|
【结 构 式】 
|
【分子编号】20949 【品名】4-Chloro-1-methylpiperidine; 4-Chloro-N-methylpiperidine; N-methyl-4-chloropiperidine 【CA登记号】55770-77-4 |
【 分 子 式 】C6H12ClN 【 分 子 量 】133.62072 【元素组成】C 53.93% H 9.05% Cl 26.53% N 10.48% |
合成路线1
该中间体在本合成路线中的序号：(IV)2,6-Dichloropyridine (I) reacts with sodium hydrogen sulfide yielding 6-chloro-2-mercaptopyridine sodium salt (II). The thioether (III) is formed through reaction of 4-chloro-N-methylpiperidine with (II). Cleavage of the N-methyl group is achieved by condensation of (III) with ethyl chloroformate followed by acidic hydrolysis.
| 【1】 Engel, J.; Jacovlev, V.; Nickel, B.; Scheffler, G.; Thiemer, K. (Degussa-Hüls AG); New pyridine-2-ethers and pyridine-2-thioethers having a nitrogen-containing cycloaliphatic ring. DE 3443968; EP 0149088; ES 8607014; GB 2152048; JP 1985169476; US 4643995 . |
| 【2】 Szelenyi, I.; Engel, J.; Scheffler, G.; Nickel, B.; Thiemer, K.; Tibes, U.; Werner, U.; ANPIRTOLINE HYDROCHLORIDE < Rec INNM >. Drugs Fut 1989, 14, 7, 614. |
| 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) | 13573 | 2,6-Dichloropyridine | 2402-78-0 | C5H3Cl2N | 详情 | 详情 |
| (II) | 20947 | 6-Chloropyridine-2-thiol sodium salt | C5H3ClNNaS | 详情 | 详情 | |
| (III) | 20948 | 6-chloro-2-pyridinyl 1-methyl-4-piperidinyl sulfide; 4-[(6-chloro-2-pyridinyl)sulfanyl]-1-methylpiperidine | C11H15ClN2S | 详情 | 详情 | |
| (IV) | 20949 | 4-Chloro-1-methylpiperidine; 4-Chloro-N-methylpiperidine; N-methyl-4-chloropiperidine | 55770-77-4 | C6H12ClN | 详情 | 详情 |
| (V) | 20950 | ethyl 4-[(6-chloro-2-pyridinyl)sulfanyl]-1-piperidinecarboxylate | C13H17ClN2O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)This compound has been obtained by two similar ways: 1. By condensation of the benzophenone derivative (I) with O-(1-methylpiperidin-4-yl)hydroxylamine by means of K2CO3 in propanol. 2. The reaction of benzophenone derivative (I) with hydroxylamine by means of K2CO3 in propanol gives the corresponding oxime (III), which is finally alkylated with 4-chloro-1-methylpiperidine (IV) by means of NaH in DMF.
| 【1】 Floch, A.; Soler, F.; Cavero, I.; Lavé, D.; Robaut, C.; RP 66681B, a water-soluble pyrrolothiazole derivative with potent and selective PAF receptor antagonist properties. Drugs Fut 1992, 17, 3, 207. |
| 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) | 43196 | (3S)-N-(3-benzoylphenyl)-3-(3-pyridinyl)-1H-pyrrolo[1,2-c][1,3]thiazole-7-carboxamide | C25H19N3O2S | 详情 | 详情 | |
| (II) | 43197 | O-(1-methyl-4-piperidinyl)hydroxylamine; 4-(aminooxy)-1-methylpiperidine | C6H14N2O | 详情 | 详情 | |
| (III) | 43198 | (3S)-N-[3-[(hydroxyimino)(phenyl)methyl]phenyl]-3-(3-pyridinyl)-1H-pyrrolo[1,2-c][1,3]thiazole-7-carboxamide | C25H20N4O2S | 详情 | 详情 | |
| (IV) | 20949 | 4-Chloro-1-methylpiperidine; 4-Chloro-N-methylpiperidine; N-methyl-4-chloropiperidine | 55770-77-4 | C6H12ClN | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The known tricyclic bromide (I) was converted to the nitrile (II) by treatment with CuCN and NaCN. Addition of the Grignard reagent (IV), prepared from 4-chloro-1-methylpiperidine (III), to the tricyclic ketone (II) furnished the tertiary alcohol (V). This was finally dehydrated to the target piperidylidene derivative upon heating in the presence of SOCl2.
