CN107118164B - 5-氯-6-(氯甲基)-2,4-(1h,3h)-嘧啶二酮的制备方法 - Google Patents
5-氯-6-(氯甲基)-2,4-(1h,3h)-嘧啶二酮的制备方法 Download PDFInfo
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- CN107118164B CN107118164B CN201710068339.9A CN201710068339A CN107118164B CN 107118164 B CN107118164 B CN 107118164B CN 201710068339 A CN201710068339 A CN 201710068339A CN 107118164 B CN107118164 B CN 107118164B
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- Prior art keywords
- chloro
- pyrimidinedione
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- chloromethyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- BXVCXZREYQLVTA-UHFFFAOYSA-N 5-chloro-6-(chloromethyl)-1h-pyrimidine-2,4-dione Chemical compound ClCC=1NC(=O)NC(=O)C=1Cl BXVCXZREYQLVTA-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title claims abstract description 11
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960005010 orotic acid Drugs 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 239000007858 starting material Substances 0.000 claims abstract description 7
- 150000001875 compounds Chemical group 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 239000012320 chlorinating reagent Substances 0.000 claims description 5
- -1 chloro orotic acid compound Chemical class 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 abstract description 12
- 238000006073 displacement reaction Methods 0.000 abstract description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- SHVCSCWHWMSGTE-UHFFFAOYSA-N 6-methyluracil Chemical compound CC1=CC(=O)NC(=O)N1 SHVCSCWHWMSGTE-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- LESKGPCWILSNGK-UHFFFAOYSA-N 5-chloro-6-(hydroxymethyl)-1H-pyrimidine-2,4-dione Chemical compound ClC=1C(NC(NC=1CO)=O)=O LESKGPCWILSNGK-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 3
- 239000011592 zinc chloride Substances 0.000 description 3
- 235000005074 zinc chloride Nutrition 0.000 description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 2
- VXEGSRKPIUDPQT-UHFFFAOYSA-N 4-[4-(4-methoxyphenyl)piperazin-1-yl]aniline Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C=CC(N)=CC=2)CC1 VXEGSRKPIUDPQT-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000005831 deiodination reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 2
- 230000026045 iodination Effects 0.000 description 2
