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【结 构 式】 
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【分子编号】10192 【品名】4-Methylpiperidine; gamma-Pipecoline 【CA登记号】626-58-4 |
【 分 子 式 】C6H13N 【 分 子 量 】99.17596 【元素组成】C 72.66% H 13.21% N 14.12% |
合成路线1
该中间体在本合成路线中的序号：(V)A more complete synthesis for LF-1695 has been reported: The reaction of 2-chloro-5-nitrobenzoic acid (I) with PCl5 in hot chlorobenzene gives the corresponding acyl chloride (II), which is condensed with chlorobenzene (III) by means of AlCl3, yielding 2,4'-dichloro-5-nitrobenzophenone (IV). The condensation of (IV) with 4-methylpiperidine (V) by means of K2CO3 at 150 C affords 4'-chloro-2-(4-methylpiperidin-1-yl)-5-nitrobenzophenone (VI), which is finally reduced with Fe or SnCl2 and HCl.
| 【1】 Ou, K.; Robin, J.; Bellamy, F.D.; Dodey, P.; Chazan, J.B.; Pascal, M.; Dutartre, P.; (Benzoylphenyl)piperidines: A new class of immunomodulators. J Med Chem 1991, 34, 5, 1545-52. |
| 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) | 10188 | 2-Chloro-5-nitrobenzoic acid | 2516-96-3 | C7H4ClNO4 | 详情 | 详情 |
| (II) | 10189 | 2-Chloro-5-nitrobenzoyl chloride | 25784-91-2 | C7H3Cl2NO3 | 详情 | 详情 |
| (III) | 10190 | 1-Chlorobenzene | 108-90-7 | C6H5Cl | 详情 | 详情 |
| (IV) | 10191 | (2-Chloro-5-nitrophenyl)(4-chlorophenyl)methanone | C13H7Cl2NO3 | 详情 | 详情 | |
| (V) | 10192 | 4-Methylpiperidine; gamma-Pipecoline | 626-58-4 | C6H13N | 详情 | 详情 |
| (VI) | 10193 | (4-Chlorophenyl)[2-(4-methylpiperidino)-5-nitrophenyl]methanone | C19H19ClN2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)A new short synthesis of argatroban has been reported: The protection of 4-methylpiperidine (I) with (Boc)2O gives the carbamate (II), which is condensed with benzyl chloroformate by means of sec-butyl lithium and TMEDA in ethyl ether to yield (±)-trans-1-(tert-butoxycarbonyl)-4-methylpiperidine-2-carboxylic acid benzyl ester (III). Deprotection of the NH group of (III) with HCl in ethyl acetate affords (±)-trans-4-methylpiperidine-2-carboxylic acid benzyl ester (IV), which is condensed with the protected arginine derivative (V) by means of isobutyl chloroformate and TEA to provide the corresponding amide as a diastereomeric mixture. Resolution of this mixture by flash chromatography furnishes the desired diastereomer (VI), which is treated with HCl in ethyl acetate in order to remove the Boc-protecting group to yield compound (VII). Condensation of compound (VII) with 3-methylquinoline-8-sulfonyl chloride (VIII) by means of TEA in dichloromethane affords the expected sulfonamide (IX). Finally, this compound is submitted to hydrogenation with H2 over Pd/C in AcOH/ethanol in order to produce debenzylation, cleavage of the NO2 group and hydrogenation of the pyridine ring to yield argatroban.
