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【结 构 式】 
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【分子编号】25030 【品名】1,4-diazepane 【CA登记号】505-66-8 |
【 分 子 式 】C5H12N2 【 分 子 量 】100.16376 【元素组成】C 59.96% H 12.08% N 27.97% |
合成路线1
该中间体在本合成路线中的序号：(IV)5-Isoquinolinesulfonic acid (I) is heated at 85 C with SOCl2 and DMF yielding 5-isoquinolinesulfonyl chloride hydrochloride (II). The reaction of (II) with hexahydro-1H-1,4-diazepine affords hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine (III) in CH2Cl2. Finally, the reaction of (III) with HCl gives hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride (IV). (scheme 10964901a)
| 【1】 Ishida, T.; Asano, T.; HA 1077. Drugs Fut 1989, 14, 12, 1159. |
合成路线2
该中间体在本合成路线中的序号：(II)Reaction of 3,3-diphenylpropylmethanesulfonate (I) with homopiperazine hydrochloride (II) and NaI in ethanol provides compound (III), which is finally condensed with 4-(methylsulfonyl)benzyl bromide by means of K2CO3 in acetonitrile or by means of NaI in ethanol.
| 【1】 Shiota, T.; et al.; Chemokine receptor antagonistic activities and structure-activity relationship of novel homopiperazine derivatives. 19th Symp Med Chem and 8th Annu Meet Div Med Chem Jpn (Nov 17-19, Tokyo) 1999, Abst 1P-10. |
| 【2】 Shiota, T.; Yamagami, S.; Kataoka, K.; Endo, N.; Tanaka, H.; Barnum, D.; Greene, J.; Moree, W.; Ramirez-Weinhouse, M.; Tarby, C. (Teijin Ltd.); Diarylalkyl cyclic diamine derivs. as chemokine receptor antagonists. EP 0914319; JP 1997309877; WO 9744329 . |
| 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) | 43552 | (3,3-diphenylpropoxy)(methyl)dimethylene-lambda(6)-sulfane | C18H22OS | 详情 | 详情 | |
| (II) | 25030 | 1,4-diazepane | 505-66-8 | C5H12N2 | 详情 | 详情 |
| (III) | 43553 | 1-(3,3-diphenylpropyl)-1,4-diazepane | C20H26N2 | 详情 | 详情 | |
| (IV) | 43554 | 4-(bromomethyl)phenyl methyl sulfone; [4-(bromomethyl)phenyl](methyl)dioxo-lambda(6)-sulfane | 53606-06-7 | C8H9BrO2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The title compound was synthesized by alkylation of homopiperazine (I) with (E)-5-(3,4,5-trimethoxyphenyl)-4-pentenyl bromide (II) in the presence of KI and K2CO3 in hot DMF.
| 【1】 Nakao, H.; Umetani, M.; Suda, M.; Nagoya, T. (Kowa Co., Ltd.); Cell adhesion inhibitor. EP 0774257; JP 1997143075; US 5723465 . |
合成路线4
该中间体在本合成路线中的序号：(XI)3,4-Dimethoxybenzoic acid (I) is converted into oxazoline (II) by known methods. This compound is treated with BuLi and I2 in ethyl ether to yield the 2-iodo derivative (III), which is treated with POCl3 in hot pyridine to afford 2-iodo-3,4-dimethoxybenzonitrile (IV). The nitration of (IV) by means of nitronium tetrafluoroborate in acetonitrile provides 2-iodo-3,4-dimethoxy-6-nitrobenzonitrile (V), which is condensed with 4-fluorophenylboronic acid (VI) by means of Pd(PPh3)4 in toluene/ethanol to give the biphenyl derivative (VII). The reduction of the nitro group of (VII) by means of sodium dithionite in DMF/water yields the corresponding amino derivative (VIII), which is condensed with 1-acetyl-4-(morpholin-4-ylcarbonyl)perhydro-1,4-diazepine (IX) by means of POCl3 in dichloromethane to afford the adduct (X). Finally, this compound is cyclized by means of LDA in THF to provide the target quinoline derivative. The intermediate 1-acetyl-4-(morpholin-4-ylcarbonyl)perhydro-1,4-diazepine (IX) has been obtained as follows: The reaction of perhydro-1,4-diazepine (XI) with Boc2O in dichloromethane gives the monoprotected diazepine (XII), which is condensed with morpholin-4-yl-carbonyl chloride (XIII) by means of TEA in dichloromethane to yield the acylated diazepine (XIV). The deprotection of (XIV) by means of HCl in dichloromethane/methanol affords the deprotected diazepine (XV), which is finally acylated with acetic anhydride and TEA in dichloromethane to provide the target intermediate (IX).
| 【1】 Collis, A.J.; Fox, D.N.A.; Newman, J. (Pfizer Inc.); Quinoline and quinazoline cpds. useful in therapy. EP 0877734; JP 1999501668; US 6103738; WO 9723462 . |
| 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) | 13439 | 3,4-Dimethoxybenzoic acid | 93-07-2 | C9H10O4 | 详情 | 详情 |
| (II) | 54071 | 2-(3,4-dimethoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole; 4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-methoxyphenyl methyl ether | n/a | C13H17NO3 | 详情 | 详情 |
| (III) | 54072 | 2-(2-iodo-3,4-dimethoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole; 3-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-iodo-6-methoxyphenyl methyl ether | n/a | C13H16INO3 | 详情 | 详情 |
| (IV) | 54073 | 2-iodo-3,4-dimethoxybenzonitrile | n/a | C9H8INO2 | 详情 | 详情 |
| (V) | 54074 | 2-iodo-3,4-dimethoxy-6-nitrobenzonitrile | n/a | C9H7IN2O4 | 详情 | 详情 |
| (VI) | 38403 | 4-fluorophenylboronic acid | 1765-93-1 | C6H6BFO2 | 详情 | 详情 |
| (VII) | 54075 | 4'-fluoro-5,6-dimethoxy-3-nitro[1,1'-biphenyl]-2-carbonitrile | n/a | C15H11FN2O4 | 详情 | 详情 |
| (VIII) | 54076 | 3-amino-4'-fluoro-5,6-dimethoxy[1,1'-biphenyl]-2-carbonitrile | n/a | C15H13FN2O2 | 详情 | 详情 |
| (IX) | 54077 | 1-[4-(4-morpholinylcarbonyl)-1,4-diazepan-1-yl]-1-ethanone | n/a | C12H21N3O3 | 详情 | 详情 |
| (X) | 54078 | 4'-fluoro-5,6-dimethoxy-3-({(E)-1-[4-(4-morpholinylcarbonyl)-1,4-diazepan-1-yl]ethylidene}amino)[1,1'-biphenyl]-2-carbonitrile | n/a | C27H32FN5O4 | 详情 | 详情 |
| (XI) | 25030 | 1,4-diazepane | 505-66-8 | C5H12N2 | 详情 | 详情 |
| (XII) | 54079 | tert-Butyl 1-homopiperazine carboxylate | n/a | C10H20N2O2 | 详情 | 详情 |
| (XIII) | 15847 | 4-morpholinecarbonyl chloride; Morpholine-4-carbonyl chloride | 15159-40-7 | C5H8ClNO2 | 详情 | 详情 |
| (XIV) | 54080 | tert-butyl 4-(4-morpholinylcarbonyl)-1,4-diazepane-1-carboxylate | n/a | C15H27N3O4 | 详情 | 详情 |
| (XV) | 54081 | 1,4-diazepan-1-yl(4-morpholinyl)methanone | n/a | C10H19N3O2 | 详情 | 详情 |