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【结 构 式】

【分子编号】17674

【品名】[(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate

【CA登记号】

【 分 子 式 】C10H14O4

【 分 子 量 】198.21876

【元素组成】C 60.59% H 7.12% O 32.29%

与该中间体有关的原料药合成路线共 4 条

合成路线1

该中间体在本合成路线中的序号:(VIII)

The condensation of the chiral oxazolidinone (I) with the pentenoic anhydride (II) by means of n-BuLi in THF gives the N-pentenoyloxazolidinone (III), which is condensed with acrolein (IV) catalyzed by TiCl4 and (-)-spartein in dichloromethane, yielding the chiral adduct (V). The ring-closing metathesis of (V) by means of a Ru catalyst in dichloromethane affords the chiral cyclopentenol derivative (VI), which is reduced to the (R,R)-5-(hydroxymethyl)-2-cyclopenten-1-ol (VII) by means of LiBH4 in THF. The reaction of diol (VII) with Ac2O; with methyl chloroformate, TEA and DMAP; or with ethyl chloroformate and pyridine gives the diacetate (VIII), the cyclic carbonate (IX) or the dicarbonate (X), respectively. The condensation of (VIII), (IX) or (X) with 2-amino-6-chloropurine (XI) by means of Pd(PPh3)4 yields the carbocyclic purines (XII), (XIII) or (XIV), respectively. Finally, these compounds are hydrolyzed with aqueous NaOH to the target carbocyclic guanine.

1 Crimmins, M.T.; et al.; An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy. J Org Chem 2000, 65, 25, 8499.
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) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(II) 17666 1,1-dimethylpropionic 4-pentenoic anhydride C10H16O3 详情 详情
(III) 17667 (4S)-4-benzyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one C15H17NO3 详情 详情
(IV) 17668 acrylaldehyde; Acrolein 107-02-8 C3H4O 详情 详情
(V) 17669 (4S)-3-[(2S,3R)-2-allyl-3-hydroxy-4-pentenoyl]-4-benzyl-1,3-oxazolidin-2-one C18H21NO4 详情 详情
(VI) 17670 (4S)-4-benzyl-3-[[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]carbonyl]-1,3-oxazolidin-2-one C16H17NO4 详情 详情
(VII) 17671 (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(VIII) 17674 [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate C10H14O4 详情 详情
(IX) 17673 (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one C7H8O3 详情 详情
(X) 17672 [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate C10H14O6 详情 详情
(XI) 11664 4-Chloro-3-nitroquinoline C9H5ClN2O2 详情 详情
(XII) 45424 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl acetate C13H14ClN5O2 详情 详情
(XIII) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情
(XIV) 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2

该中间体在本合成路线中的序号:(XXXIII)

4) The acylation of 4(S)-benzyloxazolidin-2-one (XXIV) with 4-pentenoyl pivaloyl anhydride (XXV) by means of NaH in THF gives 4(S)-benzyl-3-(4-pentenoyl)oxazolidin-2-one (XXVI), which is submitted to a diastereoselective syn aldol condensation with acrolein (XXVII), using dibutylboron triflate as catalyst, affording the aldol (XXVIII). The cyclization of (XXVIII) by means of the Grubbs catalyst in dichloromethane yields the cyclopentenol (XXIX), which is reduced with LiBH4 in THF/methanol to give the key intermediate 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (XXX). The reaction of (XXX) with methyl chloroformate/pyridine/DMAP or methyl chloroformate/triethylamine/DMAP or acetic anhydride gives the diols (XXXI), (XXXII) and (XXXIII), respectively, each of which coupled with 2-amino-6-chloropurine (XXXIV) in the presence of NaH and palladium tetrakis(triphenylphosphine) in THF/DMSO, affords the purine intermediate (IX) already reported.

1 King, B.W.; Crimmins, M.T.; An efficient asymmetric approach to carbocyclic nucleosides: Asymmetric synthesis of 1592U89, a potent inhibitor of HIV reverse transcriptase. J Org Chem 1996, 61, 13, 4192-3.
2 Graul, A.; Castaner, J.; Leeson, P.A.; Abacavir Sulfate. Drugs Fut 1998, 23, 11, 1155-1167.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情
(XXIV) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(XXV) 17666 1,1-dimethylpropionic 4-pentenoic anhydride C10H16O3 详情 详情
(XXVI) 17667 (4S)-4-benzyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one C15H17NO3 详情 详情
(XXVII) 17668 acrylaldehyde; Acrolein 107-02-8 C3H4O 详情 详情
(XXVIII) 17669 (4S)-3-[(2S,3R)-2-allyl-3-hydroxy-4-pentenoyl]-4-benzyl-1,3-oxazolidin-2-one C18H21NO4 详情 详情
(XXIX) 17670 (4S)-4-benzyl-3-[[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]carbonyl]-1,3-oxazolidin-2-one C16H17NO4 详情 详情
(XXX) 17671 (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(XXXI) 17672 [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate C10H14O6 详情 详情
(XXXII) 17673 (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one C7H8O3 详情 详情
(XXXIII) 17674 [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate C10H14O4 详情 详情
(XXXIV) 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

