JP7425734B2 - 2’-デオキシヌクレオシドを製造するための立体選択的合成およびプロセス - Google Patents
2’-デオキシヌクレオシドを製造するための立体選択的合成およびプロセス Download PDFInfo
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- JP7425734B2 JP7425734B2 JP2020542077A JP2020542077A JP7425734B2 JP 7425734 B2 JP7425734 B2 JP 7425734B2 JP 2020542077 A JP2020542077 A JP 2020542077A JP 2020542077 A JP2020542077 A JP 2020542077A JP 7425734 B2 JP7425734 B2 JP 7425734B2
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- Prior art keywords
- anomer
- pyrimidine
- mmol
- triazine
- erythro
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 45
- 230000008569 process Effects 0.000 title claims description 8
- 230000015572 biosynthetic process Effects 0.000 title description 27
- 238000003786 synthesis reaction Methods 0.000 title description 26
- 230000000707 stereoselective effect Effects 0.000 title description 10
- 239000000203 mixture Substances 0.000 claims description 56
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 44
- 150000001875 compounds Chemical class 0.000 claims description 43
- 239000002777 nucleoside Substances 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 38
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 37
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 24
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 23
- 229910003849 O-Si Inorganic materials 0.000 claims description 17
- 229910003872 O—Si Inorganic materials 0.000 claims description 17
- 125000003835 nucleoside group Chemical group 0.000 claims description 17
- 125000006239 protecting group Chemical group 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 71
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 35
- 238000002360 preparation method Methods 0.000 description 33
- 239000000243 solution Substances 0.000 description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- 235000019439 ethyl acetate Nutrition 0.000 description 29
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 25
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 25
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 25
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- HOOZQNOZVFCJNL-KVQBGUIXSA-N 4-amino-1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)thiolan-2-yl]-1,3,5-triazin-2-one Chemical compound O=C1N=C(N)N=CN1[C@@H]1S[C@H](CO)[C@@H](O)C1 HOOZQNOZVFCJNL-KVQBGUIXSA-N 0.000 description 21
- 238000007429 general method Methods 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000012230 colorless oil Substances 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- -1 substituted Chemical class 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- MFEFTTYGMZOIKO-UHFFFAOYSA-N 5-azacytosine Chemical compound NC1=NC=NC(=O)N1 MFEFTTYGMZOIKO-UHFFFAOYSA-N 0.000 description 11
- 125000004429 atom Chemical group 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- OKNSITHUXVUAEP-UHFFFAOYSA-N (4-octoxyphenyl)methanethiol Chemical compound CCCCCCCCOC1=CC=C(CS)C=C1 OKNSITHUXVUAEP-UHFFFAOYSA-N 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- PRCYIYOCMALJCX-UHFFFAOYSA-N 4,4-diethoxybut-1-ene Chemical compound CCOC(CC=C)OCC PRCYIYOCMALJCX-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- PRRAXTMLGKEPNL-VOTSOKGWSA-N [(E)-5,5-diethoxypent-2-enyl] acetate Chemical compound C(C)(=O)OC\C=C\CC(OCC)OCC PRRAXTMLGKEPNL-VOTSOKGWSA-N 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- NTIBQWRHIWWJRI-ABZYKWASSA-N (2R,3S)-2-(hydroxymethyl)-5-[(4-octoxyphenyl)methylsulfanyl]thiolan-3-ol Chemical compound O[C@H]1CC(S[C@@H]1CO)SCC1=CC=C(C=C1)OCCCCCCCC NTIBQWRHIWWJRI-ABZYKWASSA-N 0.000 description 8
- ZVOUTXZDMHWTIS-XZOQPEGZSA-N (4R)-4-[(1S)-1-[tert-butyl(diphenyl)silyl]oxy-3,3-diethoxypropyl]-1,3-oxathiolane-2-thione Chemical compound CCOC(C[C@H](O[Si](C1=CC=CC=C1)(C1=CC=CC=C1)C(C)(C)C)[C@H]1COC(=S)S1)OCC ZVOUTXZDMHWTIS-XZOQPEGZSA-N 0.000 description 8
- JEWSOKJFFIJVSC-JGVFFNPUSA-N (4r)-4-[(1s)-3,3-diethoxy-1-hydroxypropyl]-1,3-oxathiolane-2-thione Chemical compound CCOC(OCC)C[C@H](O)[C@H]1COC(=S)S1 JEWSOKJFFIJVSC-JGVFFNPUSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- HLANPBDETMAMAU-XZOQPEGZSA-N tert-butyl-[(1S)-3,3-diethoxy-1-[(2S)-thiiran-2-yl]propoxy]-diphenylsilane Chemical compound C(C)(C)(C)[Si](C1=CC=CC=C1)(C1=CC=CC=C1)O[C@@H](CC(OCC)OCC)[C@@H]1SC1 HLANPBDETMAMAU-XZOQPEGZSA-N 0.000 description 8
- BVSGXVHDNMPZSE-UHFFFAOYSA-N (4-octoxyphenyl)methanol Chemical compound CCCCCCCCOC1=CC=C(CO)C=C1 BVSGXVHDNMPZSE-UHFFFAOYSA-N 0.000 description 7
- VCUYXFURDMUFHT-JGIBFQFJSA-N (6aR,9aS)-8-[(4-octoxyphenyl)methylsulfanyl]-2,2,4,4-tetra(propan-2-yl)-6a,8,9,9a-tetrahydro-6H-thieno[3,2-f][1,3,5,2,4]trioxadisilocine Chemical compound C(C)(C)[Si]1(O[Si](OC[C@@H]2[C@@H](O1)CC(S2)SCC1=CC=C(C=C1)OCCCCCCCC)(C(C)C)C(C)C)C(C)C VCUYXFURDMUFHT-JGIBFQFJSA-N 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 7
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 7
- FHAILXXMEUYNOF-WIKAKEFZSA-N (2R,3S)-2-(hydroxymethyl)-5-(4-methoxyphenyl)sulfanylthiolan-3-ol Chemical compound OC[C@H]1SC(C[C@@H]1O)SC1=CC=C(C=C1)OC FHAILXXMEUYNOF-WIKAKEFZSA-N 0.000 description 6
- QLNKFODEAKOVCK-LAGVYOHYSA-N (2R,3S)-2-(hydroxymethyl)-5-[(4-methoxyphenyl)methylsulfanyl]thiolan-3-ol Chemical compound OC[C@H]1SC(C[C@@H]1O)SCC1=CC=C(C=C1)OC QLNKFODEAKOVCK-LAGVYOHYSA-N 0.000 description 6
- MPFYBYNGEUVWLM-MTULOOOASA-N (2R,3S)-2-(hydroxymethyl)-5-phenylsulfanylthiolan-3-ol Chemical compound OC[C@H]1SC(C[C@@H]1O)SC1=CC=CC=C1 MPFYBYNGEUVWLM-MTULOOOASA-N 0.000 description 6
- HSUZLYWVAIEFKU-WDEREUQCSA-N (4R)-4-[(1S)-3,3-diethoxy-1-trimethylsilyloxypropyl]-1,3-oxathiolane-2-thione Chemical compound CCOC(C[C@H](O[Si](C)(C)C)[C@H]1COC(=S)S1)OCC HSUZLYWVAIEFKU-WDEREUQCSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 150000002009 diols Chemical class 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- XITGTAIENUVBGY-MTULOOOASA-N (2R,3S)-5-(4-fluorophenyl)sulfanyl-2-(hydroxymethyl)thiolan-3-ol Chemical compound FC1=CC=C(C=C1)SC1C[C@@H]([C@H](S1)CO)O XITGTAIENUVBGY-MTULOOOASA-N 0.000 description 5
- QLDAIAGFSNNXPA-WIKAKEFZSA-N (2R,3S)-5-benzylsulfanyl-2-(hydroxymethyl)thiolan-3-ol Chemical compound C(C1=CC=CC=C1)SC1C[C@@H]([C@H](S1)CO)O QLDAIAGFSNNXPA-WIKAKEFZSA-N 0.000 description 5
- BUMSNWIIFNJOHR-AATRIKPKSA-N (e)-5,5-diethoxypent-2-en-1-ol Chemical compound CCOC(OCC)C\C=C\CO BUMSNWIIFNJOHR-AATRIKPKSA-N 0.000 description 5
- 239000005909 Kieselgur Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- DDYAZDRFUVZBMM-UHFFFAOYSA-N chloro-[chloro-di(propan-2-yl)silyl]oxy-di(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)O[Si](Cl)(C(C)C)C(C)C DDYAZDRFUVZBMM-UHFFFAOYSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000005549 deoxyribonucleoside Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000004808 supercritical fluid chromatography Methods 0.000 description 5
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 4
- DDFHBQSCUXNBSA-UHFFFAOYSA-N 5-(5-carboxythiophen-2-yl)thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC=C1C1=CC=C(C(O)=O)S1 DDFHBQSCUXNBSA-UHFFFAOYSA-N 0.000 description 4
- MITGKKFYIJJQGL-UHFFFAOYSA-N 9-(4-chlorobenzoyl)-6-methylsulfonyl-2,3-dihydro-1H-carbazol-4-one Chemical compound ClC1=CC=C(C(=O)N2C3=CC=C(C=C3C=3C(CCCC2=3)=O)S(=O)(=O)C)C=C1 MITGKKFYIJJQGL-UHFFFAOYSA-N 0.000 description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- IXMCPWSZUHEDNS-XAGPSQNTSA-N (6aR,9aS)-8-benzylsulfanyl-2,2,4,4-tetra(propan-2-yl)-6a,8,9,9a-tetrahydro-6H-thieno[3,2-f][1,3,5,2,4]trioxadisilocine Chemical compound S([C@@H]1CO[Si](O[Si](O[C@H]1C1)(C(C)C)C(C)C)(C(C)C)C(C)C)C1SCC1=CC=CC=C1 IXMCPWSZUHEDNS-XAGPSQNTSA-N 0.000 description 3
- QPWQXFNJDOKPRA-ZVTBYLAHSA-N (6aR,9aS)-8-phenylsulfanyl-2,2,4,4-tetra(propan-2-yl)-6a,8,9,9a-tetrahydro-6H-thieno[3,2-f][1,3,5,2,4]trioxadisilocine Chemical compound CC([Si]1(C(C)C)O[Si](C(C)C)(OC[C@H]2SC(C[C@@H]2O1)SC1=CC=CC=C1)C(C)C)C QPWQXFNJDOKPRA-ZVTBYLAHSA-N 0.000 description 3
- GODAZHXSRKSVQJ-AEJSXWLSSA-N 1-[(6aR,8S,9aS)-2,2,4,4-tetramethyl-6a,8,9,9a-tetrahydro-6H-thieno[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-4-amino-1,3,5-triazin-2-one Chemical compound NC1=NC(N(C=N1)[C@@H]1C[C@@H]2O[Si](O[Si](OC[C@H]2S1)(C)C)(C)C)=O GODAZHXSRKSVQJ-AEJSXWLSSA-N 0.000 description 3
