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【结 构 式】

【分子编号】45407

【品名】(1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate; (1S,4R)-4-acetoxy-2-cyclopentenol

【CA登记号】60410-16-4

【 分 子 式 】C7H10O3

【 分 子 量 】142.1546

【元素组成】C 59.14% H 7.09% O 33.76%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(XXX)

The preparation of the cyclopentylamino intermediates (I) and (XIX) is shown in Scheme 4. Reaction of (1S,4R)-4-acetoxy-2-cyclopentenol (XXX) with di-tert-butyl iminodicarboxylate in the presence of NaH and Pd(PPh3)4 produces the di-Boc-protected aminocyclopentenol (XXXI), which undergoes dihydroxylation to triol (XXXII) by means of N-methylmorpholine N-oxide and a catalytic amount of osmium tetroxide. After acidic deprotection of the di-Boc derivative (XXXII), the resulting amino triol (XXXIII) is converted to the key acetonide (I) upon heating with 2,2-dimethoxypropane and catalytic HCl in acetone (1, 2). The O-hydroxyethyl derivative (XIX) is prepared by protection of aminoalcohol (I) as the benzyl carbamate (XXXIV), followed by O-alkylation with ethyl bromoacetate and potassium tert-butoxide to give (XXXV). Subsequent reduction of ester (XXXV) with LiBH4 in THF furnishes the corresponding hydroxyethyl derivative (XXXVI), from which the N-(benzyloxycarbonyl) group is removed by catalytic hydrogenation over Pd/C (3). Scheme 4.

1 Guile, S., Hardern, D., Willis, P., Springthorpe, B., Ingall, A. (AstraZeneca AB; AstraZeneca plc). Novel triazolo(4,5-d)pyrimidine compounds. EP 1135391, JP 2002531567, JP 2007084551, US 2003144305, US 2006025590, US 6525060, WO 0034283.
2 Bohlin, M., Lassen, B., Cosgrove, S. (AstraZeneca AB). New crystalline and amorphous form of triazolo(4,5-d)pyrimidine compound. CA 2408596, EP 1289992, EP 1493745, JP 2003535092, US 2003181469, US 2007173518, WO 0192262.
3 Larsson, U., Magnusson, M., Musil, T., Palmgren, A. (AstraZeneca AB). Triazolo pyrimidine compounds. CA 2408914, EP 1299390, JP 2003535093, US 2003148888, US 2006041132, US 2007049755, US 7067663, WO 0192263.
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) 65443 (3aR,4S,6R,6aS)-6-Aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol; (3aS,4R,6S,6aR)-6-Hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine 155899-66-4 C8H15NO3 详情 详情
(XIX) 65458 2-[[(3aR,4S,6R,6aS)-6-Aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]ethanol 274693-55-9 C10H19NO4 详情 详情
(XXX) 45407 (1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate; (1S,4R)-4-acetoxy-2-cyclopentenol 60410-16-4 C7H10O3 详情 详情
(XXXI) 65467 (1S,4R)-4-[(N,N-di-Boc)amino]-2-cyclopentenol   C15H25NO5 详情 详情
(XXXII) 65468     C15H27NO7 详情 详情
(XXXIII) 65469     C5H11NO3.HCl 详情 详情
(XXXIV) 65470 N-[(3aS,4R,6S,6aR)-Tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]carbamicacid phenylmethyl ester 274693-53-7 C16H21NO5 详情 详情
(XXXV) 65471     C20H27NO7 详情 详情
(XXXVI) 65472 N-[(3aS,4R,6S,6aR)-Tetrahydro-6-(2-hydroxyethoxy)-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]carbamic acid phenylmethyl ester 274693-54-8 C18H25NO6 详情 详情

合成路线2

该中间体在本合成路线中的序号:(IV)

The photooxidation of cyclopentadiene (I) gives cis-4-cyclopentene-1,3-diol (II), which is acylated with Ac2O to yield the diacetate (II). Enzymatic selective hydrolysis of (II) using porcine pancreas lipase (PPL) affords the chiral monoacetate (IV), which is protected with dihydropyran (DHP) and Ts-OH to provide the tetrahydropyranyl ether (V). The hydrolysis of the acetate group of (V) with KOH in methanol gives the alcohol (VI), which is silylated with TbdmsCl and imidazole to yield the silyl ether (VII). Elimination of the THP-protecting group of (VII) with Me2AlCl in dichloromethane affords the cyclopentenol (VIII), which is oxidized with PCC to the cyclopentenone (IX). The condensation of (IX) with chloroiodomethane and BuLi in THF gives the chiral chloromethyl derivative (X), which is treated with potassium methoxide in THF to obtain the chiral epoxide (XI). Stereocontrolled opening of the epoxide ring of (XI) by means of DIBAL in hexane provides the cyclopentenyl-methanol derivative (XII), which is desilylated with TBAF in THF to give the chiral diol (XIII). The esterification of the diol (XIII) with methyl chloroformate and pyridine yields the bis-carbonate (XIV), which is condensed with 2-amino-6-chloropurine (XV) by means of Pd(PPh3)4 in DMF to afford the carbocyclic purine derivative (XVI). Finally, this compound is hydrolyzed with NaOH in refluxing water to provide the target carbocyclic guanine.

