2-[(1S)-1-Aminopropyl]-5-fluoro-3-phenyl-4(3H)-quinazolinone

The compound (S) - (1- (5-fluoro-4-oxo-3-phenyl-3, 4-dihydroquinazolin-2-yl) propyl) carbamic acidTert-butyl ester (220 mg, 0.55 mmol) was dissolved in EtOAc (2 mL) and then a solution of hydrogen chloride in ethyl acetate (2.5 mL, 3.88 M) was added in one portion at room temperature. The resulting mixture was stirred at rt overnight, the resulting suspension was dissolved in water (20 mL) and the aqueous phase was extracted with EtOAc (20 mL) and Na2CO3 powder adjusted to pH = 8 and extracted with EtOAc (20 mL x 3 ). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a white powder (163 mg, 100percent).4. preparation of (S)-2-(1-aminopropyl)-5-fluoro-3-phenyl-3H-quinazolin-4-onePreparation of (S)-2-(l-amino-propyl)-5- fluoro-3-phenyl-3H-quinazolin-4-one (5a).; A solu- tion of [1-(5-fluoro-4-oxo-3-phenyl-3, 4-dihydro- quinazolin-2-yl) -propyl]-carbamic acid tert-butyl ester 4 (33.6 g, 85 mmol) in CH2C12 (60 mL) was treated with TFA (60 mL). The reaction mixture was stirred for 1 h, concentrated in vacuo, and parti- tioned between CH2C12 (150 mL) and 10percent K2C03 (suffi- cient amount to keep the pH greated than 10). The aqueous layer was extracted with additional CH2C12 (100 mL), and the combined organic layers were washed with H20 (50 mL) and brine (50 mL). After drying with MgS04, the solution was concentrated to an off-white solid (22 g, 88percent). @H NMR (300 MHz, CDC13) 5: 7.73-7.65 (m, 1H), 7.62-7.49 (m, 4H), 7.32-7.22 (m, 2H), 7.13-7.06 (m, 1H), 3.42 (dd, J = 7.5, 5.2 Hz, 1H), 1.87-1.70 (m, 1H), 1.58-1.43 (m, 1H), 0.80 (t, J = 7.4 Hz, 3H). ESI-MS m/z 298.2 (MH+) .The (S)- [1 - (5 - fluoro -4 - oxo -3 - phenyl - 3, 4 - dihydro - quinazoline -2 - yl) - propyl] - carbamic acid isobutyl ester (7.94g) dissolved in dichloromethane (40 ml) and trifluoroacetic acid (40 ml) in, room temperature stirring 2 hours, concentrated to dry, in dichloromethane (100 ml) and 10percent potassium carbonate (100 ml) solution distribution, separating, the aqueous layer re-methylene chloride (50 ml × 2) extraction, the combined organic layer, water washing, saturated salt water washing, drying, filtering, concentrated to obtain the title compound (S)-2 - (1 - amino - propyl) -5 - fluoro -3 - phenyl - 3H - quinazoline -4 - one 5.1g, yield 85.8percent. Preparation of 2-(l-aminopropyl)-5-fluoro-3-phenyl-3H-quinazolin-4-one (S)-tert-butyl-[l-(5-fluoro-4-oxo-3-phenyl-3, 4-dihydroquinazolin-2-yl)propyl]-carbamate (50 g, 0.12 mole) was dissolved in dichloromethane (100 mL) and cooled to 8 °C- 10 °C. Trifluoroacetic acid (150 g, 1.31 mole) was slowly added. The reaction mixture was stirred at 25 °C- 28 °C for 3 to 6 hours. After completion of reaction, the reaction mixture was concentrated and the residue was dissolved in dichloromethane and water was added. The pH was adjusted to -10 with a 10percent sodium carbonate solution. The organic layer was separated, washed with water, dried on sodium sulfate, and then concentrated under vacuum. The residue was stirred with Diisopropyl ether (DIPE) to get a solid, which was filtered and washed with DIPE and dried at 55 °C- 60 °C under vacuum to get 2-( l-aminopropyl)-5-fluoro-3-phenyl-3H- quinazolin-4-one (33.2 g, 88percent molar).A mixture of tert-butyl N- [(iS)- 1 -(5-fluoro-4-oxo-3 -phenyl-quinazoline-2- yl)propyl]carbamate (100 g, 0.25 1 moles) was dissolved in acetonitrile (600 mL) and treated with concentrated hydrochloric acid (125 mL) at 25-30 °C. The reaction mixture was stirred for 5-6 hours at 25-30 °C. After completion of reaction, the reaction mass was concentrated under reduced pressure and washed with toluene. The aqueous layer was basified with liquorammonia and filtered to provide the title product as an off white solid (71.06 g).To the mixture of 8.5 g of compound (3) and 42 ml t-butanol 7.8 ml of triethylamine and 5 g of 6-chloropurine were added at 30 C. The resultant reaction mixture was heated to 85 C. and stirred for 24 hours. The reaction mixture was evaporated completely under reduced pressure at 40 C. The resultant residue was diluted with 200 ml water and stirred for 30 minutes. The precipitate was filtered and the solid was washed with 60 ml water and 100 ml n-hexane and dried for 1 hour under vacuum to obtain 7 g of idelalisib. The overall yield based on starting 2-fluoro-6-nitro-N-phenylbenzamide is 19% of the theoretical yield. The purity of isolated solid was 61% (HPLC IN).In a clean