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【结 构 式】 
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【分子编号】22305 【品名】dichloro(phosphono)methylphosphonic acid 【CA登记号】 |
【 分 子 式 】CH4Cl2O6P2 【 分 子 量 】244.892084 【元素组成】C 4.9% H 1.65% Cl 28.95% O 39.2% P 25.3% |
合成路线1
该中间体在本合成路线中的序号：(X)Diazotization of (I) with isoamyl nitrite in the presence of dipropyl disulfide afforded sulfide (III) through the intermediate diazonium salt (II). Further substitution of the chloro atom of (III) for ammonia provided 2-(propylthio)adenosine (IV). The 5'-hydroxyl group of (IV) was then phosphorylated by reaction with phosphoryl chloride in cold triethyl phosphate followed by aqueous work-up. The resulting 5'-monophosphate (V) was treated with carbonyl diimidazole and tri-n-butylamine to produce the phosphoryl imidazole intermediate (VI), 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】 Ingall, A.H.; Dixon, J.; Bailey, A.; Coombs, M.E.; Cox, D.; McInally, J.I.; Hunt, S.F.; Kindon, N.D.; Teobald, B.J.; Willis, P.A.; Humphries, R.G.; Leff, P.; Clegg, J.A.; Smith, J.A.; Tomlinson, W.; Antagonists of the platelet P2T receptor: A novel approach to antithrombotic therapy. J Med Chem 1999, 42, 2, 213. |
| 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) | 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 | |
| (II) | 22300 | 6-Chloro-9-(2'-O,3'-O,5'-O-Triacetyl-beta-D-ribofuranosyl)purine-2-diazonium cation | C16H18ClN5O7 | 详情 | 详情 | |
| (III) | 22301 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-[6-chloro-2-(propylsulfanyl)-9H-purin-9-yl]tetrahydro-3-furanyl acetate | C19H23ClN4O7S | 详情 | 详情 | |
| (IV) | 22302 | (2R,3R,4S,5R)-2-[6-amino-2-(propylsulfanyl)-9H-purin-9-yl]-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C13H19N5O4S | 详情 | 详情 | |
| (V) | 22303 | [(2R,3S,4R,5R)-5-[6-amino-2-(propylsulfanyl)-9H-purin-9-yl]-3,4-dihydroxytetrahydro-2-furanyl]methyl dihydrogen phosphate | C13H20N5O7PS | 详情 | 详情 | |
| (VI) | 22304 | [(2R,3S,4R,5R)-5-[6-amino-2-(propylsulfanyl)-9H-purin-9-yl]-3,4-dihydroxytetrahydro-2-furanyl]methyl hydrogen 1H-imidazol-1-ylphosphonate | C16H22N7O6PS | 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：(X)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3
该中间体在本合成路线中的序号：(IX)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 |
合成路线4
该中间体在本合成路线中的序号：Regioselective lithiation of the tris-O-silylated uridine (I) with sec-butyllithium in the presence of TMEDA, followed by addition to dibenzosuberenone (II) afforded the 5-(dibenzocycloheptenyl)uridine derivative (III). Subsequent reduction of the tertiary alcohol of (III) with triethylsilane in the presence of boron trifluoride, followed by re silylation with tert-butyldimethylsilyl chloride furnished (IV). The 4-thiouridine derivative (V) was then obtained by thionation of (IV) with phosphorus pentasulfide in refluxing pyridine. Removal of the O-silyl protecting groups of (V) was effected by treatment with HF-pyridine, yielding (VI). Phosphorylation of the primary hydroxyl of (VI) with phosphoryl chloride in the presence of 1,8-bis-(dimethylamino)naphthalene in trimethyl phosphate, followed by condensation with dichloromethylenebisphosphonic acid gave rise to the target triphosphate analogue, which was finally converted to the corresponding tetrasodium salt by passage through a cation-exchange resin.
| 【1】 Kindon, N.; Jewel, R.; Johnson, T.; McInally, J.; Meghani, P.; Thom, S.; SAR leading to the discovery of AR-C 85095MX, a potent and selective P2Y2 antagonist. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst P8. |
| 【2】 Meghani, P.; Kindon, N.; Thom, S. (AstraZeneca AB; AstraZeneca plc); Novel phosphate cpds. and their use as medicaments. WO 9845309 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 22305 | dichloro(phosphono)methylphosphonic acid | CH4Cl2O6P2 | 详情 | 详情 | ||
| (I) | 60690 | 1-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione | C27H54N2O6Si3 | 详情 | 详情 | |
| (II) | 29151 | 5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberenone | 2222-33-5 | C15H10O | 详情 | 详情 |
| (III) | 60691 | 1-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydro-2-furanyl]-5-(5-hydroxy-5H-dibenzo[a,d]cyclohepten-5-yl)-2,4(1H,3H)-pyrimidinedione | C42H64N2O7Si3 | 详情 | 详情 | |
| (IV) | 60692 | 1-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydro-2-furanyl]-5-(5H-dibenzo[a,d]cyclohepten-5-yl)-2,4(1H,3H)-pyrimidinedione | C42H64N2O6Si3 | 详情 | 详情 | |
| (V) | 60693 | 1-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydro-2-furanyl]-5-(5H-dibenzo[a,d]cyclohepten-5-yl)-4-thioxo-3,4-dihydro-2(1H)-pyrimidinone | C42H64N2O5SSi3 | 详情 | 详情 | |
| (VI) | 60694 | 5-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-4-thioxo-3,4-dihydro-2(1H)-pyrimidinone | C24H22N2O5S | 详情 | 详情 |