CN109535047A - A kind of preparation method of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt - Google Patents
A kind of preparation method of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt Download PDFInfo
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- CN109535047A CN109535047A CN201811448974.0A CN201811448974A CN109535047A CN 109535047 A CN109535047 A CN 109535047A CN 201811448974 A CN201811448974 A CN 201811448974A CN 109535047 A CN109535047 A CN 109535047A
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- Prior art keywords
- bromine
- ethamine
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- reaction
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- 239000002136 L01XE07 - Lapatinib Substances 0.000 title claims abstract description 32
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical group 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 32
- 229960004891 lapatinib Drugs 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- SDNXQWUJWNTDCC-UHFFFAOYSA-N 2-methylsulfonylethanamine Chemical class CS(=O)(=O)CCN SDNXQWUJWNTDCC-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims abstract description 34
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 30
- UTEGFDRMEDFKIQ-UHFFFAOYSA-N butyl methyl carbonate dimethyl carbonate Chemical class COC(OC)=O.C(CCC)OC(OC)=O UTEGFDRMEDFKIQ-UHFFFAOYSA-N 0.000 claims abstract description 9
- RHDUOFVTCTUTFX-UHFFFAOYSA-N methanesulfinic acid;sodium Chemical compound [Na].CS(O)=O RHDUOFVTCTUTFX-UHFFFAOYSA-N 0.000 claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 66
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 14
- 239000003208 petroleum Substances 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000000638 solvent extraction Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 238000007867 post-reaction treatment Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 21
- 238000007254 oxidation reaction Methods 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 230000003647 oxidation Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 238000011017 operating method Methods 0.000 abstract description 7
- 238000012805 post-processing Methods 0.000 abstract description 4
- 239000000047 product Substances 0.000 description 34
- 239000004519 grease Substances 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- 239000002994 raw material Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- -1 hydrogen peroxide methylsulfonyl compound Chemical class 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 230000001590 oxidative effect Effects 0.000 description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
- 239000002360 explosive Substances 0.000 description 6
- 239000007800 oxidant agent Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 5
- 230000000903 blocking effect Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000007711 solidification Methods 0.000 description 4
- 230000008023 solidification Effects 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Substances OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 3
- 229910052759 nickel Inorganic materials 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- CAHZAJIZZBIDFJ-UHFFFAOYSA-N 2-methylsulfanylethylazanium;chloride Chemical compound Cl.CSCCN CAHZAJIZZBIDFJ-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 150000003947 ethylamines Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CHZXTOCAICMPQR-UHFFFAOYSA-N 2-(2-bromoethyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCBr)C(=O)C2=C1 CHZXTOCAICMPQR-UHFFFAOYSA-N 0.000 description 1
- FFWASDWPUAKZQI-UHFFFAOYSA-N 2-methylsulfonylethyl 4-methylbenzenesulfonate Chemical compound CC1=CC=C(S(=O)(=O)OCCS(C)(=O)=O)C=C1 FFWASDWPUAKZQI-UHFFFAOYSA-N 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 241000255964 Pieridae Species 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 210000004209 hair Anatomy 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 238000012019 product validation Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
Abstract
The present invention provides a kind of preparation methods of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt; include the following steps: (A) by one or both of 2- bromine ethamine or 2- bromine ethylamine salt; it is reacted under alkaline condition with two dimethyl dicarbonate butyl methyl esters, obtains N- (Boc) -2- bromine ethamine；(B) N- (Boc) -2- bromine ethamine is reacted under alkaline condition to obtain N- (Boc) -2- mesyl ethamine with methyl sulfinic acid sodium；(C) by N- (Boc) -2- mesyl ethamine be acidified to get.The preparation method of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt of the embodiment of the present invention; it avoids more using method for oxidation synthesis target product unstable factor; there is also the generations for operating unsafe problem for obtained product; the preparation method operating procedure is easy; molecule availability is high, and reaction condition is easily-controllable, and operating cost is low; post-processing operation is easy, products obtained therefrom purity is high.
Description
The application is that application No. is " 201610887957.1 ", a kind of entitled " Lapatinib side chain 2- (methyl sulphurs
Acyl group) ethylamine salt preparation method ", the applying date be " on October 11st, 2016 " application for a patent for invention divisional application.