| 【1】 Belotti, D.; Cossy, J.; A short synthesis of argatroban: A potent selective thrombin inhibitor. Bioorg Med Chem Lett 2001, 11, 15, 1989. |
| 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) | 10192 | 4-Methylpiperidine; gamma-Pipecoline | 626-58-4 | C6H13N | 详情 | 详情 |
| (II) | 49427 | tert-butyl 4-methyl-1-piperidinecarboxylate | C11H21NO2 | 详情 | 详情 | |
| (III) | 49428 | 2-benzyl 1-(tert-butyl) (2R,4R)-4-methyl-1,2-piperidinedicarboxylate | C19H27NO4 | 详情 | 详情 | |
| (IV) | 49429 | benzyl (2R,4R)-4-methyl-2-piperidinecarboxylate | C14H19NO2 | 详情 | 详情 | |
| (V) | 32085 | N(G)-nitro-N2-(tert-butoxy-carbonyl)-L-arginine; Nalpha-(tert-butoxycarbonyl)-Nomega-nitro-L-arginine | C11H21N5O6 | 详情 | 详情 | |
| (VI) | 49430 | C25H38N6O7 | 详情 | 详情 | ||
| (VII) | 49431 | C20H30N6O5 | 详情 | 详情 | ||
| (VIII) | 32089 | 3-methylquinoline-8-suIfonyl chloride; 3-methyl-8-quinolinesulfonyl chloride | C10H8ClNO2S | 详情 | 详情 | |
| (IX) | 49432 | C30H37N7O7S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Treatment of (R)-2-pyrrolidine methanol (I) with di-tert-butyl dicarbonate and K2CO3 gave carbamate (II), which was converted to mesylate (III) using methanesulfonyl chloride and Et3N. Subsequent reaction of (III) with NaCN in DMF provided nitrile (IV). The catalytic hydrogenation of this nitrile in the presence of 4-methylpiperidine (V) furnished the (piperidinylethyl)pyrrolidine (VI). After Boc deprotection of (VI) with trifluoroacetic acid in refluxing CH2Cl2, the resulting pyrrolidine (VII) was finally condensed with m-toluenesulfonyl chloride (VIII) to give the target sulfonamide.
| 【1】 King, F.D.; Forbes, I.T.; Rahman, S.K. (SmithKline Beecham plc); Sulphonamide derivs. and their use in the treatment of CNS disorders. WO 9748681 . |
| 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) | 23309 | (2R)pyrrolidinylmethanol | 68832-13-3 | C5H11NO | 详情 | 详情 |
| (II) | 23310 | tert-butyl (2R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (III) | 23311 | tert-butyl (2R)-2-[[(methylsulfonyl)oxy]methyl]-1-pyrrolidinecarboxylate | C11H21NO5S | 详情 | 详情 | |
| (IV) | 23312 | tert-butyl (2R)-2-(cyanomethyl)-1-pyrrolidinecarboxylate | C11H18N2O2 | 详情 | 详情 | |
| (V) | 10192 | 4-Methylpiperidine; gamma-Pipecoline | 626-58-4 | C6H13N | 详情 | 详情 |
| (VI) | 23314 | tert-butyl (2R)-2-[2-(4-methyl-1-piperidinyl)ethyl]-1-pyrrolidinecarboxylate | C17H32N2O2 | 详情 | 详情 | |
| (VII) | 23315 | 4-methyl-1-[2-[(2R)pyrrolidinyl]ethyl]piperidine | C12H24N2 | 详情 | 详情 | |
| (VIII) | 23316 | 3-methylbenzenesulfonyl chloride | 1899-93-0 | C7H7ClO2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIII)The reaction of 4-chlorothieno[3,2-c]pyridine (I) with KOH in phenol at 140 C followed by ammonium acetate at 155 C gives thieno[3,2-c]pyridine-4-amine (II), which is benzoylated with benzoyl anhydride in pyridine yielding the benzamide (III). The formylation of (III) with DMF and LDA, followed by reduction with NaBH4 in methanol/THF affords the hydroxymethyl compound (IV), which is converted into the mesylate (V) with MsCl and TEA in dichloromethane. The reaction of (V) with LiCl in THF provides the chloromethyl compound (VI), which is condensed with the protected aminomalonate (VII) by means of sodium ethoxide in ethanol/dioxane to give the adduct (VIII). The selective decarboxylation and deprotection of (VIII) with HCl in hot acetic acid yields the amino acid (IX), which is esterified with SOCl2 and methyl to the corresponding methyl ester (X). The condensation of (X) with naphthalen-2-ylsulfonyl chloride (XI) by means of TEA in dichloromethane affords the sulfonamide (XII), which is finally condensed with 4-methylpiperidine (XIII) by means of NaOH and TBTU in DMF. Alternatively, the protection of the amino acid (IX) with Boc2O and TEA in methanol gives the carbamate (XIV), which is condensed with 4-methylpiperidine (XIII) by means of NaOH and TBTU in DMF yielding the piperidide (XV). Finally, this compound is deprotected with TFA and condensed with sulfonyl chloride (XI) and TEA to afford the target compound.
