CN106243083A - A kind of imatinib preparation method - Google Patents
A kind of imatinib preparation method Download PDFInfo
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- CN106243083A CN106243083A CN201610542560.9A CN201610542560A CN106243083A CN 106243083 A CN106243083 A CN 106243083A CN 201610542560 A CN201610542560 A CN 201610542560A CN 106243083 A CN106243083 A CN 106243083A
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- Prior art keywords
- imatinib
- pyrimidine
- pyridine
- preparation
- chloro
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Links
- 239000005517 L01XE01 - Imatinib Substances 0.000 title claims abstract description 42
- 229960002411 imatinib Drugs 0.000 title claims abstract description 42
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound 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 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 21
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 16
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 208000035126 Facies Diseases 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 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 claims description 10
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- 229960000583 acetic acid Drugs 0.000 claims description 8
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 claims description 7
- 229910052786 argon Inorganic materials 0.000 claims description 7
- 239000012362 glacial acetic acid Substances 0.000 claims description 7
- 239000003208 petroleum Substances 0.000 claims description 7
- 238000010792 warming Methods 0.000 claims description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- 239000008346 aqueous phase Substances 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000000284 extract Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000002639 sodium chloride Nutrition 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 1
- 230000006837 decompression Effects 0.000 claims 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 16
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 abstract description 8
- 239000000460 chlorine Substances 0.000 abstract description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 231100000419 toxicity Toxicity 0.000 abstract description 5
- 230000001988 toxicity Effects 0.000 abstract description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 abstract description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 3
- 150000003230 pyrimidines Chemical class 0.000 abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical class ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 abstract 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- -1 guanidine Compound Chemical class 0.000 description 12
- 238000007363 ring formation reaction Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 5
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 5
- TXZFBHYDQGYOIT-UHFFFAOYSA-N 2-(chloromethyl)benzoyl chloride Chemical class ClCC1=CC=CC=C1C(Cl)=O TXZFBHYDQGYOIT-UHFFFAOYSA-N 0.000 description 4
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- GDIIPKWHAQGCJF-UHFFFAOYSA-N 4-Amino-2-nitrotoluene Chemical compound CC1=CC=C(N)C=C1[N+]([O-])=O GDIIPKWHAQGCJF-UHFFFAOYSA-N 0.000 description 2
- QGAIPGVQJVGBIA-UHFFFAOYSA-N 4-methyl-3-n-(4-pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine Chemical compound CC1=CC=C(N)C=C1NC1=NC=CC(C=2C=NC=CC=2)=N1 QGAIPGVQJVGBIA-UHFFFAOYSA-N 0.000 description 2
- DSBIJCMXAIKKKI-UHFFFAOYSA-N 5-nitro-o-toluidine Chemical compound CC1=CC=C([N+]([O-])=O)C=C1N DSBIJCMXAIKKKI-UHFFFAOYSA-N 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- 238000006411 Negishi coupling reaction Methods 0.000 description 2
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 2
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 229960003685 imatinib mesylate Drugs 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
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 210000004214 philadelphia chromosome Anatomy 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- NYPYPOZNGOXYSU-UHFFFAOYSA-N 3-bromopyridine Chemical compound BrC1=CC=CN=C1 NYPYPOZNGOXYSU-UHFFFAOYSA-N 0.000 description 1
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 101001126417 Homo sapiens Platelet-derived growth factor receptor alpha Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102100027754 Mast/stem cell growth factor receptor Kit Human genes 0.000 description 1
- 101710087603 Mast/stem cell growth factor receptor Kit Proteins 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 102100030485 Platelet-derived growth factor receptor alpha Human genes 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 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
- 229910001431 copper ion Inorganic materials 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- YNPNDPSDUHYDEO-UHFFFAOYSA-N cyanamide(2-) Chemical compound [N-]=C=[N-] YNPNDPSDUHYDEO-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000035943 smell Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to pharmaceutical technology field, particularly to the synthesis technique of a kind of antitumor drug.It is an object of the invention to provide a kind of simple to operate, raw material is easy to get, reactions steps is short, yield is high and eco-friendly imatinib preparation method.In the imatinib preparation method of the present invention, the formation of pyrimidine ring has been abandoned the bigger cyanamide method of toxicity and has had the phosphorus oxychloride method of severe corrosive, by 2, Suzuki between 4 dichloro pyrimidines with 3 pyridine borate reacts, and one-step method quickly obtains key intermediate 2 chlorine 4 (3 pyridine radicals) pyrimidine；Make use of 2 on 2 chlorine 4 (3 pyridine radicals) pyrimidines easily by the feature of nucleopilic reagent attack, pass through nucleophilic substitution, prepare imatinib with higher conversion ratio, abandoned the metal catalysed processes etc. employed in many documents and be difficult to industrialized means.Raw material of the present invention is easy to get, reactions steps is short, yield is high and environmental friendliness.
