Phosphorus oxychloride → HCID 57999116, compound

HRID 1917527Notes

Reaction equation

HRID 1917527 reaction equation
[NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=O)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1.P(Cl)(Cl)(Cl)=O.CO/N=C1/C2C(C)=NC(N)=NC=2C[C@@H](C2C=CC(F)=CC=2C2C(F)=NC=CC=2)C/1>C(#N)C>[N:22]1([C:11]2[C:5]3[C:4]([CH3:21])=[N:3][C:2]([NH2:1])=[N:7][C:6]=3[CH2:8][C@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[N:10]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1

Participants

6

Reactant 4

HCID 24813Phosphorus oxychlorideHCID 44182572HCID 44182572, compoundHCID 57424845HCID 57424845, compoundHCID 178418385HCID 178418385, compound

Product 1

HCID 57999116HCID 57999116, compound

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
75 °C

Procedure

In a 2-neck round-bottomed flask, under a blanket of nitrogen was added (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (106a, 1.00 g, 2.85 mmol), 1H-benzo[d][1,2,3]triazole (106b, 0.678 g, 5.70 mmol) and anhydrous acetonitrile (14 mL). Phosphoryl trichloride (0.796 mL, 8.54 mmol) was added slowly to the mixture and the reaction was heated in 75° C. oil bath for 18 hours. By LC/MS about 7-10% of compound 1 remained unreacted. The reaction mixture was concentrated, then diluted with 80 mL of ethyl acetate and the resulting mixture was added slowly to 40 mL of saturated sodium bicarbonate. The layers were partitioned. The aqueous layer was washed one more time with 40 mL of ethyl acetate. The organic layers combined, washed with brine, dried over sodium sulfate, and concentrated to a yellow-light brown solid, 1.72 g, contained about 0.37 g of excess benzotriazole. The crude material was taken on to the next step without purification. MS (ES) [M+H] calc'd for C20H15BrFN7, 452; found, 452.3-454.3. 1H NMR (400 MHz, CHLOROFORM-d) δ 1.96 (s, 3H), 2.74 (dd, J=16.42, 14.91 Hz, 1H), 3.13 (dd, J=16.55, 4.17 Hz, 1H), 5.20 (dd, J=14.91, 4.04 Hz, 1H), 5.69 (s, 2H), 7.03-7.12 (m, 1H), 7.38 (dd, J=8.21, 2.65 Hz, 1H), 7.47-7.52 (m, 1H), 7.56-7.63 (m, 1H), 7.74 (dd, J=8.84, 6.06 Hz, 1H), 8.16 (d, J=9.35 Hz, 2H).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. additiondiluted with 80 mL of ethyl acetate
  3. additionthe resulting mixture was added slowly to 40 mL of saturated sodium bicarbonate
  4. customThe layers were partitioned
  5. washThe aqueous layer was washed one more time with 40 mL of ethyl acetate
  6. washwashed with brine
  7. dry with materialdried over sodium sulfate
  8. concentrationconcentrated to a yellow-light brown solid, 1.72 g
  9. customThe crude material was taken on to the next step without purification

Sources & evidence

ORD record
ord-414286c72c4b4baca93aea7de06569fe
Source dataset
uspto-grants-2013_12
Patent number
US08618290B2

Reaction notes

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