| 【1】 Rewinkel, J.B.M.; et al.; Design, synthesis and testing of amino-bicycloaryl based orally bioavailable thrombin inhibitors. Bioorg Med Chem Lett 1999, 9, 19, 2837. |
| 【2】 Van Galen, P.J.M.; Rewinkel, J.B.M.; Van Boeckel, C.A.A. (Akzo Nobel N.V.); Heterocyclic derivs. and their use as antithrombotic agents. EP 0975600; WO 9847876 . |
| 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) | 38321 | 4-chlorothieno[3,2-c]pyridine | C7H4ClNS | 详情 | 详情 | |
| (II) | 38322 | thieno[3,2-c]pyridin-4-amine; thieno[3,2-c]pyridin-4-ylamine | C7H6N2S | 详情 | 详情 | |
| (III) | 38323 | N-thieno[3,2-c]pyridin-4-ylbenzamide | C14H10N2OS | 详情 | 详情 | |
| (IV) | 38324 | N-[2-(hydroxymethyl)thieno[3,2-c]pyridin-4-yl]benzamide | C15H12N2O2S | 详情 | 详情 | |
| (V) | 38325 | N-[2-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)thieno[3,2-c]pyridin-4-yl]benzamide | C18H18N2O2S2 | 详情 | 详情 | |
| (VI) | 38326 | N-[2-(chloromethyl)thieno[3,2-c]pyridin-4-yl]benzamide | C15H11ClN2OS | 详情 | 详情 | |
| (VII) | 30060 | diethyl 2-[(tert-butoxycarbonyl)amino]malonate | C12H21NO6 | 详情 | 详情 | |
| (VIII) | 38327 | diethyl 2-[[4-(benzoylamino)thieno[3,2-c]pyridin-2-yl]methyl]-2-[(tert-butoxycarbonyl)amino]malonate | C27H31N3O7S | 详情 | 详情 | |
| (IX) | 38328 | 3-(4-aminothieno[3,2-c]pyridin-2-yl)alanine | C10H11N3O2S | 详情 | 详情 | |
| (X) | 38329 | methyl 2-amino-3-(4-aminothieno[3,2-c]pyridin-2-yl)propanoate | C11H13N3O2S | 详情 | 详情 | |
| (XI) | 27989 | 2-naphthalenesulfonyl chloride | 93-11-8 | C10H7ClO2S | 详情 | 详情 |
| (XII) | 38330 | methyl 3-(4-aminothieno[3,2-c]pyridin-2-yl)-2-[(2-naphthylsulfonyl)amino]propanoate | C21H19N3O4S2 | 详情 | 详情 | |
| (XIII) | 10192 | 4-Methylpiperidine; gamma-Pipecoline | 626-58-4 | C6H13N | 详情 | 详情 |
| (XIV) | 38331 | 3-(4-aminothieno[3,2-c]pyridin-2-yl)-N-(tert-butoxycarbonyl)alanine | C15H19N3O4S | 详情 | 详情 | |
| (XV) | 38332 | tert-butyl 1-[(4-aminothieno[3,2-c]pyridin-2-yl)methyl]-2-(4-methyl-1-piperidinyl)-2-oxoethylcarbamate | C21H30N4O3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIII)The reaction of 4-chlorothieno[3,2-c]pyridine (I) with KOH in phenol at 140 C followed by ammonium acetate at 155 C gives thieno[3,2-c]pyridine-4-amine (II), which is benzoylated with benzoyl anhydride in pyridine yielding the benzamide (III). The formylation of (III) with DMF and LDA, followed by reduction with NaBH4 in methanol/THF affords the hydroxymethyl compound (IV), which is converted into the mesylate (V) with MsCl and TEA in dichloromethane. The reaction of (V) with LiCl in THF provides the chloromethyl compound (VI), which is condensed with the protected aminomalonate (VII) by means of sodium ethoxide in ethanol/dioxane to give the adduct (VIII). The selective decarboxylation and deprotection of (VIII) with HCl in hot acetic acid yields the amino acid (IX), which is esterified with SOCl2 and methyl to the corresponding methyl ester (X). The condensation of (X) with 7-methoxynaphthalen-2-ylsulfonyl chloride (XI) by means of TEA in dichloromethane affords the sulfonamide (XII), which is finally condensed with 4-methylpiperidine (XIII) by means of NaOH and TBTU in DMF. Alternatively, the protection of the amino acid (IX) with Boc2O and TEA in methanol gives the carbamate (XIV), which is condensed with 4-methylpiperidine (XIII) by means of NaOH and TBTU in DMF yielding the piperidide (XV). Finally, this compound is deprotected with TFA and condensed with sulfonyl chloride (XI) and TEA to afford the target compound.
| 【1】 Rewinkel, J.B.M.; et al.; Design, synthesis and testing of amino-bicycloaryl based orally bioavailable thrombin inhibitors. Bioorg Med Chem Lett 1999, 9, 19, 2837. |
| 【2】 Van Galen, P.J.M.; Rewinkel, J.B.M.; Van Boeckel, C.A.A. (Akzo Nobel N.V.); Heterocyclic derivs. and their use as antithrombotic agents. EP 0975600; WO 9847876 . |
| 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) | 38321 | 4-chlorothieno[3,2-c]pyridine | C7H4ClNS | 详情 | 详情 | |
| (II) | 38322 | thieno[3,2-c]pyridin-4-amine; thieno[3,2-c]pyridin-4-ylamine | C7H6N2S | 详情 | 详情 | |
| (III) | 38323 | N-thieno[3,2-c]pyridin-4-ylbenzamide | C14H10N2OS | 详情 | 详情 | |
| (IV) | 38324 | N-[2-(hydroxymethyl)thieno[3,2-c]pyridin-4-yl]benzamide | C15H12N2O2S | 详情 | 详情 | |
| (V) | 38325 | N-[2-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)thieno[3,2-c]pyridin-4-yl]benzamide | C18H18N2O2S2 | 详情 | 详情 | |
| (VI) | 38326 | N-[2-(chloromethyl)thieno[3,2-c]pyridin-4-yl]benzamide | C15H11ClN2OS | 详情 | 详情 | |
| (VII) | 30060 | diethyl 2-[(tert-butoxycarbonyl)amino]malonate | C12H21NO6 | 详情 | 详情 | |
| (VIII) | 38327 | diethyl 2-[[4-(benzoylamino)thieno[3,2-c]pyridin-2-yl]methyl]-2-[(tert-butoxycarbonyl)amino]malonate | C27H31N3O7S | 详情 | 详情 | |
| (IX) | 38328 | 3-(4-aminothieno[3,2-c]pyridin-2-yl)alanine | C10H11N3O2S | 详情 | 详情 | |
| (X) | 38329 | methyl 2-amino-3-(4-aminothieno[3,2-c]pyridin-2-yl)propanoate | C11H13N3O2S | 详情 | 详情 | |
| (XI) | 31666 | 7-methoxy-2-naphthalenesulfonyl chloride | C11H9ClO3S | 详情 | 详情 | |
| (XII) | 38333 | methyl 3-(4-aminothieno[3,2-c]pyridin-2-yl)-2-[[(7-methoxy-2-naphthyl)sulfonyl]amino]propanoate | C22H21N3O5S2 | 详情 | 详情 | |
| (XIII) | 10192 | 4-Methylpiperidine; gamma-Pipecoline | 626-58-4 | C6H13N | 详情 | 详情 |
| (XIV) | 38331 | 3-(4-aminothieno[3,2-c]pyridin-2-yl)-N-(tert-butoxycarbonyl)alanine | C15H19N3O4S | 详情 | 详情 | |
| (XV) | 38332 | tert-butyl 1-[(4-aminothieno[3,2-c]pyridin-2-yl)methyl]-2-(4-methyl-1-piperidinyl)-2-oxoethylcarbamate | C21H30N4O3S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XIII)Acylation of 3-chloro-4-methylaniline (VII) with chloroacetonitrile in the presence of BCl3 and Et2AlCl produced the chloroacetophenone (VIII). Subsequent condensation of (VIII) with ethylmalonyl chloride gave amide (IX), which was cyclized to the quinolinone (X) upon treatment with ethanolic NaOEt. Reaction of the quinolinone (X) with POCl3 afforded chloroquinoline (XI). The ester group of (XI) was then reduced to alcohol (XII) by means of diisobutylaluminum hydride. Condensation of (XII) with 4-methylpiperidine (XIII) gave adduct (IV), which was further coupled with pyridinone (VI) under Mitsunobu conditions to yield (Xv). Finally, intramolecular Heck reaction in the presence of palladium diacetate and triphenylphosphine provided the desired pentacyclic compound, which was isolated as the hydrochloride salt.
| 【1】 Coulomb, H.; Huchet, M.; Harnett, J.; Rolland, A.; Lanco, C.; Lavergne, O.; Demarquay, D.; Lesueur-Ginot, L.; Bigg, D.C.H.; BN 80927: A novel homocamptothecin with inhibitory activities on both topoisomerase I and topoisomerase II. Bioorg Med Chem Lett 1999, 9, 17, 2599. |
| 【2】 Cazaux, J.-B.; Manginot, E.; Lavergne, O.; Le Breton, C.; Bigg, D. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Optically pure camptothecin analogues, optically pure synthesis intermediate and method for preparing same. EP 1007527; FR 2768431; WO 9911646 . |
| 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) | 33100 | (5R)-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C11H13NO4 | 详情 | 详情 | |
| (VII) | 26794 | 3-Chloro-4-methylaniline; 4-Amino-2-chlorotoluene | 95-74-9 | C7H8ClN | 详情 | 详情 |
| (VIII) | 33102 | 1-(2-amino-4-chloro-5-methylphenyl)-2-chloro-1-ethanone | C9H9Cl2NO | 详情 | 详情 | |
| (IX) | 33013 | O-[tert-butyl(diphenyl)silyl]hydroxylamine; (aminooxy)(tert-butyl)diphenylsilane | C16H21NOSi | 详情 | 详情 | |
| (X) | 33104 | ethyl 7-chloro-4-(chloromethyl)-6-methyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate | C14H13Cl2NO3 | 详情 | 详情 | |
| (XI) | 33105 | ethyl 2,7-dichloro-4-(chloromethyl)-6-methyl-3-quinolinecarboxylate | C14H12Cl3NO2 | 详情 | 详情 | |
| (XII) | 33106 | [2,7-dichloro-4-(chloromethyl)-6-methyl-3-quinolinyl]methanol | C12H10Cl3NO | 详情 | 详情 | |
| (XIII) | 10192 | 4-Methylpiperidine; gamma-Pipecoline | 626-58-4 | C6H13N | 详情 | 详情 |
| (XIV) | 33107 | [2,7-dichloro-6-methyl-4-[(4-methyl-1-piperidinyl)methyl]-3-quinolinyl]methanol | C18H22Cl2N2O | 详情 | 详情 | |
| (XV) | 33101 | (5R)-8-[(2-chloro-6,7-difluoro-3-quinolinyl)methyl]-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C21H17ClF2N2O4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XV)4-Methoxyphenylacetic acid (VII) was esterified with EtOH and p-toluenesulfonic acid. The resulting ethyl ester (VIII) was brominated by means of N-bromosuccinimide to produce bromoester (IX), which was condensed with 4-nitroimidazole (X) yielding (XI). Reduction of the nitro group of (XI) by catalytic hydrogenation over Pd/C gave amine (XII). This was coupled with acid (VI) by means of EDC and HOBt to afford amide (XIII). Then, hydrolysis of the methyl ester of (XIII) with LiOH gave rise to carboxylic acid (XIV). Finally, coupling of (XIV) with 4-methylpiperidine (XV) generated the title compound.
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 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) | 28103 | (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propionic acid | C19H28N2O6 | 详情 | 详情 | |
| (VII) | 34793 | 2-(4-methoxyphenyl)acetic acid; p-Methoxyphenyl formate; Homoanisic acid; p-Methyl benzyl formate; 4-methoxyphenylacetic acid; 4-methoxybenzeneacetic acid; p-methoxyphenylacetic acid | 104-01-8 | C9H10O3 | 详情 | 详情 |
| (VIII) | 38805 | methyl 2-(4-methoxyphenyl)acetate | 23786-14-3 | C10H12O3 | 详情 | 详情 |
| (IX) | 38806 | methyl 2-bromo-2-(4-methoxyphenyl)acetate | C10H11BrO3 | 详情 | 详情 | |
| (X) | 35764 | 4-nitro-1H-imidazole | 3034-38-6 | C3H3N3O2 | 详情 | 详情 |
| (XI) | 38807 | methyl 2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)acetate | C13H13N3O5 | 详情 | 详情 | |
| (XII) | 38808 | methyl 2-(4-amino-1H-imidazol-1-yl)-2-(4-methoxyphenyl)acetate | C13H15N3O3 | 详情 | 详情 | |
| (XIII) | 38809 | methyl 2-(4-[[(2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propanoyl]amino]-1H-imidazol-1-yl)-2-(4-methoxyphenyl)acetate | C32H41N5O8 | 详情 | 详情 | |
| (XIV) | 38810 | 2-(4-[[(2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propanoyl]amino]-1H-imidazol-1-yl)-2-(4-methoxyphenyl)acetic acid | C31H39N5O8 | 详情 | 详情 | |
| (XV) | 10192 | 4-Methylpiperidine; gamma-Pipecoline | 626-58-4 | C6H13N | 详情 | 详情 |