(S)-2-({(S)-6-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4'-cyano-biphenyl-4-yl)-propionic acid methyl ester → (S)-2-({(S)-6-(2-amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4'-cyano-biphenyl-4-yl)-propionic acid methyl ester

HRID 1711481Notes

Reaction equation

C(C1C=CC(C2C=CC(C[C@H](NC(C3CC4C=C5C(O[C@@H](C6C=CC(OCC7C=CC(Cl)=C(Cl)C=7)=CC=6)C(=O)N5C)=CC=4CN3C(O)=O)=O)C(OC)=O)=CC=2)=CC=1)#N.[CH3:59][O:60][C:61](=[O:126])[C@@H:62]([NH:78][C:79]([CH:81]1[CH2:94][C:93]2[CH:92]=[C:91]3[C:86]([O:87][C@@H:88]([C:97]4[CH:102]=[CH:101][C:100]([O:103][CH2:104][C:105]5[CH:110]=[CH:109][C:108]([Cl:111])=[C:107]([Cl:112])[CH:106]=5)=[CH:99][CH:98]=4)[C:89](=[O:96])[N:90]3[CH3:95])=[CH:85][C:84]=2[CH2:83][N:82]1[S:113]([C:116]1[S:120][C:119]([NH:121]C(=O)C)=[N:118][C:117]=1[CH3:125])(=[O:115])=[O:114])=[O:80])[CH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]2[CH:75]=[CH:74][C:73]([C:76]#[N:77])=[CH:72][CH:71]=2)=[CH:66][CH:65]=1>>[CH3:59][O:60][C:61](=[O:126])[C@@H:62]([NH:78][C:79]([CH:81]1[CH2:94][C:93]2[CH:92]=[C:91]3[C:86]([O:87][C@@H:88]([C:97]4[CH:98]=[CH:99][C:100]([O:103][CH2:104][C:105]5[CH:110]=[CH:109][C:108]([Cl:111])=[C:107]([Cl:112])[CH:106]=5)=[CH:101][CH:102]=4)[C:89](=[O:96])[N:90]3[CH3:95])=[CH:85][C:84]=2[CH2:83][N:82]1[S:113]([C:116]1[S:120][C:119]([NH2:121])=[N:118][C:117]=1[CH3:125])(=[O:115])=[O:114])=[O:80])[CH2:63][C:64]1[CH:65]=[CH:66][C:67]([C:70]2[CH:71]=[CH:72][C:73]([C:76]#[N:77])=[CH:74][CH:75]=2)=[CH:68][CH:69]=1

Participants

Reactant 2

HCID 86636874(S)-2-({(S)-6-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4'-cyano-biphenyl-4-yl)-propionic acid methyl ester

HCID 86644011(S)-7-[(S)-2-(4'-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid

Product 1

HCID 86636873(S)-2-({(S)-6-(2-amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4'-cyano-biphenyl-4-yl)-propionic acid methyl ester

Procedure

(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tent-butyl ester 7-methyl ester was hydrolyzed as described in general procedure B to furnish (S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tent-butyl ester as a mixture of diastereomers (1:1) at the morpholino center. This mixture of acids was converted to (S)-7-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tent-butyl ester using the general procedure O. This intermediate was further converted to (S)-2-({(S)-6-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester as a mixture of diastereomeres following the general procedure C and E. This sulfonamide was deacylated using the general procedure P to furnish (S)-2-({(S)-6-(2-amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester as a mixture of diastereomeres. The diasteromers were separated by flash column chromatography (DCM: EtOAc, 9:1-7:3)

Workup

additionThis mixture of acids

Sources & evidence

ORD record: ord-ed4cd69a0e164dc8a63238115c20dcad
Source dataset: uspto-grants-2010_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07790714B2

Reaction notes

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