Technical field
The present invention relates to pharmaceutical fields, in particular to a kind of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt
Preparation method.
Background technique
Lapatinib is produced by GlaxoSmithKline PLC, and a kind of oral small molecule epidermal growth factor tyrosine kinase is belonged to
Inhibitor.It is mainly used for the treatment ErbB-2 overexpression of joint capecitabine, previously received to include anthracycline, taxol,
The advanced stage of Herceptin (Trastuzumab) treatment or metastatic breast cancer.During synthesizing Lapatinib, elder generation is generally required
This intermediate of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt is synthesized, drawing is directly then prepared using the intermediate in turn
Pa replaces Buddhist nun.It can be seen that being directed to the research of the synthetic route of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt intermediate especially
It is important, because the synthesis success or not of intermediate is the key point that can be succeeded in developing concerning subsequent finished medicines.
But in the prior art, the synthetic route of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt generally operates step
Rapid comparatively laborious, the toxicity of agents useful for same is also stronger, raw material, catalyst bigger to operator and environmental pollution
There is be not easy to obtain, reaction condition is harsher, high to mating synthesis device requirement the problems such as, additionally, due in synthetic route
In mostly use oxidant greatly, can exist oxidant itself it is unstable it is variable influence reaction be normally carried out and extra oxidation
The more problem of agent unstable factor in last handling process, so virtually improves production cost, is unfavorable for
Industrialized production.Even substance sheet involved in some synthetic routes is as inflammable and explosive substances, safety coefficient when practical operation
It is low, the safety of operator is seriously threatened, there is huge security risks.
In view of the presence of problem above, the present invention is specifically proposed.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt, keep away
Exempt to use method for oxidation synthesis target product unstable factor more, there is also the hairs for operating unsafe problem for obtained product
Raw, the preparation method operating procedure is easy, and molecule availability is high, and reaction condition is easily-controllable, and operating cost is low, post-processing operation letter
Just, products obtained therefrom is with high purity, and reagent involved in preparation process is more environmentally friendly, and it is hidden that inflammable and explosive equal safety is also not present
Suffer from bigger substance, type selected by raw material, catalyst is commercial product, and cheap and easily-available, step linking in front and back is close, operation
Mild condition, the route are suitable for wide popularization and application, are highly suitable for large-scale industrial production, which is
The synthesis of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt provides a kind of very feasible operation route, in the art
The relevant technologies blank has been filled up, there is stronger reference application value.
In order to realize above-mentioned purpose of the invention, the following technical scheme is adopted:
The present invention provides a kind of preparation methods of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt intermediate, mainly
Include the following steps:
(A) by one or both of 2- bromine ethamine or 2- bromine ethylamine salt, with two dimethyl dicarbonate butyl methyl esters in alkaline item
It is reacted under part, obtains N- (Boc) -2- bromine ethamine；
(B) N- (Boc) -2- bromine ethamine is reacted under alkaline condition to obtain N- (Boc) -2- methylsulphur with methyl sulfinic acid sodium
Acyl group ethamine；
(C) by N- (Boc) -2- mesyl ethamine be acidified to get.
In the prior art, the synthetic route of universal Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt intermediate exists
Many technical problems, virtually limit its further progressive development, such as US2008/0051422 A1 patent intermediary
A kind of potassium phthalimide of having continued is the synthetic method of raw material, finally obtains purpose product by the operation of seven steps,
Reaction includes the steps that alkylation, sulfhydrylation, changes protection, oxidation, at salt for it, and not only operating procedure is too long for this method, examination used
Agent (1,2- Bromofume, iodomethane, hydrazine hydrate) strong toxicity operates dangerous.Metachloroperbenzoic acid is unstable, explosive,
There are biggish security risks in operating process.Specific reaction equation is as follows:
Describe in US2009/0118259 A1 patent using N- bromoethyl phthalimide as raw material, by with first
Sodium mercaptides react to obtain Sulfide-containing Hindered, then aoxidizing in acetic acid by hydrogen peroxide methylsulfonyl compound, finally use hydrazine hydrate
Deprotection obtains the synthetic route of product, and this method is operated in use due to the strong oxidizing property and strong corrosive of hydrogen peroxide
Inconvenience, it is unfriendly to environment and operator, and the high toxicity of hydrazine hydrate, to operator in use and last handling process
Health have apparent influence.The chemical equation of this method is as follows:
It is described in 2305634 A1 patent of EP using 1- mesyl -2- (toluene -4- sulfonyloxy)-ethane as raw material,
By the amination of dibenzylamine, active nickel catalytic hydrogenation takes off dibenzyl, and at the method that salt obtains product, raw material of this method itself is non-
It often is difficult to obtain, catalyst uses active nickel, the harsher equipment for needing to cooperate high pressure of reaction condition, not only operating cost
Height, and operation with high pressure danger coefficient is high, there is security risk, in addition nickel itself belongs to metal and is easy on fire, increases behaviour
The degree-of-difficulty factor of work.