- 238000006192 iodination reaction Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000005049 silicon tetrachloride Substances 0.000 description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical class C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102000013537 Thymidine Phosphorylase Human genes 0.000 description 1
- 229940122020 Thymidine phosphorylase inhibitor Drugs 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 238000007602 hot air drying Methods 0.000 description 1
- 238000007038 hydrochlorination reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- UUTDWTOZAWFKFW-UHFFFAOYSA-N methyl 2,4-dioxo-1h-pyrimidine-6-carboxylate Chemical compound COC(=O)C1=CC(=O)NC(=O)N1 UUTDWTOZAWFKFW-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- JLKDVMWYMMLWTI-UHFFFAOYSA-M potassium iodate Chemical compound [K+].[O-]I(=O)=O JLKDVMWYMMLWTI-UHFFFAOYSA-M 0.000 description 1
- 239000001230 potassium iodate Substances 0.000 description 1
- 235000006666 potassium iodate Nutrition 0.000 description 1
- 229940093930 potassium iodate Drugs 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IDXKTTNFXPPXJY-UHFFFAOYSA-N pyrimidin-1-ium;chloride Chemical compound Cl.C1=CN=CN=C1 IDXKTTNFXPPXJY-UHFFFAOYSA-N 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- URQGXYPRWDOYQY-UHFFFAOYSA-N selenium dioxide selenous acid Chemical compound [Se](O)(O)=O.[Se](=O)=O URQGXYPRWDOYQY-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Chemical group 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- QQHMKNYGKVVGCZ-UHFFFAOYSA-N tipiracil Chemical compound N1C(=O)NC(=O)C(Cl)=C1CN1C(=N)CCC1 QQHMKNYGKVVGCZ-UHFFFAOYSA-N 0.000 description 1
- 229960002952 tipiracil Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- PPDADIYYMSXQJK-UHFFFAOYSA-N trichlorosilicon Chemical compound Cl[Si](Cl)Cl PPDADIYYMSXQJK-UHFFFAOYSA-N 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本专利提供一种5‑氯‑6‑氯甲基‑2,4‑(1H,3H)‑嘧啶二酮的制备方法,以乳清酸为起始原料,通过α氢的氯代反应,再直接还原羧基为羟甲基,并进行氯化置换反应等三步反应,得到目标产物。本发明操作简单,工艺稳定,产率高,成本低,适合工业生产。
Description
技术领域
本发明涉及药物化学合成领域,具体涉及一种药物前体5-氯-6-(氯甲基)-2,4-(1H,3H)-嘧啶二酮的制备方法。
背景技术
5-氯-6-(氯甲基)-2,4-(1H,3H)-嘧啶二酮用于制备核苷尿嘧啶或其盐类似物替吡嘧啶盐酸盐(TPI)的重要的合成前体,其结构如下:
日本大鹏(Tahoe Oncology)公司开发的一种新型抗代谢复方新药物TAS-102片剂,FDA批准上市。它是一种由抗肿瘤核苷类似物三氟胸苷(曲氟尿苷,Trifluridine,简称FID)和胸苷磷酸化酶抑制剂替吡嘧啶(Tipiracil,替吡嘧啶盐酸盐,简称TPI)组成的复方药物,用于化疗及生物疗法不再响应的难治性转移结直肠癌患者的治疗。TAS-102是细胞毒素FTD和TPI的组合复方新药,TPI是FTD降解酶胸苷磷酸化酶的抑制剂,可阻止FTD口服后分解,TS102对于治疗不可切除的晚期复发性结直肠癌患者,意义重大,TPI是构成一种新型抗代谢复方新药物TAS-102的重要组分。
5-氯-6-(氯甲基)-2,4-(1H,3H)-嘧啶二酮(CAS:73742-45-7)简称CCMU,是构成TPI结构单元片段,文献报道CCMU是合成TPI唯一的关键性前体,直接合成TPI(替吡嘧啶盐酸盐:5-氯-6-[(2-亚氨基-1-吡咯烷)甲基]-尿嘧啶盐酸盐)。专利WO9630346等公开文献报道的制备方法如下:
