Dichloromethane → N-({1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]cyclobutyl}sulfonyl)acetamide

HRID 410599Notes

Reaction equation

HRID 410599 reaction equation
Br[C:2]1[S:6][C:5]([C:7]2([S:11]([NH:14][C:15](=[O:17])[CH3:16])(=[O:13])=[O:12])[CH2:10][CH2:9][CH2:8]2)=[N:4][CH:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([NH:34][C:35]2[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=2)[CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:18][C:19]1[CH:24]=[C:23]([C:2]2[S:6][C:5]([C:7]3([S:11]([NH:14][C:15](=[O:17])[CH3:16])(=[O:13])=[O:12])[CH2:10][CH2:9][CH2:8]3)=[N:4][CH:3]=2)[CH:22]=[C:21]([NH:34][C:35]2[N:40]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:38]=[CH:37][N:36]=2)[CH:20]=1

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 58456089N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine2×HCID 67430287N-(1-(5-bromothiazol-2-yl)cyclobutylsulfonyl)acetamide

Product 1

HCID 58456261N-({1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]cyclobutyl}sulfonyl)acetamideYield 52%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

The product of Step 1 (109 mg, 0.322 mmol), N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 3, 122 mg, 0.322 mmol), and PdCl2(dppf).CH2Cl2 (24 mg, 0.032 mmol) were combined in a vial, sealed, and purged with nitrogen (2×). Dioxane (2.0 mL) and 2 M Na2CO3 (0.48 mL, 0.97 mmol) were added, and the reaction was purged again with nitrogen (2×). The mixture was stirred in an oil bath at 100° C. overnight. The dark brown reaction was diluted with water and extracted with CH2Cl2 (2×). The combined organic layers were dried (Na2SO4), filtered and evaporated. Flash chromatography (dry load, 25-100% ethyl acetate in hexanes, then 0-10% methanol in ethyl acetate) provided an orange-brown residue. The residue was triturated with CH2Cl2, filtered, and dried to afford N-({1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}sulfonyl)acetamide (85 mg, 52%) as a colorless solid. MS ESI: [M+H]+ m/z 512.0. 1H NMR (600 MHz, DMSO-d6) δ 11.38 (s, 1H), 10.27 (s, 1H), 8.81 (d, J=4.9, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.49 (s, 1H), 7.27 (d, J=4.9, 1H), 7.21 (s, 1H), 3.23-3.06 (m, 2H), 2.76-2.61 (m, 2H), 2.31 (s, 3H), 2.10-1.89 (m, 2H), 1.84 (s, 3H). rhSYK activity=+++

Workup

  1. customsealed
  2. custompurged with nitrogen (2×)
  3. customthe reaction was purged again with nitrogen (2×)
  4. customThe dark brown reaction
  5. extractionextracted with CH2Cl2 (2×)
  6. dry with materialThe combined organic layers were dried (Na2SO4)
  7. filtrationfiltered
  8. customevaporated
  9. dry with materialFlash chromatography (dry load, 25-100% ethyl acetate in hexanes
  10. custom0-10% methanol in ethyl acetate) provided an orange-brown residue
  11. customThe residue was triturated with CH2Cl2
  12. filtrationfiltered
  13. customdried

Sources & evidence

ORD record
ord-36a1b209c6374551b426f5a14d8b4ac2
Source dataset
uspto-grants-2014_06
Patent number
US08759366B2

Reaction notes

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