CN104447713B - The preparation method of afatinib compound - Google Patents
The preparation method of afatinib compound Download PDFInfo
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- CN104447713B CN104447713B CN201410658194.4A CN201410658194A CN104447713B CN 104447713 B CN104447713 B CN 104447713B CN 201410658194 A CN201410658194 A CN 201410658194A CN 104447713 B CN104447713 B CN 104447713B
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- 229960001686 afatinib Drugs 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- -1 afatinib compound Chemical class 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 29
- 239000000126 substance Substances 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 86
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- 238000006243 chemical reaction Methods 0.000 claims description 49
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 31
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 25
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 24
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 24
- 239000011976 maleic acid Substances 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 2
- 229940113088 dimethylacetamide Drugs 0.000 claims description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000007774 longterm Effects 0.000 abstract description 2
- 238000003860 storage Methods 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 54
- 239000012074 organic phase Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000012544 monitoring process Methods 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 239000000843 powder Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 230000014759 maintenance of location Effects 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000004519 grease Substances 0.000 description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- GJOGRUGECVQJBK-UHFFFAOYSA-N 2-diphenylphosphanylacetic acid Chemical compound C=1C=CC=CC=1P(CC(=O)O)C1=CC=CC=C1 GJOGRUGECVQJBK-UHFFFAOYSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- GOLSFPMYASLXJC-UHFFFAOYSA-N 2-(dimethylamino)ethyl acetate Chemical compound CN(C)CCOC(C)=O GOLSFPMYASLXJC-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 125000003963 dichloro group Chemical group Cl* 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229960002668 sodium chloride Drugs 0.000 description 2
- KFUSEUYYWQURPO-UHFFFAOYSA-N 1,2-dichloroethene Chemical compound ClC=CCl KFUSEUYYWQURPO-UHFFFAOYSA-N 0.000 description 1
- GRWPTSXPZYCYOM-UHFFFAOYSA-N 2-(dimethylamino)acetaldehyde Chemical compound CN(C)CC=O GRWPTSXPZYCYOM-UHFFFAOYSA-N 0.000 description 1
- LYIIBVSRGJSHAV-UHFFFAOYSA-N 2-aminoacetaldehyde Chemical compound NCC=O LYIIBVSRGJSHAV-UHFFFAOYSA-N 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- ULXXDDBFHOBEHA-ONEGZZNKSA-N Afatinib Chemical compound N1=CN=C2C=C(OC3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-ONEGZZNKSA-N 0.000 description 1
- NMXSXMYQFIWFBG-UHFFFAOYSA-N C(C)CC(CC(=O)O)=O.C(C)PCC Chemical compound C(C)CC(CC(=O)O)=O.C(C)PCC NMXSXMYQFIWFBG-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229960002736 afatinib dimaleate Drugs 0.000 description 1
- USNRYVNRPYXCSP-JUGPPOIOSA-N afatinib dimaleate Chemical compound OC(=O)\C=C/C(O)=O.OC(=O)\C=C/C(O)=O.N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 USNRYVNRPYXCSP-JUGPPOIOSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 229940087158 gilotrif Drugs 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920001084 poly(chloroprene) Polymers 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- RNWDENXDCQXZLH-UHFFFAOYSA-N quinazoline-4,6-diamine Chemical class N1=CN=C(N)C2=CC(N)=CC=C21 RNWDENXDCQXZLH-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of new method of preparation afatinib compound, the raw material used and reagent have the advantages of at low cost, chemical property is stable, convenient for long-term storage；And impurity cis-isomer content is extremely low in the afatinib compound prepared.
Description
Technical field
The present invention is field of medicinal chemistry, more particularly to afatinib compound and one kind of maleic acid Afatinib
New preparation process.
Background technique
Maleic acid Afatinib (Afatinib dimaleate) is a kind of tyrosine kinase inhibitor.In July, 2013 by
U.S. FDA approval listing, trade name GILOTRIF, as first-line treatment drug for treating EGF-R ELISA
(EGFR) Metastatic Nsclc (NSCLC) patient of the missing of exons 19 or exon 21 (L858R) substitution mutation.
