SPD-756, BCH-13520, -Drug Synthesis Database

【结构式】

【药物名称】SPD-756, BCH-13520

【化学名称】(-)-(2R,4R)-4-[2-Amino-6-(cyclopropylamino)-9H-purin-9-yl]-1,3-dioxolane-2-methanol
　　　　　　(-)-(2R,4R)-4-[2-Amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-(hydroxymethyl)-1,3-dioxolane
　　　　　　N6-Cyclopropyl-9-[2(R)-(hydroxymethyl)-1,3-dioxolan-4(R)-yl]purine-2,6-diamine

【CA登记号】280138-71-8, 280138-75-2 (racemate)

【分子式】C₁₂H₁₆N₆O₃

【分子量】292.29972

【开发单位】Shire Pharmaceuticals (Originator)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Reverse Transcriptase Inhibitors

合成路线1 合成路线2

合成路线1

Ketal exchange between the chiral acetonide (I) and 2-(benzoyloxy)acetaldehyde (II) under acidic conditions affords the 2-(benzoyloxymethyl) dioxolane (III) as a diastereomeric mixture. Alternatively, diazotization of D-serine (IV) in the presence of NaNO2 and H2SO4 produces D-glyceric acid (V), which is further esterified with methanol to afford the methyl ester (VI). Condensation of dihydroxy ester (VI) with 2-(benzoyloxy)acetaldehyde dimethyl acetal (VII) then gives dioxolane (III).

参考文献中间体

【1】 Nguyen-Ba, N. (Shire BioChem Inc.); Antiviral nucleoside analogues. EP 1140937; JP 2002533470; US 6358963; WO 0039143 .
【2】 Cimpoia, A.; Janes, L.; Kazlauskas, R. (Shire BioChem Inc.); Stereoselective synthesis of nucleoside analogues. WO 0047759 .
【3】 Cimpoia, A.; Wang, Y.-F. (Shire BioChem Inc.); Stereoselective synthesis of nucleoside analogues. WO 0158894 .

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)	57514	methyl (2S,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylate		C₁₃H₁₄O₆	详情	详情
(IIIb)	57515	methyl (2R,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylate		C₁₃H₁₄O₆	详情	详情
(I)	20917	methyl (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate	52373-72-5	C₇H₁₂O₄	详情	详情
(II)	15605	2-oxoethyl benzoate		C₉H₈O₃	详情	详情
(IV)	15728	(+)-2-Amino-3-hydroxypropionic acid; D-(+)-Serine; D-serine	312-84-5	C₃H₇NO₃	详情	详情
(V)	57516	(2R)-2,3-dihydroxypropanoic acid		C₃H₆O₄	详情	详情
(VI)	20916	methyl (2R)-2,3-dihydroxypropanoate		C₄H₈O₄	详情	详情
(VII)	57517	2,2-dimethoxyethyl benzoate		C₁₁H₁₄O₄	详情	详情

合成路线2

Selective hydrolysis of the methyl esters (III) with LiOH provides the desired cis-dioxolane acid (IX) and the corresponding trans isomer (VIII), which are separated by column chromatography. Alternatively, ester (III) is subjected to enzymatic resolution with several different enzymes to provide a mixture of the undesired trans-dioxolane acid (VIII) and the unreacted cis-ester (X), separable by partition between H2O and EtOAc. The desired cis-ester (X) is then hydrolyzed with LiOH to the carboxylic acid (IX). Oxidative decarboxylation of acid (IX) employing lead tetraacetate furnishes the acetoxy dioxolane (XI). After silylation of 2-amino-6-chloropurine (XII) with hexamethyldisilazane in the presence of ammonium sulfate, coupling with the acetoxy dioxolane (XI), promoted by either trimethylsilyl triflate or by iodotrimethylsilane, gives rise to an anomeric mixture of adducts (XIII). Following chromatographic isolation of the target cis-anomer, chloride displacement with cyclopropylamine yields the diamino purine derivative (XIV). The benzoate ester group of (XIV) is finally hydrolyzed to the title compound by means of methanolic ammonia.

参考文献中间体

【1】 Nguyen-Ba, N. (Shire BioChem Inc.); Antiviral nucleoside analogues. EP 1140937; JP 2002533470; US 6358963; WO 0039143 .
【2】 Cimpoia, A.; Janes, L.; Kazlauskas, R. (Shire BioChem Inc.); Stereoselective synthesis of nucleoside analogues. WO 0047759 .
【3】 Cimpoia, A.; Wang, Y.-F. (Shire BioChem Inc.); Stereoselective synthesis of nucleoside analogues. WO 0158894 .

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)	57514	methyl (2S,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylate		C₁₃H₁₄O₆	详情	详情
(IIIb),(X)	57515	methyl (2R,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylate		C₁₃H₁₄O₆	详情	详情
(XIa)	57519	[(2R,4R)-4-(acetyloxy)-1,3-dioxolan-2-yl]methyl benzoate		C₁₃H₁₄O₆	详情	详情
(XIb)	57520	[(2R,4S)-4-(acetyloxy)-1,3-dioxolan-2-yl]methyl benzoate		C₁₃H₁₄O₆	详情	详情
(XIIIa)	57521	[(2R,4S)-4-(2-amino-6-chloro-9H-purin-9-yl)-1,3-dioxolan-2-yl]methyl benzoate		C₁₆H₁₄ClN₅O₄	详情	详情
(XIIIb)	57522	[(2R,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-1,3-dioxolan-2-yl]methyl benzoate		C₁₆H₁₄ClN₅O₄	详情	详情
(VIII)	57518	(2S,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylic acid		C₁₂H₁₂O₆	详情	详情
(IX)	57524	(2R,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylic acid		C₁₂H₁₂O₆	详情	详情
(XII)	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
(XIV)	57523	{(2R,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-1,3-dioxolan-2-yl}methyl benzoate		C₁₉H₂₀N₆O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)