870281-82-6

Basic information

• Product Name: CAL-101
• Synonyms: CAL-101;GS1101;CAL-101 (GS-1101);5-Fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-4(3H)-quinazolinone;CAL101,CAL-101;CAL-101 (Idelalisib, GS-1101);(S)-2-(1-((9H-Purin-6-yl)aMino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;Idelalisib(CAL-101)
• CAS NO: 870281-82-6
• Molecular Formula: C₂₂H₁₈FN₇O
• Molecular Weight: 415.4230232
• EINECS: 807-438-9
• Product Categories: Inhibitor;Inhibitors;Akt;mTOR;PI3K
• Mol File: 870281-82-6.mol
• Article Data: 6

Chemical Properties

• Boiling Point: 733.4±70.0 °C(Predicted)
• Appearance: /
• Density: 1.47
• Storage Temp.: -20°C
• Solubility: Soluble in DMSO (>25 mg/ml)
• PKA: 10.00±0.10(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 2 months.
• CAS DataBase Reference: CAL-101(CAS DataBase Reference)
• NIST Chemistry Reference: CAL-101(870281-82-6)
• EPA Substance Registry System: CAL-101(870281-82-6)

Safety Data

• Safety Statements: V
• Hazardous Substances Data: 870281-82-6(Hazardous Substances Data)

Usage

Description

Idelalisib (CAS 870281-82-6) is a potent (IC50 = 2.5nM) and selective (IC50’s: PI3Ka = 820nM, PI3Kb = 565nM, PI3Kg = 89nM) PI3Kd inhibitor.1,2 Useful clinical agent for the treatment of various blood cancers. Idelalisib attenuates regulatory T cells (Treg) but not conventional T cells (Tconv) resulting in a significant increase in tumor-infiltrating antigen-specific CD8 T cells in a murine lung cancer model.3 Conversely, systemic PI3Kd inactivation antagonized anti-CTLA-4 and anti-PD-L1 treatment.4 Others have found that Idelalisib minimally influenced rituximab- and obinutuzumab-mediated Ab-dependent cellular cytotoxicity in human lymphoma cells.5

Uses

CAL-101 is a PI3K/mTOR pathway inhibitor used in the treatment of myeloid leukemia through sensitizing the cells to combatting drugs. Potent PI3K-p110-delta inhibitor.

Definition

ChEBI: A member of the class of quinazolines that is 5-fluoro-3-phenylquinazolin-4-one in which the hydrogen at position 2 is replaced by a (1S)-1-(3H-purin-6-ylamino)propyl group. used for for the treatment of refractory indol nt non-Hodgkin's lymphoma and relapsed chronic lymphocytic leukemia.

References

1) Herman?et al. (2010), Phosphatidylinositol 2-kinase-d inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals; Blood?116 2078 2) Lannutti?et al. (2011), CAL-101, a p110d selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability; Blood 117 591 3) Ahmad?et al. (2017), Differential PI3Kd Signaling in CD4+ T-cell Subsets Enables Selective Targeting of T Regulatory Cells to Enhance Cancer Immunotherapy; Cancer Res. 77 1892 4) Lim?et al. (2018), Phosphoinositide 3-kinase d inhibition promotes antitumor responses but antagonizes checkpoint inhibitors; JCI Insight 3 e120626 5) Palazzo?et al.?(2018),?The PI3Kd-Selective Inhibitor Idelalisib Minimally Interferes with Immune Effector Function Mediated by Rituximab or Obinutuzumab and Significantly Augment B Cell Depletion In Vivo; J.Immunol. 200 2304

InChI:InChI=1S/C22H18FN7O/c1-2-15(28-20-18-19(25-11-24-18)26-12-27-20)21-29-16-10-6-9-14(23)17(16)22(31)30(21)13-7-4-3-5-8-13/h3-12,15H,2H2,1H3,(H2,24,25,26,27,28)

Synthetic route

C27H28FN7O4 → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
With iodine; 1,1,1,3,3,3-hexamethyl-disilazane In dichloromethane at 30℃; for 6h; Solvent; Temperature;	88%

