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【结 构 式】 
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【分子编号】20645 【品名】chloro(1-methyl-4-piperidinyl)magnesium 【CA登记号】 |
【 分 子 式 】C6H12ClMgN 【 分 子 量 】157.92572 【元素组成】C 45.63% H 7.66% Cl 22.45% Mg 15.39% N 8.87% |
合成路线1
该中间体在本合成路线中的序号：(IV)2) By reaction of 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (III) with the Grignard reagent (IV) to give the tertiary carbinol (V), which is dehydrated with 85% H2SO4 affording 8-chloro-11-piperidinylidene derivative (VI). Finally, cornpound (VI) is treated with ethyl chloroformate (II) in toluene.
| 【1】 Magatti, C.V.; Villani, F.J.; Wong, J.; Poper, T.L.; Vashi, D.B.; N-substituted 11-(4-piperidylene)-5,6-dihydro-11H-. Arzneim-Forsch Drug Res 1986, 36, 9, 1311. |
| 【2】 Magatti, C.V.; Vashi, D.B.; Wong, J.; Poper, T.L.; Villani, F.J.; Derivatives of 10,11-dihydro-5H-dibenzola[a,d]cycl. J Med Chem 1972, 15, 7, 750. |
| 【3】 Villani, F.J. (Schering Corp.); Antihistaminic 11-(4-piperidylidene)-5H-benzo-[5,6. US 4282233 . |
| 【4】 Prous, J.; Castaner, J.; Loratadine. Drugs Fut 1987, 12, 6, 544. |
| 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) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (III) | 16540 | (1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-[1-methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]phenyl]-1-propanol | C34H36ClNO3 | 详情 | 详情 | |
| (IV) | 20645 | chloro(1-methyl-4-piperidinyl)magnesium | C6H12ClMgN | 详情 | 详情 | |
| (V) | 23553 | 8-chloro-11-(1-methyl-4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol | C20H23ClN2O | 详情 | 详情 | |
| (VII) | 20647 | 8-chloro-11-(1-methyl-4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | 38092-89-6 | C20H21ClN2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Alcoholysis of 3-methylpyridine-2-carbonitrile (I) with hot tert-butanol and H2SO4 gives the N-tert-butylcarboxamide (II), which is alkylated with 3-chlorobenzyl chloride (III) and BuLi in THF, yielding N-tert-butyl-3-[2-(3-chlorophenyl)ethyl]pyridine-2-carboxamide (IV). The reaction of (IV) with refluxing POCl3 and then with NaOH affords the corresponding nitrile (V), which is condensed with 1-methylpiperidin-4-ylmagnesium chloride (VI) in THF to give the ketone (VII). Cyclization of (VII) by means of either BF3 in HF or trifluoromethanesulfonic acid yields 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII), which is reacted with cyanogen bromide in benzene to give the N-cyano compound (IX). Finally, this compound is treated with HCl in refluxing acetic acid/water. Alternatively, 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII) is treated with ethyl chloroformate in hot toluene, affording the carbamate (X) (2), which is finally decarboxylated with KOH or NaOH in refluxing ethanol/water.
| 【1】 Villani, F.J.; Wong, J.K. (Schering Corp.); Antihistaminic 8-(halo)-substituted 6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines. WO 8503707 . |
| 【2】 Castaner, J.; Leeson, P.; Graul, A.; Desloratadine. Drugs Fut 2000, 25, 4, 339. |
| 【3】 Villani, F.J. (Schering Corp.); Antihistaminic 11-(4-piperidylidene)-5H-benzo-[5,6. US 4282233 . |
| 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) | 16500 | 3-methyl-2-pyridinecarbonitrile | 20970-75-6 | C7H6N2 | 详情 | 详情 |
| (II) | 16501 | N-(tert-butyl)-3-methyl-2-pyridinecarboxamide | C11H16N2O | 详情 | 详情 | |
| (III) | 20642 | 1-chloro-3-(chloromethyl)benzene; 3-Chlorobenzyl chloride | 620-20-2 | C7H6Cl2 | 详情 | 详情 |
| (IV) | 20643 | N-(tert-butyl)-3-(3-chlorophenethyl)-2-pyridinecarboxamide | C18H21ClN2O | 详情 | 详情 | |
| (V) | 20644 | 3-(3-chlorophenethyl)-2-pyridinecarbonitrile | C14H11ClN2 | 详情 | 详情 | |
| (VI) | 20645 | chloro(1-methyl-4-piperidinyl)magnesium | C6H12ClMgN | 详情 | 详情 | |
