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【结 构 式】

【分子编号】25317

【品名】1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione

【CA登记号】101703-35-9

【 分 子 式 】C10H13N5O4

【 分 子 量 】267.24452

【元素组成】C 44.94% H 4.9% N 26.21% O 23.95%

与该中间体有关的原料药合成路线共 19 条

合成路线1

该中间体在本合成路线中的序号:(III)

Treatment of 2-decyloxy-3-(dodecylmercapto)-1-propanol (I) with phosphorus oxychloride in the presence of Et3N gave the intermediate dichlorophosphate ester (II). This was subsequently condensed with 3'-deoxy-3'-azidothymidine (AZT) (III) to produce, after aqueous hydrolysis, the target phosphate diester. The title diester was alternatively obtained by the phospholipase D-catalyzed condensation of AZT (III) with the choline monophosphate ester (IV).

1 Zilch, H.; Leinert, H.; Mertens, A.; Herrmann, D. (Roche Diagnostics GmbH); New phospholipid derivs. of nucleosides, their preparation and their use as antiviral drugs. DE 4026265; EP 0545966; JP 1994500546; WO 9203462 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 59212 2-(decyloxy)-3-(dodecylsulfanyl)-1-propanol C25H52O2S 详情 详情
(II) 59213   C25H51Cl2O3PS 详情 详情
(III) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情
(IV) 59214 9-(decyloxy)-2,2-dimethyl-6-oxo-5,7-dioxa-11-thia-2-azonia-6lambda~5~-phosphatricosan-6-olate C30H64NO5PS 详情 详情

合成路线2

该中间体在本合成路线中的序号:(III)

In a further procedure, the monophosphate ester of 3-dodecylmercapto-2-decyloxy-1-propanol (V) was directly condensed with AZT employing DCC as the coupling reagent. A related method involved previous activation of (V) as the mixed anhydride with benzenesulfonyl chloride or triisopropylbenzenesulfonyl chloride in the presence of pyridine.

1 Zilch, H.; Leinert, H.; Mertens, A.; Herrmann, D. (Roche Diagnostics GmbH); New phospholipid derivs. of nucleosides, their preparation and their use as antiviral drugs. DE 4026265; EP 0545966; JP 1994500546; WO 9203462 .
2 Zilch, H.; Kiegel, E. (Boehringer Ingelheim GmbH); Method of preparing unsymmetrical phosphoric acid diesters. WO 9520596 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情
(V) 59215 2-(decyloxy)-3-(dodecylsulfanyl)propyl dihydrogen phosphate C25H53O5PS 详情 详情

合成路线3

该中间体在本合成路线中的序号:(I)

The title compound was obtained from 3'-azido-3'-deoxythymidine (I) either by treatment with tri-n-butylammonium phosphite and DCC in pyridine or by treatment with phosphorus trichloride in the presence of imidazole and Et3N in acetonitrile or in the presence of triethyl phosphate, followed by aqueous hydrolysis.

1 Manouilov, K.K.; Fedorov, I.I.; Boudinot, F.D.; White, C.A.; Kotra, L.P.; Schinazi, R.F.; Hong, C.I.; Chu, C.K.; Lymphatic targeting of anti-HIV nucleosides: Distribution of 3'-azido-3'-deoxythymidine (AZT) and 3'-azido-2',3'-dideoxyuridine (AZdU) after administration of dipalmitoylphosphatidyl prodrugs to mice. Antivir Chem Chemother 1995, 6, 4, 230.
2 Krayevsky, A.A.; Tarussova, N.B.; Watanabe, K.A.; Matulic-Adamic, J. (Sloan-Kettering Institute); 5'-Hydrogenphosphonates and 5'-methylphosphonates of sugar modified nucleosides, compsns. and uses thereof. WO 9119727 .
3 Dyatkina, N.; et al.; Nucleoside 5'-phosphonates: Synthesis, anti-HIV activities and reactions with DNA polymerases. Antivir Res 1993, 20, Suppl. 1, Abst 24.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情

合成路线4

该中间体在本合成路线中的序号:(V)

Treatment of 4-bromophenol (I) with phosphoryl chloride gave p-bromophenyl phosphoro- dichloridate (II), which was condensed with alanine methyl ester (III) to furnish alaninyl phosphorochloridate (IV). Further coupling of (IV) with 3'-azidothimidine (V) in the presence of N-methylimidazole afforded phosphate (VI). Then, addition of methyl hypobromite, (prepared from bromine and MeOH) provided the title compound as a diastereomeric mixture.

