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

HRID 879734Notes

Reaction equation

HRID 879734 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][CH:28]=[C:27]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)[CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:53][O:54][C:55](=[O:74])[C@@H:56]([NH2:73])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][C:65]2[CH:70]=[CH:69][N:68]=[C:67]([CH3:71])[C:66]=2[CH3:72])=[CH:60][CH:59]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCN=C=NCCCN(C)C.Cl>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:19])[NH:73][C@H:56]([C:55]([O:54][CH3:53])=[O:74])[CH2:57][C:58]2[CH:59]=[CH:60][C:61]([O:64][C:65]3[CH:70]=[CH:69][N:68]=[C:67]([CH3:71])[C:66]=3[CH3:72])=[CH:62][CH:63]=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][CH:28]=[C:27]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)[CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]

Participants

7

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 58327461(3S,8S)-3-[3-(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 66719184(S)-2-Amino-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester dihydrochloride

Product 1

HCID 58327379(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yloxy)-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 6344DichloromethaneSolventHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideSolvent

Conditions

Temperature
0 °C

Procedure

(3S,8S)-3-[3-(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 (80 mg) was taken up in 2 mL of anhydrous DCM and EDCl (34 mg), HOBT (25 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester dihydrochloride (50 mg) were added and stirred for minutes. The reaction mixture was cooled to 0° C. and DIEA (85 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction was complete, it was purified by column chromatography (silica gel; 1:3 ethyl acetate/hexanes to 4% MeOH in 1:1 ethyl acetate/hexanes) (70 mg). LCMS (m/z): 869.

Workup

  1. customreaction
  2. stirringwas stirred at room temperature for 2 hours
  3. customit was purified by column chromatography (silica gel; 1:3 ethyl acetate/hexanes to 4% MeOH in 1:1 ethyl acetate/hexanes) (70 mg)

Sources & evidence

ORD record
ord-bb890d148b5f4a4d9d50587867e8cad6
Source dataset
uspto-grants-2015_03
Patent number
US08987295B2

Reaction notes

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