Sulfuric Acid → Tak-733

HRID 2090561Notes

Reaction equation

HRID 2090561 reaction equation
CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[C:13](=[O:14])[C:12]3[C:15]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=4[F:30])=[C:16]([F:21])[C:17](=[O:20])[N:18]([CH3:19])[C:11]=3[N:10]=[CH:9]2)[CH2:4][O:3]1.S(=O)(=O)(O)O>C(O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])=[C:16]([F:21])[C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1

Participants

4

Reactant 2

HCID 1118Sulfuric AcidHCID 67368877(R)-3-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Product 1

HCID 24963252Tak-733

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
75 °C

Procedure

Combine (R)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (24.75 g, 45.58 mmol) and ethanol (250 mL). Add aqueous 9N sulfuric acid (50 mL) over 5 minutes. Heat to 75° C. After 2 hour, cool to ambient temperature and then cool in an ice bath to give a solid. Collect the solid by filtration, rinse with ethanol (3×30 mL), and dry to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ10.24 (s, 1H), 8.52 (s, 1H), 7.69 (dd, 1H, J=10.4, 1.8 Hz), 7.52 (d, 1H, J=8.6 Hz), 6.98 (m, 1H), 5.14 (brs, 1H), 4.83 (brs, 1H), 4.32 (dd, 1H, J=12.9, 2.5 Hz), 3.76 (m, 1H), 3.67 (dd, 1H, J=13.1, 12.9 Hz), 3.58 (s, 3H), 3.46 (ddd, 1H, J=10.9, 5.3, 5.1 Hz), 3.38 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ161.3 (d, J=4.0 Hz), 155.6 (d, J=22.8 Hz), 154.6 (d, J=250 Hz), 152.0, 150.6, 134.3 (d, J=231 Hz), 133.8 (d, J=7.1 Hz), 133.1 (d, J=3.0 Hz), 127.8 (d, J=10.3 Hz), 125.3 (d, J=7.0 Hz), 123.9 (d, J=21.5 Hz), 95.0 (d, J=4.0 Hz), 87.1 (d, J=7.8 Hz), 68.0, 63.8, 50.1, 28.8; 19F NMR (376 MHz, DMSO-d6) δ-124.4, −149.8; MS (M+H)+m/z calcd 505.0. found 505.0.

Workup

  1. temperaturecool to ambient temperature
  2. temperaturecool in an ice bath
  3. customto give a solid
  4. customCollect the solid
  5. filtrationby filtration
  6. washrinse with ethanol (3×30 mL)
  7. customdry

Sources & evidence

ORD record
ord-43756cfe10c74421a7ed120c43d5f3ac
Source dataset
uspto-grants-2013_05
Patent number
US08436200B2

Reaction notes

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