In addition, being described in US2013/0289029, EP2607363 A1 patent and being with 2- (methyl mercapto) ethylamine hydrochloride
Starting material is protected by Boc, and the oxidation of metachloroperbenzoic acid, the ethyl acetate of hydrogen chloride is deprotected to obtain product, the road
Line is disadvantageous in that raw material 2- (methyl mercapto) ethylamine hydrochloride is expensive, and metachloroperbenzoic acid is unstable, explosive,
There can be biggish security risk in operating process.The reaction equation of this method is as follows:
In addition, being described in the patent of EP1486490 A1 using 2- (methyl mercapto) ethamine as starting material, protected by Boc
Shield, the oxidation of metachloroperbenzoic acid, the ethyl acetate of hydrogen chloride are deprotected to obtain product.The disadvantage of this method is that
Raw material 2- (methyl mercapto) ethamine is expensive, and metachloroperbenzoic acid is unstable, explosive, there is biggish peace in operation
Full hidden danger.
It can be seen that there is the problems such as step is long or cost of material is high in the synthetic method of oneself report.And due to most
Mesyl is obtained using the method for oxidation, reaction is oxidation reaction, and oxidant has unstable mutability, extra
Oxidant in last handling process also can there is a problem of operation it is dangerous and operate it is lengthy and tedious, be unfavorable for very much mass production in this way.
Exactly because many technical problems exist in the prior art, in order to solve the above technical problems, The present invention provides a kind of ratios
The preparation method of easier Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt.
Not only operating procedure is simple for method of the invention, can synthesize purpose product, operation letter only with simple three step
Just, route is short, and without using any oxidant in entire synthesis process, therefore avoids using oxidant unstable factor
It is influence the problem of being normally carried out of reaction more.
Wherein in step (A), 2- bromine ethamine strong acid salt is reacted under alkaline condition with two dimethyl dicarbonate butyl methyl esters, is obtained
To N- (Boc) -2- bromine ethamine, this step first protects the amido of 2- bromine ethamine, and the blocking group is in alkaline condition
Presence that down can be more stable, therefore step reaction is needed to control and be carried out under alkaline condition, alkali used, which can choose, to be suitable for
Add the alkali of protection group-Boc, including but not limited to potassium carbonate, sodium carbonate, triethylamine, n,N-diisopropylethylamine on amido
In one of which, either inorganic base is also possible to organic base, than being more preferably selected as triethylamine, because of triethylamine valence
Lattice itself are cheaper, and alkalinity is the most moderate, select organic base also to contact with raw material more direct.
Reaction dissolvent used in reaction process can choose as tetrahydrofuran, methylene chloride, acetonitrile, N, N- dimethyl methyl
Amide, toluene, ethyl acetate, one of or several mixing in water, but not limited to this, it is therefore an objective to reaction is provided for reaction
Media stage promotes going on smoothly for reaction, the reaction temperature in reaction process so as to can preferably merge into each other between raw material
Degree is preferably controlled between 0-30 DEG C, and the temperature appropriate that reduces can achieve the purpose of control extent of reaction, to reach so that obtaining
The higher purpose of the product purity arrived, temperature can also be 10 DEG C, 20 DEG C, 25 DEG C, the reaction time be preferably controlled in 5-15h it
Between, it can also be 6h, 7h, 8h, 9h, 10h etc., one or both of reaction raw materials 2- bromine ethamine or 2- bromine ethylamine salt, two carbon
Molar ratio between sour di-t-butyl methyl esters and alkali is preferably controlled in (1-2): (1-2): between 3, such ratio can be protected
It demonstrate,proves fully reacting to carry out, will not waste raw material, save the subsequent trouble to redundance processing, therefore raw material is preferably controlled in
In suitable proportional region.It filters after completion of the reaction, is concentrated under reduced pressure to give grease, after organic solvent dissolution washing several times,
It is concentrated under reduced pressure to give purpose product N- (Boc) -2- bromine ethamine of the step, when practical operation, organic solvent used was generally second
Acetoacetic ester, for the product yield of the step up to 95% or more, feed stock conversion is close to theoretical yield 100%.
