JP7379346B2 - 6-クロロメチルウラシルの合成方法 - Google Patents
6-クロロメチルウラシルの合成方法 Download PDFInfo
- Publication number
- JP7379346B2 JP7379346B2 JP2020541405A JP2020541405A JP7379346B2 JP 7379346 B2 JP7379346 B2 JP 7379346B2 JP 2020541405 A JP2020541405 A JP 2020541405A JP 2020541405 A JP2020541405 A JP 2020541405A JP 7379346 B2 JP7379346 B2 JP 7379346B2
- Authority
- JP
- Japan
- Prior art keywords
- methylthio
- chloromethyl
- chloromethyluracil
- hydroxy
- dihydropyrimidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- VCFXBAPEXBTNEA-UHFFFAOYSA-N 6-(chloromethyl)-1h-pyrimidine-2,4-dione Chemical compound ClCC1=CC(=O)NC(=O)N1 VCFXBAPEXBTNEA-UHFFFAOYSA-N 0.000 title claims description 18
- 238000001308 synthesis method Methods 0.000 title 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 18
- UDGZXFYXQXZEBO-UHFFFAOYSA-N 4-(chloromethyl)-4-hydroxy-2-methylsulfanyl-1,5-dihydropyrimidin-6-one Chemical compound ClCC1(CC(N=C(N1)SC)=O)O UDGZXFYXQXZEBO-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- XJZYFWNWTOAHTR-UHFFFAOYSA-N 6-(chloromethyl)-2-methylsulfanyl-1h-pyrimidin-4-one Chemical compound CSC1=NC(=O)C=C(CCl)N1 XJZYFWNWTOAHTR-UHFFFAOYSA-N 0.000 claims description 8
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- LGQWXVFWJYLQFT-UHFFFAOYSA-N 4-(chloromethyl)-2-methylsulfanylpyrimidine Chemical compound CSC1=NC=CC(CCl)=N1 LGQWXVFWJYLQFT-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 22
- 239000000047 product Substances 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 11
- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 8
- UFFDUWYBBNRDNJ-UHFFFAOYSA-N 6-(methylsulfanylmethyl)-1h-pyrimidine-2,4-dione Chemical compound CSCC1=CC(=O)NC(=O)N1 UFFDUWYBBNRDNJ-UHFFFAOYSA-N 0.000 description 7
- 239000006227 byproduct Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- BZZXQZOBAUXLHZ-UHFFFAOYSA-N (c-methylsulfanylcarbonimidoyl)azanium;sulfate Chemical compound CSC(N)=N.CSC(N)=N.OS(O)(=O)=O BZZXQZOBAUXLHZ-UHFFFAOYSA-N 0.000 description 6
- 239000012467 final product Substances 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001345 alkine derivatives Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000007344 nucleophilic reaction Methods 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- VUQNLIDVEFIQLP-UHFFFAOYSA-N 2,4-dioxo-1h-pyrimidine-6-carbaldehyde Chemical compound OC1=CC(C=O)=NC(O)=N1 VUQNLIDVEFIQLP-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- SHVCSCWHWMSGTE-UHFFFAOYSA-N 6-methyluracil Chemical compound CC1=CC(=O)NC(=O)N1 SHVCSCWHWMSGTE-UHFFFAOYSA-N 0.000 description 2
