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【结 构 式】 
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【分子编号】51476 【品名】1-(1-acetyl-1,2,3,4-tetrahydro-6-quinolinyl)-2-chloro-1-propanone 【CA登记号】 |
【 分 子 式 】C14H16ClNO2 【 分 子 量 】265.73928 【元素组成】C 63.28% H 6.07% Cl 13.34% N 5.27% O 12.04% |
合成路线1
该中间体在本合成路线中的序号：(III)Acylation of 1-acetyl-1,2,3,4-tetrahydroquinoline (I) with 2-chloropropionyl chloride (II) by means of AlCl3 provides the quinoline derivative (III), which is deacetylated by treatment with HCl to give 1,2,3,4-tetrahydro-6-(2-chloropropionyl)quinoline (IV). Condensation of compound (IV) with O-ethyl hydrazinethioformate (V) in refluxing acetonitrile yields the thiadiazinone (VI), which is then N-acylated at the quinoline ring with 3,4-dimethoxybenzoyl chloride (VII) by means of Et3N in methylene chloride to give the racemate EMD-53998 [rac-(VIII)]. Optical resolution of EMD-53998 can be performed by two different ways: a) enantioseparation via chromatography with Chiralpak AD in 100% EtOH as eluent and b) acylation of EMD-53998 with (S)-camphanoyl chloride (IX) by means of Et3N in methylene chloride followed by treatment with morpholine in the same solvent to afford a mixture of ()-EMD-53998 (EMD-57439) and the camphanoyl amide (X), which are separated by chromatography. Finally, the (+)-enantiomer, EMD-57033, is isolated by further treatment of amide (X) with morpholine in methylene chloride.
| 【1】 Strube, J.; Jupke, A.; Schmidt-Traub, H.; Schulte, M.; Epping, A.; Devant, R.; Design, optimization, and operation of SMB chromatography in the production of enantiomerically pure pharmaceuticals. Chirality 1999, 11, 440. |
| 【2】 Castaner, J.; Doggrell, S.A.; Brown, L.; EMD-57033. Drugs Fut 2002, 27, 1, 14. |
| 【3】 Jonas, R.; Piulats, J.; Lues, I.; Klockow, M. (Merck Patent GmbH); Thiadiazinones. AU 8816646; DE 3719031; DE 3744149; EP 0294647; JP 1988310886; US 4916128 . |
| 【4】 Klockow, M.; Lues, I.; Jonas, R.; Preparation of the enantiomers of the novel Ca-sensitizer EMD 53 998. Bioorg Med Chem Lett 1992, 2, 6, 589. |
| 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) | 51475 | 1-[3,4-dihydro-1(2H)-quinolinyl]-1-ethanone | C11H13NO | 详情 | 详情 | |
| (II) | 12926 | 2-Chloropropanoyl chloride; 2-Chloropropionyl chloride | 7623-09-8 | C3H4Cl2O | 详情 | 详情 |
| (III) | 51476 | 1-(1-acetyl-1,2,3,4-tetrahydro-6-quinolinyl)-2-chloro-1-propanone | C14H16ClNO2 | 详情 | 详情 | |
| (IV) | 51477 | 2-chloro-1-(1,2,3,4-tetrahydro-6-quinolinyl)-1-propanone | C12H14ClNO | 详情 | 详情 | |
| (V) | 51478 | O-ethyl 1-hydrazinecarbothioate | C3H8N2OS | 详情 | 详情 | |
| (VI) | 51479 | 6-methyl-5-(1,2,3,4-tetrahydro-6-quinolinyl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one | C13H15N3OS | 详情 | 详情 | |
| (VII) | 13488 | (2S)-3-Butyn-2-ol; (S)-(-)-3-Butyn-2-ol | 2914-69-4 | C4H6O | 详情 | 详情 |
| (VIII) | 51480 | 5-[1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-6-quinolinyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one | C22H23N3O4S | 详情 | 详情 | |
| (IX) | 16583 | (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride | 39637-74-6 | C10H13ClO3 | 详情 | 详情 |
| (X) | 51481 | 5-[1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-6-quinolinyl]-6-methyl-3-[[(4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]hept-1-yl]carbonyl]-3,6-dihydro-2H-1,3,4-thiadiazin-2-one | C32H35N3O7S | 详情 | 详情 | |
| (XI) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |