Hydrochloric Acid → HCID 68520616, compound

HRID 1157460Notes

Reaction equation

HRID 1157460 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]([CH2:18][C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[O:20])[C:16](=[O:25])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(Cl)(C)=O>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]([CH2:18][C:19]([NH:21][CH:22]([CH3:23])[CH3:24])=[O:20])[C:16](=[O:25])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 6367Acetyl chlorideHCID 11854507HCID 11854507, compound

Product 1

HCID 68520616HCID 68520616, compoundYield 37%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Procedure

A mixture of 2-amino-N-(isopropylcarbamoylmethyl)-5-(3-piperidin-1-ylpropoxy)benzamide (INTERMEDIATE VII.1) (1.40 g, 3.72 mmol) and ethyl 3-chlorobenzimidate*HCl (INTERMEDIATE III.1) (2.46 g, 11.16 mmol) in anhydrous ethanol (20 mL) was heated to 80° C. in a sealed pressure tube for 16 h. This was then cooled and concentrated in vacuo. The crude residue was partitioned between dichloromethane:2-propanol (3:1 [v/v], 80 mL) and water (50 mL) and the aqueous extracted with additional dichloromethane:2-propanol (3:1 [v/v], 3×80 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The amber oil thus obtained was purified by chromatography on silica gel with dichloromethane:methanol:NH4OH (aq.) (170:29:1, v/v) as eluent to afford a sticky light yellow solid (1.74 g). This was further purified by recrystallization from ethanol:hexane to afford a white solid (410 mg, 0.82 mmol, 22%). A second crop was obtained as follows: the filtrate was concentrated in vacuo and the crude oil partitioned between 1N HCl (aq.) (20 mL) and ethyl acetate (10 mL) and washed with additional ethyl acetate (10 mL). The aqueous phase was basified with 3N NaOH (aq.) to give a white precipitate which was collected by filtration and washed with cold water. The residue was recrystallized from 90% ethanol (aq.) giving additional product as a white solid (254 mg, 0.52 mmol, 14%). Both batches were combined to afford 2-[2-(3-chlorophenyl)-4-oxo-6-(3-piperidin-1-ylpropoxy)-4H-quinazolin-3-yl]-N-isopropylacetamide (664 mg, 1.34 mmol, 36%). 2-[2-(3-Chlorophenyl)-4-oxo-6-(3-piperidin-1-ylpropoxy)-4H-quinazolin-3-yl]-N-isopropylacetamide was treated with 4N HCl in methanol (4 mL, prepared by the addition of AcCl (4 mmol) to methanol (10 mL) dropwise at 0° C.) and concentrated in vacuo. The resultant crystalline white solid was triturated with cold diethyl ether, collected by filtration and dried in vacuo giving 2-[2-(3-chlorophenyl)-4-oxo-6-(3-piperidin-1-ylpropoxy)-4H-quinazolin-3-yl]-N-isopropylacetamide hydrochloride (EXAMPLE 3a) (743 mg, 1.39 mmol, 37%).

Workup

  1. concentrationconcentrated in vacuo
  2. customThe resultant crystalline white solid was triturated with cold diethyl ether
  3. filtrationcollected by filtration
  4. customdried in vacuo

Sources & evidence

ORD record
ord-86073498849c403fb14ef20a404b61c6
Source dataset
uspto-grants-2010_10
Patent number
US07807686B2

Reaction notes

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