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【结 构 式】 
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【分子编号】10356 【品名】1-Chloro-4-(chloromethyl)benzene; 4-Chlorobenzyl chloride 【CA登记号】104-83-6 |
【 分 子 式 】C7H6Cl2 【 分 子 量 】161.03004 【元素组成】C 52.21% H 3.76% Cl 44.03% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of 1,2-O-isopropylidene-3-O-propyl-alpha-D-glucofuranose (I) with 4-chlorobenzyl chloride (II) by means of KOH in hot dioxane gives 1',2-O-iso-propylidene-3-O-propyl-5,6-di-O-(4-chlorobenzyl)-alpha-D-glucofuranose (III), which is then hydrolyzed with ethanolic HCl.
| 【1】 Iselin, B.; Rossi, A.; Kessler, W.; Walter, A. (Novartis Corp.); Anti-inflammatory glucose derivatives. BE 0720622; DE 1793338; FR 1588563; GB 1246117; US 3655884 . |
| 【2】 Castaner, J.; Koch, H.; Serradell, M.N.; Clobenoside. Drugs Fut 1985, 10, 12, 977. |
| 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) | 29836 | (1S)-1-[(3aS,5S,6R,6aS)-2,2-dimethyl-6-propoxytetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-1,2-ethanediol | C12H22O6 | 详情 | 详情 | |
| (II) | 10356 | 1-Chloro-4-(chloromethyl)benzene; 4-Chlorobenzyl chloride | 104-83-6 | C7H6Cl2 | 详情 | 详情 |
| (III) | 29837 | (3aR,5R,6R,6aS)-5-[(1S)-1,2-bis[(4-chlorobenzyl)oxy]ethyl]-2,2-dimethyl-6-propoxytetrahydrofuro[2,3-d][1,3]dioxole; (3aR,5R,6R,6aS)-5-[(1S)-1,2-bis[(4-chlorobenzyl)oxy]ethyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl propyl ether | C26H32Cl2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The total synthesis of picumast dihydrochloride has been described: The alkylation of piperazine (I) with 4-chlorobenzyl chloride (II) in ethanol gives 1-(4-chlorobenzyl)piperazine (III), which is alkylated again with 1-bromo-3-chloropropane (IV) by means of triethylamine in a suitable solvent to yield 1-(4-chlorobenzyl)-4-(3-chloropropyl)piperazine (V). Finally, this compound is condensed with 7-hydroxy-3,4-dimethylcoumarin (VI) by means of K2CO3 in refluxing butanone. Compound (VI) is obtained by cyclization of resorcinol (VII) with ethyl 2-methylacetoacetate (VIII) by means of refluxing acetic acid containing HCl.
| 【1】 Witte, E.-C.; Chemical synthesis of picumast dihydrochloride. Arzneim-Forsch Drug Res 1989, 39, 10a, 1309. |
| 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) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (II) | 10356 | 1-Chloro-4-(chloromethyl)benzene; 4-Chlorobenzyl chloride | 104-83-6 | C7H6Cl2 | 详情 | 详情 |
| (III) | 10357 | 1-(4-Chlorobenzyl)piperazine; N-(4-Chlorobenzyl)piperazine | C11H15ClN2 | 详情 | 详情 | |
| (IV) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (V) | 10359 | 1-(4-Chlorobenzyl)-4-(3-chloropropyl)piperazine | C14H20Cl2N2 | 详情 | 详情 | |
| (VI) | 10360 | 3,4-Dimethylumbelliferone; 7-Hydroxy-3,4-dimethyl-2H-chromen-2-one | 2107-78-0 | C11H10O3 | 详情 | 详情 |
| (VII) | 10361 | 1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol | 108-46-3 | C6H6O2 | 详情 | 详情 |
| (VIII) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The condensation of 1H-indole (I) with 4-chlorobenzyl chloride (II) by means of NaH in DMSO gives 1-(4-chlorobenzyl) indole (III), which is treated with oxalyl chloride in a hot aprotic solvent yielding the intermediate acid chloride (IV). Finally, this compound is treated with pyridin-4-amine (V) in the same solvent.
