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 708730

반응식

HRID 708730 반응식
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

참가 물질

9

반응물 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

생성물 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

시약·촉매·용매 3

HCID 962Water용매HCID 6228Dimethylformamide용매HCID 6344Dichloromethane용매

실험 절차

(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.

후처리

  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)

출처 및 근거

ORD 기록
ord-dd5878c30a244f0ebf5463127dcb44c7
출처 데이터셋
uspto-grants-2015_11
특허 번호
US09175003B2

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