2-{[(2S)-2-amino(7H-purin)butanoyl]amino}-6-fluoro-N-phenylbenzamide → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
With 1,1,1,3,3,3-hexamethyl-disilazane; zinc(II) chloride In acetonitrile for 4h; Reagent/catalyst; Solvent; Reflux;	60%

aniline (62-53-3) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: thionyl chloride / N,N-dimethyl-formamide / 3 h / 85 °C 2.1: thionyl chloride / N,N-dimethyl-formamide / 3 h / 85 °C 2.2: 20.5 h / 5 - 30 °C 3.1: acetic acid; zinc / 20.5 h / 15 - 20 °C 4.1: hydrogenchloride / water; tetrahydrofuran / 2.25 h / 10 - 30 °C 5.1: triethylamine / tert-butyl alcohol / 24 h / 30 - 85 °C View Scheme
Multi-step reaction with 6 steps 1.1: thionyl chloride / N,N-dimethyl-formamide / 3 h / 85 °C 2.1: thionyl chloride / N,N-dimethyl-formamide / 3 h / 85 °C 2.2: 20.5 h / 5 - 30 °C 3.1: acetic acid; zinc / 20.5 h / 15 - 20 °C 4.1: hydrogenchloride / water; tetrahydrofuran / 2.25 h / 10 - 30 °C 5.1: triethylamine / tert-butyl alcohol / 24 h / 30 - 80 °C 6.1: palladium 10% on activated carbon; hydrogen; sodium acetate / ethanol / 16 h / 30 °C View Scheme
Multi-step reaction with 6 steps 1.1: Chloro-oxo-acetic acid / dichloromethane; N,N-dimethyl-formamide / 3 h / 20 °C 1.2: 1.5 h / 0 - 20 °C 2.1: zinc; ammonium formate / dichloromethane; water; methanol / 20 °C 3.1: benzotriazol-1-ol; 1,1'-carbonyldiimidazole / toluene / 8 - 15 °C 4.1: trifluoroacetic acid / dichloromethane / 3 h 5.1: N-ethyl-N,N-diisopropylamine; zinc(II) chloride / acetonitrile / 80 - 100 °C 6.1: zinc(II) chloride; 1,1,1,3,3,3-hexamethyl-disilazane / acetonitrile / 4 h / Reflux View Scheme

9-(triphenylmethyl)adenine (21802-46-0) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: dmap / tetrahydrofuran / 17 h / 25 - 50 °C 2: methanol; potassium carbonate / 6 h / 50 °C 3: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 21 h / 25 - 45 °C 4: trifluoroacetic acid / dichloromethane / 2.25 h / 0 - 25 °C View Scheme

adenine (66224-66-6, 66224-67-7, 66224-68-8, 66224-69-9, 134434-48-3, 134434-49-4, 134454-76-5, 134461-75-9) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: pyridine / N,N-dimethyl-formamide / 16 h / 25 °C / Inert atmosphere 2: dmap / tetrahydrofuran / 17 h / 25 - 50 °C 3: methanol; potassium carbonate / 6 h / 50 °C 4: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 21 h / 25 - 45 °C 5: trifluoroacetic acid / dichloromethane / 2.25 h / 0 - 25 °C View Scheme

di-tert-butyl (9-trityl-9H-purin-6-yl)-di-carbamate (1229622-81-4) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: methanol; potassium carbonate / 6 h / 50 °C 2: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 21 h / 25 - 45 °C 3: trifluoroacetic acid / dichloromethane / 2.25 h / 0 - 25 °C View Scheme

tert-butyl (9-trityl-9H-purin-6-yl)carbamate (1229622-72-3) + (R)-5-fluoro-2-(1-hydroxypropyl)-3-phenylquinazolin-4(3H)-one → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 21 h / 25 - 45 °C 2: trifluoroacetic acid / dichloromethane / 2.25 h / 0 - 25 °C View Scheme

(R)-2-(2-acetoxybutanamido)-6-fluorobenzoic acid → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: phosphorus trichloride / acetonitrile / 8.17 h / 25 - 50 °C 2: potassium carbonate / methanol / 1 h / 25 °C 3: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 21 h / 25 - 45 °C 4: trifluoroacetic acid / dichloromethane / 2.25 h / 0 - 25 °C View Scheme

(R)-1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl acetate → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / methanol / 1 h / 25 °C 2: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 21 h / 25 - 45 °C 3: trifluoroacetic acid / dichloromethane / 2.25 h / 0 - 25 °C View Scheme

(S)-tert-butyl(1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)(9-trityl-9H-purin-6-yl)carbamate → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
With trifluoroacetic acid In dichloromethane at 0 - 25℃; for 2.25h;	525 mg

2-fluoro-6-nitro-N-phenyl-benzamide (870281-83-7) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: thionyl chloride / N,N-dimethyl-formamide / 3 h / 85 °C 1.2: 20.5 h / 5 - 30 °C 2.1: acetic acid; zinc / 20.5 h / 15 - 20 °C 3.1: hydrogenchloride / water; tetrahydrofuran / 2.25 h / 10 - 30 °C 4.1: triethylamine / tert-butyl alcohol / 24 h / 30 - 85 °C View Scheme
Multi-step reaction with 5 steps 1.1: thionyl chloride / N,N-dimethyl-formamide / 3 h / 85 °C 1.2: 20.5 h / 5 - 30 °C 2.1: acetic acid; zinc / 20.5 h / 15 - 20 °C 3.1: hydrogenchloride / water; tetrahydrofuran / 2.25 h / 10 - 30 °C 4.1: triethylamine / tert-butyl alcohol / 24 h / 30 - 80 °C 5.1: palladium 10% on activated carbon; hydrogen; sodium acetate / ethanol / 16 h / 30 °C View Scheme
Multi-step reaction with 5 steps 1: zinc; ammonium formate / dichloromethane; water; methanol / 20 °C 2: benzotriazol-1-ol; 1,1'-carbonyldiimidazole / toluene / 8 - 15 °C 3: trifluoroacetic acid / dichloromethane / 3 h 4: N-ethyl-N,N-diisopropylamine; zinc(II) chloride / acetonitrile / 80 - 100 °C 5: zinc(II) chloride; 1,1,1,3,3,3-hexamethyl-disilazane / acetonitrile / 4 h / Reflux View Scheme

6-fluoro-2-nitrobenzoic acid (385-02-4) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: thionyl chloride / N,N-dimethyl-formamide / 3 h / 85 °C 2.1: thionyl chloride / N,N-dimethyl-formamide / 3 h / 85 °C 2.2: 20.5 h / 5 - 30 °C 3.1: acetic acid; zinc / 20.5 h / 15 - 20 °C 4.1: hydrogenchloride / water; tetrahydrofuran / 2.25 h / 10 - 30 °C 5.1: triethylamine / tert-butyl alcohol / 24 h / 30 - 85 °C View Scheme
Multi-step reaction with 6 steps 1.1: thionyl chloride / N,N-dimethyl-formamide / 3 h / 85 °C 2.1: thionyl chloride / N,N-dimethyl-formamide / 3 h / 85 °C 2.2: 20.5 h / 5 - 30 °C 3.1: acetic acid; zinc / 20.5 h / 15 - 20 °C 4.1: hydrogenchloride / water; tetrahydrofuran / 2.25 h / 10 - 30 °C 5.1: triethylamine / tert-butyl alcohol / 24 h / 30 - 80 °C 6.1: palladium 10% on activated carbon; hydrogen; sodium acetate / ethanol / 16 h / 30 °C View Scheme

