Hydrochloric Acid → HCID 44481594, compound

HRID 337694Notes

Reaction equation

C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][N:17]([CH3:20])[C:16](=[O:21])[CH:15]=2)[C@H:10]([C:22]([OH:24])=O)[CH2:9]1)=O)(C)(C)C.CN(C=O)C.C(Cl)(=O)C([Cl:33])=O.S(O)(=O)(=O)C.[Br:41][C:42]1[CH:43]=[C:44]([CH:50]=[C:51]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[C:52]=1[CH3:53])[CH2:45][NH:46][CH:47]1[CH2:49][CH2:48]1.CCN(C(C)C)C(C)C.Cl.[OH-].[Na+]>ClCCl.CC(O)C.CC(OC)(C)C.O>[ClH:33].[Br:41][C:42]1[CH:43]=[C:44]([CH2:45][N:46]([CH:47]2[CH2:48][CH2:49]2)[C:22]([C@H:10]2[C@H:11]([C:14]3[CH:19]=[CH:18][N:17]([CH3:20])[C:16](=[O:21])[CH:15]=3)[CH2:12][CH2:13][NH:8][CH2:9]2)=[O:24])[CH:50]=[C:51]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[C:52]=1[CH3:53]

Participants

Conditions

Temperature: -15 °C

Procedure

(3S,4S)-1′-Methyl-2′-oxo-3,4,5,6,1′,2′-hexahydro-2H-[4,4′]bipyridinyl-1,3-dicarboxylic acid 1-tert-butyl ester (carboxylic acid 1; 1.0 equiv.) was dissolved in dichloromethane (10 volumes). DMF (0.2 equiv.) was charged and the solution cooled to −15° C. Oxalyl chloride (0.95 equiv.) was added over 2.5 h. N-[3-Bromo-5-(3-methoxypropyl)-4-methylbenzyl]cyclopropanamine mesylate (amine 76 mesylate; 0.90 equiv.) dissolved in dichloromethane (2 volumes) and i-Pr2NEt (3.3 equiv.) was then added over 1 h at ˜−15° C. The reaction was quenched with water (10 volumes) and the layers were cut and the organic layer was washed with NaHCO3 solution. The layers were cut and the organic layer was washed with HCl solution. The organic layer was concentrated to ˜5.7 volumes. 2-Propanol (0.57 volumes) was added followed by conc. HCl (6.0 equiv.). The reaction mixture was aged for 75 min at 35° C. and then water (5.7 volumes) was added. The layers were cut and to the aqueous layer was added dichloromethane (11.4 volumes). Sodium hydroxide (6.7 equiv.) was added and the layers were cut. The organic layer was washed with water (5.7 volumes) and concentrated to ˜5 volumes. 2-Propanol was added 8 volumes) and the remaining dichloromethane was removed by distillation. Conc. HCl (0.2 equiv., 37%) in IPA 0.11 volumes) was then added and the batch was aged for 30 min. Further c. HCl (0.9 equiv., 37%) in IPA (0.5 volumes) was added over 1 h. MTBE (5.4 volumes) was added and the batch was aged for 1 h. The resultant slurry was filtered and the solids washed with MTBE to give (3S,4R)-N-({3-Bromo-4-methyl-5-[3-(methyloxy)propyl]phenyl}methyl)-N-cyclopropyl-4-(1-methyl-2-oxo-1,2-dihydro-4-pyridinyl)-3-piperidinecarboxamide hydrochloride as a white solid. 1H NMR (500 MHz, dmso-d6) δ 9.45 (br s, 2H), 7.57 (d, J=6.9 Hz, 1H), 6.96 (d, J=0.9 Hz, 1H), 6.79 (d, J=0.9 Hz, 1H), 6.13 (d, J=1.7 Hz, 1H), 6.04 (dd, J=6.9, 1.7, 1H). 4.58 (d, J=14.9 Hz, 1H), 4.12 (td, J=11.5, 3.5, 1H), 4.05 (d, J=14.9 Hz, 1H), 3.48 (dd, J=12.2, 3.5 Hz, 1H), 3.34 (s, 1H), 3.32 (m, 1H), 3.30 (t, J=6.2 Hz, 1H), 3.24 (s, 1H), 3.07-2.97 (om, 2H), 2.85 (m, 1H), 2.57 (m, 1H), 2.04 (qd, J=13.0, 3.8 Hz, 1H), 1.82 (m, 1H), 1.65 (m, 1H), 0.98 (m, 1H), 0.91-0.82 (om, 2H), 0.61 (m, 1H). HRMS (ES, M+H) Calcd 530.2018. Found 530.2008.

Workup

customThe reaction was quenched with water (10 volumes)
washthe organic layer was washed with NaHCO3 solution
washthe organic layer was washed with HCl solution
concentrationThe organic layer was concentrated to ˜5.7 volumes
addition2-Propanol (0.57 volumes) was added
washThe organic layer was washed with water (5.7 volumes)
concentrationconcentrated to ˜5 volumes
addition2-Propanol was added 8 volumes) and the remaining dichloromethane
customwas removed by distillation
waitthe batch was aged for 30 min
waitthe batch was aged for 1 h
filtrationThe resultant slurry was filtered
washthe solids washed with MTBE

Sources & evidence

ORD record: ord-098e2d9b686c44bc8bf1ed9444f8e7a0
Source dataset: uspto-grants-2014_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08889714B2

Reaction notes

Loading…