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【结 构 式】 
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【分子编号】24439 【品名】2-methyl-2-butanamine 【CA登记号】594-39-8 |
【 分 子 式 】C5H13N 【 分 子 量 】87.16496 【元素组成】C 68.9% H 15.03% N 16.07% |
合成路线1
该中间体在本合成路线中的序号：(IV)The condensation of 2'-hydroxy-3-phenylpropiophenone (I) with 1 chloro-2,3-epoxypropane (II) by means of K2CO3 gives 2'-(2,3-epoxypropoxy)-3-phenylpropiophenone (III), which is then treated with 2-methyl-2-aminobutane (IV) in refluxing methanol.
| 【1】 Petrik, G.; Sachse, R. (Helopharm KG); 2-[2'-Hydroxy-3'-(1,1-dimethylpropylamino)-propoxy]-beta-phenylpropiophenone, its physiologically acceptable acid addition salts, and pharmaceutical compsns.. DE 3133814; US 4460605 . |
| 【2】 Prous, J.; Castaner, J.; Difrafenone. Drugs Fut 1986, 11, 8, 645. |
| 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) | 24436 | 1-(2-hydroxyphenyl)-3-phenyl-1-propanone | 42772-82-7 | C15H14O2 | 详情 | 详情 |
| (II) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (III) | 24438 | 1-[2-(2-oxiranylmethoxy)phenyl]-3-phenyl-1-propanone | C18H18O3 | 详情 | 详情 | |
| (IV) | 24439 | 2-methyl-2-butanamine | 594-39-8 | C5H13N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Thiourea (III) was prepared by condensation of 3-pyridyl isothiocyanate (I) with 1,1-dimethylpropyl amine (II). Desulfuration of thiourea (III) by means of phosgene and diisopropyl ethylamine, or triphenylphosphine and CCl4 gave rise to the carbodiimide (IV). Finally, addition of cyanamide to carbodiimide (IV) furnished the target N-cyanoguanidine derivative
| 【1】 Manley, P.W.; Quast, U.; Structure-activity studies of potassium channel opening in pinacidil-type cyanoguanidines, nitroethenediamines, thioureas, and ureas. J Med Chem 1992, 35, 12, 2327. |
| 【2】 Petersen, H.J. (Leo Pharmaceutical Products Ltd. A/S); Antihypertensive pyridylguanidine compounds. DE 2557438; FR 2294703; GB 1489879; JP 51086474; US 4057636 . |
合成路线3
该中间体在本合成路线中的序号：(II)A general synthetic route to a series of novel N-aryl and N-benzyl diaminocyclobutenedione derivatives and pertinent SAR data have been reported elsewhere. KCO-616 can be conveniently synthesized in two steps as shown in Scheme 26121401a. An ethanolic solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (I) is allowed to react with tert-amylamine (II) at room temperature for a period of 24 h to give intermediate 3-(1,1-dimethylpropylamino)-4-ethoxy-3-cyclobutene-1,2-dione (III) in 90% isolated, purified yield. The condensation of this compound with 2,4-dichloro-6-methylbenzylamine (IV, recrystallized from boiling diethyl ether) in ethanol at room temperature for 24 h affords analytically pure 3-(2,4-dichloro-6-methylbenzylamino)-4-(1,1-dimethylpropylamino)-3-cyclobutene-1,2-dione (KCO-616) in 92% yield.
| 【1】 Butera, J.A.; et al.; Substituted N-aryl-1,2-diaminocyclobutene-3,4-diones. I. N-Cyanoguanidine bioisosteres possessing in vivo bladder selectivity. 214th ACS Natl Meet (Sept. 7-11, Las Vegas) 1997, Abst MEDI 044. |
| 【2】 McFarlane, G.R.; Gundersen, E.G.; Elokdah, H.; et al.; Benzylamino analogs of 1,2-diaminocyclobutene-3,4-dione as novel KATP-channel openers targeted for treatment of urge urinary incontinence . 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 35. |
| 【3】 Antane, M.M.; Butera, J.A.; Antane, S.A.; et al.; Design and SAR of novel potassium channel openers targeted for urge urinary incontinence. I. N-Cyanoguanidine bioisosteres possessing in vivo bladder selectivity. J Med Chem 2000, 43, 6, 1187-1202. |
| 【4】 Butera, J.A.; Argentieri, T.M.; KCO-616. Drugs Fut 2000, 25, 3, 239. |
| 【5】 Antane, M.M.; Argentieri, T.M.; Gilbert, A.M.; et al.; Desing and SAR of novel potassium channel openers targeted for urge urinary incontinence. 2. Selective and potent benzylamino cyclobutenediones. J Med Chem 2000, 43, 6, 1203. |
| 【6】 Antane, M.M.; Herbst, D.R.; McFarlane, G.R.; Gundersen, E.G.; Hirth, B.H.; Quagliato, D.A.; Graceffa, R.F.; Butera, J.A.; Gilbert, A.M. (American Home Products Corp.); Substd. N-arylmethylamino derivs. of cyclobutene-3, 4-diones. US 5763474; US 5780505; WO 9802413 . |
| 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) | 30975 | 3,4-diethoxy-3-cyclobutene-1,2-dione | 5231-87-8 | C8H10O4 | 详情 | 详情 |
| (II) | 24439 | 2-methyl-2-butanamine | 594-39-8 | C5H13N | 详情 | 详情 |
| (III) | 32803 | 3-ethoxy-4-(tert-pentylamino)-3-cyclobutene-1,2-dione | C11H17NO3 | 详情 | 详情 | |
| (IV) | 32804 | 2,4-dichloro-6-methylbenzylamine; (2,4-dichloro-6-methylphenyl)methanamine | 175278-27-0 | C8H9Cl2N | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)Treatment of 3,4-dibutoxy-3-cyclobutene-1,2-dione (VI) with 1,1-dimethylpropylamine (VII) yielded the amino cyclobutenedione (VIII). Subsequent condensation of (VIII) with 3-chloro-4-(aminomethyl)benzonitrile (V) in THF provided the target diamino derivative.
| 【1】 Antane, M.M.; Herbst, D.R.; McFarlane, G.R.; Gundersen, E.G.; Hirth, B.H.; Quagliato, D.A.; Graceffa, R.F.; Butera, J.A.; Gilbert, A.M. (American Home Products Corp.); Substd. N-arylmethylamino derivs. of cyclobutene-3, 4-diones. US 5763474; US 5780505; WO 9802413 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 32962 | 4-(aminomethyl)-3-chlorobenzonitrile | C8H7ClN2 | 详情 | 详情 | |
| (VI) | 32963 | 3,4-dibutoxy-3-cyclobutene-1,2-dione | 2892-62-8 | C12H18O4 | 详情 | 详情 |
| (VII) | 24439 | 2-methyl-2-butanamine | 594-39-8 | C5H13N | 详情 | 详情 |
| (VIII) | 32965 | 3-butoxy-4-(tert-pentylamino)-3-cyclobutene-1,2-dione | C13H21NO3 | 详情 | 详情 |