CN105085496B - A kind of method and intermediate for preparing Lapatinib - Google Patents
A kind of method and intermediate for preparing Lapatinib Download PDFInfo
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- CN105085496B CN105085496B CN201510593037.4A CN201510593037A CN105085496B CN 105085496 B CN105085496 B CN 105085496B CN 201510593037 A CN201510593037 A CN 201510593037A CN 105085496 B CN105085496 B CN 105085496B
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- 238000000034 method Methods 0.000 title claims abstract description 26
- 239000002136 L01XE07 - Lapatinib Substances 0.000 title claims abstract description 22
- 229960004891 lapatinib Drugs 0.000 title claims abstract description 22
- 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 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims description 50
- 238000006243 chemical reaction Methods 0.000 claims description 35
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 11
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 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
- 229910000027 potassium carbonate Inorganic materials 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
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 7
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical group [Zn] HCHKCACWOHOZIP-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
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 3
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- OITHRYPVJIVVPG-UHFFFAOYSA-N 4,5-dihydro-1,3-oxazol-4-amine Chemical compound NC1COC=N1 OITHRYPVJIVVPG-UHFFFAOYSA-N 0.000 claims 1
- FQYRLEXKXQRZDH-UHFFFAOYSA-N 4-aminoquinoline Chemical compound C1=CC=C2C(N)=CC=NC2=C1 FQYRLEXKXQRZDH-UHFFFAOYSA-N 0.000 claims 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 abstract description 6
- 230000000977 initiatory effect Effects 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 4
- 238000011084 recovery Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 150000005341 2-nitrobenzoic acids Chemical class 0.000 abstract 1
- 125000001246 bromo group Chemical group Br* 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 235000002639 sodium chloride Nutrition 0.000 description 16
- 238000003756 stirring Methods 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 13
- 239000007787 solid Substances 0.000 description 11
- -1 (2- (mesyl) ethyl) amino Chemical group 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 230000006837 decompression Effects 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 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
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- SCBZBMXPJYMXRC-UHFFFAOYSA-N 1-(bromomethyl)-3-fluorobenzene Chemical class 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
- BOFRXDMCQRTGII-UHFFFAOYSA-N 619-08-9 Chemical class OC1=CC=C([N+]([O-])=O)C=C1Cl BOFRXDMCQRTGII-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
- 239000002585 base Substances 0.000 description 3
- 230000003292 diminished effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 2
- WJTFHWXMITZNHS-UHFFFAOYSA-N 5-bromofuran-2-carbaldehyde Chemical compound BrC1=CC=C(C=O)O1 WJTFHWXMITZNHS-UHFFFAOYSA-N 0.000 description 2
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 206010013786 Dry skin Diseases 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
- 238000007792 addition Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 239000003480 eluent Substances 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
- 239000004519 grease Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000376 reactant 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
- FFWQLZFIMNTUCZ-UHFFFAOYSA-N 1-(bromomethyl)-2-fluorobenzene Chemical compound FC1=CC=CC=C1CBr FFWQLZFIMNTUCZ-UHFFFAOYSA-N 0.000 description 1
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 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
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- PVKKBPATZVNTED-UHFFFAOYSA-N Bc1ccc(CN(CCS(C)(=O)=O)Cc2ccccc2)[o]1 Chemical compound Bc1ccc(CN(CCS(C)(=O)=O)Cc2ccccc2)[o]1 PVKKBPATZVNTED-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- SINDAUSUOKUQHM-UHFFFAOYSA-N CS(CCN(Cc([o]1)ccc1Br)Cc1ccccc1)(=O)=O Chemical compound CS(CCN(Cc([o]1)ccc1Br)Cc1ccccc1)(=O)=O SINDAUSUOKUQHM-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 208000017891 HER2 positive breast carcinoma Diseases 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 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
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 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
- 230000008901 benefit Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration 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
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 238000000967 suction filtration Methods 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
- 238000005406 washing 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
A kind of method that Lapatinib or its pharmaceutically acceptable salt are prepared by novel intermediates, this method are made using 5 bromo furfurals and with 2 nitrobenzoic acids as initiation material by Suzuki coupled reactions.The method of this synthesis Lapatini can reach 32.2% total recovery.
Description
Technical field
The present invention relates to Lapatinib, and in particular to the preparation method and intermediate of Lapatinib, belongs to pharmaceutical chemistry skill
Art field.
