|
【结 构 式】 
|
【分子编号】20225 【品名】iodo(methyl)magnesium 【CA登记号】917-64-6 |
【 分 子 式 】CH3IMg 【 分 子 量 】166.24429 【元素组成】C 7.22% H 1.82% I 76.34% Mg 14.62% |
合成路线1
该中间体在本合成路线中的序号：(A)The Grignard reaction of cis-3-phenyl-4-p-acetoxyphenyl-7-methoxy-3,4-dihydrocoumarin (I) with methylmagnesium iodide (A) in THF gives erythro-2-methyl-3-phenyl4-(p-hydroxyphenyl)-4-(2-hydroxy-4-methoxyphenyl)-4-(2-hydroxy-4-methoxyphenyl)butan-2-ol (II), which is cyclized with PPA at 75-80 C yielding cis-2,2-dimethyl-3phenyl-4-p-hydroxyphenyl-7-methoxychroman (III). This compound can also be obtained by hydrogenation of 2,2-dimethyl-4-p-hydroxyphenyl-3-phenyl-7-methoxychromene (IV) with H2 over Pd/C in THF. The condensation of (III) with N-(2-chloroethyl)pyrrolidine (B) by means of K2CO3 in refluxing acetone affords 3,4-cis-2,2-dimethyl-3-phenyl-4-[p-(beta-pyrrolidinoethoxy)phenyl]-7-methoxychromane (V), which is finally isomerized with n-butyllithium in DMSO.
| 【1】 Bolger, J.W.; Process for preparation of substituted 3,4-(diphenyl)chromans. US 3822287 . |
| 【2】 Bolger, J.W.; Procede de preparation de 3,4-(diphenyl)-chromanes substitues. DE 2329201; FR 2187777 . |
| 【3】 Suprabhat, R.; et al.; Antifertility agents. 12. Structure-activity relationship of 3,4-diphenylchromenes and -chromans. J Med Chem 1976, 19, 2, 276-279. |
| 【4】 Castaner, J.; Hillier, K.; Centchroman. Drugs Fut 1977, 2, 7, 441. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 20225 | iodo(methyl)magnesium | 917-64-6 | CH3IMg | 详情 | 详情 |
| (B) | 33922 | 1-(2-Chloroethyl)pyrrolidine; N-(2-Chloroethyl)pyrrolidine | C6H12ClN | 详情 | 详情 | |
| (I) | 33918 | 4-[(3S,4R)-7-methoxy-2-oxo-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenyl acetate | C24H20O5 | 详情 | 详情 | |
| (II) | 33919 | 2-[(1R,2S)-3-hydroxy-1-(4-hydroxyphenyl)-3-methyl-2-phenylbutyl]-5-methoxyphenol | C24H26O4 | 详情 | 详情 | |
| (III) | 33920 | 4-[(3S,4R)-7-methoxy-2,2-dimethyl-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenol | C24H24O3 | 详情 | 详情 | |
| (IV) | 33921 | 4-(7-methoxy-2,2-dimethyl-3-phenyl-2H-chromen-4-yl)phenol | C24H22O3 | 详情 | 详情 | |
| (V) | 33923 | (3S,4R)-2,2-dimethyl-3-phenyl-4-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-3,4-dihydro-2H-chromen-7-yl methyl ether; 1-(2-[4-[(3S,4R)-7-methoxy-2,2-dimethyl-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenoxy]ethyl)pyrrolidine | C30H35NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(A)The Grignard reaction of trans-3-phenyl-4-p-acetoxyphenyl-7-methoxy-3,4-dihydrocoumarin (VI) with methylmagnesium iodide (A) in THF gives a mixture of cis-2,2-dimethyl-3-phenyl-4-p-hydroxy-phenyl-7-methoxychromane (VII) and threo-2-methyl-3-phenyl-4-(p-hydroxyphenyl)-4-(2-hydroxy-4-methoxyphenyl)butan-2-ol (VIII), which can be cyclized to (VII) with PPA at 75-80 C. Finally, (VII) is condensed with N-(2-chloroethyl)-pyrrolidine (B) by means of K2CO3 in refluxing acetone.