1 D'Cruz, O.; Jan, S.-T.; Shih, M.-J.; Chen, C.-L.; Uckun, F.M.; Venkatachalam, T.K.; Synthesis of dual function (5R,6R)- and (5S,6S)-5-bromo-6-methoxy-5,6-dihydro-AZT-5'-(para-bromophenyl methoxyalaninyl phosphate) as novel spermicidal and anti-HIV agents. Antivir Chem Chemother 1999, 10, 1, 39.
2 Uckun, F.M.; Venkatachalam, T.; D'Cruz, O. (Parker Hughes Institute); AZT derivs. exhibiting spermicidal and anti-viral activity. WO 9948902 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 25313 4-bromophenol 106-41-2 C6H5BrO 详情 详情
(II) 25314 Dichlorophoephoric acid 4-bromophenyl ester C6H4BrCl2O2P 详情 详情
(III) 25315 methyl 2-aminopropanoate; Alanine, methyl ester 7625-53-8 C4H9NO2 详情 详情
(IV) 25316 methyl 2-[[(4-bromophenoxy)(chloro)phosphoryl]amino]propanoate C10H12BrClNO4P 详情 详情
(V) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情
(VI) 25318 methyl 2-[[[((2S,3S,5R)-3-azido-5-[[(propionylamino)carbonyl]amino]tetrahydro-2-furanyl)methoxy](4-bromophenoxy)phosphoryl]amino]propanoate C20H24BrN6O8P 详情 详情

合成路线5

该中间体在本合成路线中的序号:(V)

In a related procedure, methyl hypobromite was added to 3'-azidothimidine (V) in MeOH, and the resulting mixture of diastereomeric 5-bromo-6-methoxypyrimidines (VII) and (VIII) was separated by column chromatography. Both the (5R,6R)- and the (5S,6S)-isomers (VII) and (VIII) were then coupled to phosphorochloridate (IV) to yield the title compound as seperated enantiomers.

1 D'Cruz, O.; Jan, S.-T.; Shih, M.-J.; Chen, C.-L.; Uckun, F.M.; Venkatachalam, T.K.; Synthesis of dual function (5R,6R)- and (5S,6S)-5-bromo-6-methoxy-5,6-dihydro-AZT-5'-(para-bromophenyl methoxyalaninyl phosphate) as novel spermicidal and anti-HIV agents. Antivir Chem Chemother 1999, 10, 1, 39.
2 Uckun, F.M.; Venkatachalam, T.; D'Cruz, O. (Parker Hughes Institute); AZT derivs. exhibiting spermicidal and anti-viral activity. WO 9948902 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 25316 methyl 2-[[(4-bromophenoxy)(chloro)phosphoryl]amino]propanoate C10H12BrClNO4P 详情 详情
(V) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情
(VII) 25319 (5R,6R)-1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-bromo-6-methoxy-5-methyldihydro-2,4(1H,3H)-pyrimidinedione C11H16BrN5O5 详情 详情
(VIII) 25320 (5S,6S)-1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-bromo-6-methoxy-5-methyldihydro-2,4(1H,3H)-pyrimidinedione C11H16BrN5O5 详情 详情

合成路线6

该中间体在本合成路线中的序号:(V)

The reaction of 4-methoxyphenol (I) with POCl3 and triethylamine in ethyl ether gives the dichlorophosphate (II), which is condensed with alanine methyl ester (III) by means of triethylamine in dichloromethane yielding the amide (IV). The condensation of (IV) with azidothymidine (V) by means of N-methylimidazole (NMI) in THF affords the 5'-phosphate derivative (VI), which is finally treated with methyl hypobromite (Br2 in methanol).