reaction flask, 4.2 g (0.01 mol) of (S)-2-((2-((tert-butoxycarbonyl)amino)-1-phenoxybutenyl)amino)-6-fluorobenzoic acid was dissolved in 50 mL of toluene. Further, 1.0 g (0.01 mol) of aniline was added, and the temperature was raised to about 55 C by heating, and the reaction was completed to completion with stirring, and then 1 M hydrochloric acid was added to promote complete cyclization. Then add strong acid concentrated hydrochloric acid to continue the reaction to remove the Boc protecting group, after the removal is complete, then, Adjust the pH of the reaction solution to more than 7 with ammonia water, then stand still, layer, separate the organic phase toluene layer, and concentrate to remove the solvent. After re-crystallization of an appropriate amount of solvent, an off-white solid product is obtained. The compound of example-2 (120g, 0.23 moles) was dissolved in ethyl acetate and added piperidine (78.5g) at 25 to 30C. The reaction mixture was stir for about 12 hours at 25 to 30C. The layers are separated and organic layer waswashed with water and distilled the organic layer completely under reduced pressure. The obtained crude product was leached with hexane at 45 to 50C and dissolved in methylene chloride and subjected to charcoal treatment. The methylene chloride layer was distilled and recrystallized with toluene to obtain the compound. Yield: 45g.HPLC purity: 99.7%General procedure: 1.634 g (4.09 mmol) of tert-butyl (S)-(1-(5-chloro-4-oxo-3-phenyl-3, 4-dihydroquinazoline-2-yl)ethyl)carbamate prepared in step 2 was dissolved in dichloromethane (15 mL), to which trifluoroacetic acid (TFA, 5 mL) was added. After the reflux at 40 C. for 3 hours, the mixture was cooled down at room temperature, to which saturated NaHCO3 aqueous solution was slowly added to neutralize the mixture. The organic layer was extracted by using ethyl acetate, which was washed with saturated brine, separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, eluent: dichloromethane/methanol, 20/1 -> dichloromethane/methanol, 5/1) to give 1.046 g of the target compound (S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazoline-4(3H)-one as a white solid (3.49 mmol, yield: 85%). 1H NMR(300 MHz, CDCl3) delta 7.60-7.64 (m, 2H), 7.51-7.59(m, 3H), 7.44-7.48 (m, 1H), 7.27-7.29 (m, 2H), 3.63-3.70 (m, 1H) , 1.83 (s, 2H) , 1.27 (d, J=6.5 Hz, 3H).The compound 6-chloro(2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine (30 mg, 0.142 mmol)(S) -2- (1-Aminopropyl) -5-fluoro-3-phenylquinazolin-4 (3H) -one(44 mg, 0.148 mmol) was suspended in n-BuOH (3 mL), Then DIPEA (37 mg, 0.284 mmol) was added thereto. The resulting mixture was heated to reflux for 25 hours and was thinly coloredThe reaction was monitored by spectroscopy (PE / EtOAc, v / v, 1/4) and the mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residueSuspended in EtOH (1.5 mL) and filtered, the filter cake was rinsed with EtOH (1 mL) and dried under reduced pressure to give the title compound as a lightYellow solid (38 mg, 56.7%).(S) -2- (1-aminopropyl) -5-fluoro-3-phenylquinazolin-4 (3H) -one (42 mg, 0.14 mmol)5- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrimidin-4- amine (30 mg, 0.14 mmol) was suspended in n-BuOH DIPEA (36 mg, 0.28 mmol) was added thereto. The reaction mixture was refluxed overnight and the reaction was monitored by thin layer chromatography (PE / EtOAc, v / v, 1/4) and the reaction mixture was then cooled to room temperature and then filtered. The resulting cake was rinsed with EtOH (10 mL x 2) The title compound was a white solid (45.3 mg, 68.5%).The compound (S) -2- (1-aminopropyl) -5-fluoro-3-phenylquinazolin-4 (3H) -one (50.5 mg, 0.17 mmol) and 6-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2- yl) pyrimidin- 4-amine (35.6 mg, 0.17 mmol)n-BuOH (2 mL), and then DIPEA (44 mg, 0.34 mmol) was added thereto. The reaction mixture is refluxed overnight and thinThe reaction was monitored by layer chromatography (PE / EtOAc, v / v, 1/4) and the reaction mixture was then cooled to room temperature to give a white suspension, The suspension was filtered and the collected solid was rinsed with EtOH (10 mL x 2) to give the title compound as a white solid (49 mg, 61%).

Molecular Weight:297.33
XLogP3:2.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:297.12774030
Monoisotopic Mass:297.12774030
Topological Polar Surface Area:58.7
Heavy Atom Count:22
Complexity:447
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes