1,1'-Carbonyldiimidazole → (S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-(3-methyl-isoxazol-5-ylcarbamoyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid

HRID 879842Notes

Reaction equation

HRID 879842 reaction equation
[CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[O:4][N:3]=1.C1N=CN([C:13](N2C=NC=C2)=[O:14])C=1.C[O:21][C:22](=[O:73])[C@@H:23]([NH:40][C:41]([C@@H:43]1[CH2:52][C:51]2[CH:50]=[C:49]3[O:53][CH2:54][C@H:55]([C:57]4[CH:62]=[CH:61][C:60]([O:63][CH2:64][C:65]5[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=5)=[CH:59][CH:58]=4)[O:56][C:48]3=[CH:47][C:46]=2[CH2:45][NH:44]1)=[O:42])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=2[CH3:39])=[CH:27][CH:26]=1>CN(C1C=CN=CC=1)C.ClCCCl>[Cl:72][C:67]1[CH:66]=[C:65]([CH:70]=[CH:69][C:68]=1[Cl:71])[CH2:64][O:63][C:60]1[CH:61]=[CH:62][C:57]([C@H:55]2[CH2:54][O:53][C:49]3=[CH:50][C:51]4[CH2:52][C@@H:43]([C:41]([NH:40][C@@H:23]([CH2:24][C:25]5[CH:26]=[CH:27][C:28]([O:31][C:32]6[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=6[CH3:39])=[CH:29][CH:30]=5)[C:22]([OH:21])=[O:73])=[O:42])[N:44]([C:13](=[O:14])[NH:7][C:5]5[O:4][N:3]=[C:2]([CH3:1])[CH:6]=5)[CH2:45][C:46]=4[CH:47]=[C:48]3[O:56]2)=[CH:58][CH:59]=1

Participants

6

Reactant 3

HCID 682631,1'-CarbonyldiimidazoleHCID 845905-Amino-3-methylisoxazoleHCID 58327121(S)-2-({(3S,8S)-3-[4-(3,4-dichloro-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-yloxy)-phenyl]-propionic acid methyl ester

Product 1

HCID 58327503(S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-(3-methyl-isoxazol-5-ylcarbamoyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 111,2-DichloroethaneSolvent2×

Conditions

Temperature
60 °C

Procedure

3-Methyl-isoxazol-5-ylamine was stirred at 60° C. with 1 eq CDI and a catalytic amount of DMAP in DCE for 1 hour, then cooled. A solution of (S)-2-({(3S,8S)-3-[4-(3,4-dichloro-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-yloxy)-phenyl]-propionic acid methyl ester (1 eq) in DCE was added and stirred at 60° C. for 1 hour. The reaction mixture was cooled, then directly purified by flash chromatography The resulting compound was hydrolyzed according to General Procedure B to give the title compound (4 mg). LCMS (m/z) 879.

Workup

  1. temperaturecooled
  2. temperatureThe reaction mixture was cooled
  3. customdirectly purified by flash chromatography The resulting compound

Sources & evidence

ORD record
ord-1a248a1de7104efb8ae53d385a091a13
Source dataset
uspto-grants-2015_03
Patent number
US08987295B2

Reaction notes

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