1,2-Dichloroethane → (S)-2-{[(3S,8S)-3-[4-(2,6-Dichloro-benzyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-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 708753Notes

Reaction equation

HRID 708753 reaction equation
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.[Cl:52][C:53]1[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[C:54]=1[CH2:55]Br.C(=O)([O-])[O-].[K+].[K+].C(Cl)CCl.[CH3:72][C:73]1[O:74][C:75]([CH3:81])=[C:76](C(O)=O)[N:77]=1>CN(C=O)C.C(Cl)Cl.O>[Cl:52][C:53]1[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[C:54]=1[CH2:55][O:51][C:48]1[CH:49]=[CH:50][C:45]([C@H:43]2[CH2:42][O:41][C:13]3=[CH:14][C:15]4[CH2:16][C@@H:17]([C:18]([NH:19][C@@H:20]([CH2:21][C:22]5[CH:27]=[CH:26][C:25]([C:28]6[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=6[CH3:35])=[CH:24][CH:23]=5)[C:36]([OH:38])=[O:37])=[O:40])[N:8]([C:6]([C:76]5[N:77]=[C:73]([CH3:72])[O:74][C:75]=5[CH3:81])=[O:7])[CH2:9][C:10]=4[CH:11]=[C:12]3[O:44]2)=[CH:46][CH:47]=1

Participants

9

Reactant 5

HCID 111,2-DichloroethaneHCID 11430Potassium CarbonateHCID 301591-Bromomethyl-2,6-dichlorobenzeneHCID 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

Product 1

HCID 58327494(S)-2-{[(3S,8S)-3-[4-(2,6-Dichloro-benzyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-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

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester was dissolved in DMF and 2,6-dichlorobenzyl bromide (2 eq.) and potassium carbonate (3 eq.) were added. The reaction mixture stirred at room temperature and was poured onto EtOAc and water. The organic layer was dried over sodium sulfate and concentrated. The mixture was purified over silica (hexanes to 1:1 hexanes EtOAc to 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 was 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 for 12 hours. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (6 mg). LCMS (m/z): 862.

Workup

  1. dry with materialThe organic layer was dried over sodium sulfate
  2. concentrationconcentrated
  3. customThe mixture was purified over silica (hexanes to 1:1 hexanes EtOAc to 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 was 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 for 12 hours
  12. customThe reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH)

Sources & evidence

ORD record
ord-04c42ceef8e54edd92f3bad23443c8eb
Source dataset
uspto-grants-2015_11
Patent number
US09175003B2

Reaction notes

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