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【结 构 式】 
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【分子编号】37011 【品名】1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinyl)-2-propen-1-one 【CA登记号】 |
【 分 子 式 】C15H20N2O 【 分 子 量 】244.33668 【元素组成】C 73.74% H 8.25% N 11.47% O 6.55% |
合成路线1
该中间体在本合成路线中的序号：(VI)The condensation of cyclohexene-epoxide (I) with pyrrolidine (II) gives trans-2-(1-pyrrolidinyl)cyclohexanol (III), which by reaction with NaH and methanesulfonyl chloride, and then with benzylamine is converted into trans-2-(1-pyrrolidinyl)-N-benzylcyclohexylamine (IV). The debenzylation of (IV) by hydrogenolysis with H2 over Pd/C affords trans-2-(1-pyrrolidinyl)cyclohexylamine (V), which is formylated with ethyl formate to the corresponding N-formyl-trans-2-(1-pyrrolidinyl)cyclohexylamine (VI). The reduction of (VI) with LiAlH4 in refluxing ether gives trans-N-methyl-2-(1-pyrrolidinyl)cyclohexylamine (VII), which is finally condensed with 3,4-dichlorophenylacetic acid (VIII) by means of carbonyl diimidazole (IX) in THF.
| 【1】 Blancafort, P.; Castaner, J.; Serradell, M.N.; U-50488. Drugs Fut 1982, 7, 6, 416. |
| 【2】 Szmuszkovicz, J.; 2-Aminocycloaliphatic amide compounds. DE 2749950; ES 463876; FR 2370723; GB 1569225; JP 53063351; JP 61233654; US 4145435 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (B) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (I) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 14637 | (1R,2R)-2-(1-pyrrolidinyl)cyclohexanol | C10H19NO | 详情 | 详情 | |
| (IV) | 37038 | N-phenyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]amine; N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]aniline | C16H24N2 | 详情 | 详情 | |
| (V) | 37040 | (1R,2R)-2-(1-pyrrolidinyl)cyclohexylamine; (1R,2R)-2-(1-pyrrolidinyl)cyclohexanamine | C10H20N2 | 详情 | 详情 | |
| (VI) | 37011 | 1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinyl)-2-propen-1-one | C15H20N2O | 详情 | 详情 | |
| (VII) | 31357 | N-methyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]amine; (1R,2R)-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine | C11H22N2 | 详情 | 详情 | |
| (VIII) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (IX) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (X) | 37039 | 7-azabicyclo[4.1.0]heptane | C6H11N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Fischer esterification of 2,2,5,5-tetramethylhexanedioic acid (I) provided diethyl ester (II), which was subjected to acyloin condensation with sodium in xylene to furnish the alpha-hydroxy cyclohexanone (III). Further oxidation of (III) with CrO3 gave diketone (IV). This was condensed with 2,3-diaminopropionic acid (V) to afford, after esterification with MeOH and H2SO4, the quinoxaline ester (VI). Reduction of (VI) to alcohol (VII) employing diisobutylaluminum hydride, followed by Swern oxidation gave rise to aldehyde (VIII). Optionally, addition of vinylmagnesium bromide to (VIII), and further Swern oxidation of the allylic alcohol (IX) provided the alpha,beta-unsaturated ketone (X). Conversion to the required diketo precursor (XII) was achieved by two related strategies. Coupling of ethyl 4-formylbenzoate (XI) with the unsaturated ketone (X) using 3-benzyl-5-(2-hydroxyethyl)-4-ethylthiazolium chloride as the catalyst gave the 1,4-diketone (XII). Alternatively, addition of vinylmagnesium bromide to ethyl 4-formylbenzoate (XI) followed by oxidation with pyridinium dichromate gave unsaturated ketone (XIII). This was then coupled with quinoxaline aldehyde (VIII) in the presence of a thiazolium salt to furnish diketone (XII).
| 【1】 Tai, K.; Yamauchi, T.; Hida, T.; Kikuchi, K.; Nagia, M.; Yoshimura, H.; Tokuhara, N.; Hibi, S.; Synthesis and structure-activity relationships of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-quinoxaline derivatives with retinoic acid receptor alpha agonistic activity. J Med Chem 2000, 43, 3, 409. |
| 【2】 Kikuchi, K.; Tagami, K.; Yoshimura, H.; Hibi, S.; Nagai, M.; Abe, S.; Okita, M.; Hida, T.; Higashi, S.; Tokuhara, N.; Kobayashi, S. (Eisai Co., Ltd.); Heterocyclic carboxylic acid derivs. and drugs containing the same. JP 1997071566; US 5977108; WO 9702244 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 | |
| (I) | 37002 | 2,2,5,5-tetramethylhexanedioic acid | C10H18O4 | 详情 | 详情 | |
| (II) | 37003 | diethyl 2,2,5,5-tetramethylhexanedioate | C14H26O4 | 详情 | 详情 | |
| (III) | 37004 | 6-hydroxy-2,2,5,5-tetramethylcyclohexanone | C10H18O2 | 详情 | 详情 | |
| (IV) | 37005 | 3,3,6,6-tetramethyl-1,2-cyclohexanedione | C10H16O2 | 详情 | 详情 | |
| (V) | 37006 | 2,3-diaminopropionic acid | 18635-45-5 | C3H8N2O2 | 详情 | 详情 |
| (VI) | 37007 | methyl 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinecarboxylate | C14H20N2O2 | 详情 | 详情 | |
| (VII) | 37008 | (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinyl)methanol | C13H20N2O | 详情 | 详情 | |
| (VIII) | 37009 | 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinecarbaldehyde | C13H18N2O | 详情 | 详情 | |
| (IX) | 37010 | 1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinyl)-2-propen-1-ol | C15H22N2O | 详情 | 详情 | |
| (X) | 37011 | 1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinyl)-2-propen-1-one | C15H20N2O | 详情 | 详情 | |
| (XI) | 10170 | methyl 4-formylbenzoate | 1571-08-0 | C9H8O3 | 详情 | 详情 |
| (XII) | 37012 | methyl 4-[4-oxo-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinyl)butanoyl]benzoate | C24H28N2O4 | 详情 | 详情 | |
| (XIII) | 35857 | methyl 4-acryloylbenzoate | C11H10O3 | 详情 | 详情 |