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【结 构 式】 
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【分子编号】11762 【品名】4-Piperidinecarboxamide; Isonipecotamide 【CA登记号】39546-32-2 |
【 分 子 式 】C6H12N2O 【 分 子 量 】128.17416 【元素组成】C 56.23% H 9.44% N 21.86% O 12.48% |
合成路线1
该中间体在本合成路线中的序号：(III)A new synthesis of [14C]-labeled E-1040 with the label in the quinuclidine ring has been reported: The reduction of [14C]-labeled bromoacetic acid (I) with borane-dimethyl sulfide complex in ethyl ether gives 2-bromoethanol (II), which is condensed with piperidine-4-carboxamide (III) by means of K2CO3 and KI in refluxing isopropanol, yielding the [14C]-labeled 1-(2-hydroxyethyl)piperidine-4-carboxamide (IV). The reaction of (IV) with SOCl2 in refluxing acetonitrile affords the 1-(2-chloroethyl)piperidine-4-carbonitrile (V), which is cyclized by means of lithium diisopropylamide in THF, giving the quinuclidine (VI). The hydrolysis of (VI) with sulfuric acid gives [14C]-labeled quinuclidine-4-carboxamide (VII), which is finally condensed with the 3-chloromethylcephalosporin (VIII) by means of Na in acetone and a treatment with trifluoroacetic acid.
| 【1】 Woolley, G.T.; Sugiyama, I.; Yamauchi, H.; Mizuo, H.; Synthesis of 14C-labelled cefclidin (E1040). J Label Compd Radiopharm 1992, 31, 9, 663. |
| 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) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
| (I) | 45074 | 2-bromoacetic acid | C2H3BrO2 | 详情 | 详情 | |
| (II) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (II) | 45075 | 2-bromo-1-ethanol | C2H5BrO | 详情 | 详情 | |
| (III) | 11762 | 4-Piperidinecarboxamide; Isonipecotamide | 39546-32-2 | C6H12N2O | 详情 | 详情 |
| (IV) | 11763 | 1-(2-Hydroxyethyl)-4-piperidinecarboxamide | C8H16N2O2 | 详情 | 详情 | |
| (IV) | 45076 | 1-(2-hydroxyethyl)-4-piperidinecarboxamide | C8H16N2O2 | 详情 | 详情 | |
| (V) | 11764 | 1-(2-Chloroethyl)-4-piperidinecarbonitrile | C8H13ClN2 | 详情 | 详情 | |
| (V) | 45077 | 1-(2-chloroethyl)-4-piperidinecarbonitrile | C8H13ClN2 | 详情 | 详情 | |
| (VI) | 11765 | 4-Quinuclidinecarbonitrile | C8H12N2 | 详情 | 详情 | |
| (VI) | 45078 | 4-quinuclidinecarbonitrile | C8H12N2 | 详情 | 详情 | |
| (VII) | 11766 | 4-Quinuclidinecarboxamide | C8H14N2O | 详情 | 详情 | |
| (VII) | 45079 | 4-quinuclidinecarboxamide | C8H14N2O | 详情 | 详情 | |
| (VIII) | 11767 | 4-methoxybenzyl (6R,7R)-7-[[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl]amino]-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C21H21ClN6O6S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)MDL-100907 can be obtained by several different ways: 1) The condensation of piperidine-4-carboxamide (I) with 2-(4-fluorophenyl)ethyl bromide (II) by means of K2CO3 in hot DMF gives 1-[2-(4-fluorophenyl)ethyl]piperidine-4-carboxamide (III), which by reaction with refluxing POCl3 is converted into the nitrile (IV). The reduction of (IV) with diisobutyl aluminum hydride (DIBAL) in THF affords the aldehyde (V), which by condensation with 1,2-dimethoxybenzene (veratrole) (VI) by means of BuLi in THF affords racemic MDL-100907 (VII). The esterification of (VII) with (S)-2-methoxy-2-phenylacetic acid (VIII) by means of dicyclohexylcarbodiimide (DCC) and dimethyl-aminopyridine (DMAP) in refluxing CHCl3 affords a mixture of diastereomers that is submitted to column chromatography over silica gel to afford the pure diastereomer (IX). Finally, (IX) is saponified with K2CO3 in methanol/ water
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 11762 | 4-Piperidinecarboxamide; Isonipecotamide | 39546-32-2 | C6H12N2O | 详情 | 详情 |
| (II) | 17394 | 1-(2-bromoethyl)-4-fluorobenzene | C8H8BrF | 详情 | 详情 | |
| (III) | 17395 | 1-(4-fluorophenethyl)-4-piperidinecarboxamide | C14H19FN2O | 详情 | 详情 | |
| (IV) | 17396 | 1-(4-fluorophenethyl)-4-piperidinecarbonitrile | C14H17FN2 | 详情 | 详情 | |
| (V) | 17397 | 1-(4-fluorophenethyl)-4-piperidinecarbaldehyde | C14H18FNO | 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 | |
| (VIII) | 17400 | (2S)-2-methoxy-2-phenylethanoic acid | C9H10O3 | 详情 | 详情 | |
| (IX) | 17401 | (R)-(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methyl (2S)-2-methoxy-2-phenylethanoate | C31H36FNO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Alkylation of isonipecotamide (I) with n-butyl bromide in the presence of potassium carbonate gives the amide (II), which is reduced with lithium aluminum hydride to afford 1-butyl-4-piperidinylmethylamine (III). Conversion of indole-3-carboxylic acid (IV) to the acid chloride (V) is carried out with oxalyl chloride in dichloromethane containing N,N-dimethylformamide (DMF). Coupling of the amine (III) with the acid chloride (V) in dichloromethane in the presence of triethylamine gives N-[(1-butyl-4-piperidinyl)methyl]indole-3-carboxamide (VI). N-[(1-butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]-oxazino[3,2-a] indole-10-carboxamide (VIII) is formed by treatment of the amide (VI) with N-chlorosuccinimide in chloroform followed by reaction with 3-bromopropanol and cyclization of the intermediate ether (VII) with potassium carbonate in acetone. Conversion to N-[(1-butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a] indole-10-carboxamide hydrochloride (SB-207266) is effected by treatment of (VIII) with anhydrous HCl in ethanol.
