3,4-Dichloro-5-isothiazolecarboxylic acid → 3,4-Dichloroisothiazole-5-carboxylic acid [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]amide

HRID 1500013Notes

Reaction equation

HRID 1500013 reaction equation
[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([OH:10])=O)[S:4][N:3]=1.[F:11][C:12]1[C:13]([NH2:27])=[N:14][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:16][CH:17]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.ClN1C(Cl)=C(C(Cl)=O)SC1>C(Cl)(=O)C(Cl)=O.CN(C)C=O.C1COCC1.O>[F:11][C:12]1[C:13]([NH:27][C:8]([C:5]2[S:4][N:3]=[C:2]([Cl:1])[C:6]=2[Cl:7])=[O:10])=[N:14][C:15]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[N:16][CH:17]=1

Participants

9

Reactant 4

HCID 498373,4-Dichloro-5-isothiazolecarboxylic acidHCID 2733832Lithium HexamethyldisilazideHCID 578185745-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-amineHCID 866332223,4-Dichlorothiazole-5-carbonyl chloride

Product 1

HCID 578192363,4-Dichloroisothiazole-5-carboxylic acid [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]amideYield 12.3%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 65578Oxalyl chlorideSolvent

Conditions

Temperature
80 °C

Procedure

To a suspension of 3,4-dichloroisothiazole-5-carboxylic acid (0.15 g, 0.76 mmol) in oxalyl chloride (2 mL) was added a catalytic amount of dimethylformamide (2 drops) and the mixture was heated to 80° C. and stirred for 2 h. The excess oxalyl chloride was removed on the rotary evaporator. Meanwhile, 5-fluoro-2-(4-fluorobenzyloxy)-pyrimidin-4-ylamine (0.17 g, 0.68 mmol) was dissolved in THF (1 mL), treated with LiHMDS (1M in THF, 0.76 mL, 0.76 mmol) and stirred for 10 min. The freshly prepared 3,4-dichlorothiazole-5-carbonyl chloride*, dissolved in THF (1 mL), was added and the reaction was capped and stirred for 12 h. The reaction was diluted with water and the target compound was extracted with CH2Cl2 (3×5 mL). The combined extracts were dried over MgSO4 and then evaporated under reduced pressure. The mixture was eluted with CH2Cl2 through an anionic-exchange solid phase extraction column and then further purified by reverse-phase chromatography to give 3,4-dichloroisothiazole-5-carboxylic acid [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]amide (0.035 g, 12%) as a tan solid: mp 87-90° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.67 (s, 1H), 7.51-7.48 (m, 2H), 7.24-7.19 (m, 2H), 5.25 (s, 2H); MS (ESI) m/z 417 (M+H)+, 415 (M−H)−. *Nagata, T.; Kogure, A.; Yonekura, N.; Hanai, R.; Kaneko, I.; Nakano, Y. JP 2007211002 A

Workup

  1. customThe excess oxalyl chloride was removed on the rotary evaporator
  2. stirringstirred for 10 min
  3. additionwas added
  4. customthe reaction was capped
  5. stirringstirred for 12 h
  6. extractionthe target compound was extracted with CH2Cl2 (3×5 mL)
  7. dry with materialThe combined extracts were dried over MgSO4
  8. customevaporated under reduced pressure
  9. washThe mixture was eluted with CH2Cl2 through an anionic-exchange solid phase extraction column
  10. customfurther purified by reverse-phase chromatography

Sources & evidence

ORD record
ord-16d4dd5ada8044129114c22da02ec662
Source dataset
uspto-grants-2015_12
Patent number
US09204653B2

Reaction notes

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