4-Methylmorpholine → (3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester

HRID 391842Notes

Reaction equation

HRID 391842 reaction equation
[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:43][O:44][C:45](=[O:63])[C@@H:46]([NH2:62])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][N:57]=[C:56]([CH3:60])[C:55]=2[CH3:61])=[CH:50][CH:49]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:19])[NH:62][C@H:46]([C:45]([O:44][CH3:43])=[O:63])[CH2:47][C:48]2[CH:49]=[CH:50][C:51]([C:54]3[CH:59]=[CH:58][N:57]=[C:56]([CH3:60])[C:55]=3[CH3:61])=[CH:52][CH:53]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 757711-HydroxybenzotriazoleHCID 58327389(3R,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl esterHCID 66719267L-Phenylalanine, 4-(2,3-dimethyl-4-pyridinyl)-, methyl ester, hydrochloride (1:2)

Product 1

HCID 58327244(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 6344DichloromethaneSolvent

Procedure

(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (260 mg), (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (190 mg), EDC (106 mg), and HOBt (78 mg) were suspended in 2 mL DCM and NMM (0.214 mL) added. The resulting mixture stirred at room temperature for 4 hours and loaded directly onto silica. The residue was purified by silica gel flash chromatography (hexanes to 1:1 hexanes/EtOAc to 1:1 hexanes/EtOAc+1% MeOH) to give 320 mg after drying under vacuum. LCMS: m/z 853.

Workup

  1. customThe residue was purified by silica gel flash chromatography (hexanes to 1:1 hexanes/EtOAc to 1:1 hexanes/EtOAc+1% MeOH)
  2. customto give 320 mg
  3. customafter drying under vacuum

Sources & evidence

ORD record
ord-d67f0832a1844896a0a84581aa8e6ceb
Source dataset
uspto-grants-2013_02
Patent number
US08383644B2

Reaction notes

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