Triphenylphosphine → (3S,8S)-3-[4-(2-cyclopentyl-ethoxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid

HRID 391971Notes

Reaction equation

HRID 391971 reaction equation
C[O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:27][CH3:28])=[O:4].[CH:35]1([CH2:40][CH2:41]O)[CH2:39][CH2:38][CH2:37][CH2:36]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)Cl>[CH:35]1([CH2:40][CH2:41][O:25][C:22]2[CH:21]=[CH:20][C:19]([C@H:17]3[CH2:16][O:15][C:11]4=[CH:12][C:13]5[CH2:14][C@@H:5]([C:3]([OH:2])=[O:4])[N:6]([C@H:26]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[CH2:27][CH3:28])[CH2:7][C:8]=5[CH:9]=[C:10]4[O:18]3)=[CH:24][CH:23]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1

Participants

6

Reactant 4

HCID 11776TriphenylphosphineHCID 69833CyclopentaneethanolHCID 5363146Diisopropyl azodicarboxylateHCID 66719659(S)-3-(4-Hydroxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester

Product 1

HCID 66719829(3S,8S)-3-[4-(2-cyclopentyl-ethoxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(S)-3-(4-Hydroxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (20 mg) was dissolved in DCM and cyclopentane-ethanol (5 eq.), 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 9:1 hexanes EtOAc to 7:3 hexanes EtOAc). This ester was hydrolyzed according to General Procedure AB to give (3S,8S)-3-[4-(2-cyclopentyl-ethoxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid. This acid was coupled with (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester dihydrochloride according to General Procedure L to give (S)-2-{[(3S,8S)-3-[4-(2-cyclopentyl-ethoxy)-phenyl]-7-((S)-1-phenyl-propyl)-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. This ester was hydrolyzed according to General Procedure B to give the title compound (5 mg). LCMS (m/z): 811.

Workup

  1. customwas directly purified over silica (hexanes to 9:1 hexanes EtOAc to 7:3 hexanes EtOAc)

Sources & evidence

ORD record
ord-4eb7661dd9324e9795741331deab2481
Source dataset
uspto-grants-2013_02
Patent number
US08383644B2

Reaction notes

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