- MOMUJZRKXYLWMH-SHYZEUOFSA-N 4-amino-1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)thiolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@@H]1S[C@H](CO)[C@@H](O)C1 MOMUJZRKXYLWMH-SHYZEUOFSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 229930182475 S-glycoside Natural products 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 238000006206 glycosylation reaction Methods 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
- MRWXACSTFXYYMV-FDDDBJFASA-N nebularine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC=C2N=C1 MRWXACSTFXYYMV-FDDDBJFASA-N 0.000 description 3
- 125000004269 oxiran-2-yl group Chemical group [H]C1([H])OC1([H])* 0.000 description 3
- 239000002212 purine nucleoside Substances 0.000 description 3
- 239000002718 pyrimidine nucleoside Substances 0.000 description 3
- 150000003230 pyrimidines Chemical class 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 125000003107 substituted aryl group Chemical group 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 150000003569 thioglycosides Chemical class 0.000 description 3
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
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Description
本出願は、2018年2月1日出願の米国仮特許出願第62/624,967号(これは、その全体において本明細書に参考として援用される)の早い方の出願日の利益を主張する。
2’-デオキシヌクレオシドを立体選択的に合成するための方法の実施形態が開示される。
2’-デオキシ-β-ペントフラノシルヌクレオシドの立体選択的合成の開発は、非常に密接に関連したシステムからの既知の化学物質の適用が、しばしば制限された成功に遭遇するという課題の経験的な性質に起因して、難題である。2’-デオキシ-β-ペントチオフラノシルヌクレオシドの立体選択的合成は、ペントフラノシルチオグリコシドとペントチオフラノシルチオグリコシドとの間の化学当量の欠如によって複雑である。そのペントチオフラノシルチオグリコシドが、erythroまたはD配置を与えるように3’αヒドロキシル,4’βヒドロキシメチルを有する場合に、さらにより大きな難題が生じる。
2’-デオキシヌクレオシド(例えば、2’-リボヌクレオシド)を立体選択的に合成し、製造するための方法が、開示される。いくつかの実施形態において、上記2’-デオキシリボヌクレオシドは、そのerythroまたはD配置に相当する3’αヒドロキシルおよび4’βヒドロキシメチルを有する2’-デオキシヌクレオシドのβ-アノマーである。
2’-デオキシヌクレオシド(例えば、2’-デオキシリボヌクレオシド)を製造するための立体選択的合成およびプロセスの実施形態が開示される。いくつかの実施形態において、そのプロセスは、少なくとも2:1のβ-アノマー対α-アノマー質量比を提供する。有利なことには、そのアノマーは、高価かつ困難なプロセス(例えば、超臨界流体クロマトグラフィー)を使用せずに分離され得る。その開示されるプロセスの実施形態は、数グラム量の2’-デオキシリボヌクレオシドを合成するために有用である。いくつかの実施形態において、その2’-デオキシリボヌクレオシドは、2’-デオキシ-β-erythro-ペントチオフラノシルヌクレオシドである。その開示される2’-デオキシ-β-erythro-ペントチオフラノシルヌクレオシドのいくつかの実施形態は、抗がん剤として有用である。例えば、4’-チオ-2’-デオキシシチジン(T-dCyd; 4-アミノ-1-((2R,4S,5R)-4-ヒドロキシ-5-(ヒドロキシメチル)テトラヒドロチオフェン-2-イル)ピリミジン-2(1H)-オン)および5-アザ-4’-チオ-2’-デオキシシチジン(5-アザ-T-dCyd; アザ-T-dCyd; アザ-T-dC; 4-アミノ-1-((2R,4S,5R)-4-ヒドロキシ-5-(ヒドロキシメチル)テトラヒドロチオフェン-2-イル)-1,3,5-トリアジン-2(1H)-オン)(4-amino-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrothiophen-2-yl)-1,3,5-trazin-2(1H)-one)のβ-アノマーは、DNAメチルトランスフェラーゼI(DNMT1)を枯渇させ、それによって、腫瘍増殖を阻害することが示されるヌクレオシドである(Tholtassery et al.,Cancer Chemother Pharmacol.2014,74(2):291-302)。
