Potassium Carbonate → 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 60497

Reaction equation

HRID 60497 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.[C:57]([O-:60])([O-])=O.[K+].[K+]>O1CCOCC1.O.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:20]4[CH2:19][CH2:16][CH2:15][CH2:57][O:60]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 3

HCID 11430Potassium CarbonateHCID 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 22%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture of 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, 120 mg, 0.22 mmol) and 3-(trifluoromethoxy)phenylboronic acid (60 mg, 0.33 mmol) in dioxane (3.2 ml) and water (0.8 mL) was added K2CO3 (92 mg, 0.67 mmol) and Pd(PPh3)4 (20 mg). The reaction was degassed with nitrogen (3×), heated at 100° C. for 18 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 TLC eluted with PE/EA (3:1) to give the intermediate 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 (15 mg) as a white solid. The intermediate was dissolved in EtOH (3 mL) and acetyl chloride (0.3 mL) was added. The reaction was stirred at RT for 30 min then concentrated to a residue which was purified by Prep HPLC to give 5-((4-chlorophenyl)(hydroxy)methyl)-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3 mg, 3% yield over 2 steps) as a white solid. 1H NMR (CDCl3) δ: 8.64 (s, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.27 (d, J=7.2 Hz, 1H), 7.21-7.17 (m, 3H), 7.05 (d, J=8.0 Hz, 2H), 6.25 (s, 1H), 4.11-4.05 (m, 2H), 3.77 (s, 3H), 3.51 (t, J=6.4 Hz, 2H), 1.79-1.74 (m, 2H). LCMS: [M++Na] 558 and TR=3.048 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 TLC
  8. washeluted with PE/EA (3:1)

Sources & evidence

ORD record
ord-12ebdf4bf7a04a738e70d66c9c24b7cf
Source dataset
uspto-grants-2016_09
Patent number
US09440972B2

Linked notes

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