Triphenylphosphine → (S)-2-{[(3S,8S)-3-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-7-((R)-1-phenyl-ethylcarbamoyl)-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 879861Notes

Reaction equation

HRID 879861 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.[N:95]([C@@H:98]([C:100]1[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=1)[CH3:99])=C=O>C(Cl)Cl>[Cl:52][C:53]1[CH:58]=[CH:57][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](=[O:7])[NH:95][C@@H:98]([C:100]6[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=6)[CH3:99])[CH2:9][C:10]=5[CH:11]=[C:12]4[O:44]3)=[CH:46][CH:47]=2)=[CH:55][CH:54]=1

Participants

7

Reactant 5

HCID 11776TriphenylphosphineHCID 74647p-Chlorophenethylic alcoholHCID 5363146Diisopropyl azodicarboxylateHCID 7018262(R)-(+)-1-Phenylethyl isocyanateHCID 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 58327258(S)-2-{[(3S,8S)-3-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-7-((R)-1-phenyl-ethylcarbamoyl)-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 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 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) was added. The mixture was stirred at room temperature for 1.5 hours and was concentrated. The residue was suspended in DCM, and TEA (3 eq.) was added to the mixture used in the following reaction sequence. ((R)-1-isocyanato-ethyl)-benzene (5 eq.) was added and reaction stirred at room temperature for 1 hour. 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): 866.

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) was added
  4. stirringThe mixture was stirred at room temperature for 1.5 hours
  5. concentrationwas concentrated
  6. customused in the following reaction sequence
  7. customreaction
  8. stirringstirred at room temperature for 1 hour
  9. 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-bff3064e35f043ebaed4b38863ee5733
Source dataset
uspto-grants-2015_03
Patent number
US08987295B2

Reaction notes

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