Phosgene → HCID 57495357, compound

HRID 242343Notes

Reaction equation

HRID 242343 reaction equation
[C:1]([Cl:4])(Cl)=[O:2].Cl.Cl.[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:30][CH2:29][C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C@H:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)[C:17]=3[CH2:16]2)=[CH:11][C:10]=1[C:31]([F:34])([F:33])[F:32].C(N(CC)CC)C>C(Cl)Cl>[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:30][CH2:29][C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C@H:24]4[CH2:28][CH2:27][N:26]([C:1]([Cl:4])=[O:2])[CH2:25]4)[C:17]=3[CH2:16]2)=[CH:11][C:10]=1[C:31]([F:34])([F:32])[F:33]

Participants

5

Reactant 3

HCID 6371PhosgeneHCID 8471TriethylamineHCID 57495351HCID 57495351, compound2×

Product 1

HCID 57495357HCID 57495357, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent4×

Conditions

Temperature
5 °C

Procedure

To CH2Cl2 (5 mL) in a round bottomed flask was added phosgene (20% solution in toluene, 0.20 mL, 0.379 mmol) and the resulting solution cooled to 5° C. under argon. A solution of 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (prepared using step 1, example 91 from intermediate 13) (50.0 mg, 0.126 mmol) and triethylamine (0.053 mL, 0.380 mmol) in CH2Cl2 (1.0 mL) was added and the mixture allowed to warm to room temperature with stirring under argon over 1 h. Evaporated to dryness by bubbling a stream of argon into the mixture to give a brown gum. Dissolved in CH2Cl2 (3 mL) to give (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl chloride as a solution in CH2Cl2. LCMS: 458.4 [M+1]+, Rt(7)=1.38 min. This solution was used without further purification. 1.5 mL of this solution was added to a solution of piperidin-4-ol (6.4 mg, 0.063 mmol) and triethylamine (0.053 mL, 0.380 mmol) in CH2Cl2 and the mixture stirred at room temperature under argon for 1 h. N,N-dimethylformamide (0.5 mL) was added and stirring continued for 2 h. Diluted with CH2Cl2 (2 mL) and washed with sat. NaHCO3(aq) (2 mL). The organic layer was filtered through a phase separation tube and evaporated in vacuo. Purification by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions by elution through an Isolute® SCX-2 cartridge, eluting with methanol, then with 2M ammonia in methanol. Basic fractions were concentrated in vacuo to give (4-hydroxy-piperidin-1-yl)-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone as a pale yellow powder (22 mg, 64% yield). 1H NMR (400 MHz, MeOH-d4, 298K) δ ppm 1.35-1.57 (m, 2H) 1.80-1.94 (m, 2H) 2.20-2.31 (m, 2H) 2.94-3.09 (m, 4H) 3.45-3.87 (m, 10H) 3.98 (s, 3H) 4.17 (s, 2H) 5.70-5.76 (m, 1H) 7.78 (d, 1H) 8.13 (d, 1H) 8.58 (s, 1H) LCMS: [M+H]+=523.2, Rt(1)=1.58 min.

Workup

  1. temperatureto warm to room temperature
  2. customEvaporated to dryness
  3. customby bubbling a stream of argon into the mixture
  4. customto give a brown gum

Sources & evidence

ORD record
ord-d99946c5828b43a2ae42d2286922a550
Source dataset
uspto-grants-2014_02
Patent number
US08653092B2

Reaction notes

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