Background technology
Lapatinib (Lapatinib), entitled N- (the chloro- 4- of 3- ((3- fluorophenyls) methoxyl group) phenyl) -6- (5- of chemistry
(((2- (mesyl) ethyl) amino) methyl) -2- furyls) -4- quinazoline amine, structural formula is：
As tyrosine kinase inhibitor, Lapatinib is directed to human epidermal factor growth receptors 2 type (HER2) excessive table
The aobvious inhibitory action of Da Youming, has preferable treatment to HER2 positive breast cancer cells, and to trastuzumab air-conditioning breast cancer
Effect.
Preparing the method for Lapatinib at present mainly has two classes, and one kind is by building compound (V), is prepared so as to realize
Lapatinib.
Such as：
It can be halogen (such as Cl, Br) that above-claimed cpd I, which has easy leaving group X, X,；Commercially available compound I and compound
Compound III is made by catalyst coupling reaction in the basic conditions in II, next uses compound III and commercial compound
VI or its reactant salt obtain compound IV, and then compound IV can be prepared into compound V；Finally by compound V and chemical combination
Thing VII carries out reacting obtained target product Lapatini.The drawbacks of this method, is which employs the expensive chemical combination of market price first
Thing II improves holistic cost, has secondly used excess in the step of compound IV synthesizes compound V as initiation material
POCl3And Et3N and by the use of toluene as reaction dissolvent, generates substantial amounts of waste gas and waste liquid, not only processing difficulty is also unfavorable for ring
Protect, and route total recovery is low.
Another kind of preparation method is to make alkali acetonitrile as solvents in potassium carbonate by the chloro- 4- nitrophenols of 2- and 3- fluoro benzyl bromides
Under conditions of react to obtain ether compound into ether by Williamson, then the nitro in the compound through Pt/C hydrogen also
Originally it was amine.Then the aniline compound does part in i-PrOH and is condensed with the chloro- 6- iodine quinazolines of 4-, and condensation products therefrom is further
With 5- dioxolanes -2- (tributyl tin alkyl)-furans under the reaction condition that DMF makees that solvent PdCl2 (PPh3) 2 is catalyst
Stille is carried out to couple to obtain coupling product.The further acidolysis of cyclic ketal of the conjugates obtains aldehyde compound, finally should
Aldehyde compound reacts with 2- (mesyl) ethamine obtains end-product drawing pa through sodium triacetoxy borohydride reduction amination again
Carry Buddhist nun.This method synthesizes crucial conjugates and employs Stille coupled reactions, and the reaction response activity is not high and result in coupling
Product yield is low, and the reaction employs organotin reagent and has severe toxicity to be unfavorable for reaction treatment and ring as raw material, the reagent
Border is protected, while the organo-tin compound price is expensive, and route synthesis cost is high, and the route entirety yield is low.
The content of the invention
Lapatinib or the method for its pharmaceutically acceptable salt, this method are prepared it is an object of the invention to provide a kind of
The Lapatinib is converted into using compounds (A1).
The object of the present invention is achieved like this：
A kind of to prepare Lapatinib or the method for its pharmaceutically acceptable salt, it, which is included, makes formula A3 compounds：
It is converted into the Lapatinib.
Above-mentioned to prepare Lapatinib or the method for its pharmaceutically acceptable salt, it reacts comprising formula A3 compound or its salts
Formula A4 compound or its salts are made：
Formula A4 compound or its salts are made with the reaction of N- (4- (3- fluorine benzyloxy) -3- chlorphenyls) -6- iodine quinazoline -4- amine
Formula A5 compound or its salts：
Formula A5 compound or its salts are converted into the Lapatinib.
It is preferred that formula A4 compound or its salts are made in above-mentioned formula A3 compound or its salts reaction
N-BuLi forms nBu2iPrMgLi compounds and compound A-13 halo site with isopropylmagnesium chloride at low temperature
React the formula of being made A4 compound or its salts after exchange with trimethylborate again；The low temperature be 0~-20 DEG C, preferably -10~-20
℃。
Above-mentioned formula A5 compound or its salts can be prepared with the following method：
Above-mentioned N- (4- (3- fluorine benzyloxy) -3- chlorphenyls) -6- iodine quinazoline -4- amine is prepared with the following method：
The chloro- 4- nitrophenols of above-mentioned 2- and 3- fluoro benzyl bromide prepare compound B3 steps, are carried out, preferably in the basic conditions
K2CO3Make alkali, acetonitrile is solvent.
