Pyridine → tert-Butyl 2-(2-(4-(hydroxyimino)-6-(methylsulfonamido)spiro[chroman-2,4'-piperidine]-1'-yl)ethoxy)ethylcarbamate

HRID 1093904Notes

Reaction equation

HRID 1093904 reaction equation
N1C=CC=CC=1.Cl.[NH2:8][OH:9].[CH3:10][S:11]([NH:14][C:15]1[CH:16]=[C:17]2[C:40](=[CH:41][CH:42]=1)[O:39][C:20]1([CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:22][CH2:21]1)[CH2:19][C:18]2=O)(=[O:13])=[O:12]>CO.ClCCl>[OH:9][N:8]=[C:18]1[C:17]2[C:40](=[CH:41][CH:42]=[C:15]([NH:14][S:11]([CH3:10])(=[O:13])=[O:12])[CH:16]=2)[O:39][C:20]2([CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH2:22][CH2:21]2)[CH2:19]1

Participants

6

Reactant 3

HCID 1049Pyridine2×HCID 443297Hydroxyamine hydrochloride4×HCID 57903876tert-Butyl 2-(2-(6-(methylsulfonamido)-4-oxospiro[chroman-2,4'-piperidine]-1'-yl)ethoxy)ethylcarbamate2×

Product 1

HCID 76637434tert-Butyl 2-(2-(4-(hydroxyimino)-6-(methylsulfonamido)spiro[chroman-2,4'-piperidine]-1'-yl)ethoxy)ethylcarbamateYield 98.1%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 6344DichloromethaneSolvent

Procedure

Anhydrous pyridine (40 μL, 0.5 mmol) and hydroxylamine hydrochloride (8 mg, 0.11 mmol) were added to a solution of tert-butyl 2-(2-(6-(methylsulfonamido)-4-oxospiro[chroman-2,4′-piperidine]-1′-yl)ethoxy)ethylcarbamate (12, 50 mg, 0.10 mmol) in 5 mL of anhydrous methanol. This solution was stirred at room temperature for ˜1 hour and then at ˜60° C. for ˜1 hour. Additional hydroxylamine hydrochloride (6.2 mg, 0.09 mmol) and anhydrous pyridine (40 μL, 0.5 mmol) were added and stirring was continued at 60-65° C. for ˜1 hour. More hydroxylamine hydrochloride (13.9 mg, 0.20 mmol) was added and stirring was continued at 60-65° C. for ˜80 minutes. Hydroxylamine hydrochloride (7 mg, 0.10 mmol) was added and stirring was continued at 60-65° C. for ˜2 hours. TLC (silica gel, 10% methanol in dichloromethane, UV visualization) showed complete disappearance of starting ketone 12 (Rf=0.35-0.4) and a single new spot (18, Rf=0.18-0.27). The reaction mixture was concentrated to dryness under reduced pressure on a rotary evaporator. The residue was dissolved in 5 mL of ethyl acetate and extracted successively with 10 mL of 0.5 M aqueous hydrochloric acid, mL of water, and 5 mL of saturated aqueous sodium chloride. TLC (as above) showed the product (18) in the combined aqueous extracts, which were adjusted to pH ˜13 by addition of sodium hydroxide pellets and then to pH ˜4 by addition of 3 M aqueous hydrochloric acid. The aqueous solution was extracted with three 20 mL portions of ethyl acetate. The combined ethyl acetate extract was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure on a rotary evaporator followed by high vacuum overnight to afford 50.3 mg (98% yield) tert-butyl 2-(2-(4-(hydroxyimino)-6-(methylsulfonamido)-spiro[chroman-2,4′-piperidine]-1′-yl)ethoxy)ethylcarbamate (18).

Workup

  1. waitat ˜60° C. for ˜1 hour
  2. stirringstirring
  3. waitwas continued at 60-65° C. for ˜1 hour
  4. stirringstirring
  5. waitwas continued at 60-65° C. for ˜80 minutes
  6. stirringstirring
  7. waitwas continued at 60-65° C. for ˜2 hours
  8. concentrationThe reaction mixture was concentrated to dryness under reduced pressure on a rotary evaporator
  9. dissolutionThe residue was dissolved in 5 mL of ethyl acetate
  10. extractionextracted successively with 10 mL of 0.5 M aqueous hydrochloric acid, mL of water, and 5 mL of saturated aqueous sodium chloride
  11. additionwere adjusted to pH ˜13 by addition of sodium hydroxide pellets
  12. additionto pH ˜4 by addition of 3 M aqueous hydrochloric acid
  13. extractionThe aqueous solution was extracted with three 20 mL portions of ethyl acetate
  14. extractionThe combined ethyl acetate extract
  15. dry with materialwas dried over anhydrous sodium sulfate
  16. filtrationfiltered
  17. customevaporated to dryness under reduced pressure on a rotary evaporator
  18. customfollowed by high vacuum overnight

Sources & evidence

ORD record
ord-669940a7a1774e27831541decd22b631
Source dataset
uspto-grants-2012_03
Patent number
US08133695B2

Reaction notes

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