4-Methylmorpholine → (S)-1-((S)-6-(5-(6-(4-(2-((1R,3S,4S)-2-((S)-4-(difluoromethoxy)-2-(methoxycarbonylamino)butanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester

HRID 71970Notes

Reaction equation

Cl.Cl.Cl.Cl.[C@H:5]12[CH2:11][C@H:8]([CH2:9][CH2:10]1)[C@@H:7]([C:12]1[NH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[CH:29]=[C:28]([C:33]4[NH:37][C:36]([C@@H:38]6[CH2:44][C:41]7([CH2:43][CH2:42]7)[CH2:40][N:39]6[C:45](=[O:55])[C@@H:46]([NH:50][C:51](=[O:54])[O:52][CH3:53])[CH:47]([CH3:49])[CH3:48])=[N:35][CH:34]=4)[CH:27]=[CH:26]5)=[CH:19][CH:18]=3)=[CH:15][N:16]=1)[NH:6]2.[F:56][CH:57]([F:70])[O:58][CH2:59][CH2:60][C@H:61]([NH:65][C:66]([O:68][CH3:69])=[O:67])[C:62](O)=[O:63].Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1.CN1CCOCC1>CN(C)C=O>[CH3:53][O:52][C:51](=[O:54])[NH:50][C@@H:46]([CH:47]([CH3:49])[CH3:48])[C:45]([N:39]1[C@H:38]([C:36]2[NH:37][C:33]([C:28]3[CH:27]=[CH:26][C:25]4[C:30](=[CH:31][CH:32]=[C:23]([C:20]5[CH:19]=[CH:18][C:17]([C:14]6[NH:13][C:12]([C@@H:7]7[C@@H:8]8[CH2:11][C@@H:5]([CH2:10][CH2:9]8)[N:6]7[C:62](=[O:63])[C@@H:61]([NH:65][C:66]([O:68][CH3:69])=[O:67])[CH2:60][CH2:59][O:58][CH:57]([F:70])[F:56])=[N:16][CH:15]=6)=[CH:22][CH:21]=5)[CH:24]=4)[CH:29]=3)=[CH:34][N:35]=2)[CH2:44][C:41]2([CH2:42][CH2:43]2)[CH2:40]1)=[O:55]

Participants

Conditions

Temperature: 0 °C

Procedure

Methyl (S)-1-((S)-6-(5-(6-(4-(2-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-ylcarbamate tetrahydrochloride (66 mg, 0.096 mmol), (S)-4-(difluoromethoxy)-2-(methoxycarbonylamino) butanoic acid (20 mg, 0.088 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (24 mg, and hydroxybenzotriazole hydrate (HOBt) (17 mg, 0.125 mmol) were all weighed out in a flask and anhydrous N,N-dimethylformamide (1 mL) was added. The mixture was cooled down in an ice bath to 0° C. and N-methylmorpholine (NMM) (58 mg, 0.576 mmol) was added from a syringe to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting mixture was then directly purified on reverse phase prep. HPLC. 37 mg, (43%). 1H-NMR: 400 MHz, (CD3OD) δ 8.08 (s, 1H), 8.01 (d, J=16 Hz, 1H), 7.86-7.66 (m, 10H), 7.38 (s, 1H), 7.27 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.58 (t, J=75.6 Hz, 1H), 5.32 (t, J=7.2 Hz, 1H), 4.70 (s, 1H), 6.6-6.25 (m, 1H), 4.51 (s, 1H), 4.14 (m, 1H), 3.98-3.78 (m, 4H), 3.63 (s, 6H), 3.50-3.46 (m, 1H), 2.70 (brs, 1H), 2.39-1.78 (m, 7H), 1.71-1.40 (m, 2H), 0.99-0.90 (m, 5H), 0.82-0.60 (m, 4H). MS (ESI) m/z 894.16 [M+H]+.

Workup

customall weighed out in a flask
customThe resulting mixture was then directly purified on reverse phase prep

Sources & evidence

ORD record: ord-06f7188291974a16badf0e49b4717f51
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08822430B2

Reaction notes

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