(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 tert-butyl 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 602910

Reaktionsgleichung

C(OC(N1C(C(=O)N[C@H](C(OC)=O)CC2C=CC(C3C=CC(C#N)=CC=3)=CC=2)CC2C=C3C(O[C@@H](C4C=CC(OCC5C=CC(Cl)=C(Cl)C=5)=CC=4)C(=O)N3C)=CC=2C1)=O)(C)(C)C.[CH3:63][O:64][C:65](=[O:130])[C@@H:66]([NH:82][C:83]([CH:85]1[CH2:98][C:97]2[CH:96]=[C:95]3[C:90]([O:91][C@@H:92]([C:101]4[CH:106]=[CH:105][C:104]([O:107][CH2:108][C:109]5[CH:114]=[CH:113][C:112]([Cl:115])=[C:111]([Cl:116])[CH:110]=5)=[CH:103][CH:102]=4)[C:93](=[O:100])[N:94]3[CH3:99])=[CH:89][C:88]=2[CH2:87][N:86]1[S:117]([C:120]1[S:124][C:123]([NH:125]C(=O)C)=[N:122][C:121]=1[CH3:129])(=[O:119])=[O:118])=[O:84])[CH2:67][C:68]1[CH:73]=[CH:72][C:71]([C:74]2[CH:79]=[CH:78][C:77]([C:80]#[N:81])=[CH:76][CH:75]=2)=[CH:70][CH:69]=1>>[CH3:63][O:64][C:65](=[O:130])[C@@H:66]([NH:82][C:83]([CH:85]1[CH2:98][C:97]2[CH:96]=[C:95]3[C:90]([O:91][C@@H:92]([C:101]4[CH:102]=[CH:103][C:104]([O:107][CH2:108][C:109]5[CH:114]=[CH:113][C:112]([Cl:115])=[C:111]([Cl:116])[CH:110]=5)=[CH:105][CH:106]=4)[C:93](=[O:100])[N:94]3[CH3:99])=[CH:89][C:88]=2[CH2:87][N:86]1[S:117]([C:120]1[S:124][C:123]([NH2:125])=[N:122][C:121]=1[CH3:129])(=[O:119])=[O:118])=[O:84])[CH2:67][C:68]1[CH:69]=[CH:70][C:71]([C:74]2[CH:75]=[CH:76][C:77]([C:80]#[N:81])=[CH:78][CH:79]=2)=[CH:72][CH:73]=1

Komponenten

Edukt 2

HCID 66922606(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 tert-butyl ester

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

Produkt 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

Versuchsvorschrift

(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-tert-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-tert-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 tert-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)

Aufarbeitung

additionThis mixture of acids

Quellen und Nachweise

ORD-Eintrag: ord-e921f9cea2f7444dacd632e167a5127c
Quelldatensatz: uspto-grants-2011_03
DOI: 10.6084/m9.figshare.5104873.v1
Patentnummer: US07906507B2

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