| (VII) | 20646 | [3-(3-chlorophenethyl)-2-pyridinyl](1-methyl-4-piperidinyl)methanone | C20H23ClN2O | 详情 | 详情 | |
| (VIII) | 20647 | 8-chloro-11-(1-methyl-4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | 38092-89-6 | C20H21ClN2 | 详情 | 详情 |
| (IX) | 34056 | 8-chloro-11-(1-cyano-4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | C20H18ClN3 | 详情 | 详情 | |
| (X) | 17877 | ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | 79794-75-5 | C22H23ClN2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Condensation of ethyl nicotinate (XI) with 3-chlorophenylacetonitrile (XII) by means of sodium ethoxide in ethanol gives 2-(3-chlorophenyl)-3-oxo-3-(3-pyridyl)propionitrile (XIII), which by refluxing with concentrated HBr yields 2-(3-chlorophenyl)-1-(3-pyridyl)ethanone (XIV). The reduction of (XIV) with hydrazine hydrate and NaOH in diethylene glycol at 235-40 C affords 3-(2-phenylethyl) pyridine (XV), which is oxidized with H2O2 in hot acetic acid to provide the corresponding N-oxide (XVI). Reaction of (XVI) with NaCN and dimethyl sulfate in water affords the previously described 3-(2-phenylethyl)pyridine-2-carbonitrile (V), which can be worked up as previously described or cyclized with polyphosphoric acid (PPA) at 180 C to give 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (XVII). The condensation of (XVII) with 1-methylpiperidin-4-ylmagnesium chloride (VI) in THF yields the corresponding carbinol (XVIII), which is dehydrated with PPA at 170 C to afford the previously reported 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII).
| 【1】 Castaner, J.; Leeson, P.; Graul, A.; Desloratadine. Drugs Fut 2000, 25, 4, 339. |
| 【2】 Villani, F.J. (Schering Corp.); Novel aza-dibenzo[a,d]cycloheptene derivatives. US 3326924 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 20644 | 3-(3-chlorophenethyl)-2-pyridinecarbonitrile | C14H11ClN2 | 详情 | 详情 | |
| (VI) | 20645 | chloro(1-methyl-4-piperidinyl)magnesium | C6H12ClMgN | 详情 | 详情 | |
| (VIII) | 20647 | 8-chloro-11-(1-methyl-4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | 38092-89-6 | C20H21ClN2 | 详情 | 详情 |
| (XI) | 23226 | ethyl nicotinate | 614-18-6 | C8H9NO2 | 详情 | 详情 |
| (XII) | 34057 | 2-(3-chlorophenyl)acetonitrile; 3-chlorophenylacetonitrile | 1529-41-5 | C8H6ClN | 详情 | 详情 |
| (XIII) | 34058 | 2-(3-chlorophenyl)-3-oxo-3-(3-pyridinyl)propanenitrile | C14H9ClN2O | 详情 | 详情 | |
| (XIV) | 34059 | 2-(3-chlorophenyl)-1-(3-pyridinyl)-1-ethanone | C13H10ClNO | 详情 | 详情 | |
| (XV) | 34060 | 3-(3-chlorophenethyl)pyridine | C13H12ClN | 详情 | 详情 | |
| (XVI) | 34061 | 3-(3-chlorophenethyl)-1-pyridiniumolate | C13H12ClNO | 详情 | 详情 | |
| (XVII) | 16504 | 8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one; 8-Chloro-10,11-dihydro-4-aza-5H-dibenzo[a,d]cycloheptan-5-one | 31251-41-9 | C14H10ClNO | 详情 | 详情 |
| (XVIII) | 23553 | 8-chloro-11-(1-methyl-4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol | C20H23ClN2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)N-tert-Butyl-3-methyl-2-pyridinecarboxamide (I) was treated with two equivalents of butyllithium at -40 C, and the resulting dianion was C-alkylated with 3-chlorobenzyl chloride (II) to provide the phenetylpyridine (III). Further refluxing with phosphoryl chloride afforded nitrile (IV), which was condensed with the piperidinyl Grignard reagent (V) to yield, after hydrolysis, ketone (VI). Acid-catalyzed cyclization of ketone (VI) produced the tricyclic compound (VII). Demethylation was then accomplished by conversion to the ethyl carbamate (VIII) by treatment with ethyl chloroformate, followed by hydrolysis to the N-unsubstituted piperidine (IX). Finally, acetylation of (IX) in the presence of pyridine provided the target amide.
