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 879835

Reaction equation

HRID 879835 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.[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

Participants

9

Reactant 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

Product 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

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

(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.

Workup

  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)

Sources & evidence

ORD record
ord-374e888e8d1a46028bd3eed4a68ba8f5
Source dataset
uspto-grants-2015_03
Patent number
US08987295B2

Linked notes

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