For example, by taking 2- bromine ethylamine salt is selected as 2- bromine ethylamine hydrochloride, alkali selection triethylamine as an example, the reaction of step (A)
Equation is as follows:
And then in step (B), product N- (the Boc) -2- bromine ethamine and methyl sulfinic acid sodium that step (A) is obtained are in alkali
Property under the conditions of reaction obtain N- (Boc) -2- mesyl ethamine, the step belongs to the committed step in entire synthetic route,
N- (Boc) -2- bromine ethamine in the step is by occurring substitution reaction with methyl sulfinic acid sodium, to introduce methyl sulphonyl base
Group, the presence of alkali are the progress in order to promote reaction, play the role of catalyst, and the alkali of the step, which can choose, to be suitable for replacing
Alkali, including but not limited to sodium hydroxide, potassium hydroxide, triethylamine, n,N-diisopropylethylamine, pyrrole used in halogen ion reaction
Pyridine, sodium carbonate, the one of which in potassium carbonate, preferably potassium carbonate.In reaction process, appropriate heating is reacted, preferably instead
Answer temperature control between 80-130 DEG C, reaction time control terminates in 10-14h or detection until reacting, and reaction temperature may be used also
Think 85 DEG C, 90 DEG C, 95 DEG C, 100 DEG C, 110 DEG C, 120 DEG C, the reaction time can also be 11h, 12h, 13h etc..If temperature mistake
It is low may the step cannot normally carry out, it is therefore desirable to raising reaction temperature appropriate, while when extending the reaction of the step
Between.
After completion of the reaction, need to add organic solvent extraction oil phase, extracting organic solvent used may include but unlimited
One of or several mixing in methylene chloride, tetrahydrofuran, ethyl acetate, toluene, dehydrated alcohol, then will extraction
Oil mutually solidified, solidify used in solvent (solvent generally selects Polarity comparision small) include petroleum ether, ether, isopropyl
Ether, acetone, one of or several mixing in n-hexane, cured temperature is preferably controlled between 0-10 DEG C, in order to add
The cured process of speed, which generally requires, is aided with stirring.For the product yield of the step up to 75% or more, feed stock conversion is close to reason
By conversion ratio.
For example, by taking 2- bromine ethylamine salt is selected as 2- bromine ethylamine hydrochloride, alkali selection potassium carbonate as an example, the reaction of step (B)
Equation is as follows:
In final step (C), N- (Boc) -2- mesyl ethamine is acidified to obtain Lapatinib side chain 2- (sulfonyloxy methyl
Base) ethylamine salt, removes blocking group to realize in acid condition, obtains target product, product is the form of salt, can be direct
For synthesizing Lapatinib, reaction dissolvent is typically chosen dehydrated alcohol, and acid is suitable for sloughing-Boc blocking group in the step
Acid, sulfuric acid, hydrochloric acid, any one in trifluoroacetic acid may be selected, reaction temperature, reaction time have no special requirements, preferably warm
Degree control between 20-30 DEG C, preferred reaction time control in 12-24h, reaction temperature can also for 21 DEG C, 22 DEG C, 23 DEG C,
24 DEG C, 25 DEG C, 26 DEG C etc., the reaction time can also be for 13h, 14h, 15h, 16h, 17h etc., and when general practical operation directly reacts
After being stirred overnight until after detection fully reacting, then to carry out subsequent step.
Subsequent processing is similar compared with step (B) after completion of the reaction, and organic solvent extraction oil phase is added after reaction, so
Afterwards by oily solidifying, final filtration obtains Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt.