- 229910000497 Amalgam Inorganic materials 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- SDDKIZNHOCEXTF-UHFFFAOYSA-N methyl carbamimidothioate Chemical compound CSC(N)=N SDDKIZNHOCEXTF-UHFFFAOYSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 239000011669 selenium Substances 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000009283 thermal hydrolysis Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- QQHMKNYGKVVGCZ-UHFFFAOYSA-N tipiracil Chemical compound N1C(=O)NC(=O)C(Cl)=C1CN1C(=N)CCC1 QQHMKNYGKVVGCZ-UHFFFAOYSA-N 0.000 description 2
- 229960002952 tipiracil Drugs 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 239000003440 toxic substance Substances 0.000 description 2
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 1
- JKQPOIFPYSSTDO-UHFFFAOYSA-N 5-chloro-4-(chloromethyl)-2-methylsulfanyl-1H-pyrimidin-6-one Chemical compound ClC=1C(NC(=NC1CCl)SC)=O JKQPOIFPYSSTDO-UHFFFAOYSA-N 0.000 description 1
- WIGTZXYNJNXPDU-UHFFFAOYSA-N 6-(chloromethyl)-1h-pyrimidine-2,4-dione Chemical compound ClCC1=CC(=O)NC(=O)N1.ClCC1=CC(=O)NC(=O)N1 WIGTZXYNJNXPDU-UHFFFAOYSA-N 0.000 description 1
- OCOHPSHRDKBGOZ-UHFFFAOYSA-N 6-methyl-2-methylsulfanyl-1h-pyrimidin-4-one Chemical compound CSC1=NC(=O)C=C(C)N1 OCOHPSHRDKBGOZ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 1
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- KQJQICVXLJTWQD-UHFFFAOYSA-N N-Methylthiourea Chemical compound CNC(N)=S KQJQICVXLJTWQD-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229940127346 Thymidine Phosphorylase Inhibitors Drugs 0.000 description 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical group O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- CKSRFHWWBKRUKA-UHFFFAOYSA-N ethyl 2-ethoxyacetate Chemical compound CCOCC(=O)OCC CKSRFHWWBKRUKA-UHFFFAOYSA-N 0.000 description 1
- RQCOPVYEHVOEMR-UHFFFAOYSA-N ethyl 4-ethoxy-3-oxobutanoate Chemical compound CCOCC(=O)CC(=O)OCC RQCOPVYEHVOEMR-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 238000011066 ex-situ storage Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229960005010 orotic acid Drugs 0.000 description 1
- 239000007800 oxidant agent Substances 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
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- 231100000701 toxic element Toxicity 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound 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 1
