• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【分子编号】22312

【品名】(2R,3S,4R,5R)-2-(hydroxymethyl)-5-[6-[[2-(methylsulfanyl)ethyl]amino]-2-[(3,3,3-trifluoropropyl)sulfanyl]-9H-purin-9-yl]tetrahydro-3,4-furandiol

【CA登记号】

【 分 子 式 】C16H22F3N5O4S2

【 分 子 量 】469.5091896

【元素组成】C 40.93% H 4.72% F 12.14% N 14.92% O 13.63% S 13.66%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(VII)

2-Mercaptoadenosine (I) was S-alkylated with 1-chloro-3,3,3-trifluoropropane (II) in the presence of NaH to give trifluoropropyl sulfide (III). Subsequent acetylation of (III) with Ac2O at 80 C provided (IV), which was N-alkylated with methylthioethyl iodide (V) and NaH yielding (VI). Further hydrolysis of the resulting (VI) with 0.1 M NaOH in refluxing MeOH furnished adenosine derivative (VII). The 5'-hydroxyl group of (VII) was then phosphorylated by reaction with phosphoryl chloride in cold triethyl phosphate followed by aqueous work-up. The resulting 5'-monophosphate (VIII) was treated with carbonyl diimidazole and tri-n-butylamine to produce the phosphoryl imidazole intermediate (IX), which was finally condensed with dichloromethylenebis(phosphonic acid) (X). The target compound was isolated as the tetrasodium salt upon treatment with NaI in methanol-acetone.

1 Cage, P.A.; Bailey, A.; Kindon, N.D.; et al.; SAR studies on AR-C 69931MX, a potent and selective intravenous anti-aggregatory/anti-thrombotic agent with a novel mechanism of action. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.281.
2 Ingall, A.H.; Cage, P.A.; Kindon, N.D. (Celltech Medeva plc); N-Alkyl-2-substd. ATP analogues. EP 0683789; JP 1996506335; US 5721219; WO 9418216 .
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) 22306 (2R,3R,4S,5R)-2-(6-amino-2-sulfanyl-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol C10H13N5O4S 详情 详情
(II) 22307 3-chloro-1,1,1-trifluoropropane C3H4ClF3 详情 详情
(III) 22308 (2R,3R,4S,5R)-2-[6-amino-2-[(3,3,3-trifluoropropyl)sulfanyl]-9H-purin-9-yl]-5-(hydroxymethyl)tetrahydro-3,4-furandiol C13H16F3N5O4S 详情 详情
(IV) 22309 (2R,3R,4R,5R)-2-[6-(acetamido)-2-[(3,3,3-trifluoropropyl)sulfanyl]-9H-purin-9-yl]-4-(acetoxy)-5-[(acetoxy)methyl]tetrahydro-3-furanyl acetate C21H24F3N5O8S 详情 详情
(V) 22310 1-iodo-2-(methylsulfanyl)ethane; 2-iodoethyl methyl sulfide C3H7IS 详情 详情
(VI) 22311 (2R,3R,4R,5R)-2-[6-[acetyl[2-(methylsulfanyl)ethyl]amino]-2-[(3,3,3-trifluoropropyl)sulfanyl]-9H-purin-9-yl]-4-(acetoxy)-5-[(acetoxy)methyl]tetrahydro-3-furanyl acetate C24H30F3N5O8S2 详情 详情
(VII) 22312 (2R,3S,4R,5R)-2-(hydroxymethyl)-5-[6-[[2-(methylsulfanyl)ethyl]amino]-2-[(3,3,3-trifluoropropyl)sulfanyl]-9H-purin-9-yl]tetrahydro-3,4-furandiol C16H22F3N5O4S2 详情 详情
(VIII) 22313 ((2R,3S,4R,5R)-3,4-dihydroxy-5-[6-[[2-(methylsulfanyl)ethyl]amino]-2-[(3,3,3-trifluoropropyl)sulfanyl]-9H-purin-9-yl]tetrahydro-2-furanyl)methyl dihydrogen phosphate C16H23F3N5O7PS2 详情 详情
(IX) 22314 ((2R,3S,4R,5R)-3,4-dihydroxy-5-[6-[[2-(methylsulfanyl)ethyl]amino]-2-[(3,3,3-trifluoropropyl)sulfanyl]-9H-purin-9-yl]tetrahydro-2-furanyl)methyl hydrogen 1H-imidazol-1-ylphosphonate C19H25F3N7O6PS2 详情 详情
(X) 22305 dichloro(phosphono)methylphosphonic acid CH4Cl2O6P2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VII)

