1,4-Dioxa-8-azaspiro(4.5)decane → HCID 58815957, compound

HRID 2245884Notes

Reaction equation

HRID 2245884 reaction equation
[CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)[C:12]2[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=2)[C:15](N(C2C=CC=C(F)C=2)C)=[O:16])[C@@H:6]([CH3:36])[CH2:5]1)[CH:2]=[CH2:3].[O:37]1[C:41]2([CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[O:40][CH2:39][CH2:38]1.C([Mg]Cl)(C)C.ClCCl.C(OCC)(=O)C>C1COCC1>[OH-:16].[NH4+:4].[CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)[C:12]2[CH:13]=[C:14]([C:15]([N:44]3[CH2:45][CH2:46][C:41]4([O:40][CH2:39][CH2:38][O:37]4)[CH2:42][CH2:43]3)=[O:16])[CH:26]=[CH:27][CH:28]=2)[C@@H:6]([CH3:36])[CH2:5]1)[CH:2]=[CH2:3]

Participants

7

Reactant 4

HCID 674351,4-Dioxa-8-azaspiro(4.5)decaneHCID 9826770DPI-3290HCID 21226138Dichloromethane ethylacetateHCID 178418918HCID 178418918, compound

Product 2

HCID 14923Ammonium HydroxideYield 2%HCID 58815957HCID 58815957, compoundYield 189.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A 250 mL 3-necked round bottom flask equipped with a magnetic stir bar, a condenser topped with a nitrogen outlet, a stopper, and a rubber septum was flushed with nitrogen and charged with 24.38 g (50 mmol, 1 eq) of 3-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-hydroxyphenyl)methyl]-N-(3-fluorophenyl)-N-methylbenzamide {DPI-3290; U.S. Pat. No. 5,574,159, Example 16}, 7.5 mL (58.5 mmol, 1.17 eq) of 1,4-dioxa-8-azaspiro-[4.5]decane, and 100 mL of anhydrous tetrahydrofuran. While stirring briskly, 55 mL (110 mmol, 2.2 eq) of 2.0 M isopropylmagnesium chloride in THF was added by syringe over 5 minutes. A vigorous, exothermic reaction ensued. After addition was completed, a heating mantle was attached and the reaction was heated to reflux for 4 hours. The reaction was cooled to room temperature overnight under nitrogen. The reaction was quenched by careful addition of 15 mL of saturated aqueous NH4Cl solution and stirred vigorously for 30 minutes. Approximately 15 g of anhydrous magnesium sulfate was added and the mixture was filtered, rinsing the solids with THF (2×25 mL). The filtrate was concentrated in vacuo and the residue was partitioned between 100 mL ethyl acetate and water. The aqueous solution was adjusted to pH=8-9 using saturated sodium bicarbonate solution. The layers were separated and the organic phase was washed with water and then brine. The organic extract was dried over sodium sulfate/magnesium sulfate and the solvent was removed in vacuo, leaving 31.85 g of crude product as an amber-colored foam. Chromatography of this material on ˜300 g of silica gel eluting with dichloromethane/ethyl acetate with 2% ammonium hydroxide yielded 23.93 g (91.5%) of {3-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-hydroxyphenyl)methyl]-phenyl}-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methanone as an off-white foam. Calculated for C30H39N3O4 0.1 CH2Cl2 0.1 C4H8O2: %C, 70.05; H, 7.71; N, 8.04. Found: %C, 69.95; H, 7.80; N, 8.05. 1H NMR (300 MHz, CDCl3): {tilde over (□)}□d, J=7.6 Hz, 1H), 7.45 (s, 1H), 7.33-7.23 (m, 2H), 7.05 (t, J=7.7 Hz, 1H), 6.56 (t, J=8.3 Hz, 2H), 6.53 (s, 1H), 5.95-5.82 (m, 1H), 5.21 (d, J=9.3Hz, 1H), 5.16 (s, 2H), 3.97 (s, 4H), 3.82 (br s, 2H), 3.45-3.38 (m, 3H), 2.90-2.80 (m, 2H), 2.63-2.45 (m, 3H), 2.13 (dd, J=1.1, 10.9 Hz, 1H), 1.91 (dd, J=1.0, 11.2 Hz, 1H), 1.78 (br s, 2H), 1.60 (br s, 2H), 1.14 (d, J=6.0 Hz, 3H), 0.99 (d, J=6.1 Hz, 3H).

Workup

  1. customA 250 mL 3-necked round bottom flask equipped with a magnetic stir bar, a condenser
  2. customtopped with a nitrogen outlet
  3. customa stopper, and a rubber septum was flushed with nitrogen
  4. customA vigorous, exothermic reaction
  5. additionAfter addition
  6. temperaturethe reaction was heated
  7. temperatureto reflux for 4 hours
  8. customThe reaction was quenched by careful addition of 15 mL of saturated aqueous NH4Cl solution
  9. stirringstirred vigorously for 30 minutes
  10. additionApproximately 15 g of anhydrous magnesium sulfate was added
  11. filtrationthe mixture was filtered
  12. washrinsing the solids with THF (2×25 mL)
  13. concentrationThe filtrate was concentrated in vacuo
  14. customthe residue was partitioned between 100 mL ethyl acetate and water
  15. customThe layers were separated
  16. washthe organic phase was washed with water
  17. extractionThe organic extract
  18. dry with materialwas dried over sodium sulfate/magnesium sulfate
  19. customthe solvent was removed in vacuo
  20. customleaving 31.85 g of crude product as an amber-colored foam

Sources & evidence

ORD record
ord-5a62ce1348b44a399cd57071da6eaeca
Source dataset
uspto-grants-2010_03
Patent number
US07683168B2

Reaction notes

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