Afatinib compound (1 compound of embodiment (10)) is disclosed in CN1481370A.
A kind of method preparing maleic acid Afatinib is disclosed in CN1867564A, by N4(the chloro- 4- fluoro-phenyl of 3-) -7-
The aryl amide that ((S)-tetrahydrofuran -3- base oxygen) quinazoline -4,6- diamines is obtained with the reaction of diethyl phosphine ethyl acetoacetic acid, then same 2-
Aminoacetaldehyde (or its acetal) occur Wittig-Horner-Emmons reaction generate Afatinib, then again with maleic acid at
Salt.The raw materials used dimethylamino acetaldehyde of the technique, dimethylamino acetal higher cost and it is easy to oxidative degradation, it is difficult to
It stores for a long time, is unfavorable for industrialized production, and the technique also needs to provide ar gas environment in process of production.The technique simultaneously
Trans double bond is constructed by Wittig-Horner-Emmons reaction, due to stereoselective difference, there are still a small amount of in product
Cis-isomer impurity.
Summary of the invention
The present invention provides a kind of new methods of preparation afatinib compound, and the Afatinib obtained by this method
Further maleic acid Afatinib obtained, the pharmaceutical composition containing the maleic acid Afatinib.Additionally provide the system
New intermediate compound used in standby maleic acid afatinib compound new method.
The new method of preparation afatinib compound provided by the invention, can be realized by following scheme:
(1) Formula IV compound reacts to obtain V compound with Formula VII compound,
(2) Formula V compound reacts in the presence of n-BuLi with formula IV compound obtains formula III compound,
(3) formula III compound passes through NaBH4Reduction obtains Formula II compound,
(4) Formula II compound is restored by NaH and obtains compound of formula I,
Reaction condition is one or more in following conditions in step (1) of the present invention: Formula IV compound and Formula VII chemical combination
The reaction dissolvent of object synthesis Formula V compound is preferably chosen from methylene chloride, 1,2- dichloroethanes, chloroform, bis- neoprene of 1,2-
One of alkane is a variety of；More preferably methylene chloride.Reaction temperature is preferably room temperature.Reaction time is preferably 1~
20 hours.The molar ratio of Formula IV compound and Formula VII compound is preferably 1:(0.85~1.15).Room temperature is 10 in the present invention
~30 DEG C, more preferably 15~25 DEG C.
Reaction condition is one or more in following conditions in step (2) of the present invention: Formula V compound and formula IV compound
The reaction dissolvent for closing compound of Formula III is preferably chosen from tetrahydrofuran and/or 2- methyltetrahydrofuran；More preferably tetrahydro
Furans.Reaction temperature is preferably room temperature.Reaction time is preferably 0.5~4 hour.Formula V compound and formula IV compound
Molar ratio is preferably 1:(0.85~1.15).The molar ratio of Formula V compound and n-BuLi is preferably 1:(0.8~1.2).
Reaction condition is one or more in following conditions in step (3) of the present invention: formula III compound is reduced to Formula II
The reaction dissolvent of compound is preferably chosen from one of methanol, ethyl alcohol, normal propyl alcohol, isopropanol or a variety of；More preferably first
Alcohol and/or ethyl alcohol.Reaction temperature is preferably 55~75 DEG C.Reaction time is preferably 0.5~6 hour.Formula III compound with
NaBH4Molar ratio be preferably 1:(1.5~0.5).
Reaction condition is one or more in following conditions in step (4) of the present invention: Formula II compound is reduced to Formulas I
Close object reaction dissolvent be preferably chosen from one of N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide or
It is a variety of；More preferably N,N-dimethylformamide.Reaction temperature is preferably 10~30 DEG C.Reaction time is preferably 0.5
~6 hours, more preferably 1~6 hour.The molar ratio of Formula II compound and NaH are preferably 1:(1.5~4), more preferably
For 1:(2~3).
