1,2-Dichloroethane → (S)-3-(4'-Cyano-biphenyl-4-yl)-2-{[(3S,8S)-3-[4-(3,4-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}-propionic acid

HRID 391978Notes

Reaction equation

HRID 391978 reaction equation
C(Cl)CCl.[CH3:5][C:6]1[O:7][C:8]([CH3:14])=[C:9]([C:11]([OH:13])=O)[N:10]=1.C[O:16][C:17](=[O:67])[C@@H:18]([NH:34][C:35]([C@@H:37]1[CH2:46][C:45]2[CH:44]=[C:43]3[O:47][CH2:48][C@H:49]([C:51]4[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]5[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=5)=[CH:53][CH:52]=4)[O:50][C:42]3=[CH:41][C:40]=2[CH2:39][NH:38]1)=[O:36])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>C(Cl)Cl>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C@H:18]([NH:34][C:35]([C@@H:37]3[CH2:46][C:45]4[CH:44]=[C:43]5[O:47][CH2:48][C@H:49]([C:51]6[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]7[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=7)=[CH:53][CH:52]=6)[O:50][C:42]5=[CH:41][C:40]=4[CH2:39][N:38]3[C:11]([C:9]3[N:10]=[C:6]([CH3:5])[O:7][C:8]=3[CH3:14])=[O:13])=[O:36])[C:17]([OH:67])=[O:16])=[CH:25][CH:24]=2)=[CH:27][CH:28]=1)#[N:33]

Participants

5

Reactant 3

HCID 111,2-DichloroethaneHCID 27954652,5-Dimethyl-1,3-oxazole-4-carboxylic acidHCID 58327184(S)-3-(4'-Cyano-biphenyl-4-yl)-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)-propionic acid methyl ester

Product 1

HCID 58327139(S)-3-(4'-Cyano-biphenyl-4-yl)-2-{[(3S,8S)-3-[4-(3,4-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}-propionic acid

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

EDC (3 eq.) and 2,5-dimethyl-oxazole-4-carboxylic acid (6 eq.) were dissolved in DCM and stirred 40 minutes. To this solution was added (S)-3-(4′-cyano-biphenyl-4-yl)-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)-propionic acid methyl ester (20 mg) and 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 (22 mg). LCMS (m/z): 860.

Workup

  1. stirringstirred for 12 hours
  2. 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-20966b122f124f1483b4400ef90c625a
Source dataset
uspto-grants-2013_02
Patent number
US08383644B2

Reaction notes

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