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【结 构 式】 
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【分子编号】23000 【品名】1,3-thiazole 【CA登记号】288-47-1 |
【 分 子 式 】C3H3NS 【 分 子 量 】85.12956 【元素组成】C 42.33% H 3.55% N 16.45% S 37.67% |
合成路线1
该中间体在本合成路线中的序号：(VI)The condensation of 2-methoxypropane-1,3-diol (I) with octadecylisocyanate (II) in pyridine gives 3-(N-octadecylcarbamoyloxy)-2-methylpropanol (III), which is esterified with 2-bromoethyl phosphorodichloridate (IV) by means of pyridine in benzene and treated with water to afford 3-(N octadecyicarbamoyloxy)-2-methoxypropyl2-bromoethyl acid phosphate (V). Finally, this compound is treated with thiazole (VI) and Ag2CO3 in hot toluene.
| 【1】 Inada, Y.; Terashita, Z.; Yoshioka, Y.; Tsushima, S.; Nishikawa, K.; Nomura, H.; CV-3988 - A specific antagonist of platelet activa. Life Sci 1983, 32, 1975. |
| 【2】 Nomura, H.; Hozumi, M.; Yoshioka, Y. (Takeda Chemical Industries, Ltd.); Carbamic acid esters, their production and use. EP 0035375 . |
| 【3】 Castaner, J.; Prous, J.; CV-3988. Drugs Fut 1987, 12, 1, 12. |
| 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) | 13579 | 2-Methoxy-1,3-propanediol | C4H10O3 | 详情 | 详情 | |
| (II) | 13586 | 1-Isocyanatooctadecane; octadecyl isocyanate | 112-96-9 | C19H37NO | 详情 | 详情 |
| (III) | 22997 | 3-hydroxy-2-methoxypropyl octadecylcarbamate | C23H47NO4 | 详情 | 详情 | |
| (IV) | 13033 | Dichlorophosphoric acid 2-bromoethyl ester | C2H4BrCl2O2P | 详情 | 详情 | |
| (V) | 22999 | 3-[[(2-bromoethoxy)(hydroxy)phosphoryl]oxy]-2-methoxypropyl octadecylcarbamate | C25H51BrNO7P | 详情 | 详情 | |
| (VI) | 23000 | 1,3-thiazole | 288-47-1 | C3H3NS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The condensation of 1-(benzyloxycarbonyl)piperidin-4-one with N-(tert-butoxycarbonyl)-2-phosphonoglycine trimethyl ester (II) by means of DBU in dichloromethane gives 2-[1-(benzyloxycarbonyl)piperidin-4-ylidene]-N-(tert-butoxycarbonyl)glycine methyl ester (III), which is selectively deprotected and reduced by hydrogenation with H2 over Pd/C in methanol yielding N-(tert-butoxycarbonyl)-2-(4-piperidyl)glycine methyl ester (IV). The reaction of (IV) with N,N'-di(tert-butoxycarbonyl)pyrazole-1-carboxamidine (V) by means of DIEA in dichloromethane gives the protected piperidine-1-carboxamidine (VI), which is treated with LiOH in methanol/water to obtain (VII) with a free carboxy group. The reaction of (VII) with O,N-dimethylhydroxylamine affords the hydroxamic ester (VIII), which is condensed with thiazole (IX) by means of butyllithium in THF yielding the fully protected intermediate (X). The deprotection of (X) with HCl in dioxane gives (XI) with free amino and amidino groups. The conddensation of (XI) with chiral acid (XII) by means of BOP and DIEA in acetonitrile yields amide (XIII) as a diastereomeric mixture that is resolved by preparative reverse-phase HPLC.
| 【1】 Plummer, J.S.; Berryman, K.A.; Cai, C.; Cody, W.L.; DiMaio, J.; Doherty, A.M.; Edmunds, J.J.; He, J.X.; Holland, D.R.; Levesque, S.; Kent, D.R.; Narasimhan, L.S.; Rubin, J.R.; Rapundalo, S.T.; Siddiqui, M.A.; Susser, A.J.; St-Denis, Y.; Winocour, P.D.; Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications. Bioorg Med Chem Lett 1998, 8, 23, 3409. |
| 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) | 26947 | benzyl 4-oxo-1-piperidinecarboxylate; N-Benzyloxycarbonyl-4-piperidone | 19099-93-5 | C13H15NO3 | 详情 | 详情 |
| (II) | 34562 | methyl 2-[(tert-butoxycarbonyl)amino]-2-(dimethoxyphosphoryl)acetate | C10H20NO7P | 详情 | 详情 | |
| (III) | 34563 | benzyl 4-[1-[(tert-butoxycarbonyl)amino]-2-methoxy-2-oxoethylidene]-1-piperidinecarboxylate | C21H28N2O6 | 详情 | 详情 | |
| (IV) | 34564 | methyl 2-[(tert-butoxycarbonyl)amino]-2-(4-piperidinyl)acetate | C13H24N2O4 | 详情 | 详情 | |
| (V) | 29482 | N,N-bis-Boc-1-guanylpyrazole; tert-butyl (E)-[(tert-butoxycarbonyl)amino](1H-pyrazol-1-yl)methylidenecarbamate | 152120-54-2 | C14H22N4O4 | 详情 | 详情 |
| (VI) | 34565 | methyl 2-[(tert-butoxycarbonyl)amino]-2-(1-[[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl]-4-piperidinyl)acetate | C24H42N4O8 | 详情 | 详情 | |
| (VII) | 34566 | 2-[(tert-butoxycarbonyl)amino]-2-(1-[[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl]-4-piperidinyl)acetic acid | C23H40N4O8 | 详情 | 详情 | |
| (VIII) | 34567 | tert-butyl (Z)-[(tert-butoxycarbonyl)amino](4-[1-[(tert-butoxycarbonyl)amino]-2-[methoxy(methyl)amino]-2-oxoethyl]-1-piperidinyl)methylidenecarbamate | C25H45N5O8 | 详情 | 详情 | |