The present invention also provides obtaining new intermediate compound in the preparation Afatinib new method, Formula II compound or
Its salt,
The present invention also provides obtain new intermediate compound, formula III compound in the preparation Afatinib new method
Or its salt,
The present invention also provides obtaining new intermediate compound in the preparation Afatinib new method, Formula V compound or
Its salt,
The Afatinib prepared by the method for the invention can also further be prepared into pharmaceutically acceptable salt, preferably
2-maleate is made in ground, can be realized by the technical solution recorded in prior art CN1867564A.It is heretofore described
Maleic acid Afatinib refer to the 2-maleate of Afatinib.
Pharmaceutical composition can also be further made in maleic acid Afatinib provided by the invention；The system of the composition
Dosage form formula can be oral solid formulation or parenteral formulations agent.In the present invention, the composition further includes pharmaceutically
Acceptable carrier；Pharmaceutically acceptable carrier be usually those of ordinary skill in the art can according to specific form of medication and
Specific choice.It can be with it is well known that technology such as routine granulation, mixing, dissolution, formation capsule, freeze-drying technique manufacture this hair
Bright pharmaceutical composition.The present composition can be made to the form for being used for various administration routes, for example, oral administration, vein
It is interior etc..Preferably, maleic acid Afatinib provided by the invention can be according to technical solution in prior art CN102056589A
The pharmaceutical composition of solid dosage form is made.
(diphenylphosphino)acetic acid and N used in preparation Afatinib new method provided by the invention, N- dimethylamino acetic acid
Ethyl ester is to be commercialized obtainable chemicals raw material, and at low cost, chemical property is stablized, convenient for long-term storage.
Present invention process respectively walk it is easy to operate, without the special gas preservation condition such as argon gas, and reaction time mild condition,
Technique is smooth, is suitble to industry amplification.
Method provided by the invention prepares the total recovery of maleic acid Afatinib up to 60% or more, has industrialized production
Value.
The salt of Afatinib or Afatinib that preparation Afatinib new method provided by the invention obtains is (including but unlimited
In maleate) in cis-isomer content it is lower, using routine HPLC methods detect result be not detected.
Detailed description of the invention
The MS map for the Afatinib that Fig. 1 embodiment 5 obtains
The HPLC map for the maleic acid Afatinib that Fig. 2 embodiment 5 obtains
The HPLC map for the maleic acid Afatinib that Fig. 3 is obtained according to the Examples 1 to 3 of CN1867564A
The LC-MS map for the maleic acid Afatinib that Fig. 4 is obtained according to the Examples 1 to 3 of CN1867564A
Specific embodiment
It is further illustrated below by the mode of embodiment, but skilled in the art realises that, following embodiments are not pair
The limitation of the scope of the present invention.
The preparation of 1 Formula V compound of embodiment
Phosphorus trichloride (0.5g) is slowly instilled to (diphenylphosphino)acetic acid (2.37g) to be dissolved in 25mL dichloromethane solution, is controlled
0 DEG C of reaction temperature processed.Drop finish 15 DEG C be stirred to react 2 hours after be cooled to 0 DEG C.By triethylamine (1.02g) and 4- [(the chloro- 4- fluorine of 3-
Phenyl)-amino] -6- amino -7- ((S)-tetrahydrofuran -3- base oxygroup)-quinazoline (3.41g) is dissolved in bis- chloroethene of 25mL1,2-
Above-mentioned solution is slowly instilled in alkane solution, drop finishes, and 25 DEG C are reacted 2 hours.20mL purified water is added after completion of the reaction for TLC monitoring
Extracting and demixing, organic phase continue to purify water washing, anhydrous sodium sulfate dry, filtering, filtrate decompression with 20mL to be concentrated into grease,
Tetrahydrofuran/isopropyl ether (1:1) 40mL is added and recrystallizes to obtain off-white powder (Formula V compound).