- 229960003962 trifluridine Drugs 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
-
- 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
-
- 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
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
Description
Heterocycl. Commun., 2013, 19(6), 401-404は、ポリリン酸(PPA)存在下における4-クロロアセト酢酸エチルと尿素の熱縮合を報告している。
本発明の目的は、以下の工程を含む、6-クロロメチルウラシルの調製方法である:
a)4-クロロアセト酢酸エチルとS-メチルイソチオ尿素ヘミスルフェートを反応させて、単離された中間体6-(クロロメチル)-6-ヒドロキシ-2-(メチルチオ)-5,6-ジヒドロピリミジン-4(1H)-オンを得る;
b)該6-(クロロメチル)-6-ヒドロキシ-2-(メチルチオ)-5,6-ジヒドロピリミジン-4(1H)-オンと硫酸水溶液との反応により、6-クロロメチルウラシルを得る。
a)4-クロロアセト酢酸エチルとS-メチルイソチオ尿素ヘミスルフェートから、好ましくは低温で、新規中間体6-(クロロメチル)-6-ヒドロキシ-2-(メチルチオ)-5,6-ジヒドロピリミジン-4(1H)-オンを得て単離する。中間体の単離は、続くウラシル骨格を形成するための加水分解工程において、メチルメルカプタン(毒性ガス)の放出を伴い、加水分解速度の変動を特に起こしやすくする結果、ガス発生の制御を不十分なものとする多くの無機塩種の除去を可能にする。この問題は、本発明の背景およびスキーム2で説明するように、同じ原料である4-クロロアセト酢酸エチルとS-メチルイソチオ尿素ヘミスルフェートからから出発して6-(クロロメチル)-2-(メチルチオ)ピリミジン-4(1H)-オンを室温で単離する際に通常遭遇する問題である。
溶媒、原料、酸または塩基の添加順序は、以下に報告するものと異なっていてもよい。
工程a):1モル当量の4-クロロアセト酢酸エチルを、1~2モル当量、好ましくは1.1~1.5モル当量の、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウムから選択される無機塩基、好ましくは炭酸ナトリウムの存在下、3~30容量、好ましくは5~10容量の水、メタノール、アセトニトリル、エタノール、アセトン、N,N-ジメチルホルムアミドおよびN,N-ジメチルアセトアミドから選択される水または有機溶媒中、好ましくは水中、-10~+10℃、好ましくは-5~+5℃の範囲の温度で、1~2モル当量、好ましくは1.1~1.5モル当量のS-メチルイソチオ尿素ヘミスルフェートと反応させる。反応の進行を、ACQUITY UPLC(登録商標) BEHカラム、C18、17μm、2.1×50mm、および溶離相として水/アセトニトリル/0.1%ギ酸を用いたUPLC/MS分析によってモニターする。反応が完了したら、得られた懸濁液を濾過し、固体を真空下、30~90℃、好ましくは40~60℃の温度で乾燥させることにより、99%を超える純度を示す。
S-メチルイソチオ尿素ヘミスルフェート(1.20当量、20.3g、145.8mmol)を120mLの水に溶解し、該溶液を窒素雰囲気下、20℃で10分間撹拌する。次いで、炭酸ナトリウム(1.15当量、14.8g、139.7mmol)を該溶液に添加し、混合物を20℃で30分間撹拌する。この後、混合物を-5℃に冷却し、4-クロロアセト酢酸エチル(1.0当量、20g、121.5mmol)を反応混合物に1時間かけて添加する。添加が完了したら、混合物を-5℃で1時間撹拌した後、濾過する。得られた白色固体を、真空下、50℃で20時間乾燥させる。中間体6-(クロロメチル)-6-ヒドロキシ-2-(メチルチオ)-5,6-ジヒドロピリミジン-4(1H)-オンが、60%(15.2g)の収率および>99%の純度で得られる。
[M-H]- 207m/z
1H-NMR(d6-DMSO、ppmで表される化学シフトは、TMSシグナルに関連する):
2.33(3H,s)、2.47(1H ジアステレオトピックCH2,d,J=16.8Hz)、2.67(1H ジアステレオトピックCH2,d,J=16.8Hz)、3.61(2H,s)、6.05(1H,OH)、10.89(1H,NH).
13C-NMR(d6-DMSO):13.3、39.7、52.7、84.8、156.2、169.2.
6-(クロロメチル)-6-ヒドロキシ-2-(メチルチオ)-5,6-ジヒドロピリミジン-4(1H)-オン(15g、71.9mmol)を5質量%硫酸水溶液75mLに懸濁し、窒素雰囲気下、80℃で30分間加熱する。反応が完了したら、混合物を5℃に冷却し、その温度で1時間撹拌した後、濾過する。得られた白色固体を、真空下、50℃で20時間乾燥させる。最終生成物である6-クロロメチルウラシルが、90%(10.4g)の収率および>99%の純度で得られる。目的の生成物の結晶中に存在する副生成物、6-((メチルチオ)メチル)ピリミジン-2,4(1H,3H)-ジオン(反応により放出されるメチルメルカプタンの塩素原子上での求核置換に由来する生成物)の量は、0.42%である。
1H-NMR(d6-DMSO、ppmで表される化学シフトは、TMSシグナルに関連する):
4.38(2H,s)、5.67(1H,s)、11.11(2H,NH).
13C-NMR(d6-DMSO):41.5、101.1、151.8、152.3、164.8.
