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【结 构 式】 
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【分子编号】26225 【品名】4-benzylpiperidine 【CA登记号】31252-42-3 |
【 分 子 式 】C12H17N 【 分 子 量 】175.27372 【元素组成】C 82.23% H 9.78% N 7.99% |
合成路线1
该中间体在本合成路线中的序号：(XI)Treatment of 2,5-dihydroxybenzoic acid (I) with dimethyl sulfate and K2CO3 afforded methyl 2-hydroxy-5-methoxybenzoate (II). Condensation of (II) with dimethylthiocarbamoyl chloride gave the O-aryl thiocarbamate (III), which underwent thermal rearrangement to the S-aryl isomer (IV) upon heating at 265 C in diphenyl ether. Subsequent hydrolysis of the thiocarbamate group of (IV) furnished the desired thiophenol compound (V). Cyclization of the mercapto ester (V) with 2-chloroethylamine (VI) gave rise to the benzothiazepinone (VII), which was further reduced to the benzothiazepine (VIII) using LiAlH4. Acylation of (VIII) with acryloyl chloride (IX) provided the acrylamide (X). Finally, Michael addition of 4-benzylpiperidine (XI) to acrylamide (X) yielded the title compound.
| 【1】 Kaneko, N.; Oosawa, T.; Sakai, T.; Oota, H. (Kirin Brewery Co., Ltd.); 1,4-Benzothiazepine derivs.. EP 0565721; US 5416066; WO 9212148 . |
| 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) | 60415 | 2,5-dihydroxybenzoic acid | C7H6O4 | 详情 | 详情 | |
| (II) | 60416 | methyl 2-hydroxy-5-methoxybenzoate | C9H10O4 | 详情 | 详情 | |
| (III) | 60417 | methyl 2-{[(dimethylamino)carbothioyl]oxy}-5-methoxybenzoate | C12H15NO4S | 详情 | 详情 | |
| (IV) | 60418 | methyl 2-{[(dimethylamino)carbonyl]sulfanyl}-5-methoxybenzoate | C12H15NO4S | 详情 | 详情 | |
| (V) | 13887 | methyl 5-methoxy-2-sulfanylbenzoate | C9H10O3S | 详情 | 详情 | |
| (VI) | 33455 | 2-chloro-1-ethanamine; 2-chloroethylamine | C2H6ClN | 详情 | 详情 | |
| (VII) | 60419 | 7-methoxy-3,4-dihydro-1,4-benzothiazepin-5(2H)-one | C10H11NO2S | 详情 | 详情 | |
| (VIII) | 60420 | 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine; methyl 2,3,4,5-tetrahydro-1,4-benzothiazepin-7-yl ether | C10H13NOS | 详情 | 详情 | |
| (IX) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (X) | 60421 | 1-[7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]-2-propen-1-one | C13H15NO2S | 详情 | 详情 | |
| (XI) | 26225 | 4-benzylpiperidine | 31252-42-3 | C12H17N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)4-Benzylpiperidine (I) was alkylated with butynyl tosylate (II) to afford the N-butynyl piperidine (III). Subsequent coupling of (III) with 4-iodophenol (IV) in the presence of Pd(PPh3)4 in pyrrolidine produced the corresponding butynyl phenol.
| 【1】 Bigge, C.F.; Serpa, K.; Wise, L.D.; Gregory, T.F.; Meltzer, L.T.; Wright, J.L.; Boxer, P.A.; Subtype-selective N-methyl-D-aspartate receptor antagonists: Synthesis and biological evaluation of 1-(arylakynyl)-4-benzylpiperidines. J Med Chem 1999, 42, 13, 2469. |
合成路线3
该中间体在本合成路线中的序号：(V)The alkylation of 5-cyanoindole (I) with methyl bromoacetate (II) in the presence of NaH in DMF provided the indolylacetate ester (III), which was hydrolyzed to the corresponding carboxylic acid (IV) with methanolic KOH. Coupling of (IV) with 4-benzylpiperidine (V) employing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-HCl (EDC) afforded amide (VI). Pinner reaction of (VI) with methanolic HCl produced imidate (VII), which was finally treated with ammonium carbonate in MeOH to yield the target amidine
| 【1】 Duffy, D.E.; Dominguez, C.; Han, Q.; et al.; Design and synthesis of potent and selective 5,6-fused heterocyclic thrombin inhibitors. Bioorg Med Chem Lett 1999, 9, 7, 925. |
| 【2】 Dominguez, C.; Han, Q.; Duffy, D.E.; Park, J.M.; Quan, M.L.; Rossi, K.A.; Wexler, R.R. (DuPont Pharmaceuticals Co.); Amidinoindoles, amidinoazoles, and analogs thereof as inhibitors of factor Xa and of thrombin. EP 0960102; WO 9801428 . |
| 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) | 31341 | 5-Cyanoindole; Indole-5-carbonitrile; 1H-Indole-5-carbonitrile | 15861-24-2 | C9H6N2 | 详情 | 详情 |
| (II) | 12309 | methyl 2-bromoacetate; methyl bromoacetate | 96-32-2 | C3H5BrO2 | 详情 | 详情 |
| (III) | 31342 | methyl 2-(5-cyano-1H-indol-1-yl)acetate | C12H10N2O2 | 详情 | 详情 | |
| (IV) | 31343 | 2-(5-cyano-1H-indol-1-yl)acetic acid | C11H8N2O2 | 详情 | 详情 | |
| (V) | 26225 | 4-benzylpiperidine | 31252-42-3 | C12H17N | 详情 | 详情 |
| (VI) | 31344 | 1-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-1H-indole-5-carbonitrile | C23H23N3O | 详情 | 详情 | |
| (VII) | 31345 | methyl 1-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-1H-indole-5-carboximidoate | C24H27N3O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)4-Benzylpiperidine (I) was alkylated with propargyl tosylate (II) to afford the N-propynyl piperidine (III). Subsequent coupling of (III) with 4-iodophenol (IV) in the presence of Pd(PPh3)4 in pyrrolidine produced the corresponding propynyl phenol.
