tert-Butyl methyl ether → 1-{4-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperazin-1-yl}-2-hydroxy-ethanone

HRID 1842003Notes

Reaction equation

HRID 1842003 reaction equation
[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[O:23][C:18]4=[N:19][CH:20]=[CH:21][CH:22]=[C:17]4[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:25]([CH2:27][O:28]C(=O)C)=[O:26].CCN(C(C)C)C(C)C.C(OC)(C)(C)C>C(Cl)Cl>[O:16]1[C:17]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[O:23][C@@H:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][N:1]3[CH2:6][CH2:5][N:4]([C:25](=[O:26])[CH2:27][OH:28])[CH2:3][CH2:2]3)=[CH:9][CH:10]=2)[CH2:15]1

Participants

6

Reactant 4

HCID 15413tert-Butyl methyl etherHCID 26297Acetoxyacetyl chlorideHCID 81531DiisopropylethylamineHCID 86695358(S)-3-(4-piperazin-1-ylmethyl-phenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine

Product 1

HCID 717371781-{4-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperazin-1-yl}-2-hydroxy-ethanone

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of Intermediate S (5.80 g, 17.7 mmol) in DCM (200 mL) at 0° C. is added acetic acid chlorocarbonylmethyl ester (2.16 mL, 19.5 mmol) followed by DIPEA (7.50 mL, 35.4 mmol) and the mixture stirred at rt for 1 h. The reaction was concentrated and the residue dissolved in 4:1 MeOH/water (100 mL) then treated with LiOH monohydrate (2.23 g, 53.1 mmol). After 72 h, the reaction is poured into ice water and the resulting solid isolated by filtration. The solid is suspended in refluxing tert-butylmethyl ether (400 mL) for 20 min and the remaining undissolved material separated out by filtration. The cooled filtrate produces a solid that is then isolated by filtration in several crops. The undissolved material from the first filtration is dissolved in refluxing 1,4-dioxane and cooled to give an additional crop of solid. The crops are combined to give the title product 253. (LC/MS method 16: ES+ m/z 370.3 [M+H]+, Rt=0.35 min)

Workup

  1. concentrationThe reaction was concentrated
  2. dissolutionthe residue dissolved in 4:1 MeOH/water (100 mL)
  3. waitAfter 72 h
  4. customthe resulting solid isolated by filtration
  5. customthe remaining undissolved material separated out by filtration
  6. customThe cooled filtrate produces a solid
  7. customthat is then isolated by filtration in several crops
  8. filtrationThe undissolved material from the first filtration
  9. dissolutionis dissolved
  10. temperaturein refluxing 1,4-dioxane
  11. temperaturecooled
  12. customto give an additional crop of solid

Sources & evidence

ORD record
ord-6578b04648d64e6cbd4a2bc1f91c6c42
Source dataset
uspto-grants-2015_02
Patent number
US08946203B2

Reaction notes

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