Hydroxylamine → (+)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)-N-hydroxyacetamide

HRID 1525903Notes

Reaction equation

HRID 1525903 reaction equation
[CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12]([CH:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:35]=[C:34]6[C:29]([CH:30]=[CH:31][CH:32]=[N:33]6)=[CH:28][CH:27]=5)=[CH:22][C:21]=4[F:36])[C:16]([O:18]C)=O)[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:37])[CH2:3][CH2:2]1.[OH-:38].[K+].[NH2:40]O>CO.O1CCCC1>[CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12]([CH:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:35]=[C:34]6[C:29]([CH:30]=[CH:31][CH:32]=[N:33]6)=[CH:28][CH:27]=5)=[CH:22][C:21]=4[F:36])[C:16]([NH:40][OH:38])=[O:18])[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:37])[CH2:2][CH2:3]1

Participants

6

Reactant 3

HCID 787HydroxylamineHCID 14797Potassium HydroxideHCID 71270934Methyl 2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)acetate

Product 1

HCID 71529427(+)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)-N-hydroxyacetamideYield 7.1%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of methyl 2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)acetate (0.560 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was treated with potassium hydroxide (1.782 mmol) and hydroxylamine (50% w/v in water, 8.16 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction solution was then concentrated to dryness under a stream of nitrogen. Purification of the residue by reverse phase HPLC (20-60% acetonitrile/water with 0.1% NH4OH) followed by chiral HPLC (Chiralpak AS-H column, acetonitrile:methanol 98:2) and lyophilization from water (w/25% acetonitrile) afforded the title compound as a white solid (20 mg, 6%). MS(ES)+ m/e 504.9 [M+H]+, >99% ee, αD=+17 deg (c=0.02, acetonitrile:methanol 98:2).

Workup

  1. concentrationThe reaction solution was then concentrated to dryness under a stream of nitrogen
  2. customPurification of the residue by reverse phase HPLC (20-60% acetonitrile/water with 0.1% NH4OH)

Sources & evidence

ORD record
ord-7f6ce25295354f41b11b0b312298fe41
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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