JP7004480B2 - ソホスブビルの調製のための改善された製造方法 - Google Patents
ソホスブビルの調製のための改善された製造方法 Download PDFInfo
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- JP7004480B2 JP7004480B2 JP2018568945A JP2018568945A JP7004480B2 JP 7004480 B2 JP7004480 B2 JP 7004480B2 JP 2018568945 A JP2018568945 A JP 2018568945A JP 2018568945 A JP2018568945 A JP 2018568945A JP 7004480 B2 JP7004480 B2 JP 7004480B2
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- Prior art keywords
- formula
- compound
- solvent
- ammonium
- sofosbuvir
- Prior art date
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- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 title claims description 23
- 229960002063 sofosbuvir Drugs 0.000 title claims description 22
- 238000004519 manufacturing process Methods 0.000 title claims description 15
- 238000002360 preparation method Methods 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 4
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 2
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 2
- BLQJIBCZHWBKSL-UHFFFAOYSA-L magnesium iodide Chemical compound [Mg+2].[I-].[I-] BLQJIBCZHWBKSL-UHFFFAOYSA-L 0.000 claims description 2
- 229910001641 magnesium iodide Inorganic materials 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 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 claims 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims 1
- 239000005695 Ammonium acetate Substances 0.000 claims 1
- 239000004254 Ammonium phosphate Substances 0.000 claims 1
- GEHMBYLTCISYNY-UHFFFAOYSA-N Ammonium sulfamate Chemical compound [NH4+].NS([O-])(=O)=O GEHMBYLTCISYNY-UHFFFAOYSA-N 0.000 claims 1
- 229940043376 ammonium acetate Drugs 0.000 claims 1
- 235000019257 ammonium acetate Nutrition 0.000 claims 1
- BVCZEBOGSOYJJT-UHFFFAOYSA-N ammonium carbamate Chemical compound [NH4+].NC([O-])=O BVCZEBOGSOYJJT-UHFFFAOYSA-N 0.000 claims 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims 1
- 229910000148 ammonium phosphate Inorganic materials 0.000 claims 1
- 235000019289 ammonium phosphates Nutrition 0.000 claims 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 239000012351 deprotecting agent Substances 0.000 claims 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims 1
- 235000019253 formic acid Nutrition 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- YWYZEGXAUVWDED-UHFFFAOYSA-N triammonium citrate Chemical compound [NH4+].[NH4+].[NH4+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O YWYZEGXAUVWDED-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- -1 2,4-dioxopyrimidine-1-yl Chemical group 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 4
- 150000004795 grignard reagents Chemical class 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000002777 nucleoside Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 241000711549 Hepacivirus C Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- YNTZRRDNQQGIMH-WFLDRPPDSA-N 1-[(2r,3r,4s,5r)-4-benzoyl-3-fluoro-4-hydroxy-5-(1-hydroxy-2-oxo-2-phenylethyl)-3-methyloxolan-2-yl]pyrimidine-2,4-dione Chemical compound OC([C@H]1O[C@H]([C@@]([C@@]1(O)C(=O)C=1C=CC=CC=1)(F)C)N1C(NC(=O)C=C1)=O)C(=O)C1=CC=CC=C1 YNTZRRDNQQGIMH-WFLDRPPDSA-N 0.000 description 2
- 0 C*C(C=CN1[C@@]([C@@](C)([C@]2OC(c3ccccc3)=O)F)OC2=COC(c2ccccc2)=O)=NC1=O Chemical compound C*C(C=CN1[C@@]([C@@](C)([C@]2OC(c3ccccc3)=O)F)OC2=COC(c2ccccc2)=O)=NC1=O 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 2
- 229940045145 uridine Drugs 0.000 description 2
- ARKKGZQTGXJVKW-VPCXQMTMSA-N 1-[(2r,3r,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]pyrimidine-2,4-dione Chemical compound C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 ARKKGZQTGXJVKW-VPCXQMTMSA-N 0.000 description 1
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical class [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- VWJSHFRVNGBWPN-ZCAHASCXSA-N C[C@@](C(=O)O)(N)P(=O)(OC1=CC=CC=C1)OC2=C(C(=C(C(=C2F)F)F)F)F Chemical compound C[C@@](C(=O)O)(N)P(=O)(OC1=CC=CC=C1)OC2=C(C(=C(C(=C2F)F)F)F)F VWJSHFRVNGBWPN-ZCAHASCXSA-N 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 108700008776 hepatitis C virus NS-5 Proteins 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- OUAUTSXQFRBHQE-JCNLWDBESA-N n-[1-[(2r,3r,4s,5r)-4-benzoyl-3-fluoro-4-hydroxy-5-(1-hydroxy-2-oxo-2-phenylethyl)-3-methyloxolan-2-yl]-2-oxopyrimidin-4-yl]benzamide Chemical compound OC([C@H]1O[C@H]([C@@]([C@@]1(O)C(=O)C=1C=CC=CC=1)(F)C)N1C(N=C(NC(=O)C=2C=CC=CC=2)C=C1)=O)C(=O)C1=CC=CC=C1 OUAUTSXQFRBHQE-JCNLWDBESA-N 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical compound NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/02—Phosphorylation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
利点:
01)グリニャール試薬を避けることができる。
02)商業的に適さない温度-20℃~-15℃を避けることができる。
03)商業的な面で非常に容易な室温で反応は行われた。
04)有機塩基を反応に使用した。
a) 式(V)の化合物を酸性条件下で脱保護して式(IV)の化合物を得る。
a) 式(V)の化合物を酸性条件下で脱保護して、式(IV)の化合物を得る。
b) 工程a)の生成物を、塩基および溶媒の存在下で加水分解して、式(III)の化合物を得る。
c) 工程b)の生成物を、金属塩、塩基および溶媒の存在下で式(II)の化合物と反応させ、
d) 式(I)の化合物を得る。
好ましくはトリエチルアミン(または)ジイソプロピルエチルアミンである。
80%酢酸水溶液(1リットル)に、N4,3’,5’-トリベンゾイル-2’-デオキシ-2’-フルオロ-2’-C-メチルシチジン(20gm)を加え、反応が完結するまで一晩還流した。冷却し室温(15℃)で放置した後、生成物の大部分が沈殿し、次いで焼結漏斗で濾過した。得られた沈殿物を水で洗浄し、トルエンと共蒸発させて、標題生成物の白色固体を得た。(収率:85~90%)
MeOH(120mL)中の3’,5’-ジベンゾイル-2’-デオキシ-2’-フルオロ-2’-C-メチルウリジン(10gm)の溶液を、MeOH(60mL)中の飽和アンモニア溶液へ加えた。反応混合物を0℃で30分間撹拌し、ゆっくりと室温まで昇温し、次いで同じ温度でさらに18時間撹拌した。得られた混合物中の溶媒を減圧下で蒸発させて残渣を得て、さらにそれをメタノールおよび水で再結晶して、純粋な標題化合物を得た。(収率:50~60%)
メカニカルスターラーおよび低温温度計を備えた2Lの3つ口丸底フラスコに、30gのフェニルジクロロホスフェートおよび300mLの無水ジクロロメタンを添加した。溶液を窒素雰囲気下で0℃に冷却し、イソ-プロピルアラネート塩酸塩(23.5g)を固体として迅速に添加した。混合物を撹拌し、ドライアイス-アセトン浴中で-55℃に冷却した。150mLのジクロロメタン中の31gのトリエチルアミンの溶液を添加漏斗から70分かけて添加した。白濁した混合物を-55℃で30分間撹拌し、次いで温度を1.5時間かけてゆっくりと-5℃に上げた。ジクロロメタン100mL中のペンタフルオロフェノールとトリエチルアミンの予め冷却した混合物を、添加漏斗を介して0℃で1時間かけて混合物に添加し、得られた混合物を0℃で4時間撹拌した。
白色沈殿物(TEA.HCl)を濾過し、ジクロロメタンでリンスした。濾過液を減圧下で濃縮し、白色固体残渣を880mLのt-ブチルメチルエーテル(TBME)中室温で1時間粉砕した。白色懸濁液を濾過し、固体をTBMEでリンスした。固体を酢酸エチルと水の混合液に分配した。有機層を分離し、水で洗浄した。有機層をMgSO4で乾燥させ、濃縮させて、白色の羽毛状の固体として与えられた。得られた固体を酢酸エチルに溶解し、さらに溶液を水/塩水で洗浄し、MgSO4で乾燥させた。得られた溶液を減圧下で濃縮して、標題化合物を得た。
(収率:70~80%)
メカニカルスターラーおよび低温温度計を備えた4Lの4つ口丸底フラスコに、ウリジン中間体100gmおよびテトラヒドロフラン(THF)1500mlを加え、窒素雰囲気下、25~30℃で5~10分間撹拌し、さらに54.8gmのMgCl2を加え、2時間撹拌し、次いで、261.0gmのホスファミド中間体をゆっくりと添加し、同じ温度で8~10時間撹拌した。反応が完了した後(HPLCで確認)、45℃以下で完全にTHFを蒸留除去し、反応塊を25~30℃で冷却させ、1.0リットルのジクロロメタンおよび1.0リットルの塩化アンモニウム水溶液を反応塊に添加し、室温で攪拌して層を分離した。
(収率:70~80%)
メカニカルスターラーおよび低温温度計を備えた4Lの4つ口丸底フラスコに、ウリジン中間体100gmおよびテトラヒドロフラン(THF)1500mLを加え、窒素雰囲気下、25~30℃で5~10分間撹拌し、さらに54.8gmのLiCl2を加え2時間撹拌し、次いで、261.0gmのホスファミド中間体をゆっくりと添加し、同じ温度で8~10時間撹拌した。反応が完了した後(HPLCで確認)、45℃以下で完全にTHFを蒸留除去し、反応塊を25~30℃で冷却させ、1.0リットルのジクロロメタンおよび1.0リットルの塩化アンモニウム水溶液を反応塊に添加し、室温で攪拌して層を分離した。
(収率:60~70%)。
Claims (5)
- 前記工程(c)の反応に使用される溶媒は、アセトン、テトラヒドロフラン(THF)、アセトニトリル、酢酸エチル、ジクロロメタン、メチル第三級ブチルエーテル、酢酸、メタノール、エタノール、イソプロパノール、水およびそれらの混合物から選択される、請求項1に記載の方法。
- 前記工程(c)の反応生成物を、ジエチルエーテル、ジイソプロピルエーテル、MTBE(メチル第三級ブチルエーテル)から選択される溶媒によって精製する、請求項1に記載の方法。
- 前記工程(b)及び(c)で使用される塩基は、トリエチルアミン、ジイソプロピルエチルアミン、ジイソプロピルアミン、ピリジン、酢酸アンモニウム、ギ酸アンモニウム、スルファミン酸アンモニウム、リン酸アンモニウム、クエン酸アンモニウム、カルバミン酸アンモニウムおよびアンモニアから選択される、請求項1に記載の方法。
- 前記工程(a)で使用される脱保護剤は、トリフルオロ酢酸、硫酸、メタンスルホン酸、酢酸、ギ酸、con.HClおよびその類から選択される、請求項1に記載の方法。
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