Description
Technical field
The present invention relates to pharmaceutical technology field, particularly to the synthesis technique of a kind of antitumor drug.
Background technology
Imatinib mesylate (Fig. 1) is a kind of tyrosine kinase micromolecular inhibitor (small molecule TKI),
Can optionally be incorporated into corresponding tyrosine kinase receptor, including C-kit receptor, (the platelet-derived life of PDGFRA receptor
Growth factor receptor body), the ATP-binding site of Bcr-Abl and stem cell factor receptor SCFR etc., stop phosphate group from ATP to egg
White matter substrate shifts, be allowed to can not the phosphorylation of catalytic tyrosine residue and activate the signal transduction of downstream effect molecule, and then
Stop the continuous proliferation of cell, and recover the normal apoptotic program of cell.This medicine may be used for treating Philadelphia Chromosome Positive
Chronic myelocytic leukemia (PH+CML) chronic phase, accelerated period and acute transformation phase patient, Philadelphia Chromosome Positive can be treated
Acute lymphoblastic leukemia (Ph+ALL) patient, it is also possible to treatment can not excise or occur the malignant gastrointestinal interstitial of transfer to swell
The adult patient of tumor (GIST).
Report that the document of imatinib (Imatinib) synthetic route is a lot of at present, be reported in the Europe of 1993 the earliest specially
Profit (EP564409).Specifically route is as shown in Figure 2: 2-methyl-5-nitro aniline (1) and cyanamide (2) react generation guanidine
Compound (3)；Pyrimidine compound (4) is formed again with intermediate (6) cyclization；Palladium carbon hydro-reduction nitro obtains intermediate (7)；Finally exist
Pyridine is condensed into imatinib with acyl chlorides (8).This route is one of the most the more commonly used imatinib synthetic method, but
The shortcoming that it exists has: 1, employ severe toxicity raw material cyanamide；2, employing Pd/C costly is reducing catalyst so that
Cost increase；3, condensation reaction uses abnormal smells from the patient and the biggest pyridine of toxicity to be solvent, is unfavorable for that production is amplified in workshop.
Within 2008, pay vertical strong grade on " Chinese Journal of Pharmaceuticals ", to report final step cyclization formation pyrimidine ring and make
The method obtaining imatinib.Concrete route is as shown in Figure 3: 3-nitro-4-methyl-aniline (9) first with to chloromethyl benzoic acid chlorides
(10) reaction generates amide (11)；Generation key intermediate (13) is reacted again with N methyl piperazine (12)；Palladium carbon hydro-reduction nitre
Base obtains compound (14)；Guanidine compound (16) is prepared with cyanamide condensation；Finally prepare her horse with intermediate (17) cyclization to replace
Buddhist nun.The shortcoming of this route has: 1, employ expensive Pd/C and the bigger cyanamide of toxicity；2, pyrimidine ring-closure reaction
Yield is relatively low, and this step is placed on final step so that overall yield is substantially reduced.
