(5-Amino-1H-pyrazol-4-yl)(thiophen-2-yl)methanone → Lorediplon

HRID 1678046Notes

Reaction equation

HRID 1678046 reaction equation
[NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([F:31])=[C:24]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:25]=1)=O>CC(O)C>[F:31][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH3:30])[C:27](=[O:29])[CH3:28]

Participants

4

Reactant 2

HCID 11550150(5-Amino-1H-pyrazol-4-yl)(thiophen-2-yl)methanoneHCID 66990275HCID 66990275, compound

Product 1

HCID 12004146LorediplonYield 85%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
5 °C

Procedure

A 300 L vessel was flushed with nitrogen. Acetic acid (40.0 L) was charged, and then 7.312 kg (37.84 moles) of (5-amino-1H-pyrazol-4-yl)-thiophen-2-yl-methanone and 10.000 kg (37.84 moles) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide were added consecutively. The mixture was heated to 120° C. (±5° C.) with stirring. The reaction was controlled by HPLC until completion (<1% of each starting material), which typically occurs in 4 hours. The reaction mass was cooled to 60-70° C. 2-Propanol (80.0 L) was charged to reaction mixture, cooled to 40-45° C. and aged for at least 1 hour. The mixture was cooled over approximately 2.5 hours to 0-5° C. and aged for at least 2 hours. Solids were filtered and washed twice with 10.0 L of chilled 2-propanol. The solid product was dried under vacuum at 50° C. (±5° C.) to remove residual solvents (<0.5% w/w of acetic acid and <0.5% w/w of 2-propanol). N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide was obtained as a crystalline material (12.686 kg). Yield 85%. Purity ≧95%.

Workup

  1. customA 300 L vessel was flushed with nitrogen
  2. additionAcetic acid (40.0 L) was charged
  3. temperatureThe reaction mass was cooled to 60-70° C
  4. temperaturecooled to 40-45° C. and aged for at least 1 hour
  5. temperatureThe mixture was cooled over approximately 2.5 hours to 0-5° C. and aged for at least 2 hours
  6. filtrationSolids were filtered
  7. washwashed twice with 10.0 L of chilled 2-propanol
  8. customThe solid product was dried under vacuum at 50° C. (±5° C.)
  9. customto remove residual solvents (<0.5% w/w of acetic acid and <0.5% w/w of 2-propanol)

Sources & evidence

ORD record
ord-7fbb058d9f2f494aab72a80f927d7903
Source dataset
uspto-grants-2011_08
Patent number
US08008486B2

Reaction notes

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