JP5046219B2 - １，３−プロパン−１−アリールジオールの新規環状リン酸ジエステルおよびそのプロドラッグへの使用 - Google Patents

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Publication number

JP5046219B2

JP5046219B2 JP2004550353A JP2004550353A JP5046219B2 JP 5046219 B2 JP5046219 B2 JP 5046219B2 JP 2004550353 A JP2004550353 A JP 2004550353A JP 2004550353 A JP2004550353 A JP 2004550353A JP 5046219 B2 JP5046219 B2 JP 5046219B2

Authority

JP

Japan

Prior art keywords

group

alkyl

salt

amino

halogen

Prior art date

2002-10-31

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.)

Expired - Fee Related

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• -1 cyclic phosphodiester Chemical class 0.000 title claims description 132
• 229940002612 prodrug Drugs 0.000 title abstract description 53
• 239000000651 prodrug Substances 0.000 title abstract description 53
• 150000001875 compounds Chemical class 0.000 claims abstract description 84
• 150000003839 salts Chemical class 0.000 claims abstract description 65
• 229960000684 cytarabine Drugs 0.000 claims abstract description 36
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims abstract description 17
• UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims abstract description 16
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 16
• 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 13
• 239000001301 oxygen Substances 0.000 claims abstract description 8
• OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 5
• 239000011574 phosphorus Substances 0.000 claims abstract description 5
• 125000000217 alkyl group Chemical group 0.000 claims description 123
• 239000000203 mixture Substances 0.000 claims description 114
• 238000000034 method Methods 0.000 claims description 113
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 96
• 238000006243 chemical reaction Methods 0.000 claims description 86
• 239000002777 nucleoside Substances 0.000 claims description 77
• 229910052736 halogen Inorganic materials 0.000 claims description 68
• 150000002367 halogens Chemical group 0.000 claims description 61
• DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 claims description 60
• 239000002904 solvent Substances 0.000 claims description 56
• 125000003118 aryl group Chemical group 0.000 claims description 55
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 52
• 239000002585 base Substances 0.000 claims description 52
• 150000003833 nucleoside derivatives Chemical class 0.000 claims description 49
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 43
• 125000001424 substituent group Chemical group 0.000 claims description 42
• 125000003545 alkoxy group Chemical group 0.000 claims description 39
• 229910052799 carbon Inorganic materials 0.000 claims description 38
• 125000003282 alkyl amino group Chemical group 0.000 claims description 36
• UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 35
• 229910052757 nitrogen Inorganic materials 0.000 claims description 31
• 230000008569 process Effects 0.000 claims description 31
• YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 30
• 125000001072 heteroaryl group Chemical group 0.000 claims description 29
• 238000006317 isomerization reaction Methods 0.000 claims description 29
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 28
• 239000000460 chlorine Substances 0.000 claims description 28
• 229910052739 hydrogen Inorganic materials 0.000 claims description 27
• 229910052717 sulfur Inorganic materials 0.000 claims description 22
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 21
• 125000004104 aryloxy group Chemical group 0.000 claims description 20
• 238000010438 heat treatment Methods 0.000 claims description 19
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 17
• 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 17
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
• 235000000346 sugar Nutrition 0.000 claims description 17
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 16
• 125000003835 nucleoside group Chemical group 0.000 claims description 16
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 15
• 229920000166 polytrimethylene carbonate Polymers 0.000 claims description 13
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
• 229910052801 chlorine Inorganic materials 0.000 claims description 11
• RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 11
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
• 239000011777 magnesium Substances 0.000 claims description 9
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 9
• 229910000104 sodium hydride Inorganic materials 0.000 claims description 9
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
• CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 claims description 7