Phosphorus trichloride (0.5g) is slowly instilled to (diphenylphosphino)acetic acid (2.37g) to be dissolved in 25mL chloroform soln, is controlled
0 DEG C of reaction temperature processed.Drop finish 25 DEG C be stirred to react 1.5 hours after be cooled to 0 DEG C.By triethylamine (1.02g) and 4- [(the chloro- 4- of 3-
Fluorophenyl)-amino] -6- amino -7- ((S)-tetrahydrofuran -3- base oxygroup)-quinazoline (3.41g) is dissolved in 25mL1,2- dichloro
Above-mentioned solution is slowly instilled in butane solution, drop finishes, and 15 DEG C are reacted 8 hours.TLC monitoring after completion of the reaction adds 20mL purified water
Enter extracting and demixing, organic phase continues to purify dry water washing, anhydrous sodium sulfate, filtering, filtrate decompression with 20mL to be concentrated into oily
Object is added tetrahydrofuran/isopropyl ether (1:1) 40mL and recrystallizes to obtain off-white powder (Formula V compound).
Phosphorus trichloride (0.5g) is slowly instilled to (diphenylphosphino)acetic acid (2.37g) to be dissolved in 25mL dichloromethane solution, is controlled
0 DEG C of reaction temperature processed.Drop finish 20 DEG C be stirred to react 2 hours after be cooled to 0 DEG C.By triethylamine (1.02g) and 4- [(the chloro- 4- fluorine of 3-
Phenyl)-amino] to be dissolved in 25mL chloroform molten for -6- amino -7- ((S)-tetrahydrofuran -3- base oxygroup)-quinazoline (3.41g)
Above-mentioned solution is slowly instilled in liquid, drop finishes, and 10 DEG C are reacted 16 hours.20mL purified water, which is added, after completion of the reaction for TLC monitoring extracts
Take layering, organic phase continues to purify dry water washing, anhydrous sodium sulfate, filtering, filtrate decompression with 20mL to be concentrated into grease, adds
Enter tetrahydrofuran/isopropyl ether (1:1) 40mL and recrystallizes to obtain off-white powder (Formula V compound).
The preparation of 2 formula III compound of embodiment
By slowly dropping type V compound (5g) is dissolved in 28mL dry four at 0 DEG C of temperature in n-BuLi (1.5M, 6ml) control
In hydrogen tetrahydrofuran solution.Drop finishes, and is cooled to -10 DEG C；Dimethylamino ethyl acetate (1.05g) is instilled in above-mentioned solution, drop finishes, and rises
To being stirred at room temperature 0.5 hour, saturated ammonium chloride solution 12mL is added into reaction solution after monitoring end of reaction by TLC, is saturated chlorination
Sodium solution 8mL, methylene chloride 12mL extracting and demixing, organic phase anhydrous magnesium sulfate is dry, filters, grease is concentrated under reduced pressure to obtain, and adds
Enter tetrahydrofuran/isopropyl ether (1:2) 40mL and recrystallizes to obtain off-white powder (formula III compound).
By slowly dropping type V compound (5g) is dissolved in the dry 2- of 28mL at 0 DEG C of temperature in n-BuLi (1.5M, 6ml) control
In methyltetrahydrofuran solution.Drop finishes, and is cooled to -10 DEG C；Dimethylamino ethyl acetate (1.05g) is instilled in above-mentioned solution,
Drop finishes, and is warmed to room temperature stirring 4 hours, and saturated ammonium chloride solution 12mL, saturation are added into reaction solution after monitoring end of reaction by TLC
Sodium chloride solution 8mL, methylene chloride 12mL extracting and demixing, organic phase anhydrous magnesium sulfate is dry, filters, oily is concentrated under reduced pressure to obtain
Object is added tetrahydrofuran/isopropyl ether (1:2) 40mL and recrystallizes to obtain off-white powder (formula III compound).
