CN105085496A - Method for preparing Lapatinib and intermediate - Google Patents
Method for preparing Lapatinib and intermediate Download PDFInfo
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- CN105085496A CN105085496A CN201510593037.4A CN201510593037A CN105085496A CN 105085496 A CN105085496 A CN 105085496A CN 201510593037 A CN201510593037 A CN 201510593037A CN 105085496 A CN105085496 A CN 105085496A
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- compound
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- salt
- lapatinibditosylate
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- 238000000034 method Methods 0.000 title claims abstract description 30
- 239000002136 L01XE07 - Lapatinib Substances 0.000 title abstract description 5
- 229960004891 lapatinib Drugs 0.000 title abstract description 5
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 title abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 229960001320 lapatinib ditosylate Drugs 0.000 claims description 20
- AZBFJBJXUQUQLF-UHFFFAOYSA-N n-(1,5-dimethylpyrrolidin-3-yl)pyrrolidine-1-carboxamide Chemical compound C1N(C)C(C)CC1NC(=O)N1CCCC1 AZBFJBJXUQUQLF-UHFFFAOYSA-N 0.000 claims description 20
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 10
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical group [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 239000011630 iodine Substances 0.000 claims description 7
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical group [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 235000015320 potassium carbonate Nutrition 0.000 claims description 5
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 claims description 5
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 3
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000011084 recovery Methods 0.000 abstract description 4
- WJTFHWXMITZNHS-UHFFFAOYSA-N 5-bromofuran-2-carbaldehyde Chemical compound BrC1=CC=C(C=O)O1 WJTFHWXMITZNHS-UHFFFAOYSA-N 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 abstract 1
- 238000006069 Suzuki reaction reaction Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 14
- 235000002639 sodium chloride Nutrition 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- -1 2-(methylsulfonyl) ethyl Chemical group 0.000 description 6
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 230000003292 diminished effect Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- SCBZBMXPJYMXRC-UHFFFAOYSA-N 1-(bromomethyl)-3-fluorobenzene Chemical compound FC1=CC=CC(CBr)=C1 SCBZBMXPJYMXRC-UHFFFAOYSA-N 0.000 description 3
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- FFWQLZFIMNTUCZ-UHFFFAOYSA-N 1-(bromomethyl)-2-fluorobenzene Chemical compound FC1=CC=CC=C1CBr FFWQLZFIMNTUCZ-UHFFFAOYSA-N 0.000 description 2
- BOFRXDMCQRTGII-UHFFFAOYSA-N 619-08-9 Chemical class OC1=CC=C([N+]([O-])=O)C=C1Cl BOFRXDMCQRTGII-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- SDNXQWUJWNTDCC-UHFFFAOYSA-N 2-methylsulfonylethanamine Chemical class CS(=O)(=O)CCN SDNXQWUJWNTDCC-UHFFFAOYSA-N 0.000 description 1
- AMYYUKGKCJKCBI-UHFFFAOYSA-N 2-methylsulfonylethanamine;hydrochloride Chemical compound Cl.CS(=O)(=O)CCN AMYYUKGKCJKCBI-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 208000017891 HER2 positive breast carcinoma Diseases 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 238000006619 Stille reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004378 air conditioning Methods 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940125904 compound 1 Drugs 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
- 239000007859 condensation product Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 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
- 238000010792 warming Methods 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
- 239000002699 waste material Substances 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
- C07D405/04—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 directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing Lapatinib or medicinal acceptable salt through a novel intermediate. According to the method, 5-bromo-2-furaldehyde and 2-nitrobenzoic acid are used as starting raw materials and subjected to Suzuki coupling reaction to prepare the Lapatinib. The method for preparing the Lapatinib through synthesis can achieve the total recovery of 32.2%.
Description
Technical field
The present invention relates to lapatinibditosylate, be specifically related to preparation method and the intermediate of lapatinibditosylate, belong to field of pharmaceutical chemistry technology.
Background technology
Lapatinibditosylate (Lapatinib); chemistry N-(the chloro-4-of 3-((3-fluorophenyl) methoxyl group) phenyl)-6-by name (5-(((2-(methylsulfonyl) ethyl) is amino) methyl)-2-furyl)-4-quinazoline amine, structural formula is:
As tyrosine kinase inhibitor, lapatinibditosylate has obvious restraining effect for type (HER2) overexpression of human epidermal factor growth receptors 2, to HER2 positive breast cancer cells, and has good therapeutic action to trastuzumab air-conditioning mammary cancer.