1 Nokami, J.; et al.; Palladium-catalyzed chemoselective reaction of allylic carbonate with nucleoside bases and its application for the synthesis of carbocyclic nucleosides. (-)-and (+)-carbovirs. Chem Lett 1994, 1071.
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) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(II) 33168 (1R,3S)-4-cyclopentene-1,3-diol C5H8O2 详情 详情
(III) 45374 (1R,4S)-4-(acetoxy)-2-cyclopenten-1-yl acetate C9H12O4 详情 详情
(IV) 45407 (1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate; (1S,4R)-4-acetoxy-2-cyclopentenol 60410-16-4 C7H10O3 详情 详情
(V) 45339   C8H11N 详情 详情
(VI) 45400 (1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-ol C11H18O3 详情 详情
(VII) 45401 tert-butyl(dimethyl)([(1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-yl]oxy)silane; tert-butyl(dimethyl)silyl (1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-yl ether C17H32O3Si 详情 详情
(VIII) 33174 (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-ol C11H22O2Si 详情 详情
(IX) 13805 (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one C11H20O2Si 详情 详情
(X) 45402 (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-(chloromethyl)-2-cyclopenten-1-ol C12H23ClO2Si 详情 详情
(XI) 45403 tert-butyl(dimethyl)silyl (3S,5R)-1-oxaspiro[2.4]hept-6-en-5-yl ether; tert-butyl(dimethyl)[(3S,5R)-1-oxaspiro[2.4]hept-6-en-5-yloxy]silane C12H22O2Si 详情 详情
(XII) 45404 ((1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-yl)methanol C12H24O2Si 详情 详情
(XIII) 45405 (1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(XIV) 45406 [(1S,4R)-4-[(methoxycarbonyl)oxy]-2-cyclopenten-1-yl]methyl methyl carbonate C10H14O6 详情 详情
(XV) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(XVI) 45398 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate C13H14ClN5O3 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 reaction of the commercially available (1S-cis)-2-cyclopentan-1,4-diol 4-acetate (I) with methyl pyrocarbonate and DMAP in THF gives the carbonate ester (II), which by reaction with nitromethane (III), triisopropyl phosphite and a Pd catalyst, yields (1R-cis)-1-acetoxy-4-(nitromethyl)-2-cyclopentene (IV). The hydrolysis of (IV) by means of Ts-OH in methanol affords the corresponding alcohol (V), which by treatment with O3, NaOMe and NaBH4 in methanol provides (1R-cis)-4-(hydroxymethyl)-2-cyclopenten-1-ol (VI). The selective monotritylation of the primary OH group of (VI) with trityl chloride (VII) in pyridine gives the trityl ether (VIII), which is condensed with 2-amino-6-chloropurine (IX) by means of Pd(PPh3)4 in THF to yield the adduct (X). The destritylation of (X) with HOAc/water affords the hydroxymethyl compound (XI), which is finally dechlorinated by hydrolysis with hot HCl or NaOH to provide the target (-)-carbovir. Alternatively, the dechlorination of (XI) can be performed by reaction of (XI) with liquid ammonia at 75-80 C in a Parr bomb to give the diaminopurine (XII), which is finally submitted to an enzymatic deamination with adenosine deaminase (from calf intestinal mucosa).

1 Vince, R.; Peterson, M.L.; Lackey, J.W.; Mook, R.A. Jr.; Partridge, J.J. (GlaxoSmithKline plc); Synthesis of purine substd. cyclopentene derivs.. US 5126452 .
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) 45407 (1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate; (1S,4R)-4-acetoxy-2-cyclopentenol 60410-16-4 C7H10O3 详情 详情
(II) 55528 (1R,4S)-4-[(methoxycarbonyl)oxy]-2-cyclopenten-1-yl acetate C9H12O5 详情 详情
(III) 39563 nitromethane 75-52-5 CH3NO2 详情 详情
(IV) 55529 (1R,4S)-4-(nitromethyl)-2-cyclopenten-1-yl acetate C8H11NO4 详情 详情
(V) 55530 (1R,4S)-4-(nitromethyl)-2-cyclopenten-1-ol C6H9NO3 详情 详情
(VI) 45405 (1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(VII) 28630 Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride 76-83-5 C19H15Cl 详情 详情
(VIII) 55531 (1R,4S)-4-[(trityloxy)methyl]-2-cyclopenten-1-ol C25H24O2 详情 详情
(IX) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(X) 55532 6-chloro-9-{(1R,4S)-4-[(trityloxy)methyl]-2-cyclopenten-1-yl}-9H-purin-2-amine; 6-chloro-9-{(1R,4S)-4-[(trityloxy)methyl]-2-cyclopenten-1-yl}-9H-purin-2-ylamine C30H26ClN5O 详情 详情
(XI) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情
(XII) 55533 [(1S,4R)-4-(2,6-diamino-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H14N6O 详情 详情
Extended Information