By slowly dropping type V compound (5g) is dissolved in 28mL dry four at 0 DEG C of temperature in n-BuLi (1.5M, 6ml) control
In hydrogen tetrahydrofuran solution.Drop finishes, and is cooled to -10 DEG C；Dimethylamino ethyl acetate (1.05g) is instilled in above-mentioned solution, drop finishes, and rises
To being stirred at room temperature 2 hours, saturated ammonium chloride solution 12mL, saturated sodium-chloride are added into reaction solution after monitoring end of reaction by TLC
Solution 8mL, methylene chloride 12mL extracting and demixing, organic phase anhydrous magnesium sulfate is dry, filters, grease is concentrated under reduced pressure to obtain, and is added
Tetrahydrofuran/isopropyl ether (1:2) 40mL recrystallizes to obtain off-white powder (formula III compound).
The preparation of 3 Formula II compound of embodiment
Sodium borohydride (0.15g) addition formula III compound (5g) is dissolved in the solution of 50mL methanol, 75 DEG C of heating 0.5
It is cooled to room temperature after hour, 50mL saturated ammonium chloride solution is added, vacuum distillation removes partial solvent, and 50mL is added and is saturated chlorination
Sodium solution, 80mL methylene chloride extracting and demixing, organic phase anhydrous magnesium sulfate is dry, filtering, is concentrated under reduced pressure, and dichloro is added in residue
Methane/normal heptane (1:3) 50mL stirring and crystallizing obtains faint yellow solid (Formula II compound).
Sodium borohydride (0.27g) addition formula III compound (5g) is dissolved in the solution of 50mL isopropanol, 65 DEG C are heated back
Stream is cooled to room temperature after 4 hours, and 50mL saturated ammonium chloride solution is added, and vacuum distillation removes partial solvent, and 50mL saturation is added
Sodium chloride solution, 80mL methylene chloride extracting and demixing, organic phase anhydrous magnesium sulfate is dry, filtering, is concentrated under reduced pressure, and residue is added
Methylene chloride/normal heptane (1:3) 50mL stirring and crystallizing obtains faint yellow solid (Formula II compound).
Sodium borohydride (0.38g) addition formula III compound (5g) is dissolved in the solution of 50mL normal propyl alcohol, 55 DEG C of heating 6
It is cooled to room temperature after hour, 50mL saturated ammonium chloride solution is added, vacuum distillation removes partial solvent, and 50mL is added and is saturated chlorination
Sodium solution, 80mL methylene chloride extracting and demixing, organic phase anhydrous magnesium sulfate is dry, filtering, is concentrated under reduced pressure, and dichloro is added in residue
Methane/normal heptane (1:3) 50mL stirring and crystallizing obtains faint yellow solid (Formula II compound).
4 compound of formula I of embodiment (Afatinib) preparation
The n,N-Dimethylformamide 30mL that the drying of Formula II compound (5g) is added in sodium hydride (80%, 0.42g) is molten
In liquid, 10 DEG C of reaction solution are stirred to react 6 hours, purified water 85mL, saturated sodium chloride solution is added in TLC monitoring after completion of the reaction
20mL, methylene chloride 50mL extract liquid separation, and gained organic phase is dry with anhydrous magnesium sulfate, are concentrated under reduced pressure, and acetic acid is added in residue
Ethyl ester/hexahydrotoluene (1:2) 60mL stirring and crystallizing obtains white powdery solids (compound of formula I).
The n,N-dimethylacetamide 30mL that the drying of Formula II compound (5g) is added in sodium hydride (80%, 0.42g) is molten
In liquid, 30 DEG C of reaction solution are stirred to react 2 hours, purified water 85mL, saturated sodium chloride solution is added in TLC monitoring after completion of the reaction
20mL, methylene chloride 50mL extract liquid separation, and gained organic phase is dry with anhydrous magnesium sulfate, are concentrated under reduced pressure, and acetic acid is added in residue
Ethyl ester/hexahydrotoluene (1:2) 60mL stirring and crystallizing obtains white powdery solids (compound of formula I).
Sodium hydride (80%, 0.42g) is added in the dimethyl sulfoxide 30mL solution of the drying of Formula II compound (5g), it will be anti-
20 DEG C of liquid are answered to be stirred to react 4 hours, purified water 85mL, saturated sodium chloride solution 20mL, dichloro is added in TLC monitoring after completion of the reaction
Methane 50mL extracts liquid separation, and gained organic phase is dry with anhydrous magnesium sulfate, is concentrated under reduced pressure, and ethyl acetate/methyl is added in residue
Hexamethylene (1:2) 60mL stirring and crystallizing obtains white powdery solids (compound of formula I).