1 Uckun, F.M.; Venkatachalam, T.; D'Cruz, O. (Parker Hughes Institute); AZT derivs. exhibiting spermicidal and anti-viral activity. WO 9948902 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 32744 4-methoxyphenol 150-76-5 C7H8O2 详情 详情
(II) 32741 Dichlorophosphoric acid 4-methoxyphenyl ester C7H7Cl2O3P 详情 详情
(III) 25315 methyl 2-aminopropanoate; Alanine, methyl ester 7625-53-8 C4H9NO2 详情 详情
(IV) 32742 methyl 2-[[chloro(4-methoxyphenoxy)phosphoryl]amino]propanoate C11H15ClNO5P 详情 详情
(V) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情
(VI) 32743 methyl 2-[[([(2S,3S,5R)-3-azido-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methoxy)(4-methoxyphenoxy)phosphoryl]amino]propanoate C21H27N6O9P 详情 详情

合成路线7

该中间体在本合成路线中的序号:(IV)

The condensation of amine (I) with 2,2-dimethylsuccinic anhydride (II) afforded amide (III). This was then coupled with azidothymidine (IV) using DCC and DMAP to furnish the title compound.

1 Kiso, Y.; Kimura, T.; Akaji, K.; Matsuda, T.; Matsumoto, H.; Hamawaki, T.; A new class of potent anti-HIV agents, conjugates of HIV protease inhibitors containing carboxylic acid with reverse transcriptase inhibitor. Symp Med Chem 1998, Abst 1-P-17.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 29294 (4R)-3-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-N-(tert-butyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide C20H31N3O3S 详情 详情
(II) 29295 3,3-dimethyldihydro-2,5-furandione 17347-61-4 C6H8O3 详情 详情
(III) 29296 4-[((1S,2S)-1-benzyl-3-[(4R)-4-[(tert-butylamino)carbonyl]-5,5-dimethyl-1,3-thiazolidin-3-yl]-2-hydroxy-3-oxopropyl)amino]-2,2-dimethyl-4-oxobutyric acid C26H39N3O6S 详情 详情
(IV) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情

合成路线8

该中间体在本合成路线中的序号:(I)

The condensation of azidothymidine (I) with 2,3-dimethylsuccinic anhydride (II) afforded amide (III). This was then coupled with amine (IV) using DCC and HOBt to furnish the title compound.

1 Kiso, Y.; Kimura, T.; Akaji, K.; Matsuda, T.; Matsumoto, H.; Hamawaki, T.; A new class of potent anti-HIV agents, conjugates of HIV protease inhibitors containing carboxylic acid with reverse transcriptase inhibitor. Symp Med Chem 1998, Abst 1-P-17.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情
(II) 29297 3,4-dimethyldihydro-2,5-furandione C6H8O3 详情 详情
(III) 29298 4-([(2S,3S,5R)-3-azido-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methoxy)-2,3-dimethyl-4-oxobutyric acid C16H21N5O7 详情 详情
(IV) 29294 (4R)-3-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-N-(tert-butyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide C20H31N3O3S 详情 详情

合成路线9

该中间体在本合成路线中的序号:(IX)

Protection of tetraazacyclotetradecane (I) with Boc2O, followed flash chromatography, provided the tri-N-Boc derivative (II) and an unseparable mixture of three isomeric di-N-Boc macrocycles (III). Alkylation of this mixture with ethyl 5-bromovalerate gave a mixture of mono- and dialkylated compounds (IV), from which the required isomer (V) was isolated by flash chromatography. Then, condensation of tri-Boc derivative (II) and monoalkylated di-Boc derivative (V) with alpha-alpha'-dibromo-p-xylene (VI) yielded the desired unsymmetrical bis-macrocycle (VII) along with two symmetrical bis-macrocycle dimers. Subsequent hydrolysis of this mixture with NaOH in the presence of a catalytic amount of Triton B, followed by chromatographic separation, provided pure carboxylic acid (VIII). Further coupling of (VIII) with azidothymidine (IX) using benzotriazol-1-yloxy-tris(pyrrolidino) phosphonium hexafluorophosphate (PyBOP), and final acid deprotection of the Boc groups furnished the title compound.

