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【结 构 式】 
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【分子编号】12945 【品名】(2R)-2-[(2-[[(1R)-1-Carboxy-2-sulfanylethyl]amino]ethyl)amino]-3-sulfanylpropionic acid 【CA登记号】 |
【 分 子 式 】C8H16N2O4S2 【 分 子 量 】268.35812 【元素组成】C 35.81% H 6.01% N 10.44% O 23.85% S 23.9% |
合成路线1
该中间体在本合成路线中的序号：(II)The reductive dimerization of thiazolidine-4(R)-carboxylic acid sodium salt (I) with Na in liquid ammonia gives N,N-ethylene-1,2-diylbis(cysteine) (II), which is esterified with ethanol and dry HCl to the corresponding diethyl ester (III). Finally, this compound is treated with sodium pertechnetate and a reducing agent such as stannous salts, NaBH4 or Na2S2O4.
| 【1】 Castaner, J.; Robinson, C.; Technetium (Tc99m) Bicisate. Drugs Fut 1995, 20, 3, 251. |
| 【2】 Bergstein, P.L.; Cheesman, E.H.; Watson, A.D. (DuPont Pharmaceuticals Co.); Ester-substd. diaminedithiols and radiolabeled complexes thereof. AU 8811748; EP 0279417; JP 1988285549 . |
| 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) | 12944 | sodium (4R)-1,3-thiazolidine-4-carboxylate | C4H6NNaO2S | 详情 | 详情 | |
| (II) | 12945 | (2R)-2-[(2-[[(1R)-1-Carboxy-2-sulfanylethyl]amino]ethyl)amino]-3-sulfanylpropionic acid | C8H16N2O4S2 | 详情 | 详情 | |
| (III) | 12946 | ethyl (2R)-2-[(2-[[(1R)-2-ethoxy-2-oxo-1-(sulfanylmethyl)ethyl]amino]ethyl)amino]-3-sulfanylpropanoate | C12H24N2O4S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Alkylation of the sodium derivative of 1,2-ethylene dicysteine (I) with benzyl chloride in liquid ammonia affords the S,S'-dibenzyl compound (II). Subsequent protection of the amino groups of (II) with benzyl chloroformate provides the bis-carbamate (III). Esterification of diacid (III) with one equivalent of MeOH in the presence of DCC and DMAP furnishes the mono-methyl ester (IV). This is then coupled with 1-aminomethylenediphosphonic acid tetraethyl ester (V) to yield amide (VI). The ethyl phosphonate ester groups of (VI) are selectively cleaved by means of trimethylsilyl bromide, producing diphosphonic acid (VII). Further hydrolysis of the methyl carboxylate ester group of (VII) under basic conditions leads to acid (VIII). Then, simultaneous removal of the S-benzyl and N-Cbz protecting groups of (VIII) is accomplished by means of Na in liquid ammonia to furnish dithiol (IX). This is finally complexed with [99mTc] sodium pertechnetate in the presence of SnCl2 to produce the target technetium conjugate.
| 【1】 Verbeke, K.; et al.; Development of a conjugate of 99mTc-EC with aminomethylenediphosphonate in the search for a bone tracer with fast clearance from soft tissue. Bioconjugate Chem 2002, 13, 1, 16. |
| 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) | 12945 | (2R)-2-[(2-[[(1R)-1-Carboxy-2-sulfanylethyl]amino]ethyl)amino]-3-sulfanylpropionic acid | C8H16N2O4S2 | 详情 | 详情 | |
| (II) | 61689 | (2R)-3-(benzylsulfanyl)-2-[(2-{[(1R)-2-(benzylsulfanyl)-1-carboxyethyl]amino}ethyl)amino]propanoic acid | C22H28N2O4S2 | 详情 | 详情 | |
| (III) | 61690 | (2R)-2-[[(benzyloxy)carbonyl](2-{[(benzyloxy)carbonyl][(1R)-2-(benzylsulfanyl)-1-carboxyethyl]amino}ethyl)amino]-3-(benzylsulfanyl)propanoic acid | C38H40N2O8S2 | 详情 | 详情 | |
| (IV) | 61691 | (2R)-2-{[(benzyloxy)carbonyl][2-([(benzyloxy)carbonyl]{(1R)-1-[(benzylsulfanyl)methyl]-2-methoxy-2-oxoethyl}amino)ethyl]amino}-3-(benzylsulfanyl)propanoic acid | C39H42N2O8S2 | 详情 | 详情 | |
| (V) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
| (VI) | 61692 | methyl (8R,13R)-9,12-bis[(benzyloxy)carbonyl]-8,13-bis[(benzylsulfanyl)methyl]-5-(diethoxyphosphoryl)-4-ethoxy-4,7-dioxo-3-oxa-6,9,12-triaza-4lambda~5~-phosphatetradecan-14-oate | C48H63N3O13P2S2 | 详情 | 详情 | |
| (VII) | 61693 | (4R,9R)-5,8-bis[(benzyloxy)carbonyl]-4,9-bis[(benzylsulfanyl)methyl]-3,10-dioxo-1-phosphono-11-oxa-2,5,8-triazadodec-1-ylphosphonic acid | C40H47N3O13P2S2 | 详情 | 详情 | |
| (VIII) | 61694 | (5R,10R)-6,9-bis[(benzyloxy)carbonyl]-5,10-bis[(benzylsulfanyl)methyl]-1,1-dihydroxy-1,4-dioxo-2-phosphono-3,6,9-triaza-1lambda~5~-phosphaundecan-11-oic acid | C39H45N3O13P2S2 | 详情 | 详情 | |
| (IX) | 61695 | (5R,10R)-1,1-dioxido-1,4-dioxo-2-phosphonato-5,10-bis(sulfidomethyl)-3,6,9-triaza-1lambda~5~-phosphaundecan-11-oate | C9H14N3O9P2S2 | 详情 | 详情 |