Loiseleur et al. (WO20030066613) reports and avoids using cyanamide is that raw material cyclization obtains pyrimidine ring,
And use the method synthesis imatinib of metal catalytic C-N coupling.Concrete route is as shown in Figure 4: intermediate (21) is directly and guanidine
(22) reaction, cyclization prepares pyrimidines (23)；Again with intermediate (20) at organophosphor ligand rac-Binap and Pd2
(dba)3Effect under, occur C-N coupling reaction, prepare imatinib.This is a relatively new synthetic route, abandons
Use the cyanamide that toxicity is bigger, but there is also some problems: the Pd/C catalyst 1, used and phosphorus part price comparison
Costliness, for industrialized production, cost is greatly improved；2, the requirement of crude drug heavy metal content is higher, this route
Final step employs heavy metal palladium, purification proposes the highest requirement, is unfavorable for industrialized production.
Document (Bioorganic&Medicinal Chemistry Letters, 2009,6,140,619-623) reports
A kind of method similar with above-mentioned Article 1 route, concrete route is as it is shown in figure 5, difference is: 1, use stannum dichloride for also
Former dose of reduction nitro；2, after Imatinib amine (29) generates, first with chloromethyl benzoic acid chlorides (30) is occurred acylation reaction, the most again with
N methyl piperazine (32) reaction generates imatinib.This route is long, and the shortcoming that simultaneously there is also includes: 1, cyanamide and
SnCl2Toxicity is relatively big, and environmental conservation can be caused bigger pressure by the waste liquid produced after latter reaction is complete；2, final step intermediate
(31), when reacting with N methyl piperazine, using high boiling DMF is solvent, easily causes end product dissolvent residual defective.
Document (US20060149061) report is prepared organic zinc reagent (34) by 3-bromopyridine (33), then with 2,4-dichloro
There is Negishi coupling reaction in pyrimidine (35), generates key intermediate (36)；Or obtain centre from compound (37) through urea cyclization
Body (38), then obtain intermediate (36) through phosphorus oxychloride chloro；Intermediate (36) and compound (39) nucleo philic substitution reaction
Obtain intermediate (42)；Also there is document (Organic Process Research&Development, 2008,12,490 495)
Report from compound (40) and (41), reacted by Ullman and obtain key intermediate (42) smoothly, concrete route such as Fig. 6 institute
Show.The most a few class schemes all have certain creativeness, but they have certain limitation for industrialized production, than
As: 1, Negishi coupling reaction condition controls strict, and prepares organic zinc reagent and need to use n-BuLi, and industrialized production is pacified
Full hidden danger is big；2, substantial amounts of strongly acid wastewater can be produced with phosphorus oxychloride chloro, big for environment pollution；3, Ullman reaction condition
Acutely, and the waste liquid that reaction produces is containing a large amount of copper ions, equally can be to environment.
Summary of the invention
It is an object of the invention to overcome the deficiencies in the prior art, it is provided that one is simple to operate, raw material is easy to get, reactions steps
Short, yield is high and eco-friendly imatinib preparation method.