| 【1】 Lebaut, G.; Menciu, C.; Kutscher, B.; Emig, P.; Szelenyi, S.; Brune, K. (Asta Medica AG); N-Substd. indol-3-glyoxylamide with antiasthmatic, antiallergic and immunosuppressive/immunomodulating effect. DE 19636150; EP 0931063; JP 2000505098; US 6008231; WO 9809946 . |
| 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) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (II) | 10356 | 1-Chloro-4-(chloromethyl)benzene; 4-Chlorobenzyl chloride | 104-83-6 | C7H6Cl2 | 详情 | 详情 |
| (III) | 30441 | 1-(4-chlorobenzyl)-1H-indole | C15H12ClN | 详情 | 详情 | |
| (IV) | 30442 | 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxoacetyl chloride | C17H11Cl2NO2 | 详情 | 详情 | |
| (V) | 25661 | 4-pyridinamine; 4-aminopyridine | 5044-74-5 | C5H6N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)Sulfenylation of the Grignard reagent derived from ethyl 5-chloroindole-2-carboxylate (I) with S-phenyl benzenethiosulfonate affords the 3-phenylsulfanyl indole (II). This is then alkylated with 4-chlorobenzyl chloride (III) in the presence of potassium hexamethyldisilazide to yield the N-benzyl indole derivative (IV). Finally, hydrolysis of ethyl ester (IV) by means of potassium trimethylsilanolate under anhydrous conditions produces the target carboxylic acid (1,2).
| 【1】 Yamamoto, H.; et al. (Sumitomo Chemical Co., Ltd.); 3-Hetero-substd.-N-benzyl-indoles. US 3907812 . |
| 【2】 Gillard, J.W.; Morton, H.E.; Fortin, R.; Guindon, Y. (Merck Frosst Canada Inc.); 3-Hetero-substd.-N-benzyl-indoles and prevention of leucotriene synthesis therewith. US 5081138 . |
| 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) | 64201 | ethyl 5-chloro-1H-indole-2-carboxylate | C11H10ClNO2 | 详情 | 详情 | |
| (II) | 64202 | ethyl 5-chloro-3-(phenylsulfanyl)-1H-indole-2-carboxylate | C17H14ClNO2S | 详情 | 详情 | |
| (III) | 10356 | 1-Chloro-4-(chloromethyl)benzene; 4-Chlorobenzyl chloride | 104-83-6 | C7H6Cl2 | 详情 | 详情 |
| (IV) | 64203 | ethyl 5-chloro-1-(4-chlorobenzyl)-3-(phenylsulfanyl)-1H-indole-2-carboxylate | C24H19Cl2NO2S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIX)Intermediates (II) and (IV) are prepared as follows. Alkylation of the sodium enolate of methyl 3-bromophenylacetate (VII) with 4-chlorobenzyl bromide (VIII) in cold THF followed by methyl ester hydrolysis with LiOH in aqueous acetonitrile affords 2-(m-bromophenyl)-3-(p-chlorophenyl)propionic acid (IX), which is converted to the corresponding Weinreb amide (X) by chlorination with oxalyl chloride and subsequent treatment with N,O-dimethylhydroxylamine. Addition of methylmagnesium bromide to the methoxyamide (X) gives the 3,4-diaryl-2-butanone (XI), which is then reduced using NaBH4 or LiBH(s-Bu)3 (L-selectride) to provide alcohol (XIIa) as the major diastereoisomer. After conversion of alcohol (XIIa) to the corresponding mesylate, displacement with NaN3 in hot DMF leads to azide (XIII), which is reduced by catalytic hydrogenation in the presence of PtO2 and Boc2O to afford the Boc-protected amine (XIV). Then, palladium-catalyzed substitution of the aryl bromide (XIV) with zinc cyanide yields the nitrile (XV), which is deprotected to (IIa) using HCl in EtOAc (2, 3). Similarly, coupling between 3-bromobenzonitrile (XVI) and isopropenyl acetate (XVII) in the presence of Pd2(dba)3 and 2-(dicyclohexylphosphino)-2’-(dimethylamino)biphenyl (DCPDMAB) gives 1-(m-cyanophenyl)acetone (XVIII), which is alkylated with 3-chlorobenzyl chloride (XIX) in the presence of cesium hydroxide and tetrabutylammonium iodide to yield the diarylbutanone (XX). Reduction of ketone (XX) with lithium tri(sec-butyl)borohydride produces alcohol (XXI), which is converted to the Boc-protected amine (XV) by mesylation followed by displacement with NaN3, and then reduction of the resulting azide (XXII) by catalytic hydrogenation in the presence of PtO2 and Boc2O (1). The ketonitrile (XX) is alternatively produced by palladium-catalyzed cyanuration of aryl bromide (XI) with either zinc cyanide or potassium ferrocyanide. The intermediate enol tosylate (IV) can be obtained by treatment of (XX) with sodium tert-butoxide and p-toluenesulfonic anhydride (5, 6). Preparation of the enantiomerically pure amine (IIb) can be accomplished by resolution at the stage of the diarylpropionic acid (IX) or, in a more efficient method, by dynamic kinetic resolution of (XI) via stereoselective hydrogenation to (XIIb) in the presence of the chiral Ru catalyst [(S)-xyl-BINAP]-[(S)-DAIPEN]RuCl2 and excess potassium tert-butoxide (4). Scheme 2.