• 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 6
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 6
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 6
• 229910000103 lithium hydride Inorganic materials 0.000 claims description 6
• 239000012312 sodium hydride Substances 0.000 claims description 6
• IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 claims description 6
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
• XPYQFIISZQCINN-QVXDJYSKSA-N 4-amino-1-[(2r,3e,4s,5r)-3-(fluoromethylidene)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one;hydrate Chemical compound O.O=C1N=C(N)C=CN1[C@H]1C(=C/F)/[C@H](O)[C@@H](CO)O1 XPYQFIISZQCINN-QVXDJYSKSA-N 0.000 claims description 5
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 5
• 229910052794 bromium Inorganic materials 0.000 claims description 5
• 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 5
• ZDTFMPXQUSBYRL-PTSYZVBVSA-N (3s,4s,5r)-2-(2,6-diaminopurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C12=NC(N)=NC(N)=C2N=CN1C1O[C@H](CO)[C@@H](O)[C@@H]1O ZDTFMPXQUSBYRL-PTSYZVBVSA-N 0.000 claims description 4
• FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 claims description 4
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
• 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 4
• GIMSJJHKKXRFGV-BYPJNBLXSA-N 4-amino-1-[(2r,3s,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-iodopyrimidin-2-one Chemical compound C1=C(I)C(N)=NC(=O)N1[C@H]1[C@@H](F)[C@H](O)[C@@H](CO)O1 GIMSJJHKKXRFGV-BYPJNBLXSA-N 0.000 claims description 4
• CKTSBUTUHBMZGZ-CHKWXVPMSA-N 4-amino-1-[(2s,4r,5s)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 CKTSBUTUHBMZGZ-CHKWXVPMSA-N 0.000 claims description 4
• HSBKFSPNDWWPSL-VDTYLAMSSA-N 4-amino-5-fluoro-1-[(2s,5r)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@@H]1C=C[C@H](CO)O1 HSBKFSPNDWWPSL-VDTYLAMSSA-N 0.000 claims description 4
• QBEIABZPRBJOFU-VDTYLAMSSA-N 4-amino-5-fluoro-1-[(2s,5r)-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)CC1 QBEIABZPRBJOFU-VDTYLAMSSA-N 0.000 claims description 4
• SWFJAJRDLUUIOA-IBCQBUCCSA-N 5-ethyl-1-[(2r,3s,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(CC)=CN1[C@H]1[C@@H](F)[C@H](O)[C@@H](CO)O1 SWFJAJRDLUUIOA-IBCQBUCCSA-N 0.000 claims description 4
• RTRQQBHATOEIAF-UHFFFAOYSA-N AICA riboside Natural products NC1=C(C(=O)N)N=CN1C1C(O)C(O)C(CO)O1 RTRQQBHATOEIAF-UHFFFAOYSA-N 0.000 claims description 4
• GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 claims description 4
• 239000002841 Lewis acid Substances 0.000 claims description 4
• RLAHNGKRJJEIJL-RFZPGFLSSA-N [(2r,4r)-4-(2,6-diaminopurin-9-yl)-1,3-dioxolan-2-yl]methanol Chemical compound C12=NC(N)=NC(N)=C2N=CN1[C@H]1CO[C@@H](CO)O1 RLAHNGKRJJEIJL-RFZPGFLSSA-N 0.000 claims description 4
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
• 239000003443 antiviral agent Substances 0.000 claims description 4
• 125000000328 arabinofuranosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 4
• 235000010300 dimethyl dicarbonate Nutrition 0.000 claims description 4
• GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 claims description 4
• ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 4
• SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 4
• ODZBBRURCPAEIQ-PIXDULNESA-N helpin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 ODZBBRURCPAEIQ-PIXDULNESA-N 0.000 claims description 4
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
• 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
• 150000007517 lewis acids Chemical class 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 239000011707 mineral Substances 0.000 claims description 4
• FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 claims description 4
• IPVFGAYTKQKGBM-BYPJNBLXSA-N 1-[(2r,3s,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-iodopyrimidine-2,4-dione Chemical compound F[C@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 IPVFGAYTKQKGBM-BYPJNBLXSA-N 0.000 claims description 3
• NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 claims description 3
• XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 claims description 3
• NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 claims description 3
• LJIRBXZDQGQUOO-KVTDHHQDSA-N 6-amino-3-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,4-dihydro-1,3,5-triazin-2-one Chemical compound C1NC(N)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 LJIRBXZDQGQUOO-KVTDHHQDSA-N 0.000 claims description 3
• JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 claims description 3
• IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 3
• 229960002756 azacitidine Drugs 0.000 claims description 3
• 229960004396 famciclovir Drugs 0.000 claims description 3