| (IX) | 23000 | 1,3-thiazole | 288-47-1 | C3H3NS | 详情 | 详情 |
| (X) | 34568 | tert-butyl (Z)-[(tert-butoxycarbonyl)amino][4-[1-[(tert-butoxycarbonyl)amino]-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1-piperidinyl]methylidenecarbamate | C26H41N5O7S | 详情 | 详情 | |
| (XI) | 34569 | 4-[1-amino-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1-piperidinecarboximidamide | C11H17N5OS | 详情 | 详情 | |
| (XII) | 34570 | (6S,8aS)-4-oxo-2-(3-phenylpropanoyl)octahydropyrrolo[1,2-a]pyrazine-6-carboxylic acid | C17H20N2O4 | 详情 | 详情 | |
| (XIII) | 34571 | (6S,8aS)-N-[1-[1-[amino(imino)methyl]-4-piperidinyl]-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-4-oxo-2-(3-phenylpropanoyl)octahydropyrrolo[1,2-a]pyrazine-6-carboxamide | C28H35N7O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Lithiation of thiazole (I) with butyllithium at -78 C, followed by quenching with chlorotrimethylsilane afforded 2-(trimethylsilyl)thiazole (II). A second lithiation generated the 5-lithio thiazole, which was converted to the stannyl derivative (III) upon reaction with tributylstannyl chloride. Then, palladium-catalyzed coupling of (III) with the iodophenyl oxazolidine (IV) in refluxing dioxan furnished the title compound.
| 【1】 Anderson, D.J.; Allwine, D.A.; Genin, M.J.; et al.; Carbon-carbon-linked 5-membered heteroarylphenyl oxazolidinones with broad-spectrum antibacterial activity. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F570. |
| 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) | 23000 | 1,3-thiazole | 288-47-1 | C3H3NS | 详情 | 详情 |
| (II) | 10720 | 2-(Trimethylsilyl)-1,3-thiazole | 79265-30-8 | C6H11NSSi | 详情 | 详情 |
| (III) | 38137 | 5-(tributylstannyl)-2-(trimethylsilyl)-1,3-thiazole | C18H37NSSiSn | 详情 | 详情 | |
| (IV) | 38138 | N-[[(5S)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide | C12H12FIN2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)Lithiation of thiazole (X) with butyllithium, and then addition to hexafluoroacetone (XI) in cold Et2O gives the carbinol adduct (XII), which is subsequently protected with 2-(trimethylsilyl)ethoxymethyl chloride (XIII), yielding the SEM ether (XIV). A further metalation of (XIV) with butyllithium, followed by addition to aldehyde (IX) provides alcohol (XV). Bromination of (XV), with simultaneous SEM group cleavage to afford (XVI), is accomplished by treatment with thionyl bromide and pyridine. Alkylation of the potassium enolate of ethyl 3-pyridylacetate N-oxide (XVII) with bromide (XVI) gives ester (XVIII). Finally, decarboethoxylation of (XVIII) by means of LiOH, followed by resolution of the racemic mixture using chiral HPLC furnishes the title enantiomer.
| 【1】 Girard, M.; Frenette, R.; Hamel, P.; Guay, D.; Ducharme, Y.; Blouin, M.; Friesen, R.; Cote, B.; Martins, E.; Laliberte, S. (Merck Frosst Canada Inc.); Tri-aryl-substd.-ethane PDE4 inhibitors. EP 1272488; US 6399636; WO 0170738 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 59749 | 3-(cyclopropyloxy)-4-(difluoromethoxy)benzaldehyde | C11H10F2O3 | 详情 | 详情 | |
| (X) | 23000 | 1,3-thiazole | 288-47-1 | C3H3NS | 详情 | 详情 |
| (XI) | 44260 | 1,1,1,3,3,3-hexafluoroacetone | 684-16-2 | C3F6O | 详情 | 详情 |
| (XII) | 59750 | 1,1,1,3,3,3-hexafluoro-2-(1,3-thiazol-2-yl)-2-propanol | C6H3F6NOS | 详情 | 详情 | |
| (XIII) | 27243 | [2-(chloromethoxy)ethyl](trimethyl)silane | 76513-69-4 | C6H15ClOSi | 详情 | 详情 |
| (XIV) | 59751 | 2-(2,2,2-trifluoro-1-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)-1,3-thiazole; [2,2,2-trifluoro-1-(1,3-thiazol-2-yl)-1-(trifluoromethyl)ethoxy]methyl 2-(trimethylsilyl)ethyl ether | C12H17F6NO2SSi | 详情 | 详情 | |
| (XV) | 59752 | [3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl][2-(2,2,2-trifluoro-1-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)-1,3-thiazol-5-yl]methanol | C23H27F8NO5SSi | 详情 | 详情 | |
| (XVI) | 59753 | 2-(5-{bromo[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl]methyl}-1,3-thiazol-2-yl)-1,1,1,3,3,3-hexafluoro-2-propanol | C17H12BrF8NO3S | 详情 | 详情 | |
| (XVII) | 59754 | 3-(2-ethoxy-2-oxoethyl)-1-pyridiniumolate | C9H11NO3 | 详情 | 详情 | |
| (XVIII) | 59755 | 3-(2-[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl]-1-(ethoxycarbonyl)-2-{2-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1,3-thiazol-5-yl}ethyl)-1-pyridiniumolate | C26H22F8N2O6S | 详情 | 详情 |