1 Dessolin, J.; Galea, P.; Vlieghe, P.; Chermann, J.-C.; Kraus, J.-L.; New bicyclam-AZT conjugates: Design, synthesis, anti-HIV evaluation, and their interaction with CXCR-4 coreceptor. J Med Chem 1999, 42, 2, 229.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IIIa) 25364 di(tert-butyl) 1,4,8,11-tetraazacyclotetradecane-1,4-dicarboxylate C20H40N4O4 详情 详情
(IIIb) 25365 di(tert-butyl) 1,4,8,11-tetraazacyclotetradecane-1,8-dicarboxylate C20H40N4O4 详情 详情
(IIIc) 25366 di(tert-butyl) 1,4,8,11-tetraazacyclotetradecane-1,11-dicarboxylate C20H40N4O4 详情 详情
(IVa),(V) 25367 di(tert-butyl) 4-(5-ethoxy-5-oxopentyl)-1,4,8,11-tetraazacyclotetradecane-1,11-dicarboxylate C27H52N4O6 详情 详情
(IVb) 25368 di(tert-butyl) 4-(5-ethoxy-5-oxopentyl)-1,4,8,11-tetraazacyclotetradecane-1,8-dicarboxylate C27H52N4O6 详情 详情
(IVc) 25369 di(tert-butyl) 8-(5-ethoxy-5-oxopentyl)-1,4,8,11-tetraazacyclotetradecane-1,4-dicarboxylate C27H52N4O6 详情 详情
(IVd) 25370 di(tert-butyl) 4,8-bis(5-ethoxy-5-oxopentyl)-1,4,8,11-tetraazacyclotetradecane-1,11-dicarboxylate C34H64N4O8 详情 详情
(IVe) 25371 di(tert-butyl) 4,11-bis(5-ethoxy-5-oxopentyl)-1,4,8,11-tetraazacyclotetradecane-1,8-dicarboxylate C34H64N4O8 详情 详情
(IVf) 25372 di(tert-butyl) 8,11-bis(5-ethoxy-5-oxopentyl)-1,4,8,11-tetraazacyclotetradecane-1,4-dicarboxylate C34H64N4O8 详情 详情
(I) 25362 1,4,8,11-Tetraazacyclotetradecane 295-37-4 C10H24N4 详情 详情
(II) 25363 tri(tert-butyl) 1,4,8,11-tetraazacyclotetradecane-1,4,8-tricarboxylate C25H48N4O6 详情 详情
(VI) 18697 1,4-bis(bromomethyl)benzene 623-24-5 C8H8Br2 详情 详情
(VII) 25373 tri(tert-butyl) 11-(4-[[4,8-bis(tert-butoxycarbonyl)-11-(5-ethoxy-5-oxopentyl)-1,4,8,11-tetraazacyclotetradecan-1-yl]methyl]benzyl)-1,4,8,11-tetraazacyclotetradecane-1,4,8-tricarboxylate C60H106N8O12 详情 详情
(VIII) 25374 5-[4,8-bis(tert-butoxycarbonyl)-11-(4-[[4,8,11-tris(tert-butoxycarbonyl)-1,4,8,11-tetraazacyclotetradecan-1-yl]methyl]benzyl)-1,4,8,11-tetraazacyclotetradecan-1-yl]pentanoic acid C58H102N8O12 详情 详情
(IX) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情

合成路线10

该中间体在本合成路线中的序号:(V)

Treatment of p-bromophenol (I) with phosphoryl chloride and triethylamine furnished p-bromophenyl phosphorodichloridate (II), which was condensed with alanine methyl ester (III) to give the intermediate phosphorochloridate (IV). Then, coupling of chloridate (IV) with azidothimidine (V) in the presence of N-methylimidazole yielded the title compound.