In order to achieve the above object, a kind of imatinib preparation method of the present invention, concrete reactions steps is as follows:
The first step: the synthesis chloro-4-of 2-(3-pyridine radicals) pyrimidine
By 2,4-dichloro pyrimidine is dissolved in the mixed solvent of Isosorbide-5-Nitrae-dioxane and water, add 3-pyridine borate, weak base and
Pd(dppf)Cl2, it is gradually heating to 70-130 DEG C after system being replaced with argon, reacts 2-6 hour；After reaction completely, system subtracts
Pressure concentrates and removes major part solvent, adds ethyl acetate and water, extracts separatory, and aqueous phase is extracted with ethyl acetate again, merges organic
Phase, then wash with water and saturated aqueous common salt, separatory, organic facies adds anhydrous sodium sulfate and is dried 3 hours, filtering and concentrating, obtain slightly
Product；Crude product adds petroleum ether and the mixed solvent of ethyl acetate, stirring to pulp 1 hour, filters, be vacuum dried to obtain product 2-
Chloro-4-(3-pyridine radicals) pyrimidine；
As preferably, in described mixed solvent, the volume ratio of Isosorbide-5-Nitrae-dioxane and water is (4-5): 1；
As preferably, described weak base is at least one in potassium carbonate, potassium acetate, cesium carbonate, sodium carbonate, triethylamine；
As preferably, described 2,4-dichloro pyrimidine, 3-pyridine borate, weak base and Pd (dppf) Cl2Mol ratio be 1:
(0.8-2.0): (1.5-3.5): (0.05-0.3)；
As further preferably, described 2,4-dichloro pyrimidine, 3-pyridine borate, weak base and Pd (dppf) Cl2Mol ratio
For 1:1.2:2:0.1；
As preferably, described argon is gradually heating to 90 DEG C after system being replaced, and reacts 4 hours；
As preferably, the volume ratio of described petroleum ether and ethyl acetate is 1:(0.1-0.5)
Second step: synthesis imatinib
N-(3-amino-4-aminomethyl phenyl)-4-(4-thyl-piperazin-1-methyl) benzamide is dissolved in organic solvent, then
It is separately added into the chloro-4-of 2-(3-pyridine radicals) pyrimidine and glacial acetic acid, is warming up to 100-120 DEG C, react 5-8 hour；After completion of the reaction
System concentrating under reduced pressure removes solvent, adds dichloromethane, respectively with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution
Washing, separatory, organic facies anhydrous sodium sulfate is dried, and filters, is concentrated to give imatinib.
N-(3-amino-4-aminomethyl phenyl)-4-(4-thyl-piperazin-1-methyl) benzamide is by patent of invention
Method in 201110055144 prepares.
As preferably, it is warming up to 110 DEG C, reacts 6 hours.
As preferably, described organic solvent be in Isosorbide-5-Nitrae-dioxane, isopropanol, n-butyl alcohol, the tert-butyl alcohol, ethylene glycol extremely
Few one.
As preferably, described N-(3-amino-4-aminomethyl phenyl)-4-(4-thyl-piperazin-1-methyl) benzamide, ice vinegar
The mol ratio of acid and the chloro-4-of 2-(3-pyridine radicals) pyrimidine is 1:(30-60): 1.
The present invention is according to 2, and the activity difference of two chlorine in 4-dichloro pyrimidine, the chlorine on 4-position is optionally phonetic with 3-boric acid
There is Suzuki reaction in pyridine, prepares the chloro-4-of 2-(3-pyridine radicals) pyrimidine；By using Pd (dppf) Cl2Catalyst and Isosorbide-5-Nitrae-two
The reaction system that oxygen six rings/water mixed solvent matches, improves reaction rate, and reaction condition gentleness is easy to control, and conversion ratio is high；
Purifying crude means are without column chromatography, but the method passed through extraction, wash and pull an oar, it is possible to obtain preferable purity, profit
In industrialized production.Under Isosorbide-5-Nitrae-dioxane solvent and acid system, intermediate is pulled out the amide generated after hydrogen
Occur nucleophilic substitution to prepare imatinib in the 2-position of the chloro-4-of 2-(3-pyridine radicals) pyrimidine；The present invention avoids using sodium hydrogen
Etc. hazardous agents, and glacial acetic acid is the relatively mild reagent that compares, the most dangerous reaction or risky operation, is in the reaction
Make solvent and make again catalyst, after reaction terminates, can concentration and recovery acetic acid, recycling.
Main advantages of the present invention are: 1, the formation of pyrimidine ring has been abandoned the bigger cyanamide method of toxicity and had strong
Corrosive phosphorus oxychloride method, by 2, the Suzuki between 4-dichloro pyrimidine with 3-pyridine borate reacts, and one-step method is quick to be obtained
To the chloro-4-of key intermediate 2-(3-pyridine radicals) pyrimidine；2, make use of the 2-position on the chloro-4-of 2-(3-pyridine radicals) pyrimidine the closeest
The feature of core reagent attack, by nucleophilic substitution, prepares imatinib with higher conversion ratio, has abandoned in many documents
The metal catalysed processes used etc. are difficult to industrialized means；3, raw material is easy to get, reactions steps is short, yield is high and environmental friendliness etc.