Preferably, organic solvent (selecting polar solvent) includes methylene chloride, ethyl acetate, tetrahydrofuran, toluene, nothing
One of which in water-ethanol；
Preferably, solidify solvent used (the selection lesser solvent of polarity) include petroleum ether, ether, isopropyl ether, acetone,
One of or several mixing in n-hexane, cured temperature control is at 0-10 DEG C.The product yield of the step is reachable
95% or more, feed stock conversion is close to theoretical yield.
For example by taking acid selects concentrated hydrochloric acid as an example, the reaction equation of step (C) is as follows:
The overall reaction equation of process route of the invention is as follows:
In short, the synthetic route of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt of the invention gropes to be inventor
It has paid and has finally decided after a large amount of creative work, operating procedure needs execute in strict accordance with the solution of the present invention,
Front and back step cannot overturn, while can not lack any one operating procedure, although step (B) belongs in entire synthetic route
Compare crucial step, but the step of upper blocking group of front and last acidification deprotection group is also step (B) energy
Enough key points smoothly implemented, there are also the concrete operations conditions of each step, including operating time, temperature, solvent used
And post-processing purification step and inventor have passed through what a large amount of practice was determined, be required to control in suitable model
In enclosing, there is no any record about the solution of the present invention in the prior art, only under the conditions of referring to the solution of the present invention
The implementation of the solution of the present invention can be smoothly completed.
Compared with prior art, the invention has the benefit that
(1) preparation method of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt of the invention is avoided using oxidation
Method synthesis target product unstable factor is more, and there is also the generations for operating unsafe problem for obtained product, has developing
Property meaning, provide a kind of easy to operate, high income for subsequent synthesis substance, the high route of product purity has very much
Reference value, the purity of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt for using synthetic method of the invention to obtain can be with
Close to 100%, almost without any impurity；
(2) the preparation method operating procedure of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt of the invention is easy, point
Sub- availability is high, and reaction condition is easily-controllable, and operating cost is low, and post-processing operation is easy, and reagent involved in preparation process compares
It is more environmentally friendly, the bigger substance of the security risks such as inflammable and explosive is also not present, type selected by raw material, catalyst is commercially available production
Product, cheap and easily-available, step linking in front and back is close, and operating condition is mild, is highly suitable for large-scale industrial production.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described.
Fig. 1 is the H-NMR of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt that the embodiment of the present invention 2 is prepared
Figure；
Fig. 2 is the mass spectrogram of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt that the embodiment of the present invention 2 is prepared.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
The conventional products that can be obtained by commercially available purchase.
Embodiment 1
1) 2- bromine ethamine sulfate, potassium carbonate are added to the water and are stirred evenly, is added dropwise (Boc)2The ethyl acetate solution of O,
It finishing, keeps 0 DEG C of reaction, reaction terminates, then is extracted twice with the ethyl acetate of same volume, merges organic liquor, it washes three times,
Anhydrous sodium sulfate is dry, organic phase filtering, is concentrated to give grease N- (Boc) -2- bromine ethamine, and TLC shows single-point, solvent 6:1/
Petroleum ether: ethyl acetate can be directly used for the next step, Y=95%；
2) N- (Boc) -2- bromine ethamine, methyl sulfinic acid sodium, sodium carbonate and solvent n,N-Dimethylformamide sequentially add
In reaction flask, 80 DEG C or so of heating is reacted.End of reaction is concentrated under reduced pressure removing solvent and obtains solids, tetrahydrofuran is added
30min is stirred, filtrate is concentrated to give grease by filtering.Grease is added ether and stirs solidification under the conditions of 0 DEG C, filters to obtain N-
(Boc) -2- mesyl ethamine, TLC show single-point, and solvent 6:1/ petroleum ether: it is anti-to can be directly used for lower step for ethyl acetate
It answers, Y=75%；
3) N- (Boc) -2- mesyl ethamine is dissolved in dehydrated alcohol, and sulfuric acid is added under room temperature, stirs evenly.It stirs
It mixes overnight, next day, dehydrated alcohol is added after reduced pressure, half grease is concentrated under reduced pressure to obtain again, 5 DEG C of stirring 2h of n-hexane, mistake is added
Solid is filtered to obtain, it is air-dried that product Lapatinib side chain 2- (methyl sulphonyl) ethamine sulfate, Y=85%, nuclear magnetic spectrum can be demonstrate,proved
Real product is target product.