Above-mentioned formula B3 prepares the reduction that B4 steps are nitro, preferably Pd/H2, zinc powder reduction.
Above-mentioned formula B1 and oxalyl chloride formula B2.
Above-mentioned formula B2 and B4 makees solvent in isopropanol and formula B5 is made.
Specifically, a kind of method for preparing Lapatinib, using following syntheti c route：
A is K2CO3；B is zinc powder；C is oxalyl chloride；D is isopropanol；E is magnesium sulfate；F is NaBH4
G is bromobenzene；H is isopropylmagnesium chloride/butyl lithium, trimethylborate；I is palladium/potassium carbonate；J is Pd
(OH)2/ C, H2。
Technique effect：
The present invention prepares Lapatinib using noval chemical compound A1 or A3, A4, A5, opens a brand-new synthesis Lapatinib
Route.The present invention uses commercially available 5-bromofuran-2-carboxaldehyde and 2- (mesyl) ethylamine salt as initiation material with suziki-
Miyaura coupled reactions react to obtain target product Lapatini as key point by 6 steps altogether, and total recovery reaches
32.2%, compared to the conventional method present invention with the cheap advantage of high efficiency and initiation material, and do not need large scale industry to set
It is standby, it is simple to operate, it is adapted to industrialized production.
Embodiment
In order that the purpose of the present invention and technical scheme are clearer, the preferred embodiments of the present invention are carried out below detailed
Description.To illustrate that：Following examples are served only for that the present invention is further detailed, and it is not intended that to this hair
The limitation of bright protection domain.Those skilled in the art according to the present invention the above make some it is nonessential improvement and
Adjustment belongs to protection scope of the present invention.
The preparation of the chloro- 6- iodine quinazolines (compound B2) of 4-：
The anhydrous DMF3.2ml of drying is added in the DCE that 10ml is dried, while the reaction system is placed in sub-cooled
0 ° of stirring in groove, then oxalyl chloride 5.3ml (60mmol) is added in the anhydrous DCE of 25ml dryings and is configured to solution, this is molten
Liquid is slowly instilled in appeal reaction system dropwise, is kept stirring for, and whole process is protected with nitrogen.Reaction system is found during dropwise addition
In have white solid precipitation, after dripping off will reaction remove sub-cooled groove, be stirred at room temperature 5 minutes.Then by the (5.0g of compound 1
Reaction system 18mmol) is added, reaction is moved into oil bath pan temperature rising reflux after adding reacts 1 hour, whole nitrogen protection.1 is small
When after reaction removed into oil bath pan be kept stirring for being cooled to room temperature, add the stirring of about 100ml frozen water and extracted with DCM (100mL × 3)
Liquid separation, water layer extract liquid separation with DCM again, merge organic phase anhydrous sodium sulfate drying, are finally concentrated under reduced pressure to give light gray
Solid 4.36g (yield 92.7%).1H NMR (400MHz, CDCl3) δ 9.06 (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- chloronitrobenzenes (compound B3)：
By the chloro- 4- nitrophenols (9.02g, 52mmol) of 2-, 3- fluoro benzyl bromides (9.85g, 52mmol) and acetonitrile 90ml add
Enter in reaction bulb, at the same potassium carbonate (7.0g, 57mmol) is added thereto two hours of 60 ° of back flow reactions under nitrogen protection and
Room temperature is down in reaction afterwards, and 80ml water is poured into reaction bulb, is filtered under diminished pressure to obtain solid, filter cake is washed twice with ethyl acetate
(50ml × 2), final solid product have (13.16g, yield 95%).1H NMR (400MHz, DMSO) δ 8.35 (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- chloroanilines (compound B4)：
By compound B3 ((8.70g, 25.1mmol) stirring and dissolving in 150ml ethanol, add zinc powder (10.10g,
Reaction 154mmol) is moved into oil bath pan and is heated to 60 ° of stirring reactions, while ammonium chloride (3.30g, 61.8mmol) water is added dropwise
Solution 30ml, the temperature is kept to stir after dripping 12 hours.Zinc powder is filtered under diminished pressure into removing, and then filtrate decompression is concentrated to give
