Potassium Phosphate, Tribasic → 6-(3-(trifluoromethoxy)benzyl)-5-(4-chlorobenzyl)-3-(3-hydroxy propyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

HRID 60509Notes

Reaction equation

HRID 60509 reaction equation
C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:15](Br)[CH:16]=[N:17][C:10]=2[N:9]([CH3:27])[C:8]1=[O:28])=O.[F:29][C:30]([F:43])([F:42])[O:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[CH2:35]B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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]>[F:29][C:30]([F:42])([F:43])[O:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[CH2:35][C:15]1[CH:16]=[N:17][C:10]2[N:9]([CH3:27])[C:8](=[O:28])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:12](=[O:13])[C:11]=2[C:14]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 75485868{[3-(Trifluoromethoxy)phenyl]methyl}boronic acidHCID 1188758893-(6-bromo-5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate2×

Product 1

HCID 1188755086-(3-(trifluoromethoxy)benzyl)-5-(4-chlorobenzyl)-3-(3-hydroxy propyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneYield 16.5%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
85 °C

Procedure

To a mixture of 3-(6-bromo-5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (See Compound 34, step 2, 80 mg, 0.171 mmol) and 3-(trifluoromethoxy) benzylboronic acid (103 mg, 0.342 mmol) in dioxane (4 mL) was added aq. 2 M K3PO4 (0.8 mL) and Pd(dppf)Cl2 (10 mg). The reaction was degassed with nitrogen (3×) and heated at 85° C. for 3 h, cooled to RT, diluted with water (10 mL) then extracted with EA (2×10 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 6-(3-(trifluoromethoxy)benzyl)-5-(4-chlorobenzyl)-3-(3-hydroxy propyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (15 mg, 16.5% yield) as a white solid. 1H NMR (CDCl3) δ: 8.63 (s, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 6.98-6.92 (m, 3H), 4.70 (s, 2H), 4.42-4.40 (m, 1H), 4.05 (s, 2H), 3.94-3.90 (m, 2H), 3.60 (s, 3H), 3.42-3.40 (m, 2H), 1.69-1.64 (m, 2H). LCMS: MH+ 534 and TR=3.262 min.

Workup

  1. customThe reaction was degassed with nitrogen (3×)
  2. temperaturecooled to RT
  3. additiondiluted with water (10 mL)
  4. extractionthen extracted with EA (2×10 mL)
  5. dry with materialThe combined organic layers were dried over Na2SO4
  6. concentrationconcentrated to a residue which
  7. customwas purified by Prep HPLC

Sources & evidence

ORD record
ord-4370807d121d4fbc9a56b061f862bc72
Source dataset
uspto-grants-2016_09
Patent number
US09440972B2

Reaction notes

Loading…