Embodiment 2
1) 2- bromine ethylamine hydrochloride, 2- bromine ethylamine hydrobromide, triethylamine are added in tetrahydrofuran and are stirred evenly, cooled down
To 10 DEG C or so, it is added dropwise (Boc)2The tetrahydrofuran solution of O (i.e. two dimethyl dicarbonate butyl methyl esters), finishes, and keeps 10 DEG C of stirrings
10h, filtering, filtrate decompression are concentrated to give grease, and grease adds ethyl acetate to dissolve, and three times, organic layer is concentrated under reduced pressure for washing
N- (Boc) -2- bromine ethamine, Y=95%, wherein mole between 2- bromine ethylamine salt, two dimethyl dicarbonate butyl methyl esters and triethylamine
Than controlling in 2:2:3；TLC shows main single-point, and solvent 6:1/ petroleum ether: ethyl acetate can be directly used for the next step；
2) N- (Boc) -2- bromine ethamine, methyl sulfinic acid sodium, potassium carbonate and solvent n,N-Dimethylformamide sequentially add
In reaction flask, heat up 80-130 DEG C or so holding 12h.End of reaction is concentrated under reduced pressure removing solvent and obtains solids, dichloromethane is added
Alkane stirs 30min, and filtrate is concentrated to give grease by filtering.Grease is added petroleum ether and stirs solidification under the conditions of 5 DEG C, filters
N- (Boc) -2- mesyl ethamine is obtained, Y=75%, TLC show main single-point, solvent 6:1/ petroleum ether: ethyl acetate, it can
It is directly used in the next step；
3) N- (Boc) -2- mesyl ethamine is dissolved in ethyl alcohol, and hydrochloric acid is added under room temperature, stirs evenly.It is stirred
Night, next day are added dehydrated alcohol and half grease are concentrated under reduced pressure to obtain again, be added between isopropyl ether and 5-10 DEG C of acetone after reduced pressure
2h is stirred, the solid was filtered, air-dries to obtain product Lapatinib side chain 2- (methyl sulphonyl) hydrochloride, Y=88%, nuclear magnetic spectrum
Confirm that product is target product, purity > 99% with mass spectrum.
It is as shown in Figs. 1-2 that the embodiment finally obtains product validation map, wherein in Fig. 1, HNMR (400MHZ, D2O)δ
In 3.67 (t, J=6.6Hz, 2H), 3.56 (t, J=6.6Hz, 2H), 3.19 (s, 3H), Fig. 2, [M+H]=124.3.
Embodiment 3
1) 2- bromine aminophenylsulfonic acid salt, n,N-diisopropylethylamine are added in tetrahydrofuran and are stirred evenly, cool to 10 DEG C
Left and right is added dropwise (Boc)2The tetrahydrofuran solution of O, finishes, and keeps 30 DEG C of stirring 5h, and filtering, filtrate decompression is concentrated to give grease,
Grease adds ethyl acetate to dissolve, and three times, N- (Boc) -2- bromine ethamine, Y=95% is concentrated under reduced pressure to obtain in organic layer for washing, wherein
Molar ratio between 2- bromine aminophenylsulfonic acid salt, two dimethyl dicarbonate butyl methyl esters and triethylamine is controlled in 1:1:3；TLC shows single-point,
Solvent 6:1/ petroleum ether: ethyl acetate can be directly used for the next step；
2) N- (Boc) -2- bromine ethamine, methyl sulfinic acid sodium, pyridine and solvent n,N-Dimethylformamide sequentially add instead
It answers in bottle, heat up 80 DEG C or so holding 10h.End of reaction is concentrated under reduced pressure removing solvent and obtains solids, methylene chloride and second is added
The mixture of acetoacetic ester stirs 30min, and filtrate is concentrated to give grease by filtering.The mixed of petroleum ether and n-hexane is added in grease
It closes object and stirs solidification under the conditions of 10 DEG C, filter to obtain N- (Boc) -2- mesyl ethamine, Y=75%；TLC shows main single
Point, solvent 6:1/ petroleum ether: ethyl acetate can be directly used for the next step；
3) N- (Boc) -2- mesyl ethamine is dissolved in ethyl alcohol, and hydrochloric acid is added under room temperature, stirs evenly.30 DEG C are stirred
12h is mixed, half grease is concentrated under reduced pressure to obtain in the mixture that dehydrated alcohol and ethyl acetate are added after reduced pressure again, and isopropyl ether is added
With 0 DEG C of stirring 2h of acetone, the solid was filtered, air-dries to obtain product Lapatinib side chain 2- (methyl sulphonyl) hydrochloride, Y=
88%, nuclear magnetic spectrum confirms that product is target product.