Light gray solid, the solid wash last product 7.63g (yield 98%) with ether1H NMR (400MHz, CDCl3)δ7.69
(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- chlorphenyls) -6- iodine quinazoline -4- amine (compound B5)：
Compound B2 (5.70g, 19.70mmol) and compound B4 (4.90g, 19.70mmol) is added in single port bottle, together
When add isopropanol 150mml heated overnight at reflux.React and temperature of reaction system is down to room temperature, solid product precipitation after terminating
Get off, solution press filtration obtains filter cake, filter cake is dried to obtain product 9.10g (yield 90.72%), the product purity is high without pure
Change.1H NMR (400MHz, DMSO) δ 9.86 (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- bases) methylene) -2- (methyl sulphonyl) ethamine (compound A1)：
In there-necked flask add 5-bromo-2-furaldehyde (5.00g, 28.56mmol) and 2- (mesyl) ethylamine hydrochloride (5.01g,
Anhydrous magnesium sulfate (3.42g, 28.50mmol) and the DCM75ml dried 31.38mmol) are then added -5 ° in sub-cooled groove
It is kept stirring for two hours, whole nitrogen protection；Triethylamine (4.75946.90mmol) is then added dropwise in the mixture, at -5 °
It is kept stirring for two hours.Decompression, which filters, after reaction terminates removes magnesium sulfate, after filtrate washed once with saturated sodium-chloride water solution
Liquid separation, organic phase anhydrous sodium sulfate drying, finally it is concentrated under reduced pressure to give light yellow solid 7.50g (yield 94.25%)1H
NMR (400MHz, CDCl3) 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- bases) methyl) -2- (methyl sulphonyl) ethamine (compound A2)：
Compound A1 (7.54g, 26.9mmol) is added in single port bottle while with dry anhydrous methanol 150ml at -4 °
Stirring and dissolving, then add after sodium borohydride (4.07g, 107.6mmol) has been loaded and mixture is warmed to room temperature and keeps room temperature
Stirring one hour.Mixture is cooled to 0 °, saturated sodium bicarbonate 60ml is instilled dropwise, then depressurized the solid in reaction
Filter, filtrate further washs filter cake with DCM (50ml × 3), and merging organic phase is washed with saturated sodium-chloride water solution once divides afterwards
Liquid, organic phase anhydrous sodium sulfate drying, finally it is concentrated under reduced pressure to give product 7.5g (yield 99.33%)1H NMR (400MHz,
cdcl3) 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- benzyls-N- ((5- bromine furans -2- bases) methyl) -2- (methyl sulphonyl) ethamine (compound A-13)：
Compound A2 (7.00g, 25.00mmol) sodium carbonate (5.29g, 50.00mmol) and 50ml are added in reaction bulb
DMF dissolves, and then adds bromobenzene (4.27g, 30.00mmol) and is warming up to 140 °, is kept stirring for reaction 3 hours.Reactant is dissolved in
Then organic layer is taken in ethyl acetate with saturated common salt water washing point, and organic layer after anhydrous sodium sulfate drying with being concentrated under reduced pressure to give
Light yellow solid 8.91g (yield 96.53%).1H NMR (400MHz, CDCl3) δ 7.39-7.29 (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) amino) methyl) furans -2- ylboronic acids (compound A4)：
Dry THF30ml is added in there-necked flask as solvent, while does nitrogen and protects and there-necked flask is moved into low temperature
0 ° is kept stirring in cooling bath.Then it is separately added into isopropylmagnesium chloride 3.75ml (7.50mmol) and butyl lithium 9.73ml
(15mmol) is stirred 15 minutes, and then interior temperature drop to -20 ° of dropwise additions is dissolved the mixture in sub-cooled groove by THF
Compound A-13 (5.4g, 15mmol) is kept for -20 ° stir 30 minutes, and trimethylborate 8.96g (60mmol) is then added dropwise.It is added dropwise
After temperature is gradually risen to 0 °, keep the temperature stirring reaction two hours.The mixture is quenched with acetic acid after reaction terminates
And add the dilution of 50ml water, aqueous layer with ethyl acetate (50ml × 3) extract and separate organic phase, then organic phase saturated aqueous common salt
Separation organic phase anhydrous sodium sulfate drying is washed once, decompression is concentrated to give semi-solid product, the product Column methods
