1,2-Dichloroethane → (S)-2-{[(3S,8S)-3-{4-[2-(4-Chloro-phenyl)-ethoxy]-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 708755Notes

Reaction equation

HRID 708755 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:58]=[CH:57][C:56]([CH2:59][CH2:60]O)=[CH:55][CH:54]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C(Cl)CCl.[CH3:99][C:100]1[O:101][C:102]([CH3:108])=[C:103](C(O)=O)[N:104]=1>C(Cl)Cl>[Cl:52][C:53]1[CH:54]=[CH:55][C:56]([CH2:59][CH2:60][O:51][C:48]2[CH:49]=[CH:50][C:45]([C@H:43]3[CH2:42][O:41][C:13]4=[CH:14][C:15]5[CH2:16][C@@H:17]([C:18]([NH:19][C@@H:20]([CH2:21][C:22]6[CH:27]=[CH:26][C:25]([C:28]7[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=7[CH3:35])=[CH:24][CH:23]=6)[C:36]([OH:38])=[O:37])=[O:40])[N:8]([C:6]([C:103]6[N:104]=[C:100]([CH3:99])[O:101][C:102]=6[CH3:108])=[O:7])[CH2:9][C:10]=5[CH:11]=[C:12]4[O:44]3)=[CH:46][CH:47]=2)=[CH:57][CH:58]=1

Participants

8

Reactant 6

HCID 111,2-DichloroethaneHCID 11776TriphenylphosphineHCID 74647p-Chlorophenethylic alcoholHCID 27954652,5-Dimethyl-1,3-oxazole-4-carboxylic acidHCID 5363146Diisopropyl azodicarboxylateHCID 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 58327459(S)-2-{[(3S,8S)-3-{4-[2-(4-Chloro-phenyl)-ethoxy]-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 1

HCID 6344DichloromethaneSolvent2×

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 (30 mg) was dissolved in DCM and 2(4-chloro-phenyl)-ethanol (5 equiv), triphenyl phosphine (5 eq.) and DIAD (4.5 eq.) added. The reaction mixture stirred at room temperature and was directly 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) added. The mixture stirred at room temperature for 1.5 hours and was concentrated. The residue was suspended in DCM, TEA (3 eq.) added 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 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. LCMS (m/z): 842.

Workup

  1. customwas directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH)
  2. dissolutionThe resulting compound was dissolved in 2 mL DCM
  3. addition1 mL 4N HCl (dioxane) added
  4. stirringThe mixture stirred at room temperature for 1.5 hours
  5. concentrationwas concentrated
  6. customused in the following reaction sequence
  7. stirringstirred 40 minutes
  8. additionThis solution was added to the above mixture
  9. stirringstirred 12 hours
  10. 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-be3f97cc77a246dba7cb1b68cdf694c8
Source dataset
uspto-grants-2015_11
Patent number
US09175003B2

Reaction notes

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