The preparation of 5 maleic acid Afatinib of embodiment
Phosphorus trichloride (4.94g, 0.036mol) is slowly instilled to (diphenylphosphino)acetic acid (23.42g, 0.09mol) to be dissolved in
In 250mL anhydrous methylene chloride solution, 0 DEG C of reaction temperature is controlled.Drop finish 20 DEG C be stirred to react 1.5 hours after be cooled to 0 DEG C.It will
Triethylamine (10.12g, 0.1mol) and 4- [(the chloro- 4- fluorophenyl of 3-)-amino] -6- amino -7- ((S)-tetrahydrofuran -3- base oxygen
Base)-quinazoline (33.73g, 0.09mol) is dissolved in 250mL anhydrous methylene chloride solution and slowly instills above-mentioned solution, and drop finishes, and 20
DEG C reaction 1.5 hours.After completion of the reaction extracting and demixing is added in 200mL purified water by TLC monitoring, and organic phase continues pure with 200mL
Change water washing, anhydrous sodium sulfate are dry, filter, filtrate decompression is concentrated into grease, are added tetrahydrofuran/isopropyl ether (1:1)
400mL recrystallizes to obtain off-white powder 52.75g, yield: 94.9%.
N-BuLi (1.5M, 62.5ml) is controlled slowly to instill at interior 0 DEG C of temperature and walks product (52.75g, 0.085mol)
It is dissolved in 280mL dry tetrahydrofuran solution.Drop finishes, and is cooled to -10 DEG C；By dimethylamino ethyl acetate (11.15g,
0.085mol) in the above-mentioned solution of instillation, drop finishes, and is warmed to room temperature stirring 1 hour, and TLC adds after monitoring end of reaction into reaction solution
Enter saturated ammonium chloride solution 120mL, saturated sodium chloride solution 80mL, methylene chloride 120mL extracting and demixing, organic phase anhydrous slufuric acid
Magnesium is dry, filter, grease is concentrated under reduced pressure to obtain, and tetrahydrofuran/isopropyl ether (1:2) 420mL is added and recrystallizes to obtain off-white powder
50.13g, yield: 83.4%.
Intermediate (50.13g, 0.071mol) being walked in sodium borohydride (1.52g, 0.04mol) addition, to be dissolved in 500mL anhydrous
It in the solution of ethyl alcohol, is cooled to room temperature after being heated to reflux 1 hour, 500mL saturated ammonium chloride solution is added, be evaporated under reduced pressure removing unit
Divide solvent, 500mL saturated sodium chloride solution, 800mL methylene chloride extracting and demixing, the drying of organic phase anhydrous magnesium sulfate, mistake is added
Filter is concentrated under reduced pressure, and residue is added methylene chloride/normal heptane (1:3) 500mL stirring and crystallizing and obtains faint yellow solid 46.05g, receives
Rate: 92.1%.
The N, N- of the drying of product (46.05g, 0.065mol) will be walked in sodium hydride (80%, 3.9g, 0.13mol) addition
In dimethylformamide 300mL solution, reaction 1 hour is stirred at room temperature in reaction solution, purified water is added in TLC monitoring after completion of the reaction
800mL, saturated sodium chloride solution 200mL, methylene chloride 500mL extract liquid separation, and gained organic phase is dry with anhydrous magnesium sulfate, subtracts
Pressure concentration, residue are added ethyl acetate/hexahydrotoluene (1:2) 570mL stirring and crystallizing and obtain white powder Afatinib
27.58g, yield: 87.3%.The MS testing result of white powder solid is [M+H]+=486.2 (map is shown in Fig. 1), moisture contains
Amount measurement result is 0.8% (Karl_Fischer method, instrument KF870).