1 Venkatachalam, T.K.; Zhu, Z.; Shih, M.-J.; Tai, H.-L.; Uckun, F.M.; Jan, S.-T.; AZT-5'-(p-bromophenyl methoxyalaninyl phosphate) as a potent and non-toxic anti-human immunodeficiency virus agent. Antivir Chem Chemother 1999, 10, 1, 47.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 25313 4-bromophenol 106-41-2 C6H5BrO 详情 详情
(II) 25314 Dichlorophoephoric acid 4-bromophenyl ester C6H4BrCl2O2P 详情 详情
(III) 25315 methyl 2-aminopropanoate; Alanine, methyl ester 7625-53-8 C4H9NO2 详情 详情
(IV) 25316 methyl 2-[[(4-bromophenoxy)(chloro)phosphoryl]amino]propanoate C10H12BrClNO4P 详情 详情
(V) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情

合成路线11

该中间体在本合成路线中的序号:(I)

By bromination of zidovudine (AZT) (I) with N-bromosuccinimide (NBS) in DMF through the nonisolated intermediate (II), which yields a diastereomeric mixture of the target (S,S) isomer along with some (R,R) isomer that have been separated by crystallization and preparative radial chromatography.

1 Brinon, M.C.; Salomon, H.; Wainberg, M.; Motura, M.; Moroni, G.; Synthesis, lipophilicity and anti-HIV activity of a new brominated analog of zidovudine. Nucleosides Nucleotides 1999, 18, 3, 337.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情
(II) 30897 1-(3-Azido-2,3-dideoxy-beta-D-ribofuranosyl)-6-bromo-5-methyl-2,4-dioxopyrimidin-5-ium C10H13BrN5O4 详情 详情

合成路线12

该中间体在本合成路线中的序号:(VI)

The esterification of 2,2-dimethyl-thiopropionic acid (I) with 2-iodoethanol (II) and DBU in toluene gives the corresponding thioester (III), which is condensed with diisopropylamidophosphoryl dichloride (IV) by means of TEA in THF to afford the phosphoramidite (V). Finally, this compound is condensed with AZT (VI) by means of 1H-tetrazole and MCPBA or 1H-tetrazole and tert-butyl peroxide, both cases in THF.

1 Lefebvre, I.; et al.; Mononucleoside phosphotriester derivatives with S-acyl-2-thioethyl bioreversible phosphate-protecting groups: Intracellular delivery of 3'-azido-2',3'-dideoxythymidine 5'-monophosphate. J Med Chem 1995, 38, 20, 3941.
2 Lannuzel, M.; et al.; Synthesis of the tBuSATE pronucleotide of AZT by two different synthetic approaches. Nucleosides Nucleotides 1999, 18, 4-5, 1001.
3 Lefebvre, I.; et al.; Synthesis, descomposition pathways and "in vitro" evaluation of bioreversible phosphotriesters of AZT. Nucleosides Nucleotides 1995, 14, 3-5, 763.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 38257 2,2-dimethylpropanethioic S-acid C5H10OS 详情 详情
(II) 38258 2-iodo-1-ethanol 624-76-0 C2H5IO 详情 详情
(III) 38259 S-(2-hydroxyethyl) 2,2-dimethylpropanethioate C7H14O2S 详情 详情
(IV) 38260   C6H14Cl2NOP 详情 详情
(V) 38261 S-[4-(diisopropylamino)-10,10-dimethyl-4,9-dioxo-3,5-dioxa-8-thia-4lambda(5)-phosphaundec-1-yl] 2,2-dimethylpropanethioate C20H40NO5PS2 详情 详情
(VI) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情

合成路线13

该中间体在本合成路线中的序号:(VI)

The phosphorylation of AZT (VI) with POCl3 trimethyl phosphate gives the 5'-O-phosphate (VII), which is then condensed with the previously described thioester (III) by means of Tps-Cl in pyridine.