| 【1】 Suprabhat, R.; et al.; Antifertility agents. 12. Structure-activity relationship of 3,4-diphenylchromenes and -chromans. J Med Chem 1976, 19, 2, 276-279. |
| 【2】 Castaner, J.; Hillier, K.; Centchroman. Drugs Fut 1977, 2, 7, 441. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 20225 | iodo(methyl)magnesium | 917-64-6 | CH3IMg | 详情 | 详情 |
| (B) | 33922 | 1-(2-Chloroethyl)pyrrolidine; N-(2-Chloroethyl)pyrrolidine | C6H12ClN | 详情 | 详情 | |
| (VI) | 33924 | 4-[(3R,4R)-7-methoxy-2-oxo-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenyl acetate | C24H20O5 | 详情 | 详情 | |
| (VII) | 33926 | 4-[(3R,4R)-7-methoxy-2,2-dimethyl-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenol | C24H24O3 | 详情 | 详情 | |
| (VIII) | 33925 | 2-[(1R,2R)-3-hydroxy-1-(4-hydroxyphenyl)-3-methyl-2-phenylbutyl]-5-methoxyphenol | C24H26O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)The condensation of diethyl 2-acetylglutarate (I) with 5-(1,1-dimethylheptyl)resorcinol (II) by means of POCl3 gives ethyl 7-(1,1-dimethylheptyl)-5-hydroxy-4-methyl-2-oxo-2H-1-benzopyran-3-propionate (III), which is cyclized by means of NaH in DMSO yielding 3-(1,1-dimethylheptyl)-7,10-dihydro-1-hydroxy-6H-dibenzo[b,d]pyran-6,9-(8H)-dione (IV). The ketalization of (IV) with ethylene glycol (A) and p-toluenesulfonic acid affords the ketal (V), which by a Grignard reaction with methylmagnesium iodide in refluxing ether is converted into dl-3-(1,1-dimethylheptyl)-6,6a,7,8-tetrahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one (VI). Finally, this compound is reduced with Li in liquid ammonia.
| 【1】 Archer, R.A.; Hexahydro-dibenzo[b,d]pyran-9-ones as analgesic drugs. US 3944673 . |
| 【2】 Archer, R.A.; Dihydroxyhexahydrodibenzo[b,d]pyrans. DE 2451934; ES 431674; FR 2249664; GB 1487637; JP 50071678; US 3968125 . |
| 【3】 Archer, R.A.; Hexahydro-dibenzo[b,d]pyran-9-ones as an anti-anxiety drug. DE 2451932; ES 431675; FR 2249663; GB 1487636; JP 50082073; NL 7414437; US 3928598 . |
| 【4】 Archer, R.A.; Hexahydro-dibenzo[b,d]pyran-9-ones as psychotropic, particularly anti-depressant drugs. US 3953603 . |
| 【5】 Castaner, J.; Weetman, D.F.; Nabilone. Drugs Fut 1978, 3, 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 |
|---|---|---|---|---|---|---|
| (A) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (I) | 15865 | Diethyl 2-acetylglutarate; diethyl 2-acetylpentanedioate | 1501-06-0 | C11H18O5 | 详情 | 详情 |
| (II) | 20233 | 5-(1,1-dimethylheptyl)-1,3-benzenediol | C15H24O2 | 详情 | 详情 | |
| (III) | 33507 | ethyl 3-[7-(1,1-dimethylheptyl)-5-hydroxy-4-methyl-2-oxo-2H-chromen-3-yl]propanoate | C24H34O5 | 详情 | 详情 | |
| (IV) | 33508 | 3-(1,1-dimethylheptyl)-1-hydroxy-7,10-dihydro-6H-benzo[c]chromene-6,9(8H)-dione | C22H28O4 | 详情 | 详情 | |
| (V) | 33509 | 3-(1,1-Dimethylheptyl)-9,9-(ethylenedioxy)-1-hydroxy-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one | C24H32O5 | 详情 | 详情 | |
| (VI) | 33510 | 3-(1,1-dimethylheptyl)-1-hydroxy-6,6-dimethyl-6,6a,7,8-tetrahydro-9H-benzo[c]chromen-9-one | C24H34O3 | 详情 | 详情 | |
| (VII) | 20225 | iodo(methyl)magnesium | 917-64-6 | CH3IMg | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The Grignard condensation of methyl imidazole-4-carboxyate (I) with 2,3-dimethylphenylmagnesium bromide (II) in THF gives 4-(2,3-dimethylbenzoyl) imidazole (III), which (without isolation) is submitted to a new Grignard condensation with methylmagnesium iodide (IV) in the same solvent to yield 1-(4-imidazolyl)-1-(2,3-dimethylphenyl)ethanol (V). The dehydration of (V) with potassium hydrogen sulfate at 136 C affords 1-(4-imidazolyl)-1-(2,3-dimethyl-phenyl)ethylene (VI), which is finally hydrogenated with H2 over Pd/C in 2N HCl.
