(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate -Drug Synthesis Database

【结构式】

【分子编号】25228

【品名】(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate

【CA登记号】

【分子式】C₁₆H₁₆Cl₂N₄O₇

【分子量】447.2312

【元素组成】C 42.97% H 3.61% Cl 15.85% N 12.53% O 25.04%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(VI)

Protection of D-alaninol (I) with di-tert-butyl dicarbonate gave rise to carbamate (II). Subsequent Mitsunobu coupling of (II) with 2-mercaptobenzothiazole (III) furnished thioether (IV), which was deprotected with HCl in EtOAc. The resulting amine (V) was condensed with dichloropurine (VI) to afford the chloroadenosine derivative (VII). Finally, cleavage of the acetate esters of (VII) was achieved by treatment with NaOMe in MeOH.

参考文献中间体

合成目标

【1】 Lau, J.; Judge, M.E.; Sheardown, M.J.; Petersen, H.; Shalmi, M.; Knutsen, L.J.S.; Hansen, A.J.; Thomsen, C.; Weis, J.U.; N-substituted adenosines as novel neuroprotective A1 agonists with diminished hypotensive effects. J Med Chem 1999, 42, 18, 3463.

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)	21414	(2R)-2-Amino-1-propanol; D-Alaninol; D-(-)-Alaninol	35320-23-1	C₃H₉NO	详情	详情
(II)	31758	tert-butyl (1R)-2-hydroxy-1-methylethylcarbamate		C₈H₁₇NO₃	详情	详情
(III)	24677	1,3-benzothiazol-2-ylhydrosulfide	149-30-4	C₇H₅NS₂	详情	详情
(IV)	31759	tert-butyl (1R)-2-(1,3-benzothiazol-2-ylsulfanyl)-1-methylethylcarbamate		C₁₅H₂₀N₂O₂S₂	详情	详情
(V)	31760	(2R)-1-(1,3-benzothiazol-2-ylsulfanyl)-2-propanamine; (1R)-2-(1,3-benzothiazol-2-ylsulfanyl)-1-methylethylamine		C₁₀H₁₂N₂S₂	详情	详情
(VI)	25228	(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate		C₁₆H₁₆Cl₂N₄O₇	详情	详情
(VII)	31761	(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-[[(1R)-2-(1,3-benzothiazol-2-ylsulfanyl)-1-methylethyl]amino]-2-chloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate		C₂₆H₂₇ClN₆O₇S₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The reaction of 2,6-dichloro-9-(2',3',5'-tri-O-acetyl-beta-D-ribofuranosyl)-9H-purine (I) with O-methylhydroxylamine in hot dioxane gives 2',3',5'-tri-O-acetyl-2-chloro-N-methoxy-adenosine (II), which is then treated with sodium methoxide in methanol.

参考文献中间体

合成目标

【1】 Knutsen, L.; Olsen, U.B.; Roberts, S.M.; Varley, D.R.; Bowler, A.N. (Novo Nordisk A/S); Novel N-alkoxyadenine derivs. acting as cytokine inhibitors. WO 9801459 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	15455	(aminooxy)methane; O-methylhydroxylamine	67-62-9	CH₅NO	详情	详情
(I)	25228	(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate		C₁₆H₁₆Cl₂N₄O₇	详情	详情
(II)	25229	(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-[2-chloro-6-(methoxyamino)-9H-purin-9-yl]tetrahydro-3-furanyl acetate		C₁₇H₂₀ClN₅O₈	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

Guanosine (I) was protected as the triacetate ester (II) and then chlorinated with POCl3 in the presence of dimethylaniline and tetraethylammonium chloride to give the 6-chloro derivative (III). Diazotization of (III) with tert-butyl nitrite, followed by a modified Sandmeyer reaction provided dichloro purine (IV). Substitution of the 6-chloro of (IV) by 2,2-diphenylethylamine (V) in the presence of diisopropylethylamine in refluxing isopropanol furnished the chloroadenosine derivative (VI), and subsequent removal of the acetate protecting groups of (VI) by hydrolysis with Na2CO3 in aqueous MeOH yielded the adenosine derivative (VII).

参考文献中间体

合成目标

【1】 Gregson, M.; Ayres, B.E.; Ewan, G.B.; Ellis, F.; Knight, J. (Glaxo Wellcome plc); 2,6-Diaminopurine derivs.. EP 0680488; JP 1996505864; US 5925624; WO 9417090 .
【2】 Keeling, S.E.; et al.; The discovery and synthesis of highly potent, A2A receptor agonists. Bioorg Med Chem Lett 2000, 10, 4, 403.

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)	38958	Guanosine; 2-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,9-dihydro-6H-purin-6-one	118-00-3	C₁₀H₁₃N₅O₅	详情	详情
(II)	38959	(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate		C₁₆H₁₉N₅O₈	详情	详情
(III)	22299	(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-amino-6-chloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate		C₁₆H₁₈ClN₅O₇	详情	详情
(IV)	25228	(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate		C₁₆H₁₆Cl₂N₄O₇	详情	详情
(V)	38962	2,2-diphenylethylamine; 2,2-diphenyl-1-ethanamine	3963-62-0	C₁₄H₁₅N	详情	详情
(VI)	38960	(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]tetrahydro-3-furanyl acetate		C₃₀H₃₀ClN₅O₇	详情	详情
(VII)	38961	(2R,3R,4S,5R)-2-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-5-(hydroxymethyl)tetrahydro-3,4-furandiol		C₂₄H₂₄ClN₅O₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(III)

The N-amination of 4-(2-pyridylthio)piperidine (I) with hydroxylamine O-sulfonic acid afforded hydrazine (II). This was condensed with dichloropurine derivative (III) to yield the piperidinyl adenosine (IV). Deacetylation of (IV) by treatment with methanolic ammonia gave (V). Finally, the primary hydroxyl group of (V) was converted to the title chloride by reaction with SOCl2 in the presence of pyridine.

参考文献中间体

合成目标

【1】 Knutsen, L. (Novo Nordisk A/S); Novel therapeutically active adenosine derivs.. WO 9816539 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	45792	2-(4-piperidinylsulfanyl)pyridine; 4-piperidinyl 2-pyridinyl sulfide	C₁₀H₁₄N₂S	详情	详情
(II)	45793	4-(2-pyridinylsulfanyl)-1-piperidinylamine; 4-(2-pyridinylsulfanyl)-1-piperidinamine	C₁₀H₁₅N₃S	详情	详情
(III)	25228	(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate	C₁₆H₁₆Cl₂N₄O₇	详情	详情
(IV)	45794	(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-chloro-6-[[4-(2-pyridinylsulfanyl)-1-piperidinyl]amino]-9H-purin-9-yl)tetrahydro-3-furanyl acetate	C₂₆H₃₀ClN₇O₇S	详情	详情
(V)	45795	(2R,3R,4S,5R)-2-(2-chloro-6-[[4-(2-pyridinylsulfanyl)-1-piperidinyl]amino]-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol	C₂₀H₂₄ClN₇O₄S	详情	详情

Extended Information