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【结 构 式】 
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【分子编号】40399 【品名】tert-butyl 4-(hydroxymethyl)-1-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C11H21NO3 【 分 子 量 】215.29268 【元素组成】C 61.37% H 9.83% N 6.51% O 22.29% |
合成路线1
该中间体在本合成路线中的序号：(X)The monosulfonation of orcinol (I) with 2-chlorobenzenesulfonyl chloride (II) in ethyl ether/aqueous NaHCO3 gives the monosulfonate (III), which is condensed with 4-(methanesulfonyloxymethyl)piperidine-1-carboxylic acid tert-butyl ester (IV) by means of NaH in DMF to yield the aryl ether (V). The deprotection of (V) with 4N HCl in dioxane affords the piperidine (VI), which is finally treated with amidinosulfonic acid (VII) and TEA in DMF. The 4-(methanesulfonyloxymethyl)piperidine-1-carboxylic acid tert-butyl ester (IV) has been obtained as follows: The reaction of piperidine-4-carboxylic acid (VIII) with Boc2O and NaHCO3 in dioxane/water gives the protected piperidine (IX), which is reduced at the carboxyl group by means of BH3/THF yielding the carbinol (X). Finally, this compound is mesylated with MsCl and TEA in dichloromethane to afford the target intermediate.
| 【1】 Soll, R.M.; Spurlino, J.; Murphy, L.; Lu, T.; Salemme, F.R.; Bone, R.; Illig, C.R.; Tomczuk, B.E.; Structure-activity and crystallographic analysis of a new class of non-amide-based thrombin inhibitor. Bioorg Med Chem Lett 2000, 10, 1, 79. |
| 【2】 Zetter, B.R.; Smith, R. (Children's Medical Center Corp.); Treatment of human prostate cancer with spermine. WO 9711691 . |
| 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) | 27257 | 5-Methyl-1,3-benzenediol; Orcinol | 505-15-4 | C7H8O2 | 详情 | 详情 |
| (II) | 30817 | 2-chlorobenzenesulfonyl chloride | 2905-23-9 | C6H4Cl2O2S | 详情 | 详情 |
| (III) | 30818 | 3-hydroxy-5-methylphenyl 2-chlorobenzenesulfonate | C13H11ClO4S | 详情 | 详情 | |
| (IV) | 40396 | tert-butyl 4-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-1-piperidinecarboxylate | C14H27NO3S | 详情 | 详情 | |
| (V) | 40397 | tert-butyl 4-[(3-[[(2-chlorophenyl)sulfonyl]oxy]-5-methylphenoxy)methyl]-1-piperidinecarboxylate | C24H30ClNO6S | 详情 | 详情 | |
| (VI) | 40398 | 3-methyl-5-(4-piperidinylmethoxy)phenyl 2-chlorobenzenesulfonate | C19H22ClNO4S | 详情 | 详情 | |
| (VII) | 15984 | amino(imino)methanesulfonic acid | CH4N2O3S | 详情 | 详情 | |
| (VIII) | 17402 | 4-nipecotic acid;piperidine-4-carboxylic acid;p-nipecotic acid; Isonipecotic acid; Hexahydroisonicotinic acid; 4-Piperidinecarboxylic acid | 498-94-2 | C6H11NO2 | 详情 | 详情 |
| (IX) | 17404 | 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid; 1-BOC-piperidine-4-carboxylic acid; N-Boc-isonipecotic acid | 84358-13-4 | C11H19NO4 | 详情 | 详情 |
| (X) | 40399 | tert-butyl 4-(hydroxymethyl)-1-piperidinecarboxylate | C11H21NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Ethyl isonipecotate (I) was protected as the N-Boc derivative (II) and then reduced to alcohol (III) using LiAlH4. Treatment of alcohol (III) with p-toluenesulfonyl chloride in the presence of DBU afforded the intermediate tosylate (IV).
