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【结 构 式】 
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【分子编号】25970 【品名】methyl (2S)-3-amino-2-[(phenylsulfonyl)amino]propanoate 【CA登记号】 |
【 分 子 式 】C10H14N2O4S 【 分 子 量 】258.29824 【元素组成】C 46.5% H 5.46% N 10.85% O 24.78% S 12.41% |
合成路线1
该中间体在本合成路线中的序号：(IX)The selective monoprotection of 4-(4-piperidyl)piperidine (I) gives the carbamate (II), which is condensed with the isothiocyante (III) in chloroform to yield the N-(ethoxycarbonyl)carbothioamide (IV). Decarboxylation of (IV) by means of NaOH in ethanol affords the free thioamide (V), which is cyclized with 2-chloro-4-methyl-3-oxopentanoic acid ethyl ester (VI) by means of triethylamine in ethanol to provide the thiazole derivative (VII). Hydrolysis of theester group of (VII) with NaOH in ethanol gives the carboxylic acid (VIII), which is condensed with 3-amino-2(S)-(phenylsulfonamido)propionic acid methyl ester (IX), by means of DCC, HOBT and triethylamine in DMF yielding the protected target compound (X). Finally, this compound is hydrolyzed and deprotected by a treatment with HCl in ethanol. The intermediate 3-amino-2(S)-(phenylsulfonamido)propionic acid methyl ester (IX) has been obtained as follows: The reaction of L-asparagine (XI) with benzenesulfonyl chloride (XII) by means of NaOH in dioxane/water gives the sulfonated asparagine (XIII), which is submitted to Hofmann degradation with Br2 and NaOH in water and finally esterified with SOCl2 and methanol.
| 【1】 Forn, J.; Merlos, M.; Garcia-Rafanell, J.; Carceller, E.; Gomez, L.A.; Novel N-(thiazolyl-5-carbonyl)-beta-alanine derivatives as potent, orally active fibrinogen receptor antagonists. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 079. |
| 【2】 Carceller, E.; Jimenez, P.J.; Salas, J. (J. Uriach & Cia., SA); Novel carboxamides as platelet aggregation inhibitors. WO 9846599 . |
| 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) | 25962 | 4,4'-bipiperidine | C10H20N2 | 详情 | 详情 | |
| (II) | 25963 | 4,4'-bipiperidine-1-carboxylic acid tert-butyl ester | C15H28N2O2 | 详情 | 详情 | |
| (III) | 25964 | 1-[(isothiocyanatocarbonyl)oxy]ethane | 16182-04-0 | C4H5NO2S | 详情 | 详情 |
| (IV) | 25965 | N-[1'-(Tert-butoxycarbonyl)-4,4'-bipiperidin-1-yl-thiocarbonyl]carbamic acid ethyl ester | C19H33N3O4S | 详情 | 详情 | |
| (V) | 25966 | 1'-(Tert-butoxycarbonyl)-4,4'-bipiperidine-1-carbothioamide | C16H29N3O2S | 详情 | 详情 | |
| (VI) | 25967 | ethyl 2-chloro-4-methyl-3-oxopentanoate | C8H13ClO3 | 详情 | 详情 | |
| (VII) | 25968 | 2-[1'-(Tert-butoxycarbonyl)-4,4'-bipiperidin-1-yl]-4-isopropylthiazole-5-carboxylic acid ethyl ester | C24H39N3O4S | 详情 | 详情 | |
| (VIII) | 25969 | 2-[1'-(Tert-butoxycarbonyl)-4,4'-bipiperidin-1-yl]-4-isopropylthiazole-5-carboxylic acid | C22H35N3O4S | 详情 | 详情 | |
| (IX) | 25970 | methyl (2S)-3-amino-2-[(phenylsulfonyl)amino]propanoate | C10H14N2O4S | 详情 | 详情 | |
| (X) | 25971 | (2(S)-(Benzenesulfonamido)-3-[2-[4-[1-tert-butoxycarbonyl)piperidin-4-yl]piperidin-4-yl]-4-isopropylthiazol-5-ylcarboxamido]propionic acid methyl ester; (2(S)-(Benzenesulfonamido)-3-[2-[4-[1-tert-butoxycarbonyl)piperidin-4-yl]piperidin-4-yl]-4-isopropylthiazol-5-ylcarboxamido]propionic acid methyl ester | C32H47N5O7S2 | 详情 | 详情 | |
| (XI) | 25972 | S-(+)-Asparagine; S-(+)-2-Aminosuccinamic acid; L-Asparagine | 70-47-3 | C4H8N2O3 | 详情 | 详情 |
| (XII) | 14713 | benzenesulfonyl chloride | 98-09-9 | C6H5ClO2S | 详情 | 详情 |
| (XIII) | 25973 | (2S)-4-amino-4-oxo-2-[(phenylsulfonyl)amino]butyric acid | C10H12N2O5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The condensation of 4-formylbenzonitrile (I) with N-methylhyddroxylamine (II) by means of Na2CO3 in dichloromethane gives the nitrone (III), which is cyclized with isobutyl 3-butenoate (IV) by heating at 100 C to afford the cis-isoxazolidinyl acetate (V) (along with some trans isomer) that is purified by chromatography. The hydrolysis of the ester (V) with LiOH in THF/water yields the free acid (VI), which is condensed with the diamino ester (VII) by means of PyBop and Et3N in DMF giving the intermediate (VIII). The treatment of (VII) with dry HCl in methanol/chloroform to convert the CN group into amidino yields derivative (IX), which is finally hydrolyzed to the free acid with aqueous HCl.
| 【1】 Confalone, P.N.; Jin, F.; Mousa, S.A.; Platelet glycoprotein IIb/IIIa receptor antagonists derived from isoxazolidines. Bioorg Med Chem Lett 1999, 9, 1, 55. |
| 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) | 17552 | 4-formylbenzonitrile; 4-Cyanobenzaldehyde | 105-07-7 | C8H5NO | 详情 | 详情 |
| (II) | 12690 | (Hydroxyamino)methane; N-Methylhydroxylamine | 593-77-1 | CH5NO | 详情 | 详情 |
| (III) | 27637 | 4-[[methyl(oxo)-lambda(5)-azanylidene]methyl]benzonitrile | C9H8N2O | 详情 | 详情 | |
| (IV) | 27638 | isobutyl 3-butenoate | 24342-03-8 | C8H14O2 | 详情 | 详情 |
| (V) | 27639 | isobutyl 2-[(3R,5S)-3-(4-cyanophenyl)-2-methylisoxazolidinyl]acetate | C17H22N2O3 | 详情 | 详情 | |
| (VI) | 27640 | 2-[(3R,5S)-3-(4-cyanophenyl)-2-methylisoxazolidinyl]acetic acid | C13H14N2O3 | 详情 | 详情 | |
| (VII) | 25970 | methyl (2S)-3-amino-2-[(phenylsulfonyl)amino]propanoate | C10H14N2O4S | 详情 | 详情 | |
| (VIII) | 27641 | methyl (2S)-3-([2-[(3R,5S)-3-(4-cyanophenyl)-2-methylisoxazolidinyl]acetyl]amino)-2-[[(4-methyl-2-pyridinyl)sulfonyl]amino]propanoate | C23H27N5O6S | 详情 | 详情 | |
| (IX) | 27642 | methyl (2S)-3-[[2-((3R,5S)-3-[4-[amino(imino)methyl]phenyl]-2-methylisoxazolidinyl)acetyl]amino]-2-[[(3-methylphenyl)sulfonyl]amino]propanoate | C24H31N5O6S | 详情 | 详情 |