The method preparing lapatinibditosylate at present mainly contains two classes, and a class is by building compound (V), thus realizes preparing lapatinibditosylate.
Such as:
It can be halogen (as Cl, Br) that above-claimed cpd I has easy leavings group X, X; Next commercially available Compound I and Compound II per obtain compound III by catalyst linked reaction in the basic conditions, and obtain compound IV with compound III and commercial compound VI or its reactant salt, then compound IV can be prepared into compound V; Finally compound V and compound VI I is carried out reacting obtained target product and draw iwan Buddhist nun.The drawback of the method is, the Compound II per that first which employs market price costliness, as starting raw material, improves holistic cost, secondly synthesizes in the step of compound V in compound IV and employs excessive POCl
3and Et
3n also uses toluene as reaction solvent, and create a large amount of waste gas and waste liquids, not only difficult treatment is also unfavorable for environmental protection, and route total recovery is low.
Another kind of preparation method is, become ether to be obtained by reacting ether compound through Williamson to be made the condition of alkali acetonitrile as solvents at salt of wormwood by the chloro-4-nitrophenols of 2-and 3-fluoro benzyl bromide under, the nitro then on this compound is amine through Pt/C hydrogen reducing.Then this aniline compound does part and the condensation of 4-chloro-6-iodine quinazoline at i-PrOH, and condensation products therefrom carries out Stille under to make solvent PdCl2 (PPh3) 2 be the reaction conditions of catalyzer at DMF with 5-dioxolane-2-(tributyl tin alkyl)-furans further and is coupled and obtains the product that is coupled.The further acidolysis of cyclic ketal of this conjugates obtains aldehyde compound, and finally this aldehyde compound and 2-(methylsulfonyl) ethamine react and obtains end product through sodium triacetoxy borohydride reduction amination again and draw iwan Buddhist nun.The method is synthesized crucial conjugates and be have employed Stille coupling reaction; this reaction response activity not high and result in coupling product yield low; and this reaction have employed organotin reagent as raw material; this reagent has severe toxicity to be unfavorable for reaction treatment and environment protection; this organo-tin compound fetch long price simultaneously; route synthesis cost is high, and the overall yield of this route is low.
Summary of the invention
The object of the present invention is to provide a kind of method preparing lapatinibditosylate or its pharmacy acceptable salt, the method adopts compounds (A1) to be converted into described lapatinibditosylate.
The object of the present invention is achieved like this:
Prepare a method for lapatinibditosylate or its pharmacy acceptable salt, it comprises makes formula A3 compound:
Be converted into described lapatinibditosylate.
The above-mentioned method preparing lapatinibditosylate or its pharmacy acceptable salt, its contained A3 compound or its salt reaction obtains formula A4 compound or its salt:
Formula A4 compound or its salt and N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-iodine quinazoline-4-amine react obtained formula A5 compound or its salt:
Formula A5 compound or its salt is converted into described lapatinibditosylate.
It is preferred that above-mentioned formula A3 compound or its salt reaction obtains formula A4 compound or its salt
N-Butyl Lithium and isopropylmagnesium chloride are formed after nBu2iPrMgLi mixture and compound A-13 halo site exchange and react obtained formula A4 compound or its salt again with trimethyl borate at low temperatures; Described low temperature is 0 ~-20 DEG C, preferably-10 ~-20 DEG C.
Above-mentioned formula A5 compound or its salt can be adopted and prepare with the following method:
Above-mentioned N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-iodine quinazoline-4-amine is adopted and is prepared with the following method:
The chloro-4-nitrophenols of above-mentioned 2-and 3-fluoro benzyl bromide prepare compd B 3 step, carry out in the basic conditions, preferred K
2cO
3make alkali, acetonitrile is solvent.
Above-mentioned formula B3 prepares the reduction that B4 step is nitro, preferred Pd/H
2, zinc powder reduction.
Above-mentioned formula B1 and oxalyl chloride preparation formula B2.
Above-mentioned formula B2 and B4 obtains formula B5 at Virahol as solvent.
Specifically, a kind of method preparing lapatinibditosylate, adopts following syntheti c route:
A is K
2cO
3; B is zinc powder; C is oxalyl chloride; D is Virahol; E is magnesium sulfate; F is NaBH
4
G is bromobenzene; H is isopropylmagnesium chloride/butyllithium, trimethyl borate; I is palladium/salt of wormwood; J is Pd (OH)
2/ C, H
2.