1 Lannuzel, M.; et al.; Synthesis of the tBuSATE pronucleotide of AZT by two different synthetic approaches. Nucleosides Nucleotides 1999, 18, 4-5, 1001.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 38259 S-(2-hydroxyethyl) 2,2-dimethylpropanethioate C7H14O2S 详情 详情
(VI) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情
(VII) 38262 [(2S,3S,5R)-3-azido-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl dihydrogen phosphate C10H14N5O7P 详情 详情

合成路线14

该中间体在本合成路线中的序号:(II)

The synthesis of the title compound has been reported by two procedures. Coupling of dipalmitoylphosphatidic acid (I) to 3'-azido-3'-deoxythimidine (AZT) (II) was carried out using triisopropylbenzenesulfonyl chloride in pyridine to provide the target phosphate diester.

1 Hostetler, K.Y.; Felgner, J.; Richman, D.D.; Selleseth, D.W.; Gardner, M.F.; Ellis, M.N.; Felgner, P.L.; Ricci, J.; Sridhar, C.N.; Phosphatidylazidothymidine and phosphatidyl-ddC: Assessment of uptake in mouse lymphoid tissues and antiviral activities in human immunodeficiency virus-infected cells and in rauscher leukemia virus-infected mice. Antimicrob Agents Chemother 1994, 38, 12, 2792.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 35626 2-(palmitoyloxy)-1-[(phosphonooxy)methyl]ethyl palmitate C35H69O8P 详情 详情
(II) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情

合成路线15

该中间体在本合成路线中的序号:(II)

3'-azido-3'-deoxythimidine (II) was phosphitylated with phosphorus trichloride in triethyl phosphate to yield the corresponding hydrogen phosphonate (III). Subsequent coupling of (III) with 1,2-dipalmitoylglycerol (IV) by means of pivaloyl chloride in pyridine produced phosphite ester (V), which was finally oxidized to the title phosphate with ethanolic iodine.

1 Manouilov, K.K.; Fedorov, I.I.; Boudinot, F.D.; White, C.A.; Kotra, L.P.; Schinazi, R.F.; Hong, C.I.; Chu, C.K.; Lymphatic targeting of anti-HIV nucleosides: Distribution of 3'-azido-3'-deoxythymidine (AZT) and 3'-azido-2',3'-dideoxyuridine (AZdU) after administration of dipalmitoylphosphatidyl prodrugs to mice. Antivir Chem Chemother 1995, 6, 4, 230.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情
(III) 35627 [(2S,3S,5R)-3-azido-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl hydrogen phosphonate C10H14N5O6P 详情 详情
(IV) 35628 2-hydroxy-1-[(palmitoyloxy)methyl]ethyl palmitate C35H68O5 详情 详情
(V) 35629 2-[[([(2S,3S,5R)-3-azido-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methoxy)(oxo)phosphoranyl]oxy]-1-[(palmitoyloxy)methyl]ethyl palmitate C45H80N5O10P 详情 详情

合成路线16

该中间体在本合成路线中的序号:(I)

The desired product can be obtained by condensation of commercial AZT (I) with N,N’-carbonyldiimidazole (CDI) in DMF followed by treatment with 1,4-butanediol (II) in the same solvent.

