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【结 构 式】 
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【分子编号】19743 【品名】3-buten-1-ol 【CA登记号】627-27-0 |
【 分 子 式 】C4H8O 【 分 子 量 】72.10692 【元素组成】C 66.63% H 11.18% O 22.19% |
合成路线1
该中间体在本合成路线中的序号：(II)The Heck coupling of 4-bromobenzoic acid methyl ester (I) with 3-buten-1-ol (II) by means of Pd(OAc)2, LiOAc, LiCl and Bu4NBr in hot DMF, followed by reaction with NaHSO3 in ethanol/water/ethyl acetate, gives the bisulfite adduct (III), which is treated with Tms-Cl in acetonitrile and brominated with Br2 to yield the desired intermediate, the 2-bromo-4-[4-methoxycarbonyl)phenyl]butyraldehyde (IV).
| 【1】 Kjell, D.P.; Slattery, B.J.; Improved route to multitargeted antifolate LY231514. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst ORG 130. |
合成路线2
该中间体在本合成路线中的序号：(XXII)The chiral piperidine (2S,4R)(VI) has been obtained as follows: The cyclization of 3-buten-1-ol (XXII) with (S)-1-phenylethylamine (XXIII) and glyoxylic acid (XXIV) by means of tosyl chloride in THF gives a mixture of the (2S,4R) and (2R,4S) lactones (XXV), which is resolved by fractional crystallyzation of their salts with the chiral camphorsulfonic acid (XXVI), followed by elimination of the acid with ammonia to afford (2S,4R)(XXVII). The reaction of lactone (XXVII) with isopropylmagnesium chloride and tert-butylamine in THF gives (2S,4R)-N-tert-butyl-4-hydroxy-1-(1(S)-phenylethyl)piperidine-2-carboxamide (XXVIII), which is debenzylated by hydrogenation and protected with tert-butoxycarbonyl anhydride yielding (2S,4R)-N-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxamide (2S,4R)(XI), which is finally condensed with 4-(chloromethyl)pyridine (XII) as before to obtain the chiral piperidine (2S,4R)(VI), already reported.
| 【1】 Beaulieu, P.L.; et al.; Practical, stereoselective synthesis of palinavir, a potent HIV protease inhibitor. J Org Chem 1997, 62, 11, 3440. |
| 【2】 Gillard, J.; et al.; Preparation of (2S,4R)-4-hydroxypipecolic acid and derivatives. J Org Chem 1996, 61, 6, 2226. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 19731 | (2S,4R)-N-(tert-butyl)-4-(4-pyridinylmethoxy)-2-piperidinecarboxamide | C16H25N3O2 | 详情 | 详情 | |
| (XI) | 19736 | tert-butyl (2S,4R)-2-[(tert-butylamino)carbonyl]-4-hydroxy-1-piperidinecarboxylate | C15H28N2O4 | 详情 | 详情 | |
| (XII) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
| (XXII) | 19743 | 3-buten-1-ol | 627-27-0 | C4H8O | 详情 | 详情 |
| (XXIII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XXIV) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (XXV) | 19746 | 2-[(1S)-1-phenylethyl]-6-oxa-2-azabicyclo[3.2.1]octan-7-one | C14H17NO2 | 详情 | 详情 | |
| (XXVI) | 19747 | (3-bromo-1,7-dimethyl-2-oxobicyclo[2.2.1]hept-7-yl)methanesulfonic acid | C10H15BrO4S | 详情 | 详情 | |
| (XXVII) | 19748 | (1S,5R)-2-[(1S)-1-phenylethyl]-6-oxa-2-azabicyclo[3.2.1]octan-7-one | C14H17NO2 | 详情 | 详情 | |
| (XXVIII) | 19749 | (2S,4R)-N-(tert-butyl)-4-hydroxy-1-[(1S)-1-phenylethyl]-2-piperidinecarboxamide | C18H28N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Condensation of bis(2-chloroethyl)phosphoramidic dichloride (I) with the sodium salt of 3-buten-1-ol (II) gave the O-butenyl phosphoramidate (III), which was subsequently reacted with methylamine to produce the phosphorodiamidate (IV). Ozonization of the double bond of (IV), followed by oxidative workup with H2O2 yielded aldehyde (V). This was finally condensed with 2-mercaptoethanesulfonic acid cyclohexylamine salt (VI) to furnish the title compound.
| 【1】 Moon, K.; Kwon, C.; N3-methyl-mafosfamide as a chemically stable, alternative prodrug of mafosfamide. Bioorg Med Chem Lett 1998, 8, 13, 1673. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 | |
| (I) | 31443 | (Bis(2-Chloroethyl)amino]phosphoryl dichloride; Bis(2-Chloroethyl)phosphoramidic dichloride | C4H8Cl4NOP | 详情 | 详情 | |
| (II) | 19743 | 3-buten-1-ol | 627-27-0 | C4H8O | 详情 | 详情 |
| (III) | 31444 | [Bis(2-chloroethyl)amino](3-butenyloxy)phosphoryl chloride | C8H15Cl3NO2P | 详情 | 详情 | |
| (IV) | 31445 | N,N-Bis(2-chloroethyl)-N'-methyldiamidophosphoric acid 3-butenyl ester | C9H19Cl2N2O2P | 详情 | 详情 | |
| (V) | 31446 | N,N-Bis(2-chloroethyl)-N'-methyldiamidophosphoric acid 2-formylethyl ester | C8H17Cl2N2O3P | 详情 | 详情 | |
| (VI) | 31447 | 2-mercxaptoethane sulfonic acid cyclothexylamine | C8H19NO3S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)Reaction of 3,5-dibromopyridine (I) with sodium ethoxide gave 3-bromo-5-ethoxypyridine (II). Palladium-catalyzed coupling of bromopyridine (II) with 3-buten-1-ol (III) yielded the pyridinylbutenol (IV), which was further converted to tosylate (V). Displacement of the tosylate group of (V) with methylamine then gave amine (VI).
| 【1】 Caldwell, W.S.; Dull, G.M.; Miller, C.H.; [3-(5-Ethoxypyridin)yl]-alkenyl 1 amine cpds.. US 5616716 . |
| 【2】 Dull, G.M.; Dobson, G.P.; Caldwell, W.S. (R.J. Reynolds Tobacco Co.); Pharmaceutical compsns. for prevention and treatment of central nervous system disorders. WO 9740011 . |
| 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) | 48045 | 3,5-dibromopyridine | 625-92-3 | C5H3Br2N | 详情 | 详情 |
| (II) | 48046 | 3-bromo-5-ethoxypyridine; 5-bromo-3-pyridinyl ethyl ether | C7H8BrNO | 详情 | 详情 | |
| (III) | 19743 | 3-buten-1-ol | 627-27-0 | C4H8O | 详情 | 详情 |
| (IV) | 48047 | (E)-4-(5-ethoxy-3-pyridinyl)-3-buten-1-ol | C11H15NO2 | 详情 | 详情 | |
| (V) | 48048 | (E)-4-(5-ethoxy-3-pyridinyl)-3-butenyl 4-methylbenzenesulfonate | C18H21NO4S | 详情 | 详情 | |
| (VI) | 48049 | N-[(E)-4-(5-ethoxy-3-pyridinyl)-3-butenyl]-N-methylamine; (E)-4-(5-ethoxy-3-pyridinyl)-N-methyl-3-buten-1-amine | C12H18N2O | 详情 | 详情 |