Embodiment 4
1) 2- bromine ethylamine hydrobromide, triethylamine are added in tetrahydrofuran and are stirred evenly, cool to 10 DEG C or so, be added dropwise
(Boc)2The tetrahydrofuran solution of O, finishes, and keeps 20 DEG C of stirring 15h, and filtering, filtrate decompression is concentrated to give grease, and grease adds
Ethyl acetate dissolution, three times, N- (Boc) -2- bromine ethamine, Y=97%, wherein 2- bromine ethamine is concentrated under reduced pressure to obtain in organic layer for washing
Molar ratio between hydrobromate, two dimethyl dicarbonate butyl methyl esters and triethylamine is controlled in 1.5:1.5:2；TLC shows main single
Point, solvent 6:1/ petroleum ether: ethyl acetate can be directly used for the next step；
2) N- (Boc) -2- bromine ethamine, methyl sulfinic acid sodium, potassium carbonate, n,N-diisopropylethylamine and solvent N, N- diformazan
Base formamide sequentially adds in reaction flask, and heat up 130 DEG C or so holding 14h.End of reaction is concentrated under reduced pressure removing solvent and obtains solid
Object is added tetrahydrofuran and stirs 30min, and filtrate is concentrated to give grease by filtering.The mixing of grease addition acetone and n-hexane
Object stirs solidification under the conditions of 0 DEG C, filters to obtain N- (Boc) -2- mesyl ethamine, Y=77%；TLC shows single-point, solvent
6:1/ petroleum ether: ethyl acetate can be directly used for the next step；
3) N- (Boc) -2- mesyl ethamine is dissolved in methylene chloride, and trifluoroacetic acid is added under room temperature, and stirring is equal
It is even.20 DEG C of stirrings are added methylene chloride for 24 hours, after reduced pressure and half grease are concentrated under reduced pressure to obtain again, and isopropyl ether and acetone 10 is added
DEG C stirring 2h, the solid was filtered, air-dry to obtain product Lapatinib side chain 2- (methyl sulphonyl) trifluoroacetate, Y=89%, core
Magnetic chart spectrum confirms that product is target product.
Comparative example 1
The Lapatinib side chain 2- (methyl being prepared using the preparation method of embodiment 1 in EP1486490 A1 patent
Sulfonyl) hydrochloride, Y=68%, purity 99%.
Although illustrate and describing the present invention with specific embodiment, it will be appreciated that without departing substantially from of the invention
Many other change and modification can be made in the case where spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (10)
1. a kind of preparation method of Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt, which comprises the steps of:
(A) by one or both of 2- bromine ethamine or 2- bromine ethylamine salt, under alkaline condition with two dimethyl dicarbonate butyl methyl esters
Reaction, obtains N- (Boc) -2- bromine ethamine；
(B) N- (Boc) -2- bromine ethamine is reacted under alkaline condition to obtain N- (Boc) -2- mesyl with methyl sulfinic acid sodium
Ethamine；
(C) N- (Boc) -2- mesyl ethamine is acidified, to obtain 2- (methyl sulphonyl) ethylamine salt.
2. preparation method according to claim 1, which is characterized in that in the step (A), 2- bromine ethamine or 2- bromine ethamine
Salt includes one of 2- bromine ethylamine hydrochloride, 2- bromine ethylamine hydrobromide, 2- bromine aminophenylsulfonic acid salt, 2- bromine ethamine sulfate；
Preferably 2- bromine ethylamine hydrobromide and 2- bromine ethylamine hydrochloride.
3. preparation method according to claim 1, which is characterized in that in the step (A), alkali used include sodium carbonate,
One of potassium carbonate, triethylamine, n,N-diisopropylethylamine, preferably triethylamine；
Preferably, reaction dissolvent is tetrahydrofuran, methylene chloride, acetonitrile, n,N-Dimethylformamide, toluene, ethyl acetate, water
One or more of mixing.
