only preferred embodiment of the present invention; be not limited to scope of the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., all should be included within protection scope of the present invention.
Claims (2)
1. prepare the preparation method such as formula the heterocyclic benzene compound shown in IIIa for one kind, it is characterized in that, the method is that formula Ia compound and formula IIa compound, under the effect of catalyst A, linked reaction is occurred, production IIIa compound, wherein catalyst A is made up of palladium part and Phosphine ligands, and, palladium part is selected from three (dibenzalacetones) and closes one in palladium (0) or tetrakis triphenylphosphine palladium (0), Phosphine ligands is selected from 2, two diphenyl phosphine-1, the 1'-dinaphthalene of 2'-or 2-dicyclohexyl phosphorus-2,4, one in 6-tri isopropyl biphenyl
2. preparation method according to claim 1, it is characterized in that, the method specifically comprises following steps: in the flask of 2L, under nitrogen protection, add N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) the is amino]-5-thiazole carboxamides of 35.0g, with 3-trifluoromethyl-4-[(4-methylpiperazine-1-yl) methyl] aniline of 27.8g, the tetrakis triphenylphosphine palladium (0) of 5.2g, 2 of 4.4g, the two diphenyl phosphine-1 of 2'-, 1'-dinaphthalene, 15.3g potassium tert.-butoxide, and 1 of 1.5L, 4-dioxane, after being heated to 120 DEG C of backflow 6h, HPLC monitors, after confirmation starting material left is less than 2%, stop heating, heat filtering, filtrate leaves standstill room temperature, again filter, drip 3ml glacial acetic acid, use the 100-200 order silica gel system of 200g husky afterwards, cross silicagel column, adopt the elution of EA:PE=1:15, obtain white solid.
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| WO2006099474A1 (en) * | 2005-03-15 | 2006-09-21 | Bristol-Myers Squibb Company | 'n-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamides metabolites |
| WO2008150446A1 (en) * | 2007-05-30 | 2008-12-11 | Congxin Liang | Inhibitors of protein kinases |
| CN101973989A (en) * | 2010-05-17 | 2011-02-16 | 苏州波锐生物医药科技有限公司 | Thiazole amide compound and medicinal application thereof for treating malignancy |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006099474A1 (en) * | 2005-03-15 | 2006-09-21 | Bristol-Myers Squibb Company | 'n-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamides metabolites |
| WO2008150446A1 (en) * | 2007-05-30 | 2008-12-11 | Congxin Liang | Inhibitors of protein kinases |
| CN101973989A (en) * | 2010-05-17 | 2011-02-16 | 苏州波锐生物医药科技有限公司 | Thiazole amide compound and medicinal application thereof for treating malignancy |
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| 胡跃飞,等.Buchwald-Hartwig偶联反应.《现代有机反应 金属催化反应》.化学工业出版社,2008,第21-23页. * |
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Address after: 210046 Nanjing economic and Technological Development Zone, Jiangsu Heng Road, No. 28 Patentee after: NANJING YOKO BIOLOGICAL PHARMACEUTICAL GROUP Co.,Ltd. Address before: 210046 Nanjing economic and Technological Development Zone, Jiangsu Heng Road, No. 28 Patentee before: Nanjing uniclever biological pharmaceutical Limited by Share Ltd. Address after: 210046 Nanjing economic and Technological Development Zone, Jiangsu Heng Road, No. 28 Patentee after: Nanjing uniclever biological pharmaceutical Limited by Share Ltd. Address before: 210046 Nanjing economic and Technological Development Zone, Jiangsu Heng Road, No. 28 Patentee before: NANJING YOKO PHARMACEUTICAL Co.,Ltd. |
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