合成路线3

该中间体在本合成路线中的序号:(VIII)

An efficient asymmetric synthesis of abacavir has been reported: Acylation of the chiral oxazolidinone (I) with the mixed anhydride (II) by means of BuLi in THF gives the N-pentenoyloxazolidinone (III), which by condensation with acrolein (IV) catalyzed by TiCl4 and (­)-spartein in dichloromethane yields the chiral adduct (V). The ring-closing metathesis of adduct (V) by means of the ruthenium catalyst (Cy3P)Cl2Ru=CHPh in dichloromethane affords the chiral cyclopentenol (VI), which is reduced to 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (VII) by means of LiBH4 in THF. Reaction of diol (VII) with a) Ac2O, TEA and DMAP, b) methyl chloroformate, TEA and DMAP or c) methyl chloroformate, pyridine and DMAP gives a) the diacetate (VIII), b) the cyclic carbonate (IX) or c) the dicarbonate (X), respectively. The condensation of diacetate (VIII), cyclic carbonate (IX) or dicarbonate (X) with 2-amino-6-chloropurine (XI) by means of Pd(PPh3)4 yields the carbocyclic purines (XII), (XIII) or (XIV), respectively. Treatment of these chloro-purines (XII), (XIII) and (XIV) with cyclopropylamine (XV) in hot DMSO provides the corresponding cyclopropylaminopurine carbonate (XVI), abacavir or cyclopropylaminopurine acetate (XVII), respectively. Finally, the protecting groups of purines (XVI) and (XVII) are hydrolyzed with aqueous NaOH.

1 Crimmins, M.T.; et al.; An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy. J Org Chem 2000, 65, 25, 8499.
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) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(II) 17666 1,1-dimethylpropionic 4-pentenoic anhydride C10H16O3 详情 详情
(III) 17667 (4S)-4-benzyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one C15H17NO3 详情 详情
(IV) 17668 acrylaldehyde; Acrolein 107-02-8 C3H4O 详情 详情
(V) 17669 (4S)-3-[(2S,3R)-2-allyl-3-hydroxy-4-pentenoyl]-4-benzyl-1,3-oxazolidin-2-one C18H21NO4 详情 详情
(VI) 17670 (4S)-4-benzyl-3-[[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]carbonyl]-1,3-oxazolidin-2-one C16H17NO4 详情 详情
(VII) 17671 (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(VIII) 17674 [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate C10H14O4 详情 详情
(IX) 17673 (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one C7H8O3 详情 详情
(X) 17672 [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate C10H14O6 详情 详情
(XI) 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
(XII) 45424 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl acetate C13H14ClN5O2 详情 详情
(XIII) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情
(XIV) 45398 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate C13H14ClN5O3 详情 详情
(XV) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XVI) 49433 [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl acetate C16H20N6O2 详情 详情
(XVII) 49434 [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl methyl carbonate C16H20N6O3 详情 详情

合成路线4

该中间体在本合成路线中的序号:(VIII)

Alternatively, 2-amino-6-chloropurine (XI) is treated with cyclopropylamine (XV) in hot DMSO to give 2-amino-6-(cyclopropylamino)purine (XVIII), which is condensed with the chiral diacetate (VIII) by means of Pd(PPh3)4 to yield the carbocyclic purine acetate (XVI). Finally, purine (XVI) is deprotected by hydrolysis with aqueous NaOH.

1 Crimmins, M.T.; et al.; An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy. J Org Chem 2000, 65, 25, 8499.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 17674 [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate C10H14O4 详情 详情
(XI) 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
(XV) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XVI) 49433 [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl acetate C16H20N6O2 详情 详情
(XVIII) 41890 N-(2-amino-9H-purin-6-yl)-N-cyclopropylamine; N(6)-cyclopropyl-9H-purine-2,6-diamine C8H10N6 详情 详情
Extended Information