HCID 66732135, compound → HCID 68498550, compound

HRID 1963427Notes

Reaction equation

HRID 1963427 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][N:10]1[C:21]([O:23][CH3:24])=[O:22]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:14][C@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][N:10]1[C:21]([O:23][CH3:24])=[O:22]

Participants

3

Reactant 1

HCID 66732135HCID 66732135, compound

Product 1

HCID 68498550HCID 68498550, compoundYield 39.1%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

Methyl 2-(2,4-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.870 g, 2.34 mmol) was subjected to chiral preparative HPLC: Separation 1: The enantiomers were separated using chiral preparative HPLC (Column: ReproSil (250×50 mm), 8 μm particle size, mobile phase: Heptane/EtOH/FA 60/40/0.1, flow rate 120 mL/min) to yield a mixture of one cis- and one trans-enantiomer. Separation 2: The enantiomers were separated using chiral preparative HPLC (Column: CelluCoat (250×20 mm), 5 μm particle size, mobile phase: Heptane/IPA/FA 80/20/0.1, flow rate 18 mL/min) (2R,4S)-Methyl 2-(2,4-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (334 mg, 38%) was isolated. Chiral purity 99.7% de, Optical rotation [α]D20=+64.0 (acetonitrile, c=1.0), 1H NMR (400 MHz, cdcl3) δ 1.79-1.92 (m, 2H), 2.25-2.48 (m, 2H), 3.02-3.13 (m, 1H), 3.53-3.64 (m, 4H), 4.12-4.21 (m, 1H), 5.16 (dd, 1H), 5.64 (s, 1H), 7.12-7.22 (m, 2H), 7.36 (d, 1H). (2S,4R)-methyl 2-(2,4-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (340 mg, 39%) was isolated. Chiral purity 99.9% de, Optical rotation [α]D20=−65.1 (acetonitrile, c=1.0), 1H NMR (400 MHz, cdcl3) δ 1.79-1.92 (m, 2H), 2.26-2.38 (m, 1H), 2.39-2.48 (m, 1H), 3.03-3.13 (m, 1H), 3.53-3.64 (m, 4H), 4.12-4.22 (m, 1H), 5.16 (dd, 1H), 5.64 (s, 1H), 7.13-7.22 (m, 2H), 7.36 (d, 1H). (2S,4S)-Methyl 2-(2,4-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (67 mg, 8%) was isolated. Chiral purity 98.7% de, Optical rotation [α]D20=+11.5 (acetonitrile, c=1.0), 1H NMR (400 MHz, cdcl3) δ 1.72 (dq, 1H), 2.01-2.19 (m, 2H), 2.40-2.49 (m, 1H), 2.74 (tt, 1H), 3.43 (dt, 1H), 3.66 (s, 3H), 4.40 (d, br., 1H), 5.61-5.71 (m, 2H), 7.14-7.24 (m, 2H), 7.40 (d, 1H). (2R,4R)-Methyl 2-(2,4-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (75 mg, 9%) was isolated. Chiral purity 98.5% de, Optical rotation [α]D20=−10.9 (acetonitrile, c=1.0), 1H NMR (400 MHz, cdcl3) δ 1.72 (dq, 1H), 2.01-2.19 (m, 2H), 2.40-2.49 (m, 1H), 2.74 (tt, 1H), 3.43 (dt, 1H), 3.68 (s, 3H), 4.40 (d, br., 1H), 5.61-5.71 (m, 2H), 7.14-7.24 (m, 2H), 7.41 (d, 1H).

Workup

  1. customSeparation 1
  2. customThe enantiomers were separated
  3. customto yield
  4. additiona mixture of one cis- and one trans-enantiomer
  5. customSeparation 2
  6. customThe enantiomers were separated
  7. customwas isolated

Sources & evidence

ORD record
ord-4999162c213643409826c6a05df05a98
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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