用語および略語の以下の説明は、本開示をよりよく記載しかつ本開示の実施において当業者をガイドするために提供される。本明細書で使用される場合、「含む、包含する(comprising)」は、「含む、包含する、が挙げられる(including)」を意味し、単数形「1つの、ある(a)」または「1つの、ある(an)」または「上記、この、その(the)」は、状況が別段明確に規定しなければ、複数形への言及を包含する。用語「または(or)」とは、状況が別段明確に示さなければ、述べられた代替の要素の単一の要素または2もしくはこれより多くの要素の組み合わせに言及する。
3’αヒドロキシル,4’βヒドロキシメチル(D、erythro)配置を有する2’-デオキシ-リボヌクレオシドのβ-アノマーを立体選択的に合成する方法の実施形態が、開示される。その方法は、式I:
2’-デオキシヌクレオシドを立体選択的に合成する一般的アプローチを、スキーム1(図1)に図示する。
スキーム2は、チオ糖の1つの合成を示す(図2)。その合成の詳細は、以下のとおりである。
スキーム3は、4-オクチルオキシフェニルメタンチオールの1つの合成を示す(図3)。その合成の詳細は、以下のとおりである。
((2R,3S)-3-((tert-ブチルジフェニルシリル)オキシ)-5-((4-オクチルオキシベンジル)チオ)-テトラヒドロチオフェン-2-イル)メチルアセテート(11a)の調製。一般的方法A:
保護された2’-デオキシヌクレオシドを、以下で記載されるように合成した。図6は、その合成した化合物を示す。
実施例1に例示される手順を使用して、チオ糖13b、13c、13d、13e、13fを独立して、5-アザシトシンと反応させて、β/αアノマーの混合物を(比は粗製1H NMRの試験によって決定)、図6に示されるようなそのβアノマーの単離収率(決定される場合)で得た。
材料: ジオール化合物12a(98%)は、一般的方法Bに概説されるように調製できた。1,3-ジクロロ-1,1,3,3,テトラ-イソプロピルジシロキサンおよびイミダゾールを、Oakwood Chemicalsから得た。アザ-シトシン(95%+)を、Matrix Scientificから得た。ヘキサメチルジシラザン(99.9%、HMDS)、N-ブロモスクシンイミド(98%、NBS)、メタノール、NH4F(98%)、およびジエチルエーテルを、Sigma-Aldrichから得た。モレキュラーシーブをAlfa-Aesarから得た。ジメチルホルムアミド、ジクロロメタンおよび(NH4)2SO4をAcros Organicsから得た。
(6aR,9aS)-2,2,4,4-テトライソプロピル-8-((4-(オクチルオキシ)ベンジル)チオ)テトラヒドロ-6H-チエノ[3,2-f][1,3,5,2,4]トリオキサジシロシン(13a)。
上記工程からの粗製生成物を、シリカゲル(kg)でのカラムクロマトグラフィーによって精製した。その生成物を、ジクロロメタン中の酢酸エチルの勾配30%から100%を用いて溶離して、4つの画分を得た:
F1: 9g(極性の低い不純物で汚染されている15a);
F2: 29.0g(純粋βアノマー);
F3: 56g(αおよび88%のβの混合物);
F4: 35g(αおよび68%のβの混合物)。
Claims (14)
- 2’-デオキシ-β-erythro-ペントチオフラノシルヌクレオシドのβ-アノマーを立体選択的に合成するための方法であって、前記方法は、
式I:
前記式Iに従う化合物と、N-ブロモスクシンイミドおよびシリル化ピリミジンまたはシリル化トリアジンとを、保護されたピリミジンベースまたはトリアジンベースの2’-デオキシ-β-erythro-ペントチオフラノシルヌクレオシドのα-アノマーおよびβ-アノマーの混合物を生成するために有効な反応条件下で合わせる工程;
前記保護されたピリミジンベースまたはトリアジンベースの2’-デオキシ-β-erythro-ペントチオフラノシルヌクレオシドの前記β-アノマーを、前記α-アノマーから分離する工程;ならびに
前記保護基を、前記保護されたピリミジンベースまたはトリアジンベースの2’-デオキシ-β-erythro-ペントチオフラノシルヌクレオシドの前記β-アノマーから除去して、ピリミジンベースまたはトリアジンベースの2’-デオキシ-β-erythro-ペントチオフラノシルヌクレオシドのβ-アノマーを提供する工程、
を包含する方法。 - RaおよびRbは独立して、C1-C4アルキル、シクロアルキル、またはフェニルである、請求項1に記載の方法。
- RaおよびRbは同じである、請求項1または請求項2に記載の方法。
- R2は、-Si(CH(CH3)2)2-O-Si(CH(CH3)2)2-、-Si(CH3)2-O-Si(CH3)2-、または-Si(C6H5)2-O-Si(C6H5)2-である、請求項1に記載の方法。
- R1は、-(CH2)n-アリールであり、前記アリールは、アルコキシ、またはフルオロで置換されたフェニルであり、n=0または1である、請求項1~4のいずれか1項に記載の方法。
- α-アノマーおよびβ-アノマーの前記混合物は、少なくとも2:1のβ/α質量比を有する、請求項1~9のいずれか1項に記載の方法。
- 前記式Iに従う化合物は、モル過剰のN-ブロモスクシンイミドと合わされる、請求項1~10のいずれか1項に記載の方法。
- 前記式Iに従う化合物は、モル過剰の前記シリル化ピリミジンまたはシリル化トリアジンと合わされる、請求項1~11のいずれか1項に記載の方法。
- 保護されたピリミジンベースまたはトリアジンベースの2’-デオキシ-β-erythro-ペントチオフラノシルヌクレオシドのα-アノマーおよびβ-アノマーの混合物を生成するために有効な反応条件は、(i)-10~10℃の範囲内の反応温度、(ii)30分間~3時間の範囲内の反応時間、または(iii) (i)および(ii)の両方を含む、請求項1~12のいずれか1項に記載の方法。
- 前記保護されたピリミジンベースまたはトリアジンベースの2’-デオキシ-β-erythro-ペントチオフラノシルヌクレオシドの前記β-アノマーを前記α-アノマーから分離する工程は、シリカゲルクロマトグラフィーを含む、請求項1~13のいずれか1項に記載の方法。
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