Feature.
Figure of description
Fig. 1 is the molecular structural formula of imatinib mesylate
Fig. 2 is imatinib synthetic route one
Fig. 3 is imatinib synthetic route two
Fig. 4 is imatinib synthetic route three
Fig. 5 is imatinib synthetic route four
Fig. 6 is imatinib synthetic route five
Fig. 7 is the synthetic route chart of the present invention
Detailed description of the invention
Embodiment 1
The first step: the synthesis chloro-4-of 2-(3-pyridine radicals) pyrimidine
In 250mL there-necked flask, 2,4-dichloro pyrimidines (5.0g, 33.56mmol) are dissolved in Isosorbide-5-Nitrae-dioxane and water
In mixed solvent (4:1,50mL), add 3-pyridine borate (4.95g, 40.27mmol), potassium carbonate (9.28g,
67.12mmol) with Pd (dppf) Cl2(2.45g,3.36mmol)；After system being replaced three times with argon, it is gradually heating to 90
DEG C, react 4 hours；System concentrating under reduced pressure removes major part solvent after completion of the reaction, adds ethyl acetate (150mL) and water
(100mL), extracting separatory, aqueous phase extracts by ethyl acetate (80mL) again, merges organic facies, then with water (80mL x 2) and saturated
Saline solution (80mL x 2) washs, separatory, adds anhydrous sodium sulfate and be dried 3 hours in organic facies, and filtering and concentrating obtains crude product；Slightly
Product add petroleum ether (32mL) and ethyl acetate (6mL) stirs 1 hour, filter, be vacuum dried to obtain product 2-chloro-4-(3-pyrrole
Piperidinyl) pyrimidine 4.8g, yield 74.6%, purity HPLC is more than 95%.
Second step: synthesis imatinib
In 100mL single port flask, N-(3-amino-4-aminomethyl phenyl)-4-(4-thyl-piperazin-1-methyl) benzamide
(3.0g, 8.86mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (30mL), then is separately added into the chloro-4-of 2-(3-pyridine radicals) pyrimidine
(1.70g, 8.86mmol) and glacial acetic acid (20mL), be warming up to 110 DEG C, reacts 6 hours；System concentrating under reduced pressure removes after completion of the reaction
Remove solvent, add dichloromethane (60mL), water-soluble with saturated sodium bicarbonate aqueous solution (40mL x 2) and saturated sodium-chloride respectively
Liquid (40mL x 2) washs, separatory, and organic facies anhydrous sodium sulfate is dried, and filters, is concentrated to give imatinib 3.7g, yield
84.5%, purity HPLC is more than 95%.
Embodiment 2
The first step: the synthesis chloro-4-of 2-(3-pyridine radicals) pyrimidine
In 250mL there-necked flask, 2,4-dichloro pyrimidines (5.0g, 33.56mmol) are dissolved in Isosorbide-5-Nitrae-dioxane and water
In mixed solvent (5:1,50mL), add 3-pyridine borate (4.95g, 40.27mmol), cesium carbonate (9.28g,
67.12mmol) with Pd (dppf) Cl2(2.45g,3.36mmol)；After system being replaced three times with argon, it is gradually heating to 70
DEG C, react 6 hours；System concentrating under reduced pressure removes major part solvent after completion of the reaction, adds ethyl acetate (150mL) and water
(100mL), extracting separatory, aqueous phase extracts by ethyl acetate (80mL) again, merges organic facies, then with water (80mL x 2) and saturated
Saline solution (80mL x 2) washs, separatory, adds anhydrous sodium sulfate and be dried 3 hours in organic facies, and filtering and concentrating obtains crude product；Slightly
Product add petroleum ether (30mL) and ethyl acetate (3mL) stirs 1 hour, filter, be vacuum dried to obtain product 2-chloro-4-(3-pyrrole
Piperidinyl) pyrimidine 4.7g, yield 73.1%, purity HPLC is more than 95%.
