Tris(hydroxymethyl)aminomethane → 5-[7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-ylethynyl]-pyridine-3-sulfonic acid (2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-amide

HRID 1293775Notes

Reaction equation

HRID 1293775 reaction equation
Br[C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[CH2:12]([OH:19])[C:13]([NH2:18])([CH2:16][OH:17])[CH2:14][OH:15].[C:20]([C:22]1[CH:23]=[N:24][N:25]2[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][C:28]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)=[N:27][C:26]=12)#[CH:21].C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[OH:19][CH2:12][C:13]([NH:18][S:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:21]#[C:20][C:22]2[CH:23]=[N:24][N:25]3[C:30]([C:31]([F:32])([F:34])[F:33])=[CH:29][C:28]([C:35]4[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][CH:36]=4)=[N:27][C:26]=23)[CH:3]=1)(=[O:10])=[O:9])([CH2:16][OH:17])[CH2:14][OH:15]

Participants

8

Reactant 5

HCID 6503Tris(hydroxymethyl)aminomethaneHCID 8471TriethylamineHCID 11776TriphenylphosphineHCID 203244745-Bromopyridine-3-sulfonyl chlorideHCID 715397323-Ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine

Product 1

HCID 118520305-[7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-ylethynyl]-pyridine-3-sulfonic acid (2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-amideYield 10%

Reagents, catalysts & solvents 2

HCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 6228DimethylformamideSolvent2×

Procedure

To a solution of 5-bromo-pyridine-3-sulfonyl chloride (Example B.2, step 2)(500 mg, 2 mmol) in DMF (5 mL) at 5° C. was added Tris (260 mg, 2 mmol) in DMF (5 mL) and the mixture was vigorously stirred at room temp. for 16 h, then addition of 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (692 mg, 2 mmol), triethylamine (0.82 mL, 6 mmol), PdCl2(PPH3)2 (41 mg, 3 mol %), PPh3 (31 mg, 6 mol %) were stirred for 10 minutes at 23° C. while being purged with Argon, then CuI (3 mg, 1 mol %) was added. Stirring was continued for 16 h at 90° C. Purification by SiO2 column chromatography (heptane/EtOAc 3:1), trituration with ether, filtration and dried to give the product as an orange solid (120 mg, 10%). MS (ISN) 613.8 [(M−H)−]; mp 230–232° C.

Workup

  1. customat 5° C.
  2. stirringwere stirred for 10 minutes at 23° C.
  3. customwhile being purged with Argon
  4. additionCuI (3 mg, 1 mol %) was added
  5. stirringStirring
  6. waitwas continued for 16 h at 90° C
  7. customPurification by SiO2 column chromatography (heptane/EtOAc 3:1), trituration
  8. filtrationwith ether, filtration
  9. customdried

Sources & evidence

ORD record
ord-db70f800c357484593a8724e70bd8b65
Source dataset
uspto-grants-2007_07
Patent number
US07238808B2

Reaction notes

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