| 【1】 Honda, H.; Mizuno, H.; Mogi, K.; Ito, Y.; Kaneko, Y.; Taido, N.; Sato, S.; Kuraishi, T. (SSP Co., Ltd.); Novel benzo[5,6]cyclohepta[1,2-b]pyridine derivs. and antiallergic agents comprising same. EP 0495484; JP 1993059040; US 5231101 . |
| 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) | 53284 | 8-bromo-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one | n/a | C14H10BrNO | 详情 | 详情 |
| (II) | 53585 | 4-[(5-bromopentyl)oxy]-1,1'-biphenyl; [1,1'-biphenyl]-4-yl 5-bromopentyl ether | n/a | C17H19BrO | 详情 | 详情 |
| (III) | 20949 | 4-Chloro-1-methylpiperidine; 4-Chloro-N-methylpiperidine; N-methyl-4-chloropiperidine | 55770-77-4 | C6H12ClN | 详情 | 详情 |
| (IV) | 20645 | chloro(1-methyl-4-piperidinyl)magnesium | C6H12ClMgN | 详情 | 详情 | |
| (V) | 53286 | 11-hydroxy-11-(1-methyl-4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine-8-carbonitrile | n/a | C21H23N3O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：HSR-609 is obtained as shown in Scheme 20067601a:Tricyclic compound (II), derived from (I) by known methods, is converted to piperidine derivative (III) by Grignard reaction and dehydration. The reaction of (III) with ClCO2Et and KOH affords (IV). Michael reaction and hydrolysis of (IV) give HSR-609.
| 【1】 Iwasaki, N.; Yasuda, S.; Kado, N.; Kato, H.; Ito, Y.; Ohashi, T.; Musoh, K.; Nishino, H.; Amphoteric drugs. III. Synthesis and antiallergic activity of 3-[(5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)piperidino] propionic acid derivatives and related compounds. J Med Chem 1995, 38, 3, 496-507. |
| 【2】 Suzuki, T.; Kato, H.; Nagata, O.; Inomata, N.; Ohashi, T.; HSR-609. Drugs Fut 1998, 23, 4, 379. |
| 【3】 Ito, Y.; Kato, H.; Yasuda, S.; Kado, N.; Iwasaki, N.; Nishino, H.; Takeshita, M. (Hokuriku Seiyaku Co., Ltd.); Amphoteric tricyclic compounds as antihistaminic and antiallergic agents. EP 0556813; JP 1994192263; US 5334594 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 20949 | 4-Chloro-1-methylpiperidine; 4-Chloro-N-methylpiperidine; N-methyl-4-chloropiperidine | 55770-77-4 | C6H12ClN | 详情 | 详情 | |
| (I) | 16352 | furo[3,4-b]pyridin-7(5H)-one | C7H5NO2 | 详情 | 详情 | |
| (II) | 16353 | 8-fluoro[1]benzoxepino[4,3-b]pyridin-11(5H)-one | C13H8FNO2 | 详情 | 详情 | |
| (III) | 16354 | 8-fluoro-11-[1-methyltetrahydro-4(1H)-pyridinylidene]-5,11-dihydro[1]benzoxepino[4,3-b]pyridine | C19H19FN2O | 详情 | 详情 | |
| (IV) | 16355 | 8-fluoro-11-tetrahydro-4(1H)-pyridinylidene-5,11-dihydro[1]benzoxepino[4,3-b]pyridine | C18H17FN2O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The title compound was synthesized by alkylation of the previously described 6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone (I) with 4-chloro-1-methylpiperidine (II) in the presence of NaH in hot DMF.
| 【1】 Akahane, A.; Kuroda, S.; Itani, H.; Shimizu, Y. (Fujisawa Pharmaceutical Co., Ltd.); Pyrazolopyridine cpd. and pharmaceutical use thereof. EP 0925299; JP 2000514821; US 6124456; WO 9803507 . |