Second step: synthesis imatinib
In 100mL single port flask, N-(3-amino-4-aminomethyl phenyl)-4-(4-thyl-piperazin-1-methyl) benzamide
(3.0g, 8.86mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (30mL), then is separately added into the chloro-4-of 2-(3-pyridine radicals) pyrimidine
(1.70g, 8.86mmol) and glacial acetic acid (20mL), be warming up to 100 DEG C, reacts 8 hours；System concentrating under reduced pressure removes after completion of the reaction
Remove solvent, add dichloromethane (60mL), water-soluble with saturated sodium bicarbonate aqueous solution (40mL x 2) and saturated sodium-chloride respectively
Liquid (40mL x 2) washs, separatory, and organic facies anhydrous sodium sulfate is dried, and filters, is concentrated to give imatinib 3.68g, yield
84.0%, purity HPLC is more than 95%.
Embodiment 3
The first step: the synthesis chloro-4-of 2-(3-pyridine radicals) pyrimidine
In 250mL there-necked flask, 2,4-dichloro pyrimidines (5.0g, 33.56mmol) are dissolved in Isosorbide-5-Nitrae-dioxane and water
In mixed solvent (4.5:1,50mL), add 3-pyridine borate (4.95g, 40.27mmol), cesium carbonate (9.28g,
67.12mmol) with Pd (dppf) Cl2(2.45g,3.36mmol)；After system being replaced three times with argon, gradually heat up and be heated to
Backflow, reacts 2 hours；System concentrating under reduced pressure removes major part solvent after completion of the reaction, adds ethyl acetate (150mL) and water
(100mL), extracting separatory, aqueous phase extracts by ethyl acetate (80mL) again, merges organic facies, then with water (80mL x 2) and saturated
Saline solution (80mL x 2) washs, separatory, adds anhydrous sodium sulfate and be dried 3 hours in organic facies, and filtering and concentrating obtains crude product；Slightly
Product add petroleum ether (32mL) and ethyl acetate (6mL) stirs 1 hour, filter, be vacuum dried to obtain product 2-chloro-4-(3-pyrrole
Piperidinyl) pyrimidine 4.65g, yield 72.3%, purity HPLC is more than 95%.
Second step: synthesis imatinib
In 100mL single port flask, N-(3-amino-4-aminomethyl phenyl)-4-(4-thyl-piperazin-1-methyl) benzamide
(3.0g, 8.86mmol) is dissolved in ethylene glycol (30mL), then be separately added into the chloro-4-of 2-(3-pyridine radicals) pyrimidine (1.70g,
8.86mmol) with glacial acetic acid (20mL), it is warming up to 100 DEG C, reacts 5 hours；System concentrating under reduced pressure removes solvent after completion of the reaction,
Add dichloromethane (60mL), respectively with saturated sodium bicarbonate aqueous solution (40mL x 2) and saturated sodium-chloride water solution (40mL
X 2) washing, separatory, organic facies anhydrous sodium sulfate is dried, and filters, is concentrated to give imatinib 3.63g, yield 82.9%, purity
HPLC is more than 95%.