• DSWNRHCOGVRDOE-UHFFFAOYSA-N n,n-dimethylmethanimidamide Chemical compound CN(C)C=N DSWNRHCOGVRDOE-UHFFFAOYSA-N 0.000 claims description 3
• 125000002524 organometallic group Chemical group 0.000 claims description 3
• 229960000329 ribavirin Drugs 0.000 claims description 3
• HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 3
• 125000005270 trialkylamine group Chemical group 0.000 claims description 3
• MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
• 239000011737 fluorine Chemical group 0.000 claims description 2
• 229910052731 fluorine Inorganic materials 0.000 claims description 2
• LMJVXGOFWKVXAW-OXOINMOOSA-N oxetanocin A Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@H]1CO LMJVXGOFWKVXAW-OXOINMOOSA-N 0.000 claims description 2
• 125000004434 sulfur atom Chemical group 0.000 claims description 2
• 150000001450 anions Chemical class 0.000 claims 6
• QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 claims 2
• 239000003513 alkali Substances 0.000 claims 2
• 150000004678 hydrides Chemical class 0.000 claims 2
• YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims 2
• SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 claims 2
• AHNJTQYTRPXLLG-UHFFFAOYSA-N lithium;diethylazanide Chemical compound [Li+].CC[N-]CC AHNJTQYTRPXLLG-UHFFFAOYSA-N 0.000 claims 2
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 2
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 2
• FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 claims 2
• RTRQQBHATOEIAF-UUOKFMHZSA-N acadesine Chemical compound NC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 RTRQQBHATOEIAF-UUOKFMHZSA-N 0.000 claims 1
• 229940124675 anti-cancer drug Drugs 0.000 claims 1
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
• 125000001369 canonical nucleoside group Chemical group 0.000 claims 1
• 238000006482 condensation reaction Methods 0.000 claims 1
• 230000000174 oncolytic effect Effects 0.000 claims 1
• ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 claims 1
• 238000002360 preparation method Methods 0.000 abstract description 21
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 6
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 198
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 153
• 239000000243 solution Substances 0.000 description 144
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 126
• 230000015572 biosynthetic process Effects 0.000 description 115
• 238000003786 synthesis reaction Methods 0.000 description 113
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 87
• 238000005160 1H NMR spectroscopy Methods 0.000 description 76
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 72
• 239000007787 solid Substances 0.000 description 64
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 63
• 239000003153 chemical reaction reagent Substances 0.000 description 53
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
• 238000003756 stirring Methods 0.000 description 49
• 230000002829 reductive effect Effects 0.000 description 47
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
• 239000010410 layer Substances 0.000 description 39
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 38
• 239000011541 reaction mixture Substances 0.000 description 37
• 229910019142 PO4 Inorganic materials 0.000 description 36
• 239000010452 phosphate Substances 0.000 description 34
• 238000004128 high performance liquid chromatography Methods 0.000 description 33
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 32
• 230000000865 phosphorylative effect Effects 0.000 description 29
• 125000002947 alkylene group Chemical group 0.000 description 26
• 150000002009 diols Chemical class 0.000 description 26
• 238000006366 phosphorylation reaction Methods 0.000 description 26
• 239000012044 organic layer Substances 0.000 description 24
• 125000004122 cyclic group Chemical group 0.000 description 23
• 235000021317 phosphate Nutrition 0.000 description 22
• 238000001816 cooling Methods 0.000 description 20
• 230000026731 phosphorylation Effects 0.000 description 20
• 238000001914 filtration Methods 0.000 description 19
• 125000003710 aryl alkyl group Chemical group 0.000 description 18
• 239000003795 chemical substances by application Substances 0.000 description 18
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 17
• 238000004440 column chromatography Methods 0.000 description 17
• 238000001514 detection method Methods 0.000 description 17
• 239000003921 oil Substances 0.000 description 17
• 239000012071 phase Substances 0.000 description 17
• 239000000047 product Substances 0.000 description 17
• BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 15
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