Technique effect:
The present invention uses new compound A1 or A3, A4, A5 prepare lapatinibditosylate, opens the route that is completely newly synthesized lapatinibditosylate.The present invention uses commercially available 5-bromofuran-2-carboxaldehyde and 2-(methylsulfonyl) ethylamine salt to draw iwan Buddhist nun using suziki-miyaura coupling reaction as key point being obtained by reacting target product through 6 steps altogether as starting raw material; total recovery reaches 32.2%; compare the advantage that traditional method the present invention has high-level efficiency and starting raw material cheapness; and do not need large industry equipment; simple to operate, be applicable to suitability for industrialized production.
Embodiment
In order to make object of the present invention and technical scheme clearly, below the preferred embodiments of the present invention are described in detail.It is noted that following examples are only for being further detailed the present invention, and limiting the scope of the invention can not be interpreted as.Some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.
The preparation of 4-chloro-6-iodine quinazoline (compd B 2):
Anhydrous for drying DMF3.2ml is added in the DCE of 10ml drying; this reaction system is placed in subcooling groove 0 ° stirring simultaneously; then oxalyl chloride 5.3ml (60mmol) is added in the dry anhydrous DCE of 25ml and be configured to solution; this dropwise is instilled slowly in appeal reaction system; keep stirring, whole process nitrogen protection.Find in dropping process that in reaction system, adularescent solid is separated out, and removes subcooling groove by reaction after dripping off, stirring at room temperature 5 minutes.Then compound 1 (5.0g18mmol) is added reaction system, after adding, reaction is moved into oil bath pan temperature rising reflux and react 1 hour, omnidistance nitrogen protection.After 1 hour, reaction being shifted out oil bath pan keeps stirring to be cooled to room temperature, add about 100ml frozen water stirring DCM (100mL × 3) extraction separatory, water layer extracts separatory with DCM again, merge organic phase anhydrous sodium sulfate drying, last concentrating under reduced pressure obtains light gray solid 4.36g (yield 92.7%).
1HNMR(400MHz，CDCl
3)δ9.06(s，1H)，8.65(d，J＝1.9Hz，1H)，8.20(dd，J＝8.8，1.9Hz，1H)，7.79(d，J＝8.8Hz，1H)。
The preparation of 4-(3-fluorine benzyloxy)-3-chloronitrobenzene (compd B 3):
By chloro-for 2-4-nitrophenols (9.02g; 52mmol); 3-fluoro benzyl bromide (9.85g; 52mmol) add in reaction flask with acetonitrile 90ml; simultaneously by salt of wormwood (7.0g; 57mmol) add wherein under nitrogen protection the then reaction in two hours of 60 ° of back flow reaction be down to room temperature; 80ml water is poured in reaction flask; filtration under diminished pressure obtains solid; filter cake ethyl acetate washes twice (50ml × 2); final solid phase prod has (13.16g, yield 95%).
1HNMR(400MHz，DMSO)δ8.35(d，J＝2.8Hz，1H)，8.26(dd，J＝9.2，2.8Hz，1H)，7.54-7.43(m，2H)，7.36-7.29(m，2H)，7.22(ddd，J＝10.9，5.3，1.4Hz，1H)，5.41(s，2H)。
The preparation of 4-(3-fluorine benzyloxy)-3-chloroaniline (compd B 4):
By compd B 3 ((8.70g, 25.1mmol) stirring and dissolving is in 150ml ethanol, add zinc powder (10.10g, 154mmol) reaction is moved into oil bath pan and be heated to 60 ° of stirring reactions, drip ammonium chloride (3.30g simultaneously, aqueous solution 30ml 61.8mmol), drips this temperature of rear maintenance and stirs 12 hours.Zinc powder filtration under diminished pressure is removed then filtrate reduced in volume and obtains light gray solid, the product 7.63g (productive rate 98%) that this solid washed with ether is last
1hNMR (400MHz, CDCl
3) δ 7.69 (td, J=8.0,5.8Hz, 1H), 7.59-7.52 (m, 2H), 7.36 (td, J=8.4,2.3Hz, 1H), 7.13 (dd, J=7.4,5.7Hz, 2H), 6.86 (dd, J=8.6,2.8Hz, 1H), 5.39 (s, 2H), 3.85 (s, 2H).
The preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-iodine quinazoline-4-amine (compd B 5):
Compd B 2 (5.70g, 19.70mmol) and compd B 4 (4.90g, 19.70mmol) are added in single port bottle, adds Virahol 150mml heated overnight at reflux simultaneously.After reaction terminates, temperature of reaction system is down to room temperature, solid product precipitates, and separates press filtration and obtains filter cake, and dried by filter cake and obtain product 9.10g (productive rate 90.72%), this product purity is high without the need to purifying.
1HNMR(400MHz，DMSO)δ9.86(s，1H)，8.96(d，J＝1.7Hz，1H)，8.62(s，1H)，8.12(dd，J＝8.7，1.8Hz，1H)，8.03(d，J＝2.6Hz，1H)，7.75(dd，J＝9.0，2.6Hz，1H)，7.57(d，J＝8.7Hz，1H)，7.47(dd，J＝8.1，6.0Hz，1H)，7.37-7.25(m，2H)，7.19(d，J＝2.2Hz，1H)，5.27(s，2H).
(E) preparation of-N-((5-bromine furans-2-base) methylene radical)-2-(methyl sulphonyl) ethamine (compd A 1):
5-bromo-2-furaldehyde (5.00g is added in there-necked flask, 28.56mmol) with 2-(methylsulfonyl) ethylamine hydrochloride (5.01g, 31.38mmol) then add anhydrous magnesium sulfate (3.42g, 28.50mmol) and dry DCM75ml in subcooling groove-5 ° keep stirring two hours, omnidistance nitrogen protection; Then drip triethylamine (4.75946.90mmol) in the mixture, keep stirring two hours at-5 °.Reaction terminates rear decompress filter removing magnesium sulfate, and filtrate washs separatory once with saturated sodium-chloride water solution, and organic phase anhydrous sodium sulfate drying, last concentrating under reduced pressure obtains light yellow solid 7.50g (productive rate 94.25%)
1hNMR (400MHz, CDCl
3) δ 7.38 (s, 1H), 7.08 (d, J=15.0Hz, 1H), 6.80 (d, J=15.0Hz, 1H), 3.89 (t, J=16.0Hz, 2H), 2.90 (t, J=15.9Hz, 2H), 2.80 (s, 3H).
The preparation of N-((5-bromine furans-2-base) methyl)-2-(methyl sulphonyl) ethamine (compd A 2):
Compd A 1 (7.54g is added in single port bottle, 26.9mmol) use dry anhydrous methyl alcohol 150ml-4 ° of stirring and dissolving simultaneously, then add sodium borohydride (4.07g, 107.6mmol) application of sample complete after mixture risen to room temperature and keep stirring at room temperature one hour.Mixture is cooled to 0 °, dropwise instill saturated sodium bicarbonate 60ml, then the solid filtration under diminished pressure in reaction is fallen, filtrate uses DCM (50ml × 3) washing leaching cake further, merge organic phase saturated sodium-chloride water solution and wash separatory once, organic phase anhydrous sodium sulfate drying, last concentrating under reduced pressure obtains product 7.5g (productive rate 99.33%)
1hNMR (400MHz, cdcl
3) δ 6.24 (d, J=3.2Hz, 1H), 6.19 (d, J=3.2Hz, 1H), 3.77 (s, 2H), 3.14 (d, J=2.5Hz, 4H), 3.00 (s, 3H), 1.84 (s, 1H).
The preparation of N-benzyl-N-((5-bromine furans-2-base) methyl)-2-(methyl sulphonyl) ethamine (compound A-13):
Compd A 2 (7.00g is added in reaction flask, 25.00mmol) sodium carbonate (5.29g, 50.00mmol) and 50mlDMF dissolve, and then add bromobenzene (4.27g, 30.00mmol) be warming up to 140 °, keep stirring reaction 3 hours.Reactant is dissolved in ethyl acetate then dividing with saturated common salt water washing gets organic layer, and after organic over anhydrous dried over sodium sulfate, concentrating under reduced pressure obtains light yellow solid 8.91g (productive rate 96.53%).