Afatinib (20g, 0.041mol) that upper step is obtained, ethyl alcohol 280mL are added in reaction flask, are warming up to 70 DEG C,
Maleic acid (9.7g, the 0.084mol) solution & stir for being dissolved in 120mL ethyl alcohol is added.Mixture is cooled to 20 after precipitating crystal
DEG C stirring 2 hours, then 0 DEG C stir 3 hours filter.Filter cake is rinsed with ethyl alcohol and is dried under reduced pressure to obtain 27.7g horse at 40 DEG C
Come sour Afatinib, yield 94.1%.
Embodiment 6
HPLC detection is carried out to the maleic acid Afatinib that embodiment 5 obtains；HPLC map is shown in Fig. 2.Foundation
Examples 1 to 3 carries out reference examples experiment in CN1867564A, carries out HPLC detection to the maleic acid Afatinib of acquisition；HPLC
Map is shown in Fig. 3.
HPLC condition are as follows:
Chromatographic column: octadecylsilane chemically bonded silica (Inertsil ODS-SP, 150mm × 4.6mm, 5 μm)
Mobile phase: ammonium acetate buffer (take ammonium acetate 7.7g, water 1000ml is added to make to dissolve, shake up to get): acetonitrile (60:
40)
Flow velocity: 1.0mL/min
Detection wavelength: 252nm
Column temperature: 30 DEG C
Sample volume: 5 μ L
As the result is shown: the chromatographic peak retention time of Afatinib is 10.663 minutes in Fig. 3, and peak area percent is
99.496%；Retention time is that 9.467 minutes chromatographic peaks represent cis-isomer impurity, peak area percent 0.318%；
The chromatographic peak that retention time is 1~2 minute is the chromatographic peak of maleic acid.The chromatographic peak retention time of Afatinib is in Fig. 2
10.679 minutes, peak area percent 99.879%；Cis-isomer impurity is not detected；The color that retention time is 1~2 minute
Spectral peak is the chromatographic peak of maleic acid.
Carry out reference examples experiment according to Examples 1 to 3 in CN1867564A, the maleic acid Afatinib of acquisition is carried out
LC-MS detection；Map is shown in Fig. 4.Abscissa is retention time (min) in Fig. 4；The peak that retention time is 7.060min is cis- different
Structure body impurity, the peak that retention time is 8.620min are Afatinib.The MS figure of substance at 7.301min is also shown in Fig. 4
Spectrum is cis-isomer impurity；It shows the MS map of substance at 9.312min, is Afatinib.
Claims (8)
1. a kind of method of afatinib compound shown in preparation formula I, the steps include:
(1) Formula IV compound reacts to obtain V compound with Formula VII compound,
(2) Formula V compound reacts in the presence of n-BuLi with formula IV compound obtains formula III compound,
(3) formula III compound passes through NaBH4Reduction obtains Formula II compound,
(4) Formula II compound is restored by NaH and obtains compound of formula I,
2. according to the method described in claim 1, it is characterized in that Formula IV compound and Formula VII compound synthesis Formula V compound
Reaction condition it is one or more in following conditions: reaction dissolvent be selected from methylene chloride, 1,2- dichloroethanes, three chloromethanes
One of alkane, 1,2- dichloroetane are a variety of；The molar ratio of Formula IV compound and Formula VII compound be 1:(0.85~
1.15)；Reaction time is 1~20 hour.
3. according to the method described in claim 1, it is characterized in that by Formula V compound and formula IV compound synthesis formula III chemical combination
The reaction condition of object is one or more in following conditions: reaction dissolvent is tetrahydrofuran and/or 2- methyltetrahydrofuran；Formula
The molar ratio of V compound and formula IV compound is 1:(0.85~1.15)；The molar ratio of Formula V compound and n-BuLi is 1:
(0.8~1.2)；Reaction time is 0.5~4 hour.
