(3S,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 → (3S,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

反応式

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].Cl.[CH3:83][O:84][C:85](=[O:103])[C@@H:86]([NH2:102])[CH2:87][C:88]1[CH:93]=[CH:92][C:91]([C:94]2[CH:99]=[CH:98][C:97]([C:100]#[N:101])=[CH:96][CH:95]=2)=[CH:90][CH:89]=1>>[C:42]([O:46][C:47]([N:49]1[C@H:58]([C:59](=[O:61])[NH:102][C@H:86]([C:85]([O:84][CH3:83])=[O:103])[CH2:87][C:88]2[CH:89]=[CH:90][C:91]([C:94]3[CH:99]=[CH:98][C:97]([C:100]#[N:101])=[CH:96][CH:95]=3)=[CH:92][CH:93]=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]

参加物

反応物 3

HCID 58327372(3S,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 58327424(3S,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 66719258(S)-2-amino-3-(4'-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride

生成物 1

HCID 66719667(3S,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収率 77.3%

実験手順

(3S,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 (708 mg) was hydrolyzed according to General Procedure B and the resulting (3S,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 (670 mg) was coupled with (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (363 mg) according to General Procedure L to give (3S,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 (750 mg). This intermediate (720 mg) was deprotected as described in General Procedure C to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(3S,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. This product was neutralized with aqueous Na2CO3 and the resulting solid was extracted with ethyl acetate (100 mL). The organic layer was washed with water, brine, dried and concentrated to furnish a white solid. The solid was purified by silica gel flash chromatography (9:1 to 1:1 DCM/EtOAc) to furnish (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(3S,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 (550 mg). LCMS (m/z): 748; 1H NMR (400 MHz, DMSO-d6): 8.25 (d, 1H), 7.85 (m, 4H), 7.70 (d, 1H), 7.65 (m, 3H), 7.42 (m, 1H), 7.31 (m, 4H), 7.02 (m, 2H), 6.60 (a, 1H), 6.65 (s, 1H), 5.12 (s, 2H) 5.06-5.08 (m, 1H), 4.6 (m, 1H), 4.27 (dd, 1H), 3.96 (m, 2H), 3.65 (bs, 1H), 3.64 (s, 3H), 3.38 (m, 1H), 3.0-3.16 (m, 2H), 2.5-2.76 (m, 2H).

出典と根拠

ORDレコード: ord-00584083bc7944c2b479f15016d2588f
出典データセット: uspto-grants-2013_02
DOI: 10.6084/m9.figshare.5104873.v1
特許番号: US08383644B2

反応ノート

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