【结 构 式】 |
【分子编号】40760 【品名】2-thiophenesulfonyl chloride 【CA登记号】16629-19-9 |
【 分 子 式 】C4H3ClO2S2 【 分 子 量 】182.65132 【元素组成】C 26.3% H 1.66% Cl 19.41% O 17.52% S 35.11% |
合成路线1
该中间体在本合成路线中的序号:(VII)The condensation of 3-cyanophenyl isocyanate (I) with N-Boc-4-aminopiperidine (II) produced the corresponding urea (III). The diazepinone system (V) was then obtained by dialkylation of the urea (III) functionality with 1,4-dibromobutane (IV) in the presence of NaH. After acid cleavage of the Boc protecting group of (V), the resulting piperidine (VI) was acylated with 2-thiophenesulfonyl chloride (VII) to give sulfonamide (VIII). Addition of methanol to the cyano group of (VIII) in the presence of anhydrous HCl in MeOAc furnished imidate (IX). This was then converted to the corresponding amidine by treatment with either methanolic ammonia or (NH4)2CO3, followed by conversion to the title hydrochloride salt.
【1】 Rossi, K.A.; Wells, B.L.; Galemmo, R.A. Jr.; et al.; The de novo design and synthesis of cyclic urea inhibitors of factor Xa: Optimization of the S4 ligand. Bioorg Med Chem Lett 2000, 10, 3, 301. |
【2】 Maduskuie, T.P. Jr.; Galemmo, R.A. Jr.; Dominguez, C.; Quan, M.L.; Rossi, K.A.; Stouten, P.F.W.; Sun, J.H.; Wells, B.L. (DuPont Pharmaceuticals Co.); N-(Amidinophenyl)-N'-(substd.)-3H-2, 4-benzodiazepin-3-one derivs. as factor Xa inhibitors. EP 0960104; US 5925635; WO 9738984 . |
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) | 40756 | 3-isocyanatobenzonitrile | 16413-26-6 | C8H4N2O | 详情 | 详情 |
(II) | 28414 | 4-Amino-1-N-Boc-piperidine; tert-butyl 4-amino-1-piperidinecarboxylate; N-Boc-4-aminopiperidine | 87120-72-7 | C10H20N2O2 | 详情 | 详情 |
(III) | 40757 | tert-butyl 4-[[(3-cyanoanilino)carbonyl]amino]-1-piperidinecarboxylate | C18H24N4O3 | 详情 | 详情 | |
(IV) | 11883 | 1,4-Dibromobutane; 1,4-Butylene bromide | 110-52-1 | C4H8Br2 | 详情 | 详情 |
(V) | 40758 | tert-butyl 4-[3-(3-cyanophenyl)-2-oxo-1,3-diazepan-1-yl]-1-piperidinecarboxylate | C22H30N4O3 | 详情 | 详情 | |
(VI) | 40759 | 3-[2-oxo-3-(4-piperidinyl)-1,3-diazepan-1-yl]benzonitrile | C17H22N4O | 详情 | 详情 | |
(VII) | 40760 | 2-thiophenesulfonyl chloride | 16629-19-9 | C4H3ClO2S2 | 详情 | 详情 |
(VIII) | 40761 | 3-[2-oxo-3-[1-(2-thienylsulfonyl)-4-piperidinyl]-1,3-diazepan-1-yl]benzonitrile | C21H24N4O3S2 | 详情 | 详情 | |
(IX) | 40762 | methyl 3-[2-oxo-3-[1-(2-thienylsulfonyl)-4-piperidinyl]-1,3-diazepan-1-yl]benzenecarboximidoate | C22H28N4O4S2 | 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 cyclization between 5-bromoisatoic anhydride (I) and D-phenylalanine methyl ester (II) in the presence of DMAP in refluxing pyridine produced the benzodiazepindione (III), which was further reduced to the benzodiazepine (IV) by treatment with borane in THF. Displacement of the bromide group of (IV) with cuprous cyanide in hot N-methylpyrrolidone furnished nitrile (V). Acylation of the aliphatic nitrogen of (V) with 2-thienylsulfonyl chloride (VI) gave rise to sulfonamide (VII). Finally, the title compound was obtained by reductive alkylation of (VII) with 4-formylimidazole (VIII) by means of either treatment with sodium triacetoxyborohydride or, in an improved procedure, using triethylsilane in the presence of trifluoroacetic acid.
【1】 Chen, B.C.; et al.; Novel triethylsilane mediated reductive N-alkylation of amines: Improved synthesis of 1-(4-imidazolyl)methyl-4-sulfonylbenzodiazepines new farnesyltransferase inhibitors. Tetrahedron Lett 2001, 42, 7, 1245. |
【3】 Ding, C.Z.; Hunt, J.T.; Kim, S.-H.; Mitt, T.; Bhide, R.; Leftheris, K. (Bristol-Myers Squibb Co.); Inhibitors of farnesyl protein transferase. EP 0892797; JP 2000502356; US 6011029; WO 9730992 . |
【2】 Batorsky, R.; Hunt, J.T.; Ding, C.Z.; et al.; Discovery of (R)-7-cyano-2,3,4,5-tetrahydro-1-(1-H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine (BMS-214662), a farnesyltransferase inhibitor with potent preclinical antitumor activity. J Med Chem 2000, 43, 20, 3557. |
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) | 47112 | 6-bromo-2H-3,1-benzoxazine-2,4(1H)-dione | C8H4BrNO3 | 详情 | 详情 | |
(II) | 12324 | methyl (2R)-2-amino-3-phenylpropanoate | 21685-51-8 | C10H13NO2 | 详情 | 详情 |
(III) | 47113 | (3R)-3-benzyl-7-bromo-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione | C16H13BrN2O2 | 详情 | 详情 | |
(IV) | 47114 | (3R)-3-benzyl-7-bromo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine | C16H17BrN2 | 详情 | 详情 | |
(V) | 47115 | (3R)-3-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carbonitrile | C17H17N3 | 详情 | 详情 | |
(VI) | 40760 | 2-thiophenesulfonyl chloride | 16629-19-9 | C4H3ClO2S2 | 详情 | 详情 |
(VII) | 47116 | (3R)-3-benzyl-4-(2-thienylsulfonyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carbonitrile | C21H19N3O2S2 | 详情 | 详情 | |
(VIII) | 41951 | 1H-imidazole-5-carbaldehyde | 3034-50-2 | C4H4N2O | 详情 | 详情 |