Dimethylformamide → HCID 86654917, compound

HRID 879789Notes

Reaction equation

[CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61]C(=O)C)=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Br[CH2:68][CH2:69][O:70][CH2:71][CH2:72][Br:73].[C:74]([O-:77])([O-])=O.[K+].[K+].[CH3:80]N(C=O)C>>[CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][CH2:68][CH2:69][O:70][CH2:71][CH:72]([C:74](=[O:77])[CH3:80])[Br:73])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:10][CH:11]=1

Participants

Reactant 4

HCID 6228Dimethylformamide

HCID 11430Potassium Carbonate

HCID 21521Bis(2-bromoethyl) ether

HCID 86654898HCID 86654898, compound

Product 1

HCID 86654917HCID 86654917, compound

Procedure

(S)-2-({(S)-7-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (30 mg) was reacted with 1-bromo-2-(2-bromo-ethoxy)-ethane and K2CO3 in DMF according to General Procedure O to give (S)-2-({(S)-7-{2-[2-(2-acetyl-2-bromo-ethoxy)-ethylamino]-4-methyl-thiazole-5-sulfonyl}-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester. This product was deacylated according to General Procedure N to give (S)-2-({(S)-7-{2-[2-(2-bromo-ethoxy)-ethylamino]-4-methyl-thiazole-5-sulfonyl}-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester. This intermediate was cyclized using K2CO3 in DMF at 50° C. to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(4-methyl-2-morpholin-4-yl-thiazole-5-sulfonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester (16 mg) (LCMS (m/z): 997). This ester, upon hydrolysis according to General Procedure B, gave the title compound (12 mg). LCMS (m/z): 984.

Sources & evidence

ORD record: ord-abd9cdfce86d42c3b228a0268062c9f6
Source dataset: uspto-grants-2015_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08987295B2

Reaction notes

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