4. according to the method described in claim 1, it is characterized in that formula III compound is reduced to the reaction condition of Formula II compound
One or more in following conditions: reaction dissolvent is selected from one of methanol, ethyl alcohol, normal propyl alcohol, isopropanol or a variety of；Instead
Answering temperature is 55~75 DEG C；Formula III compound and NaBH4Molar ratio be 1:(1.5~0.5)；Reaction time is 0.5~6 small
When.
5. according to the method described in claim 1, it is characterized in that Formula II compound is reduced to the reaction condition choosing of compound of formula I
One or more from following conditions: reaction dissolvent is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide
One of or it is a variety of；Reaction temperature is 10~30 DEG C；The molar ratio of Formula II compound and NaH are 1:(1.5~4)；When reaction
Between be 0.5~6 hour.
6. a kind of method for preparing maleic acid Afatinib, it is characterised in that by method according to any one of claims 1 to 5
Afatinib is prepared, obtains maleic acid Afatinib at salt with maleic acid.
7. Formula II compound or its salt,
8. formula III compound or its salt,
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| WO2016185485A2 (en) * | 2015-05-18 | 2016-11-24 | Msn Laboratories Private Limited | Process for the preparation of n-[4-[(3-chloro-4-fluoro phenyl) amino]-7-[[(3s)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4- (dimethyl amino)-(2e)-2-butenamide (2z)-2-butenedioate (1 :2) and its polymorphs thereof |
| CN104892584B (en) * | 2015-05-27 | 2018-03-23 | 重庆泰濠制药有限公司 | Double maleate unformed shapes of a kind of Afatinib and preparation method thereof, preparation |
| CN104926800A (en) * | 2015-06-26 | 2015-09-23 | 河北神威药业有限公司 | Crystal form of afatinib di-meleate and method for preparing crystal form |
| CN105717226B (en) * | 2016-02-02 | 2018-03-23 | 北京科莱博医药开发有限责任公司 | A kind of method with high performance liquid chromatography detection maleic acid Afatinib isomers and principal degradation impurity |
| CN107490646A (en) * | 2016-06-10 | 2017-12-19 | 山东新时代药业有限公司 | A kind of method with high effective liquid chromatography for measuring afatinib intermediate content |
| CN107490629A (en) * | 2016-06-10 | 2017-12-19 | 山东新时代药业有限公司 | A kind of HPLC analytical method of afatinib intermediate |
| CN106243092B (en) * | 2016-07-28 | 2019-02-15 | 南京臣功制药股份有限公司 | A kind of highly selective method for preparing maleic acid Afatinib |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1867564A (en) * | 2003-10-17 | 2006-11-22 | 贝林格尔·英格海姆国际有限公司 | Process for preparing amino crotonyl compounds |
| WO2007085638A1 (en) * | 2006-01-26 | 2007-08-02 | Boehringer Ingelheim International Gmbh | Process for preparing aminocrotonylamino-substituted quinazoline derivatives |
| CN103755688A (en) * | 2013-12-24 | 2014-04-30 | 江苏奥赛康药业股份有限公司 | Preparation method for afatinib compound |
-
2014
- 2014-11-18 CN CN201410658194.4A patent/CN104447713B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1867564A (en) * | 2003-10-17 | 2006-11-22 | 贝林格尔·英格海姆国际有限公司 | Process for preparing amino crotonyl compounds |
| WO2007085638A1 (en) * | 2006-01-26 | 2007-08-02 | Boehringer Ingelheim International Gmbh | Process for preparing aminocrotonylamino-substituted quinazoline derivatives |
| CN103755688A (en) * | 2013-12-24 | 2014-04-30 | 江苏奥赛康药业股份有限公司 | Preparation method for afatinib compound |
Non-Patent Citations (2)
| Title |
|---|
| A facile synthesis of 5,6-dihydro-5-hydroxy-2(1H)-pyridone;Puspesh K. Upadhyay,等;《Tetrahedron Letters》;20090311;第50卷;第2440-2442页 |
| A novel facile synthesis of carbamoylmethylphosphine oxides in ionic liquids;Sharova, Elena V.，等;《Tetrahedron Letters》;20080108;第49卷(第10期);第1641-1644页 |
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