Phosphorus oxychloride → Ethyl 2-[4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2-yl]acetate

HRID 928613Notes

Reaction equation

HRID 928613 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15](=O)[NH:14][C:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>C(N(CC)C1C=CC=CC=1)C>[Cl:26][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][S:10][C:11]=2[N:12]=[C:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:14]=1

Participants

4

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 68623660Ethyl 2-[5-(4-fluorophenyl)-4-oxo-4-H-thieno[2,3-d]pyrimidin-2-yl]acetate

Product 1

HCID 87518468Ethyl 2-[4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2-yl]acetate

Reagents, catalysts & solvents 1

HCID 7061N,N-DiethylanilineSolvent

Procedure

Ethyl 2-[5-(4-fluorophenyl)-4-oxo-4-H-thieno[2,3-d]pyrimidin-2-yl]acetate (10 g, 0.0301 mol) in N,N-diethylaniline (50 mL) and phosphorous oxychloride (150 mL) was heated to 115° C. for 4.5 hrs. The mixture was concentrated in vacuo and the residue poured into ice-water and allowed to stand overnight. The aqueous solution was neutralized with sodium bicarbonate, filtered, then extracted with DCM. The reaction was repeated on a further 10 g of ethyl 2-[5-(4-fluorophenyl)-4-oxo-4-H-thieno[2,3-d]pyrimidin-2-yl]acetate and the DCM extract combined with that of the first batch. The solvent was removed in vacuo and the residue purified by silica column chromatography eluting first with petroleum ether/DCM 50:50 v/v, then petroleum ether/DCM 25:75 v/v, followed by DCM (100%). Further fractions were eluted from the column with 25% diethyl ether in DCM. Fractions were analysed by TLC, combined and concentrated to give ethyl 2-[4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2-yl]acetate as a brown solid (14 g). LCMS RT=4.83 min, M+1=351.

Workup

  1. concentrationThe mixture was concentrated in vacuo
  2. additionthe residue poured into ice-water
  3. filtrationfiltered
  4. extractionextracted with DCM
  5. extractionthe DCM extract
  6. customThe solvent was removed in vacuo
  7. customthe residue purified by silica column chromatography
  8. washeluting first with petroleum ether/DCM 50:50 v/v
  9. washFurther fractions were eluted from the column with 25% diethyl ether in DCM
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-8ed06b4f8d0045f898ea60b97c774ce8
Source dataset
uspto-grants-2016_03
Patent number
US09290511B2

Reaction notes

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