1,2-Dichloroethane → HCID 66563118, compound

HRID 1481835Notes

Reaction equation

HRID 1481835 reaction equation
COC1C=CC(C[N:8]2[C:12](=[O:13])[C:11]3([CH2:25][C:16]4=[N:17][CH:18]=[C:19]([C:21](OC)=[O:22])[CH:20]=[C:15]4[CH2:14]3)[N:10]([CH3:26])[C:9]2=[O:27])=CC=1.Cl.[NH2:31][C@H:32]1[CH2:37][C@@H:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[C:40]([F:45])[C:39]=2[F:46])[C@@H:35]([CH3:47])[N:34]([CH2:48][C:49]([F:52])([F:51])[F:50])[C:33]1=[O:53].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:26][N:10]1[C@:11]2([CH2:25][C:16]3=[N:17][CH:18]=[C:19]([C:21]([NH:31][C@H:32]4[CH2:37][C@@H:36]([C:38]5[C:43]([F:44])=[CH:42][CH:41]=[C:40]([F:45])[C:39]=5[F:46])[C@@H:35]([CH3:47])[N:34]([CH2:48][C:49]([F:52])([F:51])[F:50])[C:33]4=[O:53])=[O:22])[CH:20]=[C:15]3[CH2:14]2)[C:12](=[O:13])[NH:8][C:9]1=[O:27]

Participants

8

Reactant 6

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 86665213HCID 86665213, compound2×HCID 86707877HCID 86707877, compound2×

Product 1

HCID 66563118HCID 66563118, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred mixture of 3′-methyl-2′,5′-dioxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-imidazolidine]-3-carboxylic acid (described in Intermediate 1, 20 mg, 0.077 mmol), (3S,5S,6R)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride (described in Intermediate 5, 22 mg, 0.058 mmol), HOBT (12 mg, 0.078 mmol), and EDC (15 mg, 0.078 mmol) in DMF (0.5 mL) was added N,N-diisopropylethylamine (0.031 mL, 0.175 mmol), and the resulting mixture was stirred at ambient temperature for 18 h. The reaction mixture was poured into saturated aqueous sodium bicarbonate (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH:NH4OH 100:0:0 to 90:10:1, to give the desired product as a mixture of isomers. Separation of the stereoisomers was achieved by SFC using a ChiralPak IC column, eluting with CO2:MeOH:Et2NH—75:25:0.1, to give (6S)-3′-methyl-N-[(3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2′,5′-dioxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-imidazolidine]-3-carboxamide, which was the first major peak to elute, and the title compound, which was the second major peak to elute. HRMS: m/z=584.1715 (M+1), calculated m/z=584.1727 for C26H24F6N5O4. 1H NMR (500 MHz, CD3OD) δ 8.87 (s, 1H), 8.14 (s, 1H), 7.28 (qd, 1H, J=9.0, 4.6 Hz), 7.02 (m, 1H), 4.79 (m, 1H), 4.54 (dd, 1H, J=11.7, 6.8 Hz), 4.02 (m, 1H), 3.93 (m, 1H), 3.68 (dq, 1H, J=15.4, 8.8 Hz), 3.55 (d, 1H, J=18.1 Hz), 3.54 (d, 1H, J=17.6 Hz), 3.40 (d, 2H, J=17.8 Hz), 3.20 (m, 1H), 2.72 (s, 3H), 2.34 (m, 1H), 1.33 (d, 3H, J=6.4 Hz).

Workup

  1. extractionextracted with EtOAc (2×10 mL)
  2. washThe combined organic layers were washed with brine
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified by silica gel chromatography
  6. washeluting with a gradient of CH2Cl2:MeOH:NH4OH 100:0:0 to 90:10:1

Sources & evidence

ORD record
ord-21e4e48fd2934e1e9b942e4a0bf56738
Source dataset
uspto-grants-2016_08
Patent number
US09409916B2

Reaction notes

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