| 【1】 Hagmann, W.K., Lin, L.S., Shah, S.K. et al. (Merck & Co., Inc.). Substituted amides. CA 2478183, EP 1496838, JP 2005519958, JP 2006257090, US 2004058820, US 6972295, WO 03077847. |
| 【2】 Hagmann, W.K., Lin, L.S., Shah, S.K. et al. (Merck & Co., Inc.). Substituted amides active at the cannabinoid-1 receptor. WO 2004048317. |
| 【3】 Lin, L.S., Lanza, T.J. Jr., Jewell, J.P. et al. Discovery of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. J Med Chem 2006, 49(26): 7584-7. |
| 【4】 Chen, C., Frey, L.F., Shultz, S. et al. Catalytic, enantioselective synthesis of taranabant, a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. Org Proc Res Devel 2007, 11(3): 616-23. |
| 【5】 Campos, K.R., Klapars, A., McWilliams, J.C. et al. (Merck & Co., Inc.). Formation of tetra-substituted enamides and stereoselective reduction thereof. WO 2006017045. |
| 【6】 Weissman, S.A. (Merck & Co., Inc.). Cyanation of aromatic halides. US 2006106223. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIIa) | 65595 | C16H16BrClO | 详情 | 详情 | ||
| (XIIb) | 65596 | C16H16BrClO | 详情 | 详情 | ||
| (Iia) | 65586 | 3-[(1RS,2RS)-2-Amino-1-[(4-Chlorophenyl)Methyl]Propyl]Benzonitrile | C17H17ClN2 | 详情 | 详情 | |
| (Iib) | 65587 | 3-[(1S,2S)-2-Amino-1-[(4-Chlorophenyl)Methyl]Propyl]Benzonitrile | 732982-66-0 | C17H17ClN2 | 详情 | 详情 |
| (IV) | 65582 | (R )-(-)-4-Penten-2-ol | 64584-92-5 | C5H10O | 详情 | 详情 |
| (VII) | 50901 | methyl 2-(3-bromophenyl)acetate | 150529-73-0 | C9H9BrO2 | 详情 | 详情 |
| (VIII) | 16481 | 1-(bromomethyl)-4-chlorobenzene | 622-95-7 | C7H6BrCl | 详情 | 详情 |
| (IX) | 65592 | C15H12BrClO2 | 详情 | 详情 | ||
| (X) | 65593 | C17H17BrClNO2 | 详情 | 详情 | ||
| (XI) | 65594 | 3-(3-Bromophenyl)-4-(4-Chlorophenyl)Butan-2-One | 848310-98-5 | C16H14BrClO | 详情 | 详情 |
| (XIII) | 65597 | C16H15BrClN3 | 详情 | 详情 | ||
| (XIV) | 65598 | C21H25BrClNO2 | 详情 | 详情 | ||
| (XV) | 65599 | C22H25ClN2O2 | 详情 | 详情 | ||
| (XVI) | 26573 | 3-bromobenzonitrile | 6952-59-6 | C7H4BrN | 详情 | 详情 |
| (XVII) | 21178 | isopropenyl acetate | 108-22-5 | C5H8O2 | 详情 | 详情 |
| (XVIII) | 65600 | (3-Cyanophenyl)Acetone | C10H9NO | 详情 | 详情 | |
| (XIX) | 10356 | 1-Chloro-4-(chloromethyl)benzene; 4-Chlorobenzyl chloride | 104-83-6 | C7H6Cl2 | 详情 | 详情 |
| (XX) | 65601 | C17H14ClNO | 详情 | 详情 | ||
| (XXI) | 65602 | C17H16ClNO | 详情 | 详情 | ||
| (XXII) | 65603 | C17H15ClN4 | 详情 | 详情 |