6-(クロロメチル)-6-ヒドロキシ-2-(メチルチオ)-5,6-ジヒドロピリミジン-4(1H)-オン(20g、95.9mmol)を、5質量%硫酸水溶液100mLに懸濁し、混合物を窒素雰囲気下、25℃で1時間撹拌して、6-(クロロメチル)-2-(メチルチオ)ピリミジン-4(1H)-オンへ完全に変換する(UPLC-MSおよびHPLC分析より)。次に、混合物を80℃で30分間加熱する。反応が終了したら、混合物を5℃に冷却し、その温度で1時間撹拌した後、濾過する。得られた白色固体を、真空下、50℃で20時間乾燥させる。最終生成物である6-クロロメチルウラシルが、88%(13.6g)の収率および>99%の純度で得られる。目的の生成物の結晶中に存在する副生成物、6-((メチルチオ)メチル)ピリミジン-2,4(1H,3H)-ジオン(反応により放出されるメチルメルカプタンの塩素原子上での求核置換に由来する生成物)の量は、0.45%である。
生成物の分析データは、例2において記載したものと同一である。
6-(クロロメチル)-6-ヒドロキシ-2-(メチルチオ)-5,6-ジヒドロピリミジン-4(1H)-オン(15g、71.9mmol)を6N塩酸水溶液75mLに懸濁し、窒素雰囲気下、100℃で16時間加熱する。反応が終了したら、混合物を5℃に冷却し、その温度で1時間撹拌した後、濾過する。得られた白色/淡黄色固体を、真空下、50℃で20時間乾燥させる。最終生成物である6-クロロメチルウラシルが、60%(10.4g)の収率および85%の純度で得られる。目的の生成物の結晶中に存在する副生成物、6-((メチルチオ)メチル)ピリミジン-2,4(1H,3H)-ジオン(反応により放出されるメチルメルカプタンの塩素原子上での求核置換に由来する生成物)の量は8.5%である。
Claims (6)
- 以下の工程を含む、6-クロロメチルウラシルの調製方法:
a)4-クロロアセト酢酸エチルとS-メチルイソチオ尿素ヘミスルフェートとの反応により、単離された中間体6-(クロロメチル)-6-ヒドロキシ-2-(メチルチオ)-5,6-ジヒドロピリミジン-4(1H)-オンを得る工程;
b)該6-(クロロメチル)-6-ヒドロキシ-2-(メチルチオ)-5,6-ジヒドロピリミジン-4(1H)-オンと硫酸水溶液との反応により、6-クロロメチルウラシルを得る工程、
であって、工程a)が、無機塩基の存在下、-10℃~10℃の範囲の温度で実施される、6-クロロメチルウラシルの調製方法。 - 前記無機塩基が、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウムおよび炭酸水素カリウムから選択される、請求項1に記載の方法。
- 前記無機塩基が炭酸ナトリウムである、請求項2に記載の方法。
- 工程b)が40~120℃の温度で実施される、請求項1~3のいずれか1項に記載の方法。
- 工程b)が、6-(クロロメチル)-6-ヒドロキシ-2-(メチルチオ)-5,6-ジヒドロピリミジン-4(1H)-オンから、中間体6-クロロメチル-2-(メチルチオ)ピリミジン-4(1H)-オンまたはその互変異性体の形態である6-(クロロメチル)-2-(メチルチオ)ピリミジン-4-オールへのインサイチュ(in situ)での変換を含み、それらが6-クロロメチルウラシルに変換される、請求項1に記載の方法。
- 化合物6-(クロロメチル)-6-ヒドロキシ-2-(メチルチオ)-5,6-ジヒドロピリミジン-4(1H)-オン。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT102018000003134 | 2018-02-28 | ||
IT102018000003134A IT201800003134A1 (it) | 2018-02-28 | 2018-02-28 | Processo per la sintesi di 6-clorometiluracile |
PCT/IB2019/051155 WO2019166901A1 (en) | 2018-02-28 | 2019-02-13 | Process for the synthesis of 6-chloromethyluracil |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2021514937A JP2021514937A (ja) | 2021-06-17 |
JP7379346B2 true JP7379346B2 (ja) | 2023-11-14 |
Family
ID=62167829
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020541405A Active JP7379346B2 (ja) | 2018-02-28 | 2019-02-13 | 6-クロロメチルウラシルの合成方法 |
Country Status (7)
Country | Link |
---|---|
US (1) | US11028057B2 (ja) |
EP (1) | EP3759082B1 (ja) |
JP (1) | JP7379346B2 (ja) |
ES (1) | ES2913128T3 (ja) |
IT (1) | IT201800003134A1 (ja) |
PT (1) | PT3759082T (ja) |
WO (1) | WO2019166901A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114933567B (zh) * | 2022-04-29 | 2023-07-11 | 武汉工程大学 | 一种2-甲硫基-4-嘧啶酮的制备方法 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106892902A (zh) * | 2017-03-01 | 2017-06-27 | 国药心制药有限公司 | 一种盐酸替匹嘧啶及其中间体6‑氯甲基尿嘧啶的合成方法 |
-
2018
- 2018-02-28 IT IT102018000003134A patent/IT201800003134A1/it unknown
-
2019
- 2019-02-13 WO PCT/IB2019/051155 patent/WO2019166901A1/en unknown