| 【1】 Bigge, C.F.; Serpa, K.; Wise, L.D.; Gregory, T.F.; Meltzer, L.T.; Wright, J.L.; Boxer, P.A.; Subtype-selective N-methyl-D-aspartate receptor antagonists: Synthesis and biological evaluation of 1-(arylakynyl)-4-benzylpiperidines. J Med Chem 1999, 42, 13, 2469. |
合成路线5
该中间体在本合成路线中的序号：(V)Coupling of 3-butyn-1-ol (I) with 4-iodo-1-phenylsulfonylimidazole (II) in the presence of CuI and Pd(PPh3)4 afforded the imidazolylbutynol (III), which was activated as the tosylate (IV) with p-toluenesulfonyl chloride in pyridine. Subsequent displacement of the tosylate group of (IV) by 4-benzylpiperidine (V) using NaHCO3 in hot DMF produced the corresponding N-(imidazolylbutynyl)piperidine with simultaneous cleavage of the benzenesulfonyl protecting group.
| 【1】 Serpa, K.A.; Wise, L.D.; Meltzer, L.T.; Gregory, T.F.; Wright, J.L.; Boxer, P.A.; Discovery of subtype-selective NMDA receptor ligands: 4-benzyl-1-piperidinylalkynylpyrroles, pyrazoles and imidazoles as NR1A/2B antagonists. Bioorg Med Chem Lett 1999, 9, 19, 2815. |
| 【2】 Boxer, P.A.; Woodward, R.M.; Meltzer, L.T.; D'Wise, L.; Gregory, T.F.; Novel series of 4-benzyl-N-(4-imidazole-1-alkynyl)piperidines as potent subtype selective NMDA receptor antagonists. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 94. |
| 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) | 32507 | 3-butyn-1-ol | 927-74-2 | C4H6O | 详情 | 详情 |
| (II) | 32508 | 4-iodo-1-(phenylsulfonyl)-1H-imidazole | C9H7IN2O2S | 详情 | 详情 | |
| (III) | 32509 | 4-[1-(phenylsulfonyl)-1H-imidazol-4-yl]-3-butyn-1-ol | C13H12N2O3S | 详情 | 详情 | |
| (IV) | 32510 | 4-[1-(phenylsulfonyl)-1H-imidazol-4-yl]-3-butynyl 4-methylbenzenesulfonate | C20H18N2O5S2 | 详情 | 详情 | |
| (V) | 26225 | 4-benzylpiperidine | 31252-42-3 | C12H17N | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IX)Treatment of piperidine (I) with 9-BBN in refluxing THF followed by reaction with bromo derivative (II) by means of K2CO3, PdCl2(dppf) and Ph3As in DMF/H2O provides chlorophenylsulfonyl derivative (III), whose Boc group is removed by means of TFA in CH2Cl2/H2O to afford secondary amine (IV). Reductive amination between amine (IV) and piperidone (V) by means of NaB(OAc)3H in CH2Cl2 in the presence of HOAc furnishes compound (VI), which is then deprotected by means of TFA in CH2Cl2/H2O to yield bipiperidinyl derivative (VII). Finally, coupling of (VII) with 2-amino-3-methyl benzoic acid (VIII) by means of HOBt, DIEA and EDCI in DMF provides the target product. Alternatively, the synthesis of intermediate (VII) can be performed as follows: Protection of the piperidine moiety of (IX) by means of trifluoroacetic anhydride in CH2Cl2 followed by treatment with methanesulfonic acid and dibromodimethylhydantoin (DBDMH) affords bromo derivative (X), whose trifluoroacetate moiety is then removed by reaction with K2CO3 in MeOH/H2O to give piperidine derivative (XI). Reductive amination between (XI) and piperidone (V) by means of NaB(OAc)3H in CH2Cl2 in the presence of HOAc furnishes compound (XII), which is condensed with 3-chlorbenzenesulfonyl fluoride (XIII) by means of BuLi in THF and finally treated with TFA in CH2Cl2/H2O for Boc removal to provide the intermediate chlorophenylsulfonyl derivative (VII).