(elution polarity DCM/EA=2/1) obtains the pure 3.10g of compound 9 (yield 63.39%).1H NMR (400MHz, DMSO) δ
7.31-7.13 (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：
It is separately added into compound A4 (5.9017.49mmol) in 500ml reaction bulb, compound B5 (7.90g,
15.62mmol), palladium (0.29g1.3mmol), potassium carbonate (4.83g, 22.40mmol), and add absolute ethyl alcohol 150ml and
Anhydrous THF150ml is as solvent, by two hours of the mixture heating reflux reaction.The mixture is then down to room temperature, nothing
The decompression of machine salt, which filters, to be separated and washs filter cake with 50ml ethanol and 50mlTHF, then abandons inorganic salts filter cake.Filtrate is merged and washed
Wash liquid to move into the 1L single port bottle with dropping funel, 300ml water (about with one hour) is slowly added dropwise, gradually there is consolidating for yellow
Body separates out, and holding is stirred at room temperature 1.5 hours, and yellow solid is depressurized suction filtration and separates and washed once with 50ml frozen ethanols, Gu
Body enters decompression 60 ° of dryings of baking oven and obtains yellow solid in 16 hours.The solid refines (eluant, eluent DCM/EA=with Column methods
5/1) pure target product 8.97g (yield 90.42%) is obtained.1H NMR (400MHz, CDCl3) δ 8.67 (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)
The preparation of end-product Lapatini：
Compound A-45 (5.00g, 7.61mmol) is dissolved in the solution that concentration 0.1M is configured in methanol, adds
The palladium dydroxide (20%) of (0.11g, 0.76mmol) carbon load is used as catalyst, gives Hydrogen Vapor Pressure about 50-55psi reaction
Environment, reaction is stirred at room temperature.TLC monitors reaction process, and raw material point is filtered under diminished pressure catalyst after disappearing and methanol washs filter cake,
Merging filtrate cleaning solution is dried under reduced pressure to obtain grease, and the grease purifies (eluant, eluent DCM/EA=3/1) through post and obtains pure drawing
Iwan Buddhist nun 3.61g (81.67%), purity 99.3%.1H NMR (300MHz, d6-DMSO)：δ 2.98 (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 synthesizes end-product Lapatini, total recovery 32.2%, significantly larger than existing preparation Lapatini by 6 steps
Method, and purity of the present invention reaches more than 99.0%, in end-product compound A1-A5 residual quantity be respectively less than thousand/
One, it is adapted to medicinal requirements.
Claims (7)
1. a kind of prepare Lapatinib or the method for its pharmaceutically acceptable salt, it includes formula A3 compound or its salts reaction system
It is standby to obtain formula A4 compound or its salts；Formula A4 compound or its salts and N- (4- (3- fluorine benzyloxy) -3- chlorphenyls) -6- iodine quinoline azoles
Formula A5 compound or its salts are made in the reaction of quinoline -4- amine；Formula A5 compound or its salts are converted into the Lapatinib；
The formula A5 compound or its salts are prepared with the following method：
2. the method as described in claim 1, it is characterised in that：Formula A4 chemical combination is made in the formula A3 compound or its salts reaction
Thing or its salt form nBu2iPrMgLi compounds and compound A-13 halo position for n-BuLi at low temperature and isopropylmagnesium chloride
Point reacts the formula of being made A4 compound or its salts with trimethylborate again after exchanging；The low temperature is 0~-20 DEG C.
3. the method as described in claim 1, it is characterised in that：N- (4- (3- fluorine benzyloxy) -3- the chlorphenyls) -6- iodine quinolines
Oxazoline -4- amine is prepared with the following method：
4. the method for preparing Lapatinib as claimed in claim 1, using following syntheti c route：
Wherein, a K2CO3；B is zinc powder；C is oxalyl chloride；D is isopropanol；E is magnesium sulfate；F is NaBH4；G is bromomethyl benzene；h
For isopropylmagnesium chloride/butyl lithium, trimethylborate；I is palladium/potassium carbonate；J is Pd (OH)2/ C, H2。
5. a kind of formula A1 compounds, structure are as follows：
6. a kind of formula A3 compounds, structure are as follows：
7. a kind of formula A4 compounds, structure are as follows：
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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