Claims (10)
1. an imatinib preparation method, it is characterised in that: comprise the steps:
The first step: the synthesis chloro-4-of 2-(3-pyridine radicals) pyrimidine
By 2,4-dichloro pyrimidine is dissolved in the mixed solvent of Isosorbide-5-Nitrae-dioxane and water, adds 3-pyridine borate, weak base and Pd
(dppf)Cl2, it is gradually heating to 70-130 DEG C after system being replaced with argon, reacts 2-6 hour；System decompression after reaction completely
Concentrating and remove major part solvent, add ethyl acetate and water, extract separatory, aqueous phase is extracted with ethyl acetate again, merges organic facies,
Again with water and saturated aqueous common salt washing, separatory, organic facies adds anhydrous sodium sulfate and is dried 3 hours, filtering and concentrating, obtain crude product；
Crude product adds petroleum ether and the mixed solvent of ethyl acetate, stirring to pulp 1 hour, filters, be vacuum dried to obtain the chloro-4-of product 2-
(3-pyridine radicals) pyrimidine；
Second step: synthesis imatinib
N-(3-amino-4-aminomethyl phenyl)-4-(4-thyl-piperazin-1-methyl) benzamide is dissolved in Isosorbide-5-Nitrae-dioxane, then
It is separately added into the chloro-4-of 2-(3-pyridine radicals) pyrimidine and glacial acetic acid, is warming up to 100-120 DEG C, react 5-8 hour；After completion of the reaction
System concentrating under reduced pressure removes solvent, adds dichloromethane, respectively with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution
Washing, separatory, organic facies anhydrous sodium sulfate is dried, and filters, is concentrated to give imatinib.
A kind of imatinib preparation method the most according to claim 1, it is characterised in that: in mixed solvent described in the first step
The volume ratio of 1,4-dioxane and water is (4-5): 1.
A kind of imatinib preparation method the most according to claim 1, it is characterised in that: weak base described in the first step is carbonic acid
At least one in potassium, potassium acetate, cesium carbonate, sodium carbonate, triethylamine.
A kind of imatinib preparation method the most according to claim 1, it is characterised in that: described in the first step 2,4-dichloro is phonetic
Pyridine, 3-pyridine borate, weak base and Pd (dppf) Cl2Mol ratio be 1:(0.8-2.0): (1.5-3.5): (0.05-0.3).
A kind of imatinib preparation method the most according to claim 4, it is characterised in that: described in the first step 2,4-dichloro is phonetic
Pyridine, 3-pyridine borate, weak base and Pd (dppf) Cl2Mol ratio be 1:1.2:2:0.1.
A kind of imatinib preparation method the most according to claim 1, it is characterised in that: system is put by first step argon
It is gradually heating to 90 DEG C after changing, reacts 4 hours.
A kind of imatinib preparation method the most according to claim 1, it is characterised in that: petroleum ether described in the first step and second
The volume ratio of acetoacetic ester is 1:(0.1-0.5).
A kind of imatinib preparation method the most according to claim 1, it is characterised in that: second step is warming up to 110 DEG C, instead
Answer 6 hours.
A kind of imatinib preparation method the most according to claim 1, it is characterised in that: organic solvent described in second step is
At least one in 1,4-dioxane, isopropanol, n-butyl alcohol, the tert-butyl alcohol, ethylene glycol.
A kind of imatinib preparation method the most according to claim 1, it is characterised in that: (the 3-ammonia of N-described in second step
Base-4-aminomethyl phenyl)-4-(4-thyl-piperazin-1-methyl) benzamide, the rubbing of glacial acetic acid and the chloro-4-of 2-(3-pyridine radicals) pyrimidine
That ratio is 1:(30-60): 1.
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| CN102548987A (en) * | 2009-07-14 | 2012-07-04 | 江苏迈度药物研发有限公司 | Fluoro-substituted compounds as kinase inhibitors and methods of use thereof |
| WO2013066839A2 (en) * | 2011-10-31 | 2013-05-10 | Glaxosmithkline Llc | Compounds and methods |
| CN104230885A (en) * | 2013-06-09 | 2014-12-24 | 北大方正集团有限公司 | A preparing method of imatinib |
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| CN102548987A (en) * | 2009-07-14 | 2012-07-04 | 江苏迈度药物研发有限公司 | Fluoro-substituted compounds as kinase inhibitors and methods of use thereof |
| WO2013066839A2 (en) * | 2011-10-31 | 2013-05-10 | Glaxosmithkline Llc | Compounds and methods |
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