因此,符合技术规格要求的CCMU及其制备方法,是决定TPI产品质量和成本的关键性因素。
涉及CCMU制备方法的相关报道,有很多公开文献。如Thomas I Kalman,Li Lai等(Nucleosides,Nucleotides&Nucleic Acids,2005,24(5-7):367-373);Corelli,Federico等(Farmaco,2004,59(12):987-992),McNally,Virginia A.等(Journal of Pharmacy andPharmacology,2007,59(4):537-547),Sun,lingyi等(European Journal of MedicinalChemistry,2013,70:400-410),Yano,Shingo等(Bioorganic&Medicinal Chemistry,2004,12(13):3431-3441),Murray,Paul E.等(Bioorganic&Medicinal Chemistry,2002,10(3):525-530),Cole,Christian等(Journal of Medicinal Chemistry,2003,46(2):207-209),Jansa,Petr等(Collection of Czech.Chem.Communications,2011:76(9),1121-1131),以及专利WO9630346等众多文献报道CCMU合成路线如下:
这些文献报道CCMU制备都是以6-甲基尿嘧啶(化合物A0)为原料,通过氧化、还原、6位氯化和5位氯代等步骤合成出CCMU,其总收率仅为18%。反应过程中,化合物A2和A3,在大多数有机溶剂溶解性极低,产品纯化精制工艺复杂,质量稳定性差,且CCMU的制备成本会成倍增加(成本达十几万元/公斤),进一步影响TPI产品质量和成本。因此,这一工艺路线存在影响成品质量和生产成本的缺陷。袁金桥等在专利CN105906573A申请中,提出CCMU合成新路线如下:
与WO9630346等相比,CN105906573A以6-甲基尿嘧啶A0为原料,试图通过碘代、还原、脱碘得到化合物A3,A3总收率达33%,再通过类似WO9630346方法,合成出CCMU,其中采用了价格较贵碘化试剂碘化钾和碘酸钾,选择对水敏感的有机金属试剂正丁基锂作为脱碘试剂,反应过程需要在无水无氧和极低温度(-80℃以下)极苛刻工况条件完成,尽管过程中中间体溶解性有所改善,合成路线有新意,但这一路线有6步反应步骤,从提高成品质量和降低制造成本的角度来讲,这一合成路线存在技术优势不显著的缺陷。孙平等在专利CN104945384A申请中提出改进CCMU合成路线如下:
这一专利路线,以6-甲基尿嘧啶A0为原料,通过氧化、5位氯代、还原和6位氯化步骤,合成出化合物A1、A’2和A’3,再氯化合成出CCMU。与WO9630346相比,化合物A’2和A’3的溶解性,比相对应的化合物A2和A3的溶解性有很大改善,CCMU总收率提高两倍(37%),成品质量提高,生产成本有望降低。
由上可知,上述提及的所有公开文献的技术路线,都是以6-甲基尿嘧啶A0为起始原料,这决定了不可避免要采用选择性氧化剂二氧化硒(亚硒酸)。众所周知,二氧化硒具有急性毒性,剧毒品,对皮肤粘膜刺激作用似二氧化硫,大鼠吸入二氧化硒蒸汽150~600mg/m3动物立即死亡,该品根据《危险化学品安全管理条例》受公安部门管制,原料不易得,而且价格昂贵。
发明内容
本发明目的在于解决上述技术问题,提供一种纯度高、收率高的CCMU制备方法。采用价格低廉规模化原料,不以6-甲基尿嘧啶为起始原料,避免采用选择性氧化剂二氧化硒所带来的困扰,该制备方法操作简单,适合工业化,有利于进一步合成高质量低成本的TPI。
本发明是通过以下技术方案实现的:
CCMU制备方法,包括以下步骤:
a.以乳清酸B0(无水或含有结晶水)为起始原料在有机溶剂A中,加入氯化剂,催化剂,于合适的温度下通过氯代反应得到化合物B1;
b.化合物B1在有机溶剂B中,于合适的温度下采用还原剂,在催化剂作用下,将6位还原,得到6-羟甲基化合物B2;
c.化合物B2在有机溶剂C中,于合适的温度下,加入氯化剂,将6-羟甲基化合物B2中6位羟基氯化置换反应得到CCMU;
优先的,所述的有机溶剂A选自水,二氯甲烷,二氯乙烷,三氯乙烷,四氯乙烷,冰醋酸,三氟乙酸,乙腈,更优选的是冰醋酸。
优先的,步骤a中所述的氯化剂选自磺酰氯,N-氯代丁二酰亚胺,四氯化硅,四氯化钛,氯气,次氯酸,高氯酸,更优选的是磺酰氯。
优先的,步骤a中催化剂选自醋酐,三氟甲磺酸酐,三氟乙酸酐,三氯化铁,二氯化铁,三氯化铝,三氟化硼,更优选的是醋酐和三氯化铁。
优先的,步骤a中所述的合适温度范围为10~100℃,更优选的温度是80~100℃。
优先的,所述的有机溶剂B选自水,甲醇,乙醇,三氟乙醇,乙二醇单甲醚,四氢呋喃,二甲基亚砜,N,N-二甲基甲酰胺,乙腈,或其混合溶剂,更优选的是四氢呋喃和甲醇混合物溶剂。
优先的,步骤b中所述的还原剂选自氢化锂铝、红铝(双(2-甲氧乙氧基)氢化铝钠),双(二乙基氨基)氢化铝钠,硼氢化钠,硼氢化钾,硼氢化锌,硼氢化锂,硼氢化钙,更优选的是硼氢化钠。
优先的,步骤b中所述的催化剂选自单质碘,三氯化铝,三氯氢硅,氯化锌更优选的是氯化锌。
优先的,步骤c中所述的合适温度范围为-10~50℃,更优选的温度是0~10℃。
优先的,所述的有机溶剂C选自二氯甲烷,二氯乙烷,三氯乙烷,四氯乙烷,冰醋酸,三氟乙酸,乙腈,更优选的是二氯甲烷。