- 2019-02-13 EP EP19709566.4A patent/EP3759082B1/en active Active
- 2019-02-13 US US16/975,800 patent/US11028057B2/en active Active
- 2019-02-13 JP JP2020541405A patent/JP7379346B2/ja active Active
- 2019-02-13 PT PT197095664T patent/PT3759082T/pt unknown
- 2019-02-13 ES ES19709566T patent/ES2913128T3/es active Active
Non-Patent Citations (2)
Title |
---|
Bioorganic & Medicinal Chemistry,1999年,7(9),P.1925-1931 |
Journal fuer Praktische Chemie (Leipzig),1988年,330(4),P.607-616 |
Also Published As
Publication number | Publication date |
---|---|
EP3759082A1 (en) | 2021-01-06 |
JP2021514937A (ja) | 2021-06-17 |
IT201800003134A1 (it) | 2019-08-28 |
US11028057B2 (en) | 2021-06-08 |
ES2913128T3 (es) | 2022-05-31 |
PT3759082T (pt) | 2022-05-09 |
US20200407330A1 (en) | 2020-12-31 |
WO2019166901A1 (en) | 2019-09-06 |
EP3759082B1 (en) | 2022-04-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7379346B2 (ja) | 6-クロロメチルウラシルの合成方法 | |
KR20150093226A (ko) | 4-아미노-3-할로-6-(치환된)피콜리네이트 및 4-아미노-5-플루오로-3-할로-6-(치환된)피콜리네이트의 제조 방법 | |
CA2630463C (en) | Novel process for the preparation of 5-amino-3h-thiazolo[4,5-d]pyrimidin-2-one | |
JP4231479B2 (ja) | 9−[4−アセトキシ−3−(アセトキシメチル)ブタ−1−イル]−2−アミノプリンの製造方法 | |
US10472325B2 (en) | Process for the synthesis of pirfenidone | |
EP2982673B1 (en) | Process for manufacturing 5-chloromethyl-2,3-dicarboxylic anhydride | |
JPH0578324A (ja) | 3−置換−5−ハロゲノピリジン誘導体 | |
JP6477187B2 (ja) | 2−アミノ−6−メチルニコチン酸エステルの製造方法 | |
US6455696B2 (en) | Process for preparing 2,6-dichloropurine | |
JP4542480B2 (ja) | マレオニトリル類の製造方法 | |
JP5243729B2 (ja) | 2,6−ジクロロプリンの製造方法 | |
WO2010029756A1 (ja) | 5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造方法 | |
WO1999044969A1 (fr) | Techniques permettant d'effectuer de maniere hautement selective une o-alkylation de composes d'amide a l'aide de sels de cuivre | |
PL197892B1 (pl) | Sposób wytwarzania pochodnych kwasu tiobarbiturowego | |
KR100580940B1 (ko) | 2-아미노-4-클로로-5-니트로-6(1h)-피리미디논의 제조방법 | |
JPH05213952A (ja) | アミノクロロプリンの製法 | |
WO2010079813A1 (ja) | イノシン誘導体の製造方法 | |
JPS6350358B2 (ja) | ||
TW201639814A (zh) | 製備哌啶-4-硫代甲醯胺鹽酸鹽之方法 | |
JP2001302639A (ja) | アミノシアノピリジンの製造方法 | |
JPH06256316A (ja) | 2−n−ブチル−4−イミダゾールジチオカルボン酸 | |
JP2010285368A (ja) | アミノピリジン類の製造方法 | |
JPH0684360B2 (ja) | ウラシル類の製造法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220131 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20230126 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230214 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230508 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230808 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20231010 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20231101 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7379346 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |