(3R,8S)-3-[4-(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 8-methyl ester → (3R,8S)-8-[(S)-2-(4'-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester

HRID 391873Notes

Reaction equation

COC([C@@H]1CC2C=C3OC[C@@H](C4C=CC(OCC5C=CC(Cl)=C(Cl)C=5)=CC=4)OC3=CC=2CN1C(OC(C)(C)C)=O)=O.[C:42]([O:46][C:47]([N:49]1[C@H:58]([C:59]([OH:61])=O)[CH2:57][C:56]2[CH:55]=[C:54]3[O:62][CH2:63][C@@H:64]([C:66]4[CH:71]=[CH:70][C:69]([O:72][CH2:73][C:74]5[CH:79]=[CH:78][C:77]([Cl:80])=[C:76]([Cl:81])[CH:75]=5)=[CH:68][CH:67]=4)[O:65][C:53]3=[CH:52][C:51]=2[CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43].[CH3:82][O:83][C:84](=[O:102])[C@@H:85]([NH2:101])[CH2:86][C:87]1[CH:92]=[CH:91][C:90]([C:93]2[CH:98]=[CH:97][C:96]([C:99]#[N:100])=[CH:95][CH:94]=2)=[CH:89][CH:88]=1>>[C:42]([O:46][C:47]([N:49]1[C@H:58]([C:59](=[O:61])[NH:101][C@H:85]([C:84]([O:83][CH3:82])=[O:102])[CH2:86][C:87]2[CH:88]=[CH:89][C:90]([C:93]3[CH:98]=[CH:97][C:96]([C:99]#[N:100])=[CH:95][CH:94]=3)=[CH:91][CH:92]=2)[CH2:57][C:56]2[CH:55]=[C:54]3[O:62][CH2:63][C@@H:64]([C:66]4[CH:71]=[CH:70][C:69]([O:72][CH2:73][C:74]5[CH:79]=[CH:78][C:77]([Cl:80])=[C:76]([Cl:81])[CH:75]=5)=[CH:68][CH:67]=4)[O:65][C:53]3=[CH:52][C:51]=2[CH2:50]1)=[O:48])([CH3:43])([CH3:44])[CH3:45]

Participants

Reactant 3

HCID 58327259(3R,8S)-3-[4-(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 8-methyl ester

HCID 58327389(3R,8S)-3-[4-(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

HCID 59337513Methyl (s)-2-amino-3-(4'-cyano-[1,1'-biphenyl]-4-yl)propanoate

Product 1

HCID 66719392(3R,8S)-8-[(S)-2-(4'-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl esterYield 76.7%

Procedure

(3R,8S)-3-[4-(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 8-methyl ester (200 mg) was hydrolyzed according to General Procedure B. The resulting (3R,8S)-3-[4-(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 (172 mg) was coupled with (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (126 mg) according to General Procedure A to give (3R,8S)-8-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (191 mg). Boc-cyano-biphenyl ester (188 mg) was treated as described in General Procedure C to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(3R,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester hydrochloride salt (155 mg). LCMS: (m/z) 749; 1H NMR (400 MHz, Methanol-d6): 8.54 (d, 1H), 7.95 (s, 1H), 7.87 (d, 1H), 7.81-7.72 (m, 2H), 7.63-51 (m, 4H), 7.50-7.47 (m, 2H), 7.38-7.32 (m, 3H), 7.01 (d, 2H), 6.99 (d, 2H), 5.07 (s, 2H) 5.04-5.03 (m, 1H), 4.34-4.31 (m, 1H), 4.12-4.08 (m, 1H), 4.01-3.96 (m, 3H), 3.75 (s, 3H), 3.74-3.63 (m, 4H), 3.11-2.97 (m, 2H).

Sources & evidence

ORD record: ord-a6500b9b2ed54ec492daf8695bd7aac0
Source dataset: uspto-grants-2013_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08383644B2

Reaction notes

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