(S)-[1-(2-fluoro-6-nitro-benzoy)phenylaminocarbonyl]propyl carbamic acid tert-butyl ester (870281-84-8) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: acetic acid; zinc / 20.5 h / 15 - 20 °C 2: hydrogenchloride / water; tetrahydrofuran / 2.25 h / 10 - 30 °C 3: triethylamine / tert-butyl alcohol / 24 h / 30 - 85 °C View Scheme
Multi-step reaction with 4 steps 1: acetic acid; zinc / 20.5 h / 15 - 20 °C 2: hydrogenchloride / water; tetrahydrofuran / 2.25 h / 10 - 30 °C 3: triethylamine / tert-butyl alcohol / 24 h / 30 - 80 °C 4: palladium 10% on activated carbon; hydrogen; sodium acetate / ethanol / 16 h / 30 °C View Scheme

(S)-(1-(5-fluoro-4-carbonyl-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)carbamic acid tert-butyl ester (870281-85-9) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / water; tetrahydrofuran / 2.25 h / 10 - 30 °C 2: triethylamine / tert-butyl alcohol / 24 h / 30 - 85 °C View Scheme
Multi-step reaction with 3 steps 1: hydrogenchloride / water; tetrahydrofuran / 2.25 h / 10 - 30 °C 2: triethylamine / tert-butyl alcohol / 24 h / 30 - 80 °C 3: palladium 10% on activated carbon; hydrogen; sodium acetate / ethanol / 16 h / 30 °C View Scheme

(S)-2-(1-((2-chloro-7H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (Chloro-idelalisib) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen; sodium acetate In ethanol at 30℃; for 16h;

(S)-2-(1-((9H-purin-6-yl-2,8-d2)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (870281-86-0) + 6-chloro-7H-purine (87-42-3) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
With triethylamine In tert-butyl alcohol at 30 - 85℃; for 24h; Concentration; Reagent/catalyst;	3.1 g

(S)-2-(1-((9H-purin-6-yl-2,8-d2)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (870281-86-0) + 2,6-dichloro-7H-purine (5451-40-1) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / tert-butyl alcohol / 24 h / 30 - 80 °C 2: palladium 10% on activated carbon; hydrogen; sodium acetate / ethanol / 16 h / 30 °C View Scheme

(S)-2-(1-((9H-purin-6-yl-2,8-d2)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (870281-86-0) + 6-bromopurine (767-69-1) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tert-butyl alcohol at 85 - 90℃;	62.5 g

5-fluoro-2H-benzo[d][1,3]-oxazine-2,4(1H)-dione (78755-94-9) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: acetonitrile / 40 - 82 °C 2: isobutyl chloroformate; 4-methyl-morpholine / tetrahydrofuran / 20 h / -5 - 28 °C 3: triethylamine; chloro-trimethyl-silane / acetonitrile / 24 h / 15 - 95 °C / 750.08 - 1500.15 Torr 4: trifluoroacetic acid / dichloromethane / 8 - 28 °C 5: N-ethyl-N,N-diisopropylamine / tert-butyl alcohol / 85 - 90 °C View Scheme

2-amino-6-fluorobenzoic acid (434-76-4) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions

Yield

Multi-step reaction with 6 steps 1: pyridine / acetonitrile; dichloromethane / 50 - 60 °C 2: acetonitrile / 40 - 82 °C 3: isobutyl chloroformate; 4-methyl-morpholine / tetrahydrofuran / 20 h / -5 - 28 °C 4: triethylamine; chloro-trimethyl-silane / acetonitrile / 24 h / 15 - 95 °C / 750.08 - 1500.15 Torr 5: trifluoroacetic acid / dichloromethane / 8 - 28 °C 6: N-ethyl-N,N-diisopropylamine / tert-butyl alcohol / 85 - 90 °C View Scheme

2-amino-6-fluoro-N-phenyl-benzamide → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: isobutyl chloroformate; 4-methyl-morpholine / tetrahydrofuran / 20 h / -5 - 28 °C 2: triethylamine; chloro-trimethyl-silane / acetonitrile / 24 h / 15 - 95 °C / 750.08 - 1500.15 Torr 3: trifluoroacetic acid / dichloromethane / 8 - 28 °C 4: N-ethyl-N,N-diisopropylamine / tert-butyl alcohol / 85 - 90 °C View Scheme
Multi-step reaction with 4 steps 1: 4-methyl-morpholine; isobutyl chloroformate / tetrahydrofuran / 4 h / 0 - 60 °C 2: 1,1,1,3,3,3-hexamethyl-disilazane; iodine / dichloromethane / 36 h / Reflux 3: N-ethyl-N,N-diisopropylamine / tert-butyl alcohol / 6 h / 50 °C 4: hydrogenchloride / water; ethanol / 4 h / 50 °C View Scheme
Multi-step reaction with 4 steps 1: benzotriazol-1-ol; 1,1'-carbonyldiimidazole / toluene / 8 - 15 °C 2: trifluoroacetic acid / dichloromethane / 3 h 3: N-ethyl-N,N-diisopropylamine; zinc(II) chloride / acetonitrile / 80 - 100 °C 4: zinc(II) chloride; 1,1,1,3,3,3-hexamethyl-disilazane / acetonitrile / 4 h / Reflux View Scheme

(S)-N-[2-[[3-fluoro-2-[(phenylamino)carbonyl]phenyl]amino]-1-ethyl-2-oxoethyl]-carbamic acid tert-butyl ester → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine; chloro-trimethyl-silane / acetonitrile / 24 h / 15 - 95 °C / 750.08 - 1500.15 Torr 2: trifluoroacetic acid / dichloromethane / 8 - 28 °C 3: N-ethyl-N,N-diisopropylamine / tert-butyl alcohol / 85 - 90 °C View Scheme
Multi-step reaction with 3 steps 1: 1,1,1,3,3,3-hexamethyl-disilazane; iodine / dichloromethane / 36 h / Reflux 2: N-ethyl-N,N-diisopropylamine / tert-butyl alcohol / 6 h / 50 °C 3: hydrogenchloride / water; ethanol / 4 h / 50 °C View Scheme
Multi-step reaction with 3 steps 1: trifluoroacetic acid / dichloromethane / 3 h 2: N-ethyl-N,N-diisopropylamine; zinc(II) chloride / acetonitrile / 80 - 100 °C 3: zinc(II) chloride; 1,1,1,3,3,3-hexamethyl-disilazane / acetonitrile / 4 h / Reflux View Scheme

6-chloro-7H-purine (87-42-3) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: dichloromethane / 2 h / 30 °C 2: N-ethyl-N,N-diisopropylamine / tert-butyl alcohol / 6 h / 50 °C 3: hydrogenchloride / water; ethanol / 4 h / 50 °C View Scheme

5-fluoro-3-phenyl-2-[(1S)-1-[[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino]propyl]-3,4-dihydroquinazolin-4-one → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
With hydrogenchloride In ethanol; water at 50℃; for 4h;	28 g

2-{[(2S)-2-aminobutanoyl]amino}-6-fluoro-N-phenylbenzamide → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; zinc(II) chloride / acetonitrile / 80 - 100 °C 2: zinc(II) chloride; 1,1,1,3,3,3-hexamethyl-disilazane / acetonitrile / 4 h / Reflux View Scheme

2-fluoro-5-nitrobenzoic acid (7304-32-7) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: Chloro-oxo-acetic acid / dichloromethane; N,N-dimethyl-formamide / 3 h / 20 °C 1.2: 1.5 h / 0 - 20 °C 2.1: zinc; ammonium formate / dichloromethane; water; methanol / 20 °C 3.1: benzotriazol-1-ol; 1,1'-carbonyldiimidazole / toluene / 8 - 15 °C 4.1: trifluoroacetic acid / dichloromethane / 3 h 5.1: N-ethyl-N,N-diisopropylamine; zinc(II) chloride / acetonitrile / 80 - 100 °C 6.1: zinc(II) chloride; 1,1,1,3,3,3-hexamethyl-disilazane / acetonitrile / 4 h / Reflux View Scheme