| 【1】 Miller, M.W.; Clader, J.W.; McCombie, S.W.; Vice, S.F.; Kozlowski, J.A. (Schering Corp.); Muscarinic antagonists. WO 0121590 . |
| 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) | 48124 | tert-butyl 4-methylene-1-piperidinecarboxylate | C11H19NO2 | 详情 | 详情 | |
| (II) | 48125 | (4-bromophenyl)(3-chlorophenyl)dioxo-lambda(6)-sulfane; 4-bromophenyl 3-chlorophenyl sulfone | C12H8BrClO2S | 详情 | 详情 | |
| (III) | 48126 | tert-butyl 4-[4-[(3-chlorophenyl)sulfonyl]benzyl]-1-piperidinecarboxylate | C23H28ClNO4S | 详情 | 详情 | |
| (IV) | 48127 | 3-chlorophenyl 4-(4-piperidinylmethyl)phenyl sulfone; 4-[4-[(3-chlorophenyl)sulfonyl]benzyl]piperidine | C18H20ClNO2S | 详情 | 详情 | |
| (V) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (VI) | 48128 | C28H37ClN2O4S | 详情 | 详情 | ||
| (VII) | 48129 | C23H29ClN2O2S | 详情 | 详情 | ||
| (VIII) | 48130 | 2-amino-3-methylbenzoic acid | 4389-45-1 | C8H9NO2 | 详情 | 详情 |
| (IX) | 26225 | 4-benzylpiperidine | 31252-42-3 | C12H17N | 详情 | 详情 |
| (X) | 48131 | 1-[4-(4-bromobenzyl)-1-piperidinyl]-2,2,2-trifluoro-1-ethanone | C14H15BrF3NO | 详情 | 详情 | |
| (XI) | 48132 | 4-(4-bromobenzyl)piperidine | C12H16BrN | 详情 | 详情 | |
| (XII) | 48133 | C22H33BrN2O2 | 详情 | 详情 | ||
| (XIII) | 48134 | 3-chlorobenzenesulfonyl fluoride | C6H4ClFO2S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VI)Treatment of the N-aryl oxalamic acid ethyl ester (I) with butylamine in toluene provides the oxalic diamide (II). The nitro group of (II) is then reduced to the corresponding amine (III) by catalytic hydrogenation over Pd/C. Subsequent thermal cyclization of the N-acyl phenylenediamine (III) leads to benzimidazole (IV). Hydrolysis of both the methyl ether and amide functions of (IV) with concentrated HBr furnishes 6-hydroxy-1H-benzimidazole-2-carboxylic acid (V). Then, coupling of acid (V) with 4-benzylpiperidine (VI) in the presence of TBTU gives rise to the desired amide
| 【1】 Nagy, J.; Domany, G.; Farkas, S.; Borza, I.; Horvath, C.; Bartane Szalai, G.; Kolok, S. (Gedeon Richter Ltd.); Amine derivs. as NMDA receptor antagonists. WO 0234718 . |
| 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) | 60885 | ethyl 2-(4-methoxy-2-nitroanilino)-2-oxoacetate | C11H12N2O6 | 详情 | 详情 | |
| (II) | 60886 | 2-(butylamino)-N-(4-methoxy-2-nitrophenyl)-2-oxoacetamide | C13H17N3O5 | 详情 | 详情 | |
| (III) | 60893 | N-(2-amino-4-methoxyphenyl)-2-(butylamino)-2-oxoacetamide | C13H19N3O3 | 详情 | 详情 | |
| (IV) | 60894 | N-butyl-6-methoxy-1H-benzimidazole-2-carboxamide | C13H17N3O2 | 详情 | 详情 | |
| (V) | 60985 | 6-[4-(3-hydroxybutyl)-1-piperazinyl]-N-(6-methoxy-8-quinolinyl)hexanamide | C24H36N4O3 | 详情 | 详情 | |
| (VI) | 26225 | 4-benzylpiperidine | 31252-42-3 | C12H17N | 详情 | 详情 |