| 【1】 Gaster, L.M.; Sanger, G.J.; SB-204070: 5-HT4 receptor antagonists and their potential therapeutic utility. Drugs Fut 1994, 19, 109-21. |
| 【2】 Ford, A.P.D.W.; Clarke, D.E.; The 5-HT4 receptor. Med Res Rev 1993, 13, 633-62. |
| 【3】 Gaster, L.; SB-207266A. Drugs Fut 1997, 22, 12, 1325. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 | |
| (I) | 11762 | 4-Piperidinecarboxamide; Isonipecotamide | 39546-32-2 | C6H12N2O | 详情 | 详情 |
| (II) | 17150 | 1-butyl-4-piperidinecarboxamide | C10H20N2O | 详情 | 详情 | |
| (III) | 17151 | (1-butyl-4-piperidinyl)methanamine; (1-butyl-4-piperidinyl)methylamine | C10H22N2 | 详情 | 详情 | |
| (IV) | 17152 | 1H-Indole-3-carboxylic acid; Indole-3-Carboxylic acid; 3-Indolecarboxylic acid | 771-50-6 | C9H7NO2 | 详情 | 详情 |
| (V) | 17153 | 1H-indole-3-carbonyl chloride | C9H6ClNO | 详情 | 详情 | |
| (VI) | 17154 | N-[(1-butyl-4-piperidinyl)methyl]-1H-indole-3-carboxamide | C19H27N3O | 详情 | 详情 | |
| (VII) | 17155 | 2-(3-bromopropoxy)-N-[(1-butyl-4-piperidinyl)methyl]-1H-indole-3-carboxamide | C22H32BrN3O2 | 详情 | 详情 | |
| (VIII) | 17156 | N-[(1-butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide | C22H31N3O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)Ibodutant is synthesized (1) starting from commercially available methyl tetrahydro-2H-pyran-4-carboxylate (I), which is hydrolyzed to the corresponding carboxylic acid by treatment with sodium hydroxide (1 M) and immediately transformed to the acyl chloride (II) with oxalyl chloride and catalytic DMF in dichloromethane. Reaction of (II) with isonipecotamide (III) in DMF/dichloromethane in the presence of triethylamine gives the diamide (IV), which is successfully reduced to the corresponding diamine (V) using lithium aluminum hydride in refluxing THF. Coupling of (V) with tert-butyloxycarbonyl-(R )-phenylalanine N-hydroxysuccinimide ester (Boc-D-Phe-OSu) in THF and Boc deprotection with HCl/dioxane gives (VI). Further coupling of (VI) with the N-Boc derivative of aminocyclopentanecarboxylic acid (VII) in the presence of EDC.HCl and HOBT, and deprotection of the Boc group with HCl/dioxane, provides 1-aminocyclopentanecarboxylic acid [2-phenyl-1-(R)-[[1-(tetrahydropyran-4-ylmethyl)piperidin-4-ylmethyl]carbamoyl]ethyl]amide (VIII). The free amine compound (VIII) is in turn coupled with 6-methylbenzo[b]thiophene-2-carbonyl chloride (IX), obtained from the corresponding carboxylic acid by reaction with oxalyl chloride under the usual conditions, finally giving ibodutant. Scheme 1.
| 【1】 Fedi, V., Altamura, M., Catalioto, R.M. et al. Discovery of a series of potent and selective linear tachykinin NK2 receptor antagonists. J Med Chem 2007, 50(20): 4793-807. |
| 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) | 65548 | Methyl tetrahydropyran-4-carboxylate; Tetrahydropyran-4-carboxylic acid methyl ester; THPE | 110238-91-0 | C7H12O3 | 详情 | 详情 |
| (II) | 50860 | tetrahydro-2H-pyran-4-carbonyl chloride | 40191-32-0 | C6H9ClO2 | 详情 | 详情 |
| (III) | 11762 | 4-Piperidinecarboxamide; Isonipecotamide | 39546-32-2 | C6H12N2O | 详情 | 详情 |
| (IV) | 65549 | C12H20N2O3 | 详情 | 详情 | ||
| (V) | 65550 | C12H24N2O | 详情 | 详情 | ||
| (VI) | 65551 | C21H33N3O2 | 详情 | 详情 | ||
| (VII) | 33149 | 1-aminocyclopentanecarboxylic acid | 52-52-8 | C6H11NO2 | 详情 | 详情 |
| (VIII) | 65552 | C27H42N4O3 | 详情 | 详情 | ||
| (IX) | 65553 | 6-Methyl-1-Benzothiophene-2-Carbonyl Chloride; 6-Methyl-Benzo[B]Thiophene-2-Carbonyl Chloride | C10H7ClOS | 详情 | 详情 |