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【结 构 式】 
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【分子编号】31883 【品名】2-bromoacetonitrile 【CA登记号】590-17-0 |
【 分 子 式 】C2H2BrN 【 分 子 量 】119.94862 【元素组成】C 20.03% H 1.68% Br 66.62% N 11.68% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of ethyl 2-sulfanylacetate (I) with 2-bromoacetonitrile (II) by means of NaOEt in ethanol gives ethyl 2-(cyanomethylsulfanyl)acetate (III), which is cyclized with diethyl oxalate (IV) by means of NaOEt in ethanol yielding 5-cyano-3,4-dihydroxythiophene-2-carboxylic acid ethyl ester (V). The protection of the hydroxyl groups of (V) with 2-methoxyethoxymethyl chloride (Mem-Cl) and DIEA in dichloromethane affords the protected thiophene (VI), which is reduced with (t-BuO)2AlH in THF providing the carbinol (VII). The oxidation of (VII) with MnO2 in dichloromethane yields the carbaldehyde (VIII), which is condensed with malonodinitrile (IX) by means of piperidine in dioxane giving the alkylidenemalonodinitrile (X). The epoxidation of (X) with tert-butyl hydroperoxide and TEA in dioxane yields the epoxide (XI), which is treated with HCl in THF to afford 2-chloro-2-[5-cyano-3,4-bis(2-methoxyethoxymethoxy) thiophen-2-yl]acetic acid (XII). The esterification of (XII) with diphenyldiazomethane affords the corresponding diphenylmethyl ester (XIII), which is condensed with N-hydroxyphthalimide (XIV) and NaHCO3 in dichloromethane providing the adduct (XV). The cleavage of the phthalimido group of (XV) with hydrazine in methanol gives 2-(aminooxy)-2-[5-cyano-3,4-bis(2-methoxyethoxymethoxy)thiophen-2-yl]acetic acid diphenylmethyl ester (XVI), which is condensed with 2-oxo-2-[2-(tritylamino)thiazol-4-yl]acetic acid (XVII) yielding the corresponding alcoxyimino derivative (XVIII).
| 【1】 Aszodi, J.; Dini, C.; Fauveau, P. (Aventis Pharma SA); Cephalosporins having in position 7 as substd. axymino radical, intermediates, processes for their preparation and their use as medicaments. CA 2111164; EP 0628562; JP 1994345776 . |
| 【2】 Dini, C.; Aszodi, J.; Synthesis of a dihydroxythiophene analogue of catechosporines. Bioorg Med Chem Lett 2000, 10, 4, 349. |
| 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) | 23995 | ethyl 2-sulfanylacetate | 2713-34-0 | C4H8O2S | 详情 | 详情 |
| (II) | 31883 | 2-bromoacetonitrile | 590-17-0 | C2H2BrN | 详情 | 详情 |
| (III) | 35506 | ethyl 2-[(cyanomethyl)sulfanyl]acetate | C6H9NO2S | 详情 | 详情 | |
| (IV) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (V) | 35507 | ethyl 5-cyano-3,4-dihydroxy-2-thiophenecarboxylate | C8H7NO4S | 详情 | 详情 | |
| (VI) | 35508 | ethyl 5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thiophenecarboxylate | C16H23NO8S | 详情 | 详情 | |
| (VII) | 35509 | 5-(hydroxymethyl)-3,4-bis[(2-methoxyethoxy)methoxy]-2-thiophenecarbonitrile | C14H21NO7S | 详情 | 详情 | |
| (VIII) | 35510 | 5-formyl-3,4-bis[(2-methoxyethoxy)methoxy]-2-thiophenecarbonitrile | C14H19NO7S | 详情 | 详情 | |
| (X) | 35511 | 2-([5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]methylene)malononitrile | C17H19N3O6S | 详情 | 详情 | |
| (XI) | 35512 | 3-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]-2,2-oxiranedicarbonitrile | C17H19N3O7S | 详情 | 详情 | |
| (XII) | 35513 | 2-chloro-2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]acetic acid | C15H20ClNO8S | 详情 | 详情 | |
| (XIII) | 35514 | benzhydryl 2-chloro-2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]acetate | C28H30ClNO8S | 详情 | 详情 | |
| (XIV) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (XV) | 35515 | benzhydryl 2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]acetate | C36H34N2O11S | 详情 | 详情 | |
| (XVI) | 35516 | benzhydryl 2-(aminooxy)-2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]acetate | C28H32N2O9S | 详情 | 详情 | |
| (XVII) | 23008 | 2-oxo-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C24H18N2O3S | 详情 | 详情 | |
| (XVIII) | 35517 | 2-[(2-(benzhydryloxy)-1-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]-2-oxoethoxy)imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C52H48N4O11S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The reaction of 4-cyano-3-(trifluoromethyl)aniline (I) with phosgene afforded isocyanate (II). Subsequent condensation with 2-amino-2-methylpropionitrile (III) in the presence of Et3N in dichloroethane yielded the iminoimidazolidinone (IV), which was hydrolyzed to hydantoin (V) with refluxing 0.5 M HCl. Finally, alkylation with bromoacetonitrile (VI) in the presence of NaH in DMF provided the cyanomethyl compound.
