Water → 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenyl)pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione

HRID 60498

Reaction equation

HRID 60498 reaction equation
[Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:32]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[OH:33])=[C:20](C3C=CC=CC=3C(C)C)[CH:21]=[N:22][C:15]=2[N:14]([CH3:41])[C:13]1=[O:42])(C(C)(C)C)(C)C.[F:43][C:44]([F:56])([F:55])[O:45][C:46]1[CH:47]=[C:48](B(O)O)[CH:49]=[CH:50][CH:51]=1.O.[C:58]([O-])([O-])=O.[K+].[K+].O1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([CH:32]([OH:33])[C:19]2[C:16]3[C:17](=[O:18])[N:12]([CH2:11][CH2:10][CH2:9][O:8][CH:68]4[CH2:69][CH2:58][CH2:65][CH2:66][O:67]4)[C:13](=[O:42])[N:14]([CH3:41])[C:15]=3[N:22]=[CH:21][C:20]=2[C:50]2[CH:49]=[CH:48][CH:47]=[C:46]([O:45][C:44]([F:56])([F:55])[F:43])[CH:51]=2)=[CH:39][CH:38]=1

Participants

7

Reactant 5

HCID 962WaterHCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 27343853-(Trifluoromethoxy)phenylboronic Acid (contains varying amounts of Anhydride)HCID 1317370933-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-((4-chlorophenyl) (hydroxy)methyl)-6-(2-isopropylphenyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione2×

Product 1

HCID 1188755535-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenyl)pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dioneYield 17.4%

Reagents, catalysts & solvents 1

HCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
100 °C

Procedure

6-bromo-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 20, step 5, 500 mg, 0.931 mmol) and 3-(trifluoromethoxy)phenylboronic acid (288 mg, 1.40 mmol) were combined in dioxane (15 ml) and water (4 mL) then K2CO3 (385 mg, 2.79 mmol) and Pd(PPh3)4 (60 mg) were added. The reaction was degassed with nitrogen (3×), heated at 100° C. for 18 h, cooled to RT, diluted with water (10 mL) and extracted with EA (2×50 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (8:1) to give 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(3-(trifluoromethoxy)phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 17.4% yield) as a yellow solid. LCMS: [MH+-THP] 536 and TR=1.013 min.

Workup

  1. customThe reaction was degassed with nitrogen (3×)
  2. temperaturecooled to RT
  3. additiondiluted with water (10 mL)
  4. extractionextracted with EA (2×50 mL)
  5. dry with materialThe combined organic layers were dried over Na2SO4
  6. concentrationconcentrated to a residue which
  7. customwas purified by chromatography
  8. washeluted with PE/EA (8:1)

Sources & evidence

ORD record
ord-9c6cd1a3ecf943178c57f43eeea640e1
Source dataset
uspto-grants-2016_09
Patent number
US09440972B2

Linked notes

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