1HNMR(400MHz，CDCl
3)δ7.39-7.29(m，5H)，6.28(d，J＝3.2Hz，1H)，6.22(d，J＝3.2Hz，1H)，3.67(d，J＝9.9Hz，4H)，3.08(d，J＝1.9Hz，4H)，2.98(s，3H)。The preparation of 5-((benzyl (2-(methyl sulphonyl) ethyl) is amino) methyl) furans-2-ylboronic acid (compd A 4):
In there-necked flask, add dry THF30ml as solvent, do nitrogen protection simultaneously and there-necked flask is moved into 0 ° of maintenance in subcooling groove and stir.Then add isopropylmagnesium chloride 3.75ml (7.50mmol) respectively and butyllithium 9.73ml (15mmol) stirs 15 minutes, then interior temperature drop is dripped to-20 ° the compound A-13 (5.4g dissolved by THF by this mixture in subcooling groove, 15mmol) keep-20 ° to stir 30 minutes, then drip trimethyl borate 8.96g (60mmol).Gradually temperature is risen to 0 ° after dropwising, keep this temperature stirring reaction two hours.This mixture acetic acid cancellation after reaction terminates also adds the dilution of 50ml water, aqueous layer with ethyl acetate (50ml × 3) extracting and separating organic phase, then organic phase saturated common salt water washing flash liberation organic phase anhydrous sodium sulfate drying, decompress(ion) concentrates to obtain semi-solid product, and this product Column methods (wash-out polarity DCM/EA=2/1) obtains pure compound 93.10g (productive rate 63.39%).
1HNMR(400MHz，DMSO)δ7.31-7.13(m，5H)，6.12(s，1H)，3.76(s，2H)，3.60(s，2H)，3.15(d，J＝3.9Hz，3H)，3.03(s，1H)，2.80(s，3H)，1.55(s，2H).
The preparation of compound A-45:
Compd A 4 (5.9017.49mmol) is added respectively in the reaction flask of 500ml, compd B 5 (7.90g, 15.62mmol), palladium (0.29g1.3mmol), salt of wormwood (4.83g, 22.40mmol), and add dehydrated alcohol 150ml and anhydrous THF150ml as solvent, by this mixture heating reflux reaction two hours.Then this mixture is down to room temperature, inorganic salt decompress filter is separated and uses 50ml ethanol and 50mlTHF washing leaching cake, then abandons inorganic salt filter cake.Filtrate is merged washings move into 1L with in the single port bottle of dropping funnel, slow dropping 300ml water (about using one hour), yellow solid is had to separate out gradually, keep stirring at room temperature 1.5 hours, yellow solid is depressurized suction filtration and is separated and uses 50ml frozen ethanol to wash once, and solid enters the 60 ° of dryings of decompression baking oven and obtains yellow solid in 16 hours.This solid Column methods refining (eluent DCM/EA=5/1) obtains pure target product 8.97g (productive rate 90.42%).
1HNMR(400MHz，CDCl
3)δ8.67(s，1H)，8.59(s，1H)，8.42(s，1H)，7.89(dt，J＝12.0，8.8Hz，2H)，7.68(dd，J＝8.8，2.4Hz，1H)，7.39-7.29(m，3H)，7.25-7.18(m，1H)，7.00(dd，J＝18.3，8.7Hz，1H)，6.73(d，J＝3.2Hz，1H)，6.27(d，J＝3.2Hz，1H)，5.15(s，1H)，3.78(s，1H)，3.68(s，1H)，3.45-3.26(m，2H)，2.92(s，2H).
End product draws the preparation of iwan Buddhist nun:
Compound A-45 (5.00g, 7.61mmol) be dissolved in methyl alcohol the solution being configured to concentration 0.1M, add (0.11g again, 0.76mmol) palladium hydroxide (20%) of carbon load is as catalyzer, give the reaction environment that hydrogen pressure is about 50-55psi, stirring at room temperature is reacted.TLC monitors reaction process, by catalyzer filtration under diminished pressure and methanol wash filter cake after raw material point disappears, merging filtrate washings drying under reduced pressure obtains oily matter, this oily matter obtains pure drawing iwan Buddhist nun 3.61g (81.67%) through column purification (eluent DCM/EA=3/1), and purity is 99.3%.
1HNMR(300MHz，d
6-DMSO)：δ2.98(t，J＝6.75Hz，1H)，3.04(s，1H)，3.29(t，J＝6.6Hz，1H)，3.83(s，1H)，5.28(s，1H)，6.50(d，J＝3.0Hz，1H)，7.08(d，J＝3.3Hz，1H)，7.20(m，1H)，7.33(m，4H)，7.48(m，1H)，7.76(m，1H)，7.80(d，J＝9Hz，1H)，8.04(d，J＝2.75Hz，1H)，8.17(dd，J＝8.7Hz，J＝1.8Hz，1H)，8.56(s，1H)，8.75(d，J＝1.8Hz，1H)。
The present invention draws iwan Buddhist nun by 6 step synthesis end products, total recovery 32.2%, draws the method for iwan Buddhist nun far away higher than existing preparation, and purity of the present invention reaches more than 99.0%, in end product, the residual quantity of compd A 1-A5 is all less than thousandth, is applicable to medicinal requirements.