| 【1】 Battmann, T.; et al.; Pharmacological profile of RU 58642, a potent systemic antiandrogen for the treatment of androgen-dependent disorders. J Steroid Biochem Mol Biol 1998, 64, 1-2, 103. |
| 【2】 Gaillard-Kelly, M.; Goubet, F.; Philibert, D.; Teutsch, J.-G. (Aventis Pharma SA); Phenylimidazolidines, their process for fabrication, their application as medicaments and the pharmaceutical compsns. containing them. EP 0494819; FR 2671348; JP 1992308579; US 5411981 . |
| 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) | 18743 | 4-amino-2-(trifluoromethyl)benzonitrile；5-Amino-2-cyanobenzotrifluoride | 654-70-6 | C8H5F3N2 | 详情 | 详情 |
| (II) | 18744 | 4-isocyanato-2-(trifluoromethyl)benzonitrile | C9H3F3N2O | 详情 | 详情 | |
| (III) | 18745 | 2-amino-2-methylpropanenitrile | 19355-69-2 | C4H8N2 | 详情 | 详情 |
| (IV) | 18746 | 4-(5-imino-4,4-dimethyl-2-oxo-1-imidazolidinyl)-2-(trifluoromethyl)benzonitrile | C13H11F3N4O | 详情 | 详情 | |
| (V) | 18747 | 4-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-(trifluoromethyl)benzonitrile | C13H10F3N3O2 | 详情 | 详情 | |
| (VI) | 31883 | 2-bromoacetonitrile | 590-17-0 | C2H2BrN | 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 alkylation of dimethyl L-glutamate (I) with 2-bromoacetonitrile (II) by means of LiHMDS in THF gives stereoselectively the cyanomethyl derivative (III), which is reduced with H2 over PtO2 in methanol/CHCl3 to yield the corresponding 2-aminoethyl derivative (IV). The cyclization of (IV) by means of Na2CO3 in the same solvent affords the pyrrolidinone (V), whose ester group is reduced with NaBH4 in methanol/THF to provide the propanol derivative (VI). The oxidation of (VI) with SO3/pyridine and DIEA in DMSO/dichloromethane gives the aldehyde (VII), which is finally condensed with ethyl 2-bromoacetate (VIII) by means of Et3P in dichloromethane to yield the chiral 4-(tert-butoxycarbonyl)-5-(2-oxopyrrolidin-3-yl)-2-pentanoic acid ethyl ester (IX), the desired target key intermediate.
| 【1】 Tian, Q.; et al.; An efficient synthesis of a key intermediate for the preparation of the rhinovirus protease inhibitor AG7088 via asymmetric dianionic cyanomethylation of N-Boc-L-(+)-glutamic acid dimethyl ester. Tetrahedron Lett 2001, 42, 39, 6807. |
| 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) | 55035 | dimethyl (2S)-2-[(tert-butoxycarbonyl)amino]pentanedioate | C12H21NO6 | 详情 | 详情 | |
| (II) | 31883 | 2-bromoacetonitrile | 590-17-0 | C2H2BrN | 详情 | 详情 |
| (III) | 55036 | dimethyl (2S,4R)-2-[(tert-butoxycarbonyl)amino]-4-(cyanomethyl)pentanedioate | C14H22N2O6 | 详情 | 详情 | |
| (IV) | 55037 | dimethyl (2S,4S)-2-(2-aminoethyl)-4-[(tert-butoxycarbonyl)amino]pentanedioate | C14H26N2O6 | 详情 | 详情 | |
| (V) | 55038 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[(3S)-2-oxopyrrolidinyl]propanoate | C13H22N2O5 | 详情 | 详情 | |
| (VI) | 55039 | tert-butyl (1S)-2-hydroxy-1-{[(3S)-2-oxopyrrolidinyl]methyl}ethylcarbamate | C12H22N2O4 | 详情 | 详情 | |
| (VII) | 55040 | tert-butyl (1S)-1-formyl-2-[(3S)-2-oxopyrrolidinyl]ethylcarbamate | C12H20N2O4 | 详情 | 详情 | |
| (VIII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (IX) | 55041 | ethyl (E,4S)-4-[(tert-butoxycarbonyl)amino]-5-[(3S)-2-oxopyrrolidinyl]-2-pentenoate | C16H26N2O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：Alkylation of aminotetralin (I) with bromoacetonitrile in boiling acetone gave cyanomethyl compound (II). This was subsequently reduced to diamine (III) using LiAlH4. Condensation of (III) with benzoyl chloride under Schotten-Baumann conditions then yielded the corresponding benzamide.
