(2-(Dimethylamino)ethyl)triphenylphosphonium bromide → N,N-dimethyl-N-((2Z)-3-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridin-2-yl}prop-2-enyl)amine

HRID 1765087Notes

Reaction equation

HRID 1765087 reaction equation
[Br-].[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:38][CH2:39][CH2:40][O:41][C:42]1[C:43]([CH:48]=O)=[N:44][CH:45]=[CH:46][CH:47]=1>C1COCC1.CC(O)(C)C>[CH3:2][N:3]([CH3:25])[CH2:4]/[CH:5]=[CH:48]\[C:43]1[C:42]([O:41][CH2:40][CH2:39][O:38][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][O:32]2)=[CH:47][CH:46]=[CH:45][N:44]=1

Participants

6

Reactant 3

HCID 2724136(2-(Dimethylamino)ethyl)triphenylphosphonium bromideHCID 211066753-[2-(Tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine-2-carbaldehydeHCID 23665647Potassium tert-butoxide

Product 1

HCID 69498118N,N-dimethyl-N-((2Z)-3-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridin-2-yl}prop-2-enyl)amineYield 10.4%

Reagents, catalysts & solvents 2

HCID 6386tert-ButanolSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a suspension of [2-(dimethylamino)ethyl](triphenyl)phosphonium bromide (32.1 g, 77.4 mmol) in dry THF (150 mL) was added a solution of potassium tert-butoxide (9.4 g, 83.7 mmol) in dry t-BuOH (100 mL). The suspension was sonicated for 15 minutes whereafter a solution of 3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine-2-carbaldehyde (from Step 1; 18.3 g, 72.8 mmol) in THF (30 mL) was added to the yellow suspension and stirred at room temperature for one hour and then for a further hour at 60° C. The solvent was removed under reduced pressure and the residue was mixed with water (0.8 L) and the pH was adjusted to 3–4 with HOAc (˜10 mL) and then extracted twice with CHCl3. The aqueous phase was made basic and extracted with CHCl3 (×3), the combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The crude product, consisting of the cis and trans* isomers were separated with preparative HPLC on an YMC ODS-AQ column (30×250 mm) with different gradients of 0.1% TFA in water/CH3CN. The cis isomer was isolated as a light yellow oil (2.33 g, 10%). HRMS m/z calcd for C17H26N2O3 (M)+ 306.1943. found 306.1942. *The corresponding trans isomer is described in Example 21, Step 1.

Workup

  1. additionwas added to the yellow suspension
  2. waitfor a further hour at 60° C
  3. customThe solvent was removed under reduced pressure
  4. additionthe residue was mixed with water (0.8 L)
  5. extractionextracted twice with CHCl3
  6. extractionextracted with CHCl3 (×3)
  7. dry with materialthe combined organic phases were dried (MgSO4)
  8. customthe solvent was removed under reduced pressure
  9. customwere separated with preparative HPLC on an YMC ODS-AQ column (30×250 mm) with different gradients of 0.1% TFA in water/CH3CN

Sources & evidence

ORD record
ord-7cd17dd07be147319d152a65f3dcd390
Source dataset
uspto-grants-2007_06
Patent number
US07226925B2

Reaction notes

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