Alkylation of mercaptopurine (I) with 3-chloro-1,1,1-trifluoropropane (II) in the presence of NaH gave thioether (III). After protection of the amino group of (III) as the acetamide (IV) by means of Ac2O and NaOAc, N-alkylation with 2-(methylthio)ethyl iodide (V) yielded (VI), which was deacetylated by hydrolysis with NaOH in refluxing MeOH. Subsequent treatment with POCl3 produced the intermediate phosphoryl chloride (VIII). Then, condensation of this acid chloride with dichloromethylene bisphosphonic acid (IX) in the presence of tributylamine in triethyl phosphate yielded the title compound, which was isolated as the tetrasodium salt. Alternatively, hydrolysis of acid chloride (VIII) in the presence of ammonium bicarbonate gave phosphate salt (X), which was treated with carbonyldiimidazole, and the activated intermediate (XI) was then condensed with bisphosphonate (IX) to furnish the target compound.

1 Cage, P.A.; Bailey, A.; Kindon, N.D.; et al.; SAR studies on AR-C 69931MX, a potent and selective intravenous anti-aggregatory/anti-thrombotic agent with a novel mechanism of action. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.281.
2 Ingall, A.H.; Cage, P.A.; Kindon, N.D. (Celltech Medeva plc); N-Alkyl-2-substd. ATP analogues. EP 0683789; JP 1996506335; US 5721219; WO 9418216 .
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) 22306 (2R,3R,4S,5R)-2-(6-amino-2-sulfanyl-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol C10H13N5O4S 详情 详情
(II) 22307 3-chloro-1,1,1-trifluoropropane C3H4ClF3 详情 详情
(III) 22308 (2R,3R,4S,5R)-2-[6-amino-2-[(3,3,3-trifluoropropyl)sulfanyl]-9H-purin-9-yl]-5-(hydroxymethyl)tetrahydro-3,4-furandiol C13H16F3N5O4S 详情 详情
(IV) 30047 N-[9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-[(3,3,3-trifluoropropyl)sulfanyl]-9H-purin-6-yl]acetamide C15H18F3N5O5S 详情 详情
(V) 22310 1-iodo-2-(methylsulfanyl)ethane; 2-iodoethyl methyl sulfide C3H7IS 详情 详情
(VI) 30048 N-[9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-[(3,3,3-trifluoropropyl)sulfanyl]-9H-purin-6-yl]-N-[2-(methylsulfanyl)ethyl]acetamide C18H24F3N5O5S2 详情 详情
(VII) 22312 (2R,3S,4R,5R)-2-(hydroxymethyl)-5-[6-[[2-(methylsulfanyl)ethyl]amino]-2-[(3,3,3-trifluoropropyl)sulfanyl]-9H-purin-9-yl]tetrahydro-3,4-furandiol C16H22F3N5O4S2 详情 详情
(VIII) 30049 5'-O-(Dichlorophosphoryl)-N6-[2-(methylsulfanyl)ethyl]-2-(3,3,3-trifluoropropylsulfanyl)adenosine C16H21Cl2F3N5O5PS2 详情 详情
(IX) 22305 dichloro(phosphono)methylphosphonic acid CH4Cl2O6P2 详情 详情
(X) 30050 5'-O-(Dihydroxyphosphoryl)-N6-[2-(methylsulfanyl)ethyl]-2-(3,3,3-trifluoropropylsulfanyl)adenosine monoammonium salt C16H26F3N6O7PS2 详情 详情
(XI) 22314 ((2R,3S,4R,5R)-3,4-dihydroxy-5-[6-[[2-(methylsulfanyl)ethyl]amino]-2-[(3,3,3-trifluoropropyl)sulfanyl]-9H-purin-9-yl]tetrahydro-2-furanyl)methyl hydrogen 1H-imidazol-1-ylphosphonate C19H25F3N7O6PS2 详情 详情
Extended Information