| 【1】 Homan, E.J.; Copinga, S.; Elfström, L.; van der Veen, T.; Hallema, J.-P.; Mohell, N.; Unelius, L.; Johansson, R.; Wikström, H.V.; Grol, C.J.; 2-Aminotetralin-derived substituted benzamides with mixed dopamine D2, D3, and serotonin 5-HT1A receptor binding properties: A novel class of potential atypical antipsychotic agents. Bioorg Med Chem 1998, 6, 11, 2111. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 | |
| 31883 | 2-bromoacetonitrile | 590-17-0 | C2H2BrN | 详情 | 详情 | |
| (I) | 14648 | N-(5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-propylamine; 5-methoxy-N-propyl-1,2,3,4-tetrahydro-2-naphthalenamine | C14H21NO | 详情 | 详情 | |
| (II) | 27938 | 2-[(5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)(propyl)amino]acetonitrile | C16H22N2O | 详情 | 详情 | |
| (III) | 27939 | N-(2-aminoethyl)-N-(5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-propylamine | C16H26N2O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The acylation of 5-methoxy-1,2,3,4-tetrahydronaphthalene-2-(R)-amine (I) with propionyl chloride (II) and NaOH in dichloromethane/water gives the corresponding amide (III), which is reduced with LiAlH4 in refluxing THF yielding the corresponding secondary amine (IV). The alkylation of (IV) with bromoacetonitrile (V) by means of K2CO3 in refluxing acetone affords the expected tertiary amine (VI), which is reduced with LiAlH4 in refluxing THF providing the ethylenediamine (VII). Finally, this compound is benzoylated with benzoyl chloride and NaOH in dichloromethane/water.
| 【1】 Homan, E.J.; Grol, C.J.; Unelius, L.; Wilkstrom, H.V.; Copinga, S.; Jackson, D.M.; Synthesis and pharmacology of the enantiomers of the potential atypical antipsychotic agents 5-OMe-BPAT and 5-OMe-(2,6-di-OMe)-BPAT. Bioorg Med Chem 1999, 7, 7, 1263. |
| 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) | 31886 | (2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine; (2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine | C11H15NO | 详情 | 详情 | |
| (II) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (III) | 31882 | N-[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide; N-[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide | C14H19NO2 | 详情 | 详情 | |
| (IV) | 14649 | (2S)-5-methoxy-N-propyl-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(2S)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylamine | C14H21NO | 详情 | 详情 | |
| (V) | 31883 | 2-bromoacetonitrile | 590-17-0 | C2H2BrN | 详情 | 详情 |
| (VI) | 31884 | 2-[[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl](propyl)amino]acetonitrile | C16H22N2O | 详情 | 详情 | |
| (VII) | 31885 | N(1)-[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N(1)-propyl-1,2-ethanediamine; N-(2-aminoethyl)-N-[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylamine | C16H26N2O | 详情 | 详情 | |
| (VIII) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)The condensation of 6-methoxy-2-tetralone (I) with pyrrolidine (II) in methanol gives the enamine (III), which is treated with 2-bromoacetonitrile (IV) to yield the pyrrolidinium salt (V). The hydrolysis of (V) with acetic acid in dichloromethane/methanol affords 2-(2-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)acetonitrile (VI), which is cyclized with ammonium acetate and NaBH3CN in refluxing methanol to provide the benzoindole derivative (VII). The condensation of (VII) with trans-4-(phenylsulfonamidomethyl)cyclohexanecarboxylic acid (VIII) by means of HBTU and DIEA in DMF gives the corresponding amide (IX), which is reduced with LiAlH4 in THF to yield the secondary amine (X). Finally, this compound is demethylated by means of BBr3 in dichloromethane.
| 【1】 Dax, S.; McNally, J. (Ortho-McNeil Pharmaceutical, Inc.); 3a,4,5,9b-Tetrahydro-1H-benz[e]indol-2-yl amine-derived neuropeptide Y receptor ligands useful in the treatment of obesity and other disorders. WO 0068197 . |
| 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) | 47506 | 6-Methoxy-2-tetralone; 6-methoxy-3,4-dihydro-2(1H)-naphthalenone | 2472-22-2 | C11H12O2 | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 47507 | methyl 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenyl ether; 1-(6-methoxy-3,4-dihydro-2-naphthalenyl)pyrrolidine | C15H19NO | 详情 | 详情 | |
| (IV) | 31883 | 2-bromoacetonitrile | 590-17-0 | C2H2BrN | 详情 | 详情 |
| (V) | 47508 | 1-[1-(cyanomethyl)-6-methoxy-3,4-dihydro-2(1H)-naphthalenylidene]pyrrolidinium | C17H21N2O | 详情 | 详情 | |
| (VI) | 47509 | 2-(6-methoxy-2-oxo-1,2,3,4-tetrahydro-1-naphthalenyl)acetonitrile | C13H13NO2 | 详情 | 详情 | |
| (VII) | 47510 | (3aS,9bR)-7-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-amine; (3aS,9bR)-7-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-ylamine | C13H16N2O | 详情 | 详情 | |
| (VIII) | 37020 | 4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxylic acid | C14H19NO4S | 详情 | 详情 | |
| (IX) | 47511 | N-[(3aS,9bR)-7-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-yl]-4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxamide | C27H33N3O4S | 详情 | 详情 | |
| (X) | 47512 | N-[[4-([[(3aS,9bR)-7-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-yl]amino]methyl)cyclohexyl]methyl]benzenesulfonamide | C27H35N3O3S | 详情 | 详情 |