| 【1】 Hennequin, L.F.A.; Stokes, E.S.E.; Thomas, A.P. (AstraZeneca AB; AstraZeneca plc); Quinazoline derivs. as VEGF inhibitors. WO 0132651 . |
| 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) | 17410 | Ethyl isonipecotate; ethyl 4-piperidinecarboxylate | 1126-09-6 | C8H15NO2 | 详情 | 详情 |
| (II) | 49847 | 1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine | 142851-03-4 | C13H23NO4 | 详情 | 详情 |
| (III) | 40399 | tert-butyl 4-(hydroxymethyl)-1-piperidinecarboxylate | C11H21NO3 | 详情 | 详情 | |
| (IV) | 49848 | tert-butyl 4-([[(4-methylphenyl)sulfonyl]oxy]methyl)-1-piperidinecarboxylate | C18H27NO5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The condensation of 7-hydroxy-6-methoxy-3-(pivaloyloxymethyl)quinazolin-3(4H)-one (I) with N-(tert-butoxycarbonyl)piperidine-4-methanol (II) by means of DEAD and PPh3 in dichloromethane or K2CO3 in DMF gives the aryl ether (III), which is deprotected with TFA to yield the free piperidine (IV). The reductive methylation of (IV) with HCHO and NaBH3CN in methanol/THF affords the methylated piperidine (V), which is deprotected with NH3 in methanol to provide the quinazolinone (VI). The reaction of (VI) with SOCl2 in DMF gives the 4-chloroquinazoline (VII), which is finally condensed with 4-chloro-2-fluoroaniline (VIII) by means of NaH in DMF to yield the target quinazoline-4-amine.
| 【1】 Hennequin, L.F.; et al.; Novel 4-anilinoquinazolines with C-7 basic side chains: Design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors. J Med Chem 2002, 45, 6, 1300. |
| 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) | 51967 | [7-hydroxy-6-methoxy-4-oxo-3(4H)-quinazolinyl]methyl pivalate | C15H18N2O5 | 详情 | 详情 | |
| (II) | 40399 | tert-butyl 4-(hydroxymethyl)-1-piperidinecarboxylate | C11H21NO3 | 详情 | 详情 | |
| (III) | 51968 | tert-butyl 4-[[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-6-methoxy-4-oxo-3,4-dihydro-7-quinazolinyl)oxy]methyl]-1-piperidinecarboxylate | C26H37N3O7 | 详情 | 详情 | |
| (IV) | 51969 | [6-methoxy-4-oxo-7-(4-piperidinylmethoxy)-3(4H)-quinazolinyl]methyl pivalate | C21H29N3O5 | 详情 | 详情 | |
| (V) | 51971 | [6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]-4-oxo-3(4H)-quinazolinyl]methyl pivalate | C22H31N3O5 | 详情 | 详情 | |
| (VI) | 51970 | 6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]-4(3H)-quinazolinone | C16H21N3O3 | 详情 | 详情 | |
| (VII) | 51972 | 4-chloro-6-methoxy-7-quinazolinyl (1-methyl-4-piperidinyl)methyl ether; 4-chloro-6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]quinazoline | C16H20ClN3O2 | 详情 | 详情 | |
| (VIII) | 51973 | 2-Fluoro-4-chloroaniline; 4-Chloro-2-fluorobenzenamine; 4-Chloro-2-fluoroaniline | 57946-56-2 | C6H5ClFN | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIX)4-(Hydroxymethyl)piperidine (XVIII) is protected as the N-Boc derivative (XIX) with Boc2O in CH2Cl2. Conversion of alcohol (XIX) into the corresponding mesylate, followed by treatment with NaI in acetone, furnishes the alkyl iodide (XX). Quaternization of triphenylphosphine with iodide (XX) in refluxing acetonitrile gives rise to the phosphonium salt (XXI).
| 【1】 Mills, S.G.; Kim, D.; Hale, J.; MacCoss, M.; Berk, S.; Chapman, K.; Lynch, C.; Caldwell, C.; Willoughby, C.; Rosauer, K. (Merck & Co., Inc.); Pyrrolidine modulators of chemokine receptor activity. US 6265434; WO 0059503 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 32954 | 4-piperidinylmethanol | C6H13NO | 详情 | 详情 | |
| (XIX) | 40399 | tert-butyl 4-(hydroxymethyl)-1-piperidinecarboxylate | C11H21NO3 | 详情 | 详情 | |
| (XX) | 41239 | tert-butyl 4-(iodomethyl)-1-piperidinecarboxylate | C11H20INO2 | 详情 | 详情 | |
| (XXI) | 65138 | {[1-(tert-butoxycarbonyl)-4-piperidinyl]methyl}(triphenyl)phosphonium iodide | C29H35INO2P | 详情 | 详情 |