1-Hydroxybenzotriazole → (S)-2-{[(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-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-yloxy)-phenyl]-propionic acid

HRID 391987Notes

Reaction equation

HRID 391987 reaction equation
[CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.C[O:24][C:25](=[O:76])[C@@H:26]([NH:43][C:44]([C@@H:46]1[CH2:55][C:54]2[CH:53]=[C:52]3[O:56][CH2:57][C@H:58]([C:60]4[CH:65]=[CH:64][CH:63]=[C:62]([O:66][CH2:67][C:68]5[CH:73]=[CH:72][C:71]([Cl:74])=[C:70]([Cl:75])[CH:69]=5)[CH:61]=4)[O:59][C:51]3=[CH:50][C:49]=2[CH2:48][NH:47]1)=[O:45])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[C:36]=2[CH3:42])=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCN=C=NCCCN(C)C.CCOC(C)=O.CO>[Cl:75][C:70]1[CH:69]=[C:68]([CH:73]=[CH:72][C:71]=1[Cl:74])[CH2:67][O:66][C:62]1[CH:61]=[C:60]([C@H:58]2[CH2:57][O:56][C:52]3=[CH:53][C:54]4[CH2:55][C@@H:46]([C:44]([NH:43][C@@H:26]([CH2:27][C:28]5[CH:29]=[CH:30][C:31]([O:34][C:35]6[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[C:36]=6[CH3:42])=[CH:32][CH:33]=5)[C:25]([OH:76])=[O:24])=[O:45])[N:47]([C:7]([C:5]5[N:6]=[C:2]([CH3:1])[O:3][C:4]=5[CH3:10])=[O:9])[CH2:48][C:49]=4[CH:50]=[C:51]3[O:59]2)[CH:65]=[CH:64][CH:63]=1

Participants

9

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27954652,5-Dimethyl-1,3-oxazole-4-carboxylic acidHCID 66719635(S)-2-({(3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]-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 dihydrochloride

Product 1

HCID 58327457(S)-2-{[(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-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-yloxy)-phenyl]-propionic acidYield 72.9%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent2×HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideSolvent

Conditions

Temperature
0 °C

Procedure

2,5-Dimethyl-oxazole-4-carboxylic acid (6 mg) was taken in 1 mL of anhydrous DCM and EDCI (9 mg), HOBT (7 mg) and (S)-2-({(3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]-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 dihydrochloride (25 mg) and stirred for 5 minutes. The reaction mixture was cooled to 0° C. and DIEA (25 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was loaded onto a silica gel column (1:3 EtOAc:hexanes to 4% MeOH in 1:1 EtOAc:hexanes) to get purified (S)-2-{[(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-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-yloxy)-phenyl]-propionic acid methyl ester (23 mg). This was hydrolyzed according to General Procedure B to give the title compound (19 mg). LCMS (m/z): 878.

Workup

  1. customreaction
  2. customto get
  3. custompurified (S)-2-{[(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-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-yloxy)-phenyl]-propionic acid methyl ester (23 mg)

Sources & evidence

ORD record
ord-491b9616e0294e0f9c70ccc442593cb0
Source dataset
uspto-grants-2013_02
Patent number
US08383644B2

Reaction notes

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