4. preparation method according to claim 1, which is characterized in that in the step (A), reaction temperature is controlled in 0-30
Between DEG C, the reaction time is controlled in 5-15h；
Preferably, between one or both of 2- bromine ethamine or 2- bromine ethylamine salt, two dimethyl dicarbonate butyl methyl esters and alkali
Molar ratio is controlled at (1-2): (1-2): between 3.
5. preparation method according to claim 1, which is characterized in that in the step (B), alkali used includes hydroxide
One of sodium, potassium hydroxide, triethylamine, n,N-diisopropylethylamine, pyridine, sodium carbonate, potassium carbonate, preferably potassium carbonate.
6. preparation method according to claim 1, which is characterized in that in the step (B), reaction temperature is controlled in 80-
Between 130 DEG C, the reaction time is controlled in 10-14h.
7. preparation method according to claim 1, which is characterized in that in the step (B), during post-reaction treatment,
Organic solvent extraction oil phase, filtering and concentrating are added, N- (Boc) -2- mesyl ethamine is obtained by filtration in oily solidifying；
Preferably, organic solvent includes one or more of methylene chloride, tetrahydrofuran, toluene, ethyl acetate, dehydrated alcohol
Mixing；
Preferably, solidifying solvent used includes the mixed of one or more of petroleum ether, ether, isopropyl ether, acetone, n-hexane
It closes；
Preferably, cured temperature control is at 0-10 DEG C.
8. preparation method according to claim 1, which is characterized in that in the step (C), acid used includes sulfuric acid, salt
One of acid, trifluoroacetic acid.
9. preparation method according to claim 1, which is characterized in that in the step (C), reaction temperature is controlled in 20-
Between 30 DEG C, the reaction time is controlled between 12-24h.
10. preparation method according to claim 1, which is characterized in that in the step (C), added after reaction organic molten
Lapatinib side chain 2- (methyl sulphonyl) ethylamine salt is obtained by filtration in oily solidifying by agent extraction oil phase；
Preferably, organic solvent includes one of methylene chloride, tetrahydrofuran, ethyl acetate, toluene, dehydrated alcohol；
Preferably, solidifying solvent used includes the mixed of one or more of petroleum ether, ether, isopropyl ether, acetone, n-hexane
It closes；
Cured temperature is preferably controlled between 0-10 DEG C.
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| EP1486490A1 (en) * | 2002-02-28 | 2004-12-15 | Takeda Chemical Industries, Ltd. | Azole compounds |
| US20100234351A1 (en) * | 2006-02-23 | 2010-09-16 | Takeda Pharmaceutical Company Limited | Fused nitrogen-comprising heterocyclic compound |
| CN102146075A (en) * | 2010-02-06 | 2011-08-10 | 浙江九洲药业股份有限公司 | Preparation method of quinazoline compound |
| CN102372710A (en) * | 2010-08-18 | 2012-03-14 | 山东轩竹医药科技有限公司 | Fused cyclic compound being taken as mineral corticoid recept antagonist |
| CN104945411A (en) * | 2014-03-27 | 2015-09-30 | 南京勇山生物科技有限公司 | Thieno-[3,2-c] pyridine type compound as well as preparation method and application thereof |
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2016
- 2016-10-11 CN CN201811448974.0A patent/CN109535047A/en active Pending
- 2016-10-11 CN CN201610887957.1A patent/CN106478473A/en active Pending
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| EP1486490A1 (en) * | 2002-02-28 | 2004-12-15 | Takeda Chemical Industries, Ltd. | Azole compounds |
| US20100234351A1 (en) * | 2006-02-23 | 2010-09-16 | Takeda Pharmaceutical Company Limited | Fused nitrogen-comprising heterocyclic compound |
| CN102146075A (en) * | 2010-02-06 | 2011-08-10 | 浙江九洲药业股份有限公司 | Preparation method of quinazoline compound |
| CN102372710A (en) * | 2010-08-18 | 2012-03-14 | 山东轩竹医药科技有限公司 | Fused cyclic compound being taken as mineral corticoid recept antagonist |
| CN104945411A (en) * | 2014-03-27 | 2015-09-30 | 南京勇山生物科技有限公司 | Thieno-[3,2-c] pyridine type compound as well as preparation method and application thereof |
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