C16H15FN6O3 + aniline (62-53-3) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
With acetic anhydride In toluene at 80 - 120℃;

9-tert-butoxycarbonyl-6-chloro-9H-purine (851165-38-3) → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / tert-butyl alcohol; ethanol / 30 h / 90 °C / Inert atmosphere 2.1: sodium hydroxide; water / tetrahydrofuran / 10 h / Reflux 3.1: 4-methyl-morpholine; isobutyl chloroformate / tetrahydrofuran / 3 h / -10 °C / Inert atmosphere 3.2: -10 - 60 °C 4.1: iodine; 1,1,1,3,3,3-hexamethyl-disilazane / dichloromethane / 6 h / 30 °C View Scheme

C16H23N5O4 → 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide; water / tetrahydrofuran / 10 h / Reflux 2.1: 4-methyl-morpholine; isobutyl chloroformate / tetrahydrofuran / 3 h / -10 °C / Inert atmosphere 2.2: -10 - 60 °C 3.1: iodine; 1,1,1,3,3,3-hexamethyl-disilazane / dichloromethane / 6 h / 30 °C View Scheme

5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-3,4-dihydroquinazolin-4-one (870281-82-6) → C22H16(2)H2FN7O

Conditions	Yield
With deuterium In N,N-dimethyl acetamide at 80℃; under 1500.15 Torr; for 36h; Reagent/catalyst; Glovebox;

Upstream product

• 7304-32-7 2-fluoro-5-nitrobenzoic acid 
• 62-53-3 aniline 
• 851165-38-3 9-tert-butoxycarbonyl-6-chloro-9H-purine 
• 87-42-3 6-chloro-7H-purine 
• 1417456-04-2 2-amino-6-fluoro-N-phenyl-benzamide 
• 434-76-4 2-amino-6-fluorobenzoic acid 
• 78755-94-9 5-fluoro-2H-benzo[d][1,3]-oxazine-2,4(1H)-dione 
• 870281-86-0 (S)-2-(1-((9H-purin-6-yl-2,8-d2)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one 
• 767-69-1 6-bromopurine 
• 5451-40-1 2,6-dichloro-7H-purine 
• 870281-85-9 (S)-(1-(5-fluoro-4-carbonyl-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)carbamic acid tert-butyl ester 
• 870281-84-8 (S)-[1-(2-fluoro-6-nitro-benzoy)phenylaminocarbonyl]propyl carbamic acid tert-butyl ester 
• 385-02-4 6-fluoro-2-nitrobenzoic acid 
• 870281-83-7 2-fluoro-6-nitro-N-phenyl-benzamide 

Relevant articles and documents

A novel strategy for the manufacture of idelalisib: Controlling the formation of an enantiomer

A novel and scalable synthesis of 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-4(3H)-quinazolinone, idelalisib 1, has been developed. This strategy controls the desfluoro impurity of 13 during reduction of nitro intermediate 4, and also arrests the formation of the enantiomer during cyclisation of diamide 17, without affecting the neighbouring chiral centre. This process is demonstrated on a larger scale in the laboratory and achieved good chemical and chiral purities coupled with good yields.

Novel idelalisib preparation method

The invention belongs to the field of medicine synthesis and provides a novel idelalisib preparation method. The novel idelalisib preparation method includes steps: in an appropriate solvent, subjecting a compound A to nucleophilic substitution reaction with B in existence of an acid-binding agent to obtain an intermediate C; hydrolyzing the compound C into an intermediate D under appropriate alkali action; subjecting the intermediate D and a compound E to condensation to obtain an intermediate F; in an appropriate solvent, subjecting the intermediate F to ring closing reaction under a catalytic system of HMDS (hexamethyl disilazane)/lewis acid to obtain a final product namely idelalisib.

PROCESS FOR THE PREPARATION OF AMORPHOUS IDELALISIB AND ITS PREMIX

Processes for the preparation of amorphous idelalisib are provided. Processes for the preparation of a premix of amorphous idelalisib are also provided.