Claims (10)
1. prepare a method for lapatinibditosylate or its pharmacy acceptable salt, it comprises makes formula A3 compound:
Be converted into described lapatinibditosylate.
2. the method for claim 1, is characterized in that: its contained A3 compound or its salt reaction prepares formula A4 compound or its salt:
Formula A4 compound or its salt and N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-iodine quinazoline-4-amine react obtained formula A5 compound or its salt:
Formula A5 compound or its salt is converted into described lapatinibditosylate.
3. method as claimed in claim 2, is characterized in that: described formula A3 compound or its salt reaction obtains formula A4 compound or its salt and to react with trimethyl borate after nBu2iPrMgLi mixture and compound A-13 halo site exchange for n-Butyl Lithium and isopropylmagnesium chloride are at low temperatures formed again and obtain formula A4 compound or its salt.
4. method as claimed in claim 2, is characterized in that: described formula A5 compound or its salt can be adopted and prepare with the following method:
5. method as claimed in claim 2, is characterized in that: described N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-iodine quinazoline-4-amine is adopted and prepared with the following method:
6. prepare a method for lapatinibditosylate, adopt following syntheti c route:
Wherein, a is K
2cO
3; B is zinc powder; C is oxalyl chloride; D is Virahol; E is magnesium sulfate; F is NaBH
4; G is bromobenzene; H is isopropylmagnesium chloride/butyllithium, trimethyl borate; I is palladium/salt of wormwood; J is Pd (OH)
2/ C, H
2.
7. a formula A1 compound,
8. a formula A3 compound,
9. a formula A4 compound,
10. a formula A5 compound
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106631715A (en) * | 2016-12-22 | 2017-05-10 | 山东轩德医药科技有限公司 | Preparation method of 3-chloro-4-(3-fluorobenzyloxy) aniline |
| CN108285421A (en) * | 2018-01-26 | 2018-07-17 | 黑龙江鑫创生物科技开发有限公司 | A kind of method of micro passage reaction synthesis lapatinib intermediate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001004111A1 (en) * | 1999-07-09 | 2001-01-18 | Glaxo Group Limited | Anilinoquinazolines as protein tyrosine kinase inhibitors |
| CN102295638A (en) * | 2010-06-24 | 2011-12-28 | 齐鲁制药有限公司 | Novel method for preparing lapatinib |
| CN102675297A (en) * | 2012-04-17 | 2012-09-19 | 武汉人福医药集团股份有限公司 | Preparation method of Lapatinib |
| CN103483324A (en) * | 2012-06-12 | 2014-01-01 | 武汉人福医药集团股份有限公司 | New preparation method of lapatinib |
| CN103923070A (en) * | 2013-01-14 | 2014-07-16 | 意大利合成制造有限公司 | Efficient Process For The Preparation Of Lapatinib And Salts Thereof By Means Of New Intermediates |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001004111A1 (en) * | 1999-07-09 | 2001-01-18 | Glaxo Group Limited | Anilinoquinazolines as protein tyrosine kinase inhibitors |
| CN102295638A (en) * | 2010-06-24 | 2011-12-28 | 齐鲁制药有限公司 | Novel method for preparing lapatinib |
| CN102675297A (en) * | 2012-04-17 | 2012-09-19 | 武汉人福医药集团股份有限公司 | Preparation method of Lapatinib |
| CN103483324A (en) * | 2012-06-12 | 2014-01-01 | 武汉人福医药集团股份有限公司 | New preparation method of lapatinib |
| CN103923070A (en) * | 2013-01-14 | 2014-07-16 | 意大利合成制造有限公司 | Efficient Process For The Preparation Of Lapatinib And Salts Thereof By Means Of New Intermediates |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106631715A (en) * | 2016-12-22 | 2017-05-10 | 山东轩德医药科技有限公司 | Preparation method of 3-chloro-4-(3-fluorobenzyloxy) aniline |
| CN108285421A (en) * | 2018-01-26 | 2018-07-17 | 黑龙江鑫创生物科技开发有限公司 | A kind of method of micro passage reaction synthesis lapatinib intermediate |
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