Ammonium Hydroxide → HCID 58020341, compound

HRID 1632069Notes

Reaction equation

HRID 1632069 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[C:28](O)=[O:29])=[N:21][CH:22]=3)[C:9]=2[F:31])[CH:5]=[CH:6][CH:7]=1.C([N:35](C(C)C)CC)(C)C.C(OC(Cl)=O)C(C)C.[OH-].[NH4+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[C:28]([NH2:35])=[O:29])=[N:21][CH:22]=3)[C:9]=2[F:31])[CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 14923Ammonium HydroxideHCID 62365Isobutyl chloroformateHCID 81531DiisopropylethylamineHCID 57703785HCID 57703785, compound

Product 1

HCID 58020341HCID 58020341, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
2.5 °C

Procedure

To a cooled (0-5° C.) and stirred solution of (S)-1-[5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-pyrrolidine-2-carboxylic acid (I-143, 0.15 g, 0.34 mmol) in THF (2 mL) was added diisopropylethylamine (0.05 g, 0.37 mmol). The reaction mixture was stirred for 5 min, isobutylchloroformate (0.05 g, 0.37 mmol) was added, stirred at 0-5° C. for 45 min. Ammonium hydroxide (28%, 4.0 mL) was added, the reaction warmed to ambient temperature, stirred for 1.5 h. The reaction mixture was diluted with water (5 mL). The organic layer was separated, the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane followed by preparative thin layer chromatography using 5% methanol in dichloromethane to afford 0.074 g (49%) of P-612 as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): 8.27 (d, J=2.4 Hz, 1H), 7.34-7.46 (m, 4H), 8.2 (d, J=8.8 Hz, 1H), 7.65 (dd, J=8.8, 2.4 Hz, 1H), 7.4-7.46 (m, 2H), 7.37 (br s, 1H), 7.26-7.38 (m, 2H), 6.94 (d, J=8.0 Hz, 1H), 3.92-3.98 (m 3H), 3.93 (s, 2H), 3.73 (s, 3H), 2.55 (t, J=8.4 Hz, 2H), 1.98-2.06 (m, 2H) ppm; MS (APCI+): 441.1 (M+1), LC-MS: 97.0%; HPLC 97.1% pure.

Workup

  1. stirringstirred at 0-5° C. for 45 min
  2. temperaturethe reaction warmed to ambient temperature
  3. stirringstirred for 1.5 h
  4. customThe organic layer was separated
  5. extractionthe aqueous layer was extracted with ethyl acetate (2×20 mL)
  6. dry with materialThe combined organic layers were dried with Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by silica gel column chromatography
  10. customto afford 0.074 g (49%) of P-612 as an off-white solid

Sources & evidence

ORD record
ord-7484ee30f31e4f24b2d658d8c28fb544
Source dataset
uspto-grants-2014_07
Patent number
US08791267B2

Reaction notes

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