| 【1】 Billah, M.M.; Green, M.J.; Wong, J.K.; Piwinski, J.J.; West, R.E. Jr.; Ganguly, A.K.; Kreutner, W.; Dual antagonists of platelet activating factor and histamine. Identification of structural requirements for dual activity of N-acyl-4-(5,6-dihydro-11H-benzo[5,6]cyclohepta-[1,2-b]pyridin-11-ylidene)piperidines. J Med Chem 1991, 34, 1, 457. |
| 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) | 16501 | N-(tert-butyl)-3-methyl-2-pyridinecarboxamide | C11H16N2O | 详情 | 详情 | |
| (II) | 20642 | 1-chloro-3-(chloromethyl)benzene; 3-Chlorobenzyl chloride | 620-20-2 | C7H6Cl2 | 详情 | 详情 |
| (III) | 20643 | N-(tert-butyl)-3-(3-chlorophenethyl)-2-pyridinecarboxamide | C18H21ClN2O | 详情 | 详情 | |
| (IV) | 20644 | 3-(3-chlorophenethyl)-2-pyridinecarbonitrile | C14H11ClN2 | 详情 | 详情 | |
| (V) | 20645 | chloro(1-methyl-4-piperidinyl)magnesium | C6H12ClMgN | 详情 | 详情 | |
| (VI) | 20646 | [3-(3-chlorophenethyl)-2-pyridinyl](1-methyl-4-piperidinyl)methanone | C20H23ClN2O | 详情 | 详情 | |
| (VII) | 20647 | 8-chloro-11-(1-methyl-4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | 38092-89-6 | C20H21ClN2 | 详情 | 详情 |
| (VIII) | 17877 | ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | 79794-75-5 | C22H23ClN2O2 | 详情 | 详情 |
| (IX) | 17840 | 8-chloro-11-(4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | C19H19ClN2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)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6
该中间体在本合成路线中的序号：(A)Compound can be prepared in two ditferent ways both starting from 9,10-dibromo-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-4-one (II): 1) The reaction of compound (II) with refluxing methanol affords 9-bromo-10-methoxy-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-4-one (III), which is dehydrobrominated with KOH in refluxing methanol giving 10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-4-one (IV). The condensation of compound (IV) with the magnesium derivative of 4-chloro-1-methylpiperidine (A) in THF yields 10-methoxy-4-(1-methyl-4-piperidyl)-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-4-ol (V), which is finally dehydrated and demethylated with 3N HCl at 95-100 C. 2) The dehydrobromination of compound (II) with KOH in refluxing methanol affords 10-bromo-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-4-one (VI), which is then condensed with the magnesium derivative of 4-chloro-1-methylpiperidine in THF giving 10-bromo-4-(1-methyl-4-piperidyl)-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-4-ol (VII). This compound is dehydrated with 14% ethanolic HBr at 100 C giving 10-bromo-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophene (VIII) (2,3), which is finally hydrolyzed with 50% H2SO4 at 100 C. Compound (VIII) can be also be treated with piperidine and potassium terbutylate in dioxane at 130 C to give 10-piperidino-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophene (IX), which is finally hydrolyzed with refluxing 2N HCl. The starting material (II) is prepared by bromination of 9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-4-one (I) with N-bromosuccinimide (B) and benzoyl peroxide in carbon tetrachloride.
| 【1】 Bourquin, J.P.; et al.; Substittued 4H-benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-ones. CA 947767; DE 2144490; FR 2107917; GB 1355537; US 3682930 . |
| 【2】 Bourquin, J.P.; et al.; Substittued 4H-benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-ones. DE 2111071; FR 2107917; GB 1355537; US 3682930 . |
| 【3】 Castañer, J.; Hillier, K.; Ketotifen. Drugs Fut 1977, 2, 2, 108. |
| 【4】 Bourquin, J.P.; et al. (Novartis AG); Process for the production of benzocycloheptathiophenone derivative. DE 2302970; FR 2169091; FR 2401153; GB 1422443; GB 1422444; JP 48081869; JP 55129282 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
| (A) | 20645 | chloro(1-methyl-4-piperidinyl)magnesium | C6H12ClMgN | 详情 | 详情 | |
| (I) | 40065 | 9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one | 1622-55-5 | C13H10OS | 详情 | 详情 |
| (II) | 40066 | 9,10-dibromo-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one | C13H8Br2OS | 详情 | 详情 | |
| (III) | 40067 | 9-bromo-10-methoxy-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one | C14H11BrO2S | 详情 | 详情 | |
| (IV) | 40068 | 10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one | C14H10O2S | 详情 | 详情 | |
| (V) | 40069 | 10-methoxy-4-(1-methyl-4-piperidinyl)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ol | C20H23NO2S | 详情 | 详情 | |
| (VI) | 40070 | 10-bromo-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one | C13H7BrOS | 详情 | 详情 | |
| (VII) | 40071 | 10-bromo-4-(1-methyl-4-piperidinyl)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ol | C19H20BrNOS | 详情 | 详情 | |
| (VIII) | 40072 | 4-(10-bromo-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-1-methylpiperidine | C19H18BrNS | 详情 | 详情 | |
| (IX) | 40073 | 1-methyl-4-[10-(1-piperidinyl)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene]piperidine | C24H28N2S | 详情 | 详情 |