1,2-Dichloroethane → (S)-2-({(3S,8S)-7-(2,5-Dimethyl-oxazole-4-carbonyl)-3-[4-(3-methyl-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid

HRID 391941

反応式

HRID 391941 の反応式
C(O[C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38]C)=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])(C)(C)C.[CH3:52][C:53]1[CH:54]=[C:55]([CH:58]=[CH:59][CH:60]=1)[CH2:56]Br.C(=O)([O-])[O-].[K+].[K+].C(Cl)CCl.[CH3:71][C:72]1[O:73][C:74]([CH3:80])=[C:75](C(O)=O)[N:76]=1>CN(C=O)C.C(Cl)Cl.O>[CH3:71][C:72]1[O:73][C:74]([CH3:80])=[C:75]([C:6]([N:8]2[C@H:17]([C:18]([NH:19][C@@H:20]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=4[CH3:35])=[CH:26][CH:27]=3)[C:36]([OH:38])=[O:37])=[O:40])[CH2:16][C:15]3[CH:14]=[C:13]4[O:41][CH2:42][C@H:43]([C:45]5[CH:46]=[CH:47][C:48]([O:51][CH2:52][C:53]6[CH:60]=[CH:59][CH:58]=[C:55]([CH3:56])[CH:54]=6)=[CH:49][CH:50]=5)[O:44][C:12]4=[CH:11][C:10]=3[CH2:9]2)=[O:7])[N:76]=1

参加物

9

反応物 5

HCID 111,2-DichloroethaneHCID 11430Potassium CarbonateHCID 12099m-Xylyl bromideHCID 27954652,5-Dimethyl-1,3-oxazole-4-carboxylic acidHCID 58327310(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethyl-carbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester

生成物 1

HCID 49800413(S)-2-({(3S,8S)-7-(2,5-Dimethyl-oxazole-4-carbonyl)-3-[4-(3-methyl-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid

試薬・触媒・溶媒 3

HCID 962Water溶媒HCID 6228Dimethylformamide溶媒HCID 6344Dichloromethane溶媒

実験手順

(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethyl-carbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (30 mg) was dissolved in DMF and 3-methylbenzyl bromide (2 eq.) and potassium carbonate (3 eq.) added. The reaction mixture was stirred at room temperature and was then poured onto EtOAc and water. The organic layer was dried over sodium sulfate and concentrated. The mixture was purified over silica (hexanes; 1:1 hexanes EtOAc; 1:1 hexanes EtOAc+1% MeOH). The resulting compound was dissolved in 2 mL DCM and 1 mL 4N HCl (dioxane) was added. The mixture stirred at room temperature for 1.5 hours and was concentrated. The residue was suspended in DCM, TEA (3 eq.) added and the mixture used in the following reaction sequence. In a separate vial EDC (3 eq.) and 2,5-dimethyl-oxazole-4-carboxylic acid (6 eq.) were dissolved in DCM and stirred 40 minutes. This solution was added to the above mixture stirred 12 hours. The reaction mixture was directly purified over silica (hexanes; 1:1 hexanes/EtOAc; 1:1 hexanes EtOAc+1% MeOH; 1:1 hexanes EtOAc+2% MeOH; 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 808.

後処理

  1. dry with materialThe organic layer was dried over sodium sulfate
  2. concentrationconcentrated
  3. customThe mixture was purified over silica (hexanes; 1:1 hexanes EtOAc; 1:1 hexanes EtOAc+1% MeOH)
  4. dissolutionThe resulting compound was dissolved in 2 mL DCM
  5. addition1 mL 4N HCl (dioxane) was added
  6. stirringThe mixture stirred at room temperature for 1.5 hours
  7. concentrationwas concentrated
  8. customthe mixture used in the following reaction sequence
  9. stirringstirred 40 minutes
  10. additionThis solution was added to the above mixture
  11. stirringstirred 12 hours
  12. customThe reaction mixture was directly purified over silica (hexanes; 1:1 hexanes/EtOAc; 1:1 hexanes EtOAc+1% MeOH; 1:1 hexanes EtOAc+2% MeOH; 1:1 hexanes EtOAc+3% MeOH)

出典と根拠

ORDレコード
ord-6a85c93ebcce49a1ac1b53acf0840bbf
出典データセット
uspto-grants-2013_02
特許番号
US08383644B2

関連ノート

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