| 【1】 Hillier, K.; Acta Univ Oul 1981, 8, 4, A125. |
| 【2】 Karjalainen, A.J.; Kurkela, K.O.A.; Pohjala, E.K. (Orion Pharma); Antihypertensive subtituted imidazole derivates. GB 2101114; US 4639464 . |
| 【3】 Castaner, R.M.; Serradell, M.N.; Castaner, J.; Medetomidine. Drugs Fut 1987, 12, 11, 1021. |
| 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) | 27998 | methyl 1H-imidazole-4-carboxylate | 17325-26-7 | C5H6N2O2 | 详情 | 详情 |
| (II) | 27999 | bromo(2,3-dimethylphenyl)magnesium | C8H9BrMg | 详情 | 详情 | |
| (III) | 11040 | (2,3-Dimethylphenyl)(1H-imidazol-4-yl)methanone | C12H12N2O | 详情 | 详情 | |
| (IV) | 20225 | iodo(methyl)magnesium | 917-64-6 | CH3IMg | 详情 | 详情 |
| (V) | 28000 | 1-(2,3-dimethylphenyl)-1-(1H-imidazol-4-yl)-1-ethanol | C13H16N2O | 详情 | 详情 | |
| (VI) | 28001 | 4-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazole | C13H14N2 | 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 Grignard reaction of ethyl heptanoate (I) with deuterated methylmagnesium iodide (II) in ether gives deuterated 2-methyl-2-octanol (III), which is treated with deuterium oxide to yield heptadeuterated 2-methyl-2-octanol (IV). The condensation of (IV) with monodeuterated 2,6-dimethoxyphenol (V) (obtained by treatment of 2,6-dimethoxyphenol (VI) with deuterium oxide) by means of deuterated trifluoromethylsulfonic acid affords the alkylated phenol (VII), which is phosphorylated with diethyl phosphite and triethylamine giving the phosphate (VIII). The reduction of (VIII) with Li/NH3 yields the deuterated dimethoxybenzene (IX), which is demethylated with boron tribromide in dichloromethane to afford the deuterated resorcinol (X). The condensation of (X) with alpha-pinene-3,10-diol 10-O-pivalic ester (XI) by means of boron trifluoride etherate in methylene chloride gives the deuterated target compound as its monopivalic ester (XII), which is finally treated with LiAlH4 in THF to eliminate the ester group.
