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【结 构 式】 
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【分子编号】17404 【品名】1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid; 1-BOC-piperidine-4-carboxylic acid; N-Boc-isonipecotic acid 【CA登记号】84358-13-4 |
【 分 子 式 】C11H19NO4 【 分 子 量 】229.2762 【元素组成】C 57.63% H 8.35% N 6.11% O 27.91% |
合成路线1
该中间体在本合成路线中的序号：(XII)2) Racemic MDL-100907 (VII) can also be obtained by reaction of piperidine-4-carboxylic acid (X) with di-tert-butyl dicarbonate (XI) by means of NaOH in tert-butanol/ water, giving piperidine-1,4-dicarboxylic acid 1-mono-tert-butyl ester (XII), which is treated with N,O-dimethylhydroxylamine (XIII) and carbonyldiimidazole (CDI) in dichloromethane to afford the methoxy(methyl)amide (XIV). The condensation of (XIV) with veratrole (VI) by means of BuLi in THF gives 4-(2,3-dimethoxybenzoyl)-piperidine-1-carboxylic acid tert-butyl ester (XV), which is decarboxylated by means of trifluoroacetic acid, yielding ketone (XVI). The condensation of (XVI) with 2-(4-fluorophenyl)ethyl bromide (II) by means of K2CO3 in DMF affords 1-(2,3-dimethoxyphenyl)-1-[1-[2-(4-fluorophenyl)-ethyl]piperidin-4-yl]methanone (XVII). Finally, this compound is reduced with NaBH4 in methanol
| 【1】 Castaner, J.; Sorbera, L.A.; Silvestre, J.S.; MDL-100907. Drugs Fut 1998, 23, 9, 955. |
| 【2】 Carr, A.A.; Kane, J.M.; Hay, D.A. (Merrell Pharmaceuticals, Inc.); (+)-*-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol. EP 0531410; JP 1993507482; US 5134149; WO 9118602 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 17394 | 1-(2-bromoethyl)-4-fluorobenzene | C8H8BrF | 详情 | 详情 | |
| (VI) | 17398 | 2-methoxyphenyl methyl ether; Veratrole; 1,2-dimethoxybenzene | 91-16-7 | C8H10O2 | 详情 | 详情 |
| (VII) | 17399 | (2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanol | C22H28FNO3 | 详情 | 详情 | |
| (X) | 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 |
| (XI) | 13214 | Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate | 24424-99-5 | C10H18O5 | 详情 | 详情 |
| (XII) | 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 |
| (XIII) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (XIV) | 17406 | tert-butyl 4-[[methoxy(methyl)amino]carbonyl]tetrahydro-1(2H)-pyridinecarboxylate | C13H24N2O4 | 详情 | 详情 | |
| (XV) | 17407 | tert-butyl 4-(2,3-dimethoxybenzoyl)tetrahydro-1(2H)-pyridinecarboxylate | C19H27NO5 | 详情 | 详情 | |
| (XVI) | 17408 | (2,3-dimethoxyphenyl)(4-piperidinyl)methanone | C14H19NO3 | 详情 | 详情 | |
| (XVII) | 17409 | (2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanone | C22H26FNO3 | 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 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3
该中间体在本合成路线中的序号：(V)The condensation between 5-chloro-2-nitrobenzoyl chloride (I) and 2-amino-5-chloropyridine (II) produced the corresponding amide (III). Subsequent catalytic hydrogenation of the nitro group of (III) gave aniline (IV). Acid chloride (VI), prepared from N-Boc-isonipecotic acid (V) and oxalyl chloride, was then coupled to aniline (IV) to furnish amide (VII). Further trifluoroacetic acid-promoted cleavage of the Boc protecting group of (VII) yielded piperidine (VIII). Finally, reductive alkylation with acetone in the presence of sodium triacetoxyborohydride gave rise to the target N-isopropyl piperidine.
| 【1】 Kyle, J.A.; et al.; SAR investigations of N-aryl-2-[(piperidin-4-ylcarbonyl)amino]benzamide factor Xa inhibitors. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 288. |
| 【2】 Aromatic amides. WO 0039118 . |
| 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) | 44133 | 5-chloro-2-nitrobenzoyl chloride | C7H3Cl2NO3 | 详情 | 详情 | |
| (II) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (III) | 44134 | 5-chloro-N-(5-chloro-2-pyridinyl)-2-nitrobenzamide | C12H7Cl2N3O3 | 详情 | 详情 | |
| (IV) | 44135 | 2-amino-5-chloro-N-(5-chloro-2-pyridinyl)benzamide | C12H9Cl2N3O | 详情 | 详情 | |
| (V) | 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 |
| (VI) | 44136 | tert-butyl 4-(chlorocarbonyl)-1-piperidinecarboxylate | C11H18ClNO3 | 详情 | 详情 | |
| (VII) | 44137 | tert-butyl 4-[(4-chloro-2-[[(5-chloro-2-pyridinyl)amino]carbonyl]anilino)carbonyl]-1-piperidinecarboxylate | C23H26Cl2N4O4 | 详情 | 详情 | |
| (VIII) | 44138 | N-(4-chloro-2-[[(5-chloro-2-pyridinyl)amino]carbonyl]phenyl)-4-piperidinecarboxamide | C18H18Cl2N4O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)Treatment of 1-bromo-3,3-dimethyl-2-butanone (I) with hexamethylenetetraamine affords the quaternary salt (II), which is then hydrolyzed to amino ketone (III) under acidic conditions (1-3). Alternatively, reaction of butanone (I) with sodium azide in acetone gives the azido derivative (IV), which is reduced with H2 over Pd/C in methanol to yield 1-amino-3,3-dimethyl-2-butanone (III). Acylation of amine (III) with 2-chloroacetyl chloride by means of triethylamine in dichloromethane yields the chloroacetamide (V), which is cyclized in POCl3 at 105 ºC to provide 5-tert-butyl-2-(chloromethyl)oxazole (VI) (1-4). Condensation of chloride (VI) with thiourea gives the S-alkylated thiouronium salt (VII), which is then submitted to alkaline hydrolysis followed by condensation with 2-amino-5-bromothiazole (VIII) under phase-transfer conditions in the presence of tetrabutylammonium sulfate, leading to thioether (IX) (1-3). Acylation of aminothiazole (IX) with 1-Boc-piperidine-4-carboxylic acid (X) —obtained by reaction of piperidine-4-carboxylic acid (XI) with Boc2O and NaOH in dioxane/acetonitrile— by means of EDAC and DMAP in DMF/dichloromethane yields the carboxamide (XII), which is finally deprotected upon treatment with trifluoroacetic acid (1-3) or by means of HCl in hot dioxane/CHCl (4). Scheme 1.
| 【1】 Xiao, H.-Y., Misra, R.N. (Bristol-Myers Squibb Co.). N-[5-[[[5-Alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases. CA 2394552, EP1240166, JP 2003516987, WO 2001044242. |
| 【2】 Xiao, H.-Y., Misra, R.N. (Bristol-Myers Squibb Co.). N-[5-[[[5-Alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases. CA 2417254, EP 1303513, JP 2004509857, WO 2002010162. |
| 【3】 Kim, K.S., Kimball, D., Cai, Z.-W. et al. (Bristol-Myers Squibb Co.). Aminothiazole inhibitors of cyclin dependent kinases. US 6262096. |
| 【4】 Misra, N.R., Xiao, H., Kim, K.S. et al. N-(Cycloalkylamino)acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2. N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (BMS-387032), a highly efficacious and selective antitumor agent. J Med Chem 2004, 47(7): 1719-28. |
| 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) | 30809 | 1-bromo-3,3-dimethyl-2-butanone | 5469-26-1 | C6H11BrO | 详情 | 详情 |
| (II) | 65780 | C12H23BrN4O | 详情 | 详情 | ||
| (III) | 58415 | 1-amino-3,3-dimethyl-2-butanone | 82962-91-2 | C6H13NO | 详情 | 详情 |
| (IV) | 58414 | 1-azido-3,3-dimethyl-2-butanone | 76779-98-1 | C6H11N3O | 详情 | 详情 |
| (V) | 58416 | 2-chloro-N-(3,3-dimethyl-2-oxobutyl)acetamide | C8H14ClNO2 | 详情 | 详情 | |
| (VI) | 58417 | 5-(tert-butyl)-2-(chloromethyl)-1,3-oxazole | 224441-73-0 | C8H12ClNO | 详情 | 详情 |
| (VII) | 58418 | 2-({[amino(imino)methyl]sulfanyl}methyl)-5-(tert-butyl)-1,3-oxazole | 345629-22-3 | C9H15N3OS | 详情 | 详情 |
| (VIII) | 65781 | 2-Amino-5-bromothiazole monohydrobromide; 5-Bromothiazol-2-amine monohydrobromide | 61296-22-8 | C3H3BrN2S.HBr | 详情 | 详情 |
| (IX) | 58420 | 5-({[5-(tert-butyl)-1,3-oxazol-2-yl]methyl}sulfanyl)-1,3-thiazol-2-amine; 5-({[5-(tert-butyl)-1,3-oxazol-2-yl]methyl}sulfanyl)-1,3-thiazol-2-ylamine | 224436-97-9 | C11H15N3OS2 | 详情 | 详情 |
| (X) | 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 |
| (XI) | 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 |
| (XII) | 65782 | tert-Butyl 4-[[5-[[(5-tert-butyloxazol-2-yl)methyl]thio]thiazol-2-yl]carbamoyl]piperidine-1-carboxylate | 345629-23-4 | C22H32N4O4S2 | 详情 | 详情 |