2 Vlieghe, P.; Bihel, F.; Clerc, T.; et al.; New 3'-azido-3'-deoxythymidin-5'-yl O-(omega-hydroxyalkyl) carbonate prodrugs: Synthesis and anti-HIV evaluation. J Med Chem 2001, 44, 5, 777.
3 Kraus, J.-L.; Clerc, T.; Salles, J.-P.; Vlieghe, P. (Laboratoires Laphal); Novel cpds. derived from nucleosides, preparation methods and pharmaceutical compsns. containing same. FR 2794752; WO 0077020 .
4 Vlieghe, P.; Salles, J.-P.; Clerc, T.; Kraus, J.-L. (Laboratoires Laphal); Novel esters derived from nucleosides, preparation methods and pharmaceutical compsns. containing them. FR 2796384; WO 0104134 .
1 Clerc, T.; Pannecouque, C.; Vlieghe, P.; Kraus, J.-L.; Salles, J.-P.; De Clercq, E.; Witvrouw, M.; New 3'-azido-3' deoxythymidin-5'-yl O-(4-hydroxyalyl or -alkenyl or -alkylepoxide) carbonate prodrugs: Synthesis and anti-HIV evaluation. J Med Chem 2001, 44, 18, 3014.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情
(II) 43160 1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol 110-63-4 C4H10O2 详情 详情

合成路线17

该中间体在本合成路线中的序号:(IV)

The title compound was prepared following two alternative synthetic sequences: Condensation of the known dipeptide amide (I) with 2,2-dimethylsuccinic anhydride (II) in the presence of DMAP produced regioselectively the succinic monoamide (III). This was then coupled to AZT (IV) by using DCC and DMAP to furnish the corresponding AZT ester.

1 Kimura, T.; Matsuda, T.; Akaji, K.; Kiso, Y.; Matsumoto, H.; Hamawaki, T.; Synthesis and activity of a new type of anti-HIV agents, conjugate of HIV protease inhibitor with reverse transcriptase inhibitor. Pept Sci 1999, 305.
2 Kimura, T.; Kiso, Y.; Matsumoto, H.; Akaji, K.; Hamawaki, T.; Matsuda, T.; A new class of anti-HIV agents: Synthesis and activity of conjugates of HIV protease inhibitors with a reverse transcriptase inhibitor. Bioorg Med Chem Lett 1999, 9, 6, 803.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51181 (4R)-3-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-N-(2-methylbenzyl)-1,3-thiazolidine-4-carboxamide C24H31N3O3S 详情 详情
(II) 29295 3,3-dimethyldihydro-2,5-furandione 17347-61-4 C6H8O3 详情 详情
(III) 51182 4-[[(1S,2S)-1-benzyl-3-((4R)-5,5-dimethyl-4-[[(2-methylbenzyl)amino]carbonyl]-1,3-thiazolidin-3-yl)-2-hydroxy-3-oxopropyl]amino]-2,2-dimethyl-4-oxobutyric acid C30H39N3O6S 详情 详情
(IV) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情

合成路线18

该中间体在本合成路线中的序号:(IV)

In an alternative procedure, 2,2-dimethylsuccinic anhydride (II) was reacted with p-methoxybenzyl alcohol (V) in the presence of dicyclohexylamine to afford the beta,beta-dimethyl p-methoxybenzyl ester (VI) as the major product, along with minor amounts of the alpha,alpha-dimethyl regioisomer. Condensation of hemiester (VI) with AZT (IV) by using DCC and DMAP produced diester (VII). The p-methoxybenzyl group of (VII) was then removed by treatment with trifluoroacetic acid to give (VIII). Acid (VIII) was finally coupled with the dipeptide amide (I) in the presence of BOP and HOBt.