优先的,步骤c中所述的氯化剂选自甲磺酸氯,氯化亚砜,N-氯代丁二酰亚胺,四氯化硅,四氯化钛,氯气,次氯酸,高氯酸,更优选的是氯化亚砜。
优先的,步骤c中所述的合适温度范围为0~80℃,更优选的温度是20~50℃。
特别优先的,所述制备方法合成路线如下:
本发明的有益效果在于:
本发明以乳清酸为起始原料,先通过乳清酸α-位氯代反应,得到α-氯代乳清酸化合物B1,直接对羧基进行还原为羟甲基,再进行氯代反应。本发明避免采用选择性氧化剂剧毒品二氧化硒,安全可靠。
以起始原料乳清酸经过α位氯代反应得到α-氯代乳清酸(化合物B1),具有良好溶解性,有利于进行还原和氯化置换反应,可制备出高质量化合物CCMU,合成步骤短,总收率达73%以上,是文献报道总收率(18%)4倍,是孙平等人申请的专利CN104945384A公开的总收率2倍。
本发明起始原料来源于工业化规模生产,价格低廉,生产成本低,工艺稳定可靠,对制备高质量的替吡嘧啶盐酸盐(TPI)提供关键性药物前体,有利于工业化生产。
具体实施方式
以下将结合实施例对本发明进行详细描述。但发明的内容并非局限于这些实施例,所有实例方式并不限制本发明。本领域的普通技术人员根据这些实施方式所做出的方法上的变换均包含在本发明的保护范围内。
步骤a反应式:
实施例1:
将78g(0.50mol)乳清酸(B0)加入700ml醋酸中,并加入25ml醋酐和催化量三氯化铁,加热到90-95℃,滴加108g(0.80mol)磺酰氯(FW135),加料完毕,升温回流过夜,直到乳清酸甲酯完全氯代(TLC检测)停止反应,将反应溶液降温到10℃,过滤得到固体,依次用醋酸和水淋洗,热风干燥,得到黄色固体,测熔点:mp:288℃,得到88.0g(0.46mol)α-氯代乳清酸(B1),摩尔收率92%。
1HNMR(400MHz,DMSO-d6)δH11.82(1H,s),11.61(1H,s),3.82(3H,s)
实施例2:
将67g(0.35mol)乳清酸加入含%NaOH 500ml水溶液,加热30-45℃完全溶解,加入70g(0.45mol)N-氯代丁二酰亚胺,加热到过夜,直到乳清酸完全氯代(TLC检测)停止反应,将反应溶液降温到10℃,慢慢加入5%HCl溶液,调节pH=1.0,过滤得到固体,用乙醇重结晶,热风干燥,得到浅黄色固体,测熔点:mp:285℃,得到57.0g(0.30mol)α-氯代乳清酸(B1),摩尔收率86%。
1H NMR(400MHz,DMSO-d6)δH11.80(1H,s),11.60(1H,s)
步骤b反应式:
实施例3:
将46g(0.24mol)α-氯代乳清酸(B1)和38g(1.0mol)硼氢化钠粉末分散在200ml四氢呋喃溶液中,强力搅拌,慢慢加入25ml甲醇,回流14小时,TLC检测反应,冷却到室温,加入300mlNH4Cl水溶液,继续搅拌10h,分出有机层,水相用300ml乙酸乙酯分三次萃取,合并有机相,用硫酸镁干燥并过滤除去,得到浅黄色有机相,浓缩至干,用乙醇重结晶,得到浅黄色固体,得到40g(0.22mol)5-氯-6-(羟甲基)--2,4-(1H,3H)-嘧啶二酮(B2),摩尔收率90%。。
1HNMR(400MHz,DMSO-d6)δH11.30(1H,s),11.40(1H,s),4.65(2H,s)
实施例4:
在强力搅拌下,将25g(0.66mol)硼氢化钠粉末和5g(0.04mol)氯化锌粉末,分散在150ml四氢呋喃溶液中,慢慢加入19g(0.10mol)α-氯代乳清酸(B1),回流14小时以上,冷却到室温,加入20mlNH4Cl水溶液,继续搅拌15h,分出有机层,水相用200ml乙酸乙酯分三次萃取,合并有机相,用硫酸镁干燥并过滤除去,得到黄色有机相,浓缩至干,用乙醇重结晶,得浅黄色固体,测熔点,得到5-氯-6-(羟甲基)--2,4-(1H,3H)-嘧啶二酮(B2)。
步骤c反应式:
实施例5:
在25-30℃温度下将60g(0.34mol)5-氯-6-(羟甲基)--2,4-(1H,3H)-嘧啶二酮(B2)和20mlDMF依次加入到600ml二氯甲烷溶剂中,升温加热至回流,慢慢滴加400g氯化亚砜(重蒸),加料完毕,继续回流直至化合物B3物料消失终止反应,冷至室温过滤,滤饼用二氯甲烷淋洗,用热水洗涤,收集滤饼,在50-60℃温度下,热风烘干,得到62g(0.32mol)黄色固体,5-氯-6-(氯甲基)-2,4-(1H,3H)-嘧啶二酮(CCMU)收率92%。
IR(KBr)3161,3042,2844,1702,1694,1428,1287,826,744cm-1
1H NMR(DMSO-d6)δ4.73(s,2H),11.1(br,s,2H).
13C NMR(DMSO-d6)δ163(c),151(C),150(C),100(CH),50(CHz).
MS 194.9(M+H)+
Claims (2)
1.一种5-氯-6-(氯甲基)-2,4-(1H,3H)-嘧啶二酮(CAS:73742-45-7,简称CCMU)的制备方法,其特征在于,合成路线为:
包括以下步骤:
a.以乳清酸为起始原料在有机溶剂A中,加入氯代试剂,催化剂,于合适的温度下通过氯代反应得到α氯代乳清酸化合物B1;
b.化合物B1在有机溶剂B中,于合适的温度下采用还原剂试剂,在催化剂作用下,将6位还原,得到6-羟甲基化合物B2;
c.化合物B2在有机溶剂C中,于合适的温度下,加入氯化试剂,将B2的6位羟基氯化得到目标产物5-氯-6-(氯甲基)-2,4-(1H,3H)-嘧啶二酮CCMU。
2.根据权利要求1所述的5-氯-6-(氯甲基)-2,4-(1H,3H)-嘧啶二酮的制备方法,其特征在于,所述的起始原料是乳清酸。
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