| 【1】 Pop, E.; et al.; Synthesis of deuterated dexanabinol, a nonpsychotropic cannabinoid with neuroprotective properties. J Label Compd Radiopharm 1998, 41, 10, 885. |
| 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) | 20224 | ethyl heptanoate | 106-30-9 | C9H18O2 | 详情 | 详情 |
| (II) | 20225 | iodo(methyl)magnesium | 917-64-6 | CH3IMg | 详情 | 详情 |
| (II) | 63794 | iodo(methyl)magnesium | CH3IMg | 详情 | 详情 | |
| (III) | 20226 | 2-methyl-2-octanol | C9H20O | 详情 | 详情 | |
| (III) | 63795 | 2-methyl-2-octanol | C9H20O | 详情 | 详情 | |
| (IV) | 20226 | 2-methyl-2-octanol | C9H20O | 详情 | 详情 | |
| (IV) | 63796 | 2-methyl-2-octanol | C9H20O | 详情 | 详情 | |
| (V) | 20228 | 2,6-dimethoxyphenol | 91-10-1 | C8H10O3 | 详情 | 详情 |
| (V) | 63797 | 2,6-dimethoxyphenol | 91-10-1 | C8H10O3 | 详情 | 详情 |
| (VI) | 20228 | 2,6-dimethoxyphenol | 91-10-1 | C8H10O3 | 详情 | 详情 |
| (VII) | 20230 | 4-(1,1-dimethylheptyl)-2,6-dimethoxyphenol | C17H28O3 | 详情 | 详情 | |
| (VII) | 63798 | 4-(1,1-dimethylheptyl)-2,6-dimethoxyphenol | C17H28O3 | 详情 | 详情 | |
| (VIII) | 20231 | 4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl diethyl phosphate | C21H37O6P | 详情 | 详情 | |
| (VIII) | 63799 | 4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl diethyl phosphate | C21H37O6P | 详情 | 详情 | |
| (IX) | 20232 | 1-(1,1-dimethylheptyl)-3,5-dimethoxybenzene; 3-(1,1-dimethylheptyl)-5-methoxyphenyl methyl ether | C17H28O2 | 详情 | 详情 | |
| (IX) | 63800 | 3-(1,1-dimethylheptyl)-5-methoxyphenyl methyl ether; 1-(1,1-dimethylheptyl)-3,5-dimethoxybenzene | C17H28O2 | 详情 | 详情 | |
| (X) | 20233 | 5-(1,1-dimethylheptyl)-1,3-benzenediol | C15H24O2 | 详情 | 详情 | |
| (X) | 63601 | methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-[(13S,15S)-17-ethyl-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-4(12),5,7,9,17-pentaen-13-yl]-5-hydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate | C46H56N4O8 | 详情 | 详情 | |
| (XI) | 20234 | (4-hydroxy-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl pivalate | C15H24O3 | 详情 | 详情 | |
| (XII) | 20235 | [(6aS,10aS)-3-(1,1-dimethylheptyl)-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-9-yl]methyl pivalate | C30H46O4 | 详情 | 详情 | |
| (XII) | 63802 | [(6aS,10aS)-3-(1,1-dimethylheptyl)-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-9-yl]methyl pivalate | C30H46O4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(A)The reaction of N-carbobenzoxy-4-piperidylacetic acid (I) with refluxing SOCl2 yields the corresponding acyl chloride (II), which by condensation with indole (III) by means of methylmagnesium iodide (A) in ether gives rise to 3-indolyl-(4-piperidylmethyl)ketone (IV). Finally, this compound is reduced with LiAlH4 in THF.
| 【1】 Blancafort, P.; Owen, R.T.; Castañer, J.; Serradell, M.N.; Indalpine. Drugs Fut 1979, 4, 12, 873. |
| 【2】 Champseix, A.; et al.; US 4064255 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 20225 | iodo(methyl)magnesium | 917-64-6 | CH3IMg | 详情 | 详情 |
| (I) | 39633 | 2-[1-(2-phenylacetyl)-4-piperidinyl]acetic acid | C15H19NO3 | 详情 | 详情 | |
| (II) | 39634 | 2-[1-(2-phenylacetyl)-4-piperidinyl]acetyl chloride | C15H18ClNO2 | 详情 | 详情 | |
| (III) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (IV) | 39635 | 1-(1H-indol-3-yl)-2-(4-piperidinyl)-1-ethanone | C15H18N2O | 详情 | 详情 |