HCID 131733565, compound → HCID 86724154, compound

HRID 1748831Notes

Reaction equation

HRID 1748831 reaction equation
[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1[CH:14]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[CH3:27])[CH2:15][CH2:16][C:17]([O-:19])=[O:18]>C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1[CH:14]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[CH3:27])[CH2:15][CH2:16][C:17]([OH:19])=[O:18]

Participants

4

Reactant 1

HCID 131733565HCID 131733565, compound

Product 1

HCID 86724154HCID 86724154, compoundYield 100%

Reagents, catalysts & solvents 2

HCID 311Citric AcidSolventHCID 6344DichloromethaneSolvent

Procedure

Chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.068 g, 0.277 mmol), (S)-1-[(RP)-2-[Bis(4-methoxy-3,5-dimethylphenyl)phosphino]ferrocenyl}ethyldi-tert-butylphosphine (0.182 g, 0.277 mmol), and 2-methylpropan-2-aminium (Z)-4-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)but-3-enoate (13.17 g, 27.7 mmol) were combined in a 250 mL stainless steel pressure bottle. A stir bar was added, and the system was degassed with 20 psi argon, and then vented. Argon-degassed MeOH (131 mL) was added against an argon stream by cannula, and the vessel was again sealed and degassed with argon. The system was shaken for about 30 min at about 50° C. The reactor was pressurized to 55 psi with hydrogen shaken at about 70° C. for about 14.5 h. The mixture was filtered through glass wool and concentrated in vacuo to give 2-methylpropan-2-aminium 4-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)butanoate (13.2 g, 100%) as a foam. 4-(5-Chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)butanoate (14.4 g, 30.2 mmol) in DCM (250 mL) and was washed with 20% citric acid (2×300 mL). The combined aqueous layers were extracted with DCM (250 mL). The combined organic layers were washed with H2O (400 mL). The aqueous layer was extracted with EtOAc (250 mL). The combined organic layers were concentrated in vacuo. The residue was dissolved in THF (150 mL) and loaded on a silica gel pad (600 g) then eluted with THF. The product containing fractions were concentrated in vacuo. The material was dissolved in 2-methyltetrahydrofuran (500 mL) then washed with 20% citric acid (400 mL), H2O (3×400 mL) and brine (400 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 4-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)butanoic acid (12.2 g, 100%): LC-MS (Table 1, Method g) Rt=2.37 min, m/z 404/406 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 11.98 (s, 1H), 8.60-8.56 (m, 1H), 7.86-7.79 (m, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.36-7.28 (m, 1H), 7.19-7.14 (m, 1H), 7.13-7.11 (m, 1H), 5.30-5.24 (m, 1H), 3.83 (s, 3H), 2.45-2.32 (m, 1H), 2.29-2.14 (m, 3H), 2.08 (s, 3H).

Workup

  1. extractionThe combined aqueous layers were extracted with DCM (250 mL)
  2. washThe combined organic layers were washed with H2O (400 mL)
  3. extractionThe aqueous layer was extracted with EtOAc (250 mL)
  4. concentrationThe combined organic layers were concentrated in vacuo
  5. dissolutionThe residue was dissolved in THF (150 mL)
  6. washthen eluted with THF
  7. additionThe product containing fractions
  8. concentrationwere concentrated in vacuo
  9. dissolutionThe material was dissolved in 2-methyltetrahydrofuran (500 mL)
  10. washthen washed with 20% citric acid (400 mL), H2O (3×400 mL) and brine (400 mL)
  11. dry with materialThe organic layer was dried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-7e4984654f534777ab16fe36381350d1
Source dataset
uspto-grants-2015_10
Patent number
US09150592B2

Reaction notes

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