1 Kimura, T.; Matsuda, T.; Akaji, K.; Kiso, Y.; Matsumoto, H.; Hamawaki, T.; Synthesis and activity of a new type of anti-HIV agents, conjugate of HIV protease inhibitor with reverse transcriptase inhibitor. Pept Sci 1999, 305.
2 Kimura, T.; Kiso, Y.; Matsumoto, H.; Akaji, K.; Hamawaki, T.; Matsuda, T.; A new class of anti-HIV agents: Synthesis and activity of conjugates of HIV protease inhibitors with a reverse transcriptase inhibitor. Bioorg Med Chem Lett 1999, 9, 6, 803.
3 Mitoguchi, T.; Kiso, Y.; Nakata, S.; Hayashi, Y.; Matsuda, T.; Matsumoto, H.; Kimura, T.; Synthesis and biological evaluation of prodrug-type anti-HIV agents. Ester conjugates of carboxylic acid-containing dipeptide HIV protease inhibitors and a reverse transcriptase inhibitor. Bioorg Med Chem 2001, 9, 2, 417.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51181 (4R)-3-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-N-(2-methylbenzyl)-1,3-thiazolidine-4-carboxamide C24H31N3O3S 详情 详情
(II) 29295 3,3-dimethyldihydro-2,5-furandione 17347-61-4 C6H8O3 详情 详情
(IV) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情
(V) 38861 4-Methoxybenzenemethanol; (4-methoxyphenyl)methanol; 4-Methoxybenzyl alcohol; Anis alcohol; Anisyl Alcohol; 4-Anisic Alcohol; p-Anisyl alcohol; Anise alcohol 105-13-5 C8H10O2 详情 详情
(VI) 51183 4-[(4-methoxybenzyl)oxy]-2,2-dimethyl-4-oxobutyric acid C14H18O5 详情 详情
(VII) 51184 1-([(2S,3S,5R)-3-azido-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl) 4-(4-methoxybenzyl) 2,2-dimethylsuccinate C24H29N5O8 详情 详情
(VIII) 51185 4-([(2S,3S,5R)-3-azido-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methoxy)-3,3-dimethyl-4-oxobutyric acid C16H21N5O7 详情 详情

合成路线19

该中间体在本合成路线中的序号:(VIII)

Tetrazole-catalyzed phosphitylation of the tyrosinamide derivative (V) with O-2-(pivaloylthio)ethyl-N,N,N',N'-tetraisopropylphosphorodiamidite (VI) yields phosphoramidite (VII). This is subsequently coupled to azidothimidine (VIII) to furnish phosphite (IX), which is then oxidized to the corresponding phosphate (X) with t-butyl hydroperoxide. The N-Boc protecting groups of (X) are finally removed under acidic conditions to provide the title compound.

1 Peyrottes, S.; Coussot, G.; Lefebvre, I.; Imbach, J.-L.; Gosselin, G.; Aubertin, A.-M.; Perigaud, C.; S-acyl-2-thioethyl aryl phosphotriester derivatives of AZT: Synthesis, antiviral activity, and stability study. J Med Chem 2003, 46, 5, 782.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 64281 (7S)-5-(tert-butoxycarbonyl)-7-(4-{[tert-butyl(dimethyl)silyl]oxy}benzyl)-2,2,11,11-tetramethyl-4,6,9-trioxo-3,10-dioxa-5,8-diazadodecane C30H50N2O8Si 详情 详情
(VI) 64282 S-(2-{[bis(diisopropylamino)phosphino]oxy}ethyl) 2,2-dimethylpropanethioate C19H41N2O2PS 详情 详情
(VII) 64283 (7S)-5-(tert-butoxycarbonyl)-7-{4-[((diisopropylamino){2-[(2,2-dimethylpropanoyl)sulfanyl]ethoxy}phosphino)oxy]benzyl}-2,2,11,11-tetramethyl-4,6,9-trioxo-3,10-dioxa-5,8-diazadodecane C37H62N3O10PS 详情 详情
(VIII) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情
(IX) 64284 1-{(2R,4S,5S)-4-azido-5-[3-(4-{(2S)-3-[bis(tert-butoxycarbonyl)amino]-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}phenoxy)-9,9-dimethyl-8-oxo-2,4-dioxa-7-thia-3-phosphadec-1-yl]tetrahydro-2-furanyl}-5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine C41H60N7O14PS 详情 详情
(X) 64285 1-{(2R,4S,5S)-4-azido-5-[3-(4-{(2S)-3-[bis(tert-butoxycarbonyl)amino]-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}phenoxy)-9,9-dimethyl-3,8-dioxo-2,4-dioxa-7-thia-3lambda~5~-phosphadec-1-yl]tetrahydro-2-furanyl}-5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine C41H60N7O15PS 详情 详情
Extended Information