2-Amino-N-[2,3-dihydro-7-methoxy-8-[3-(4-morpholinyl)propoxy]imidazo[1,2-c]quinazolin-5-yl]-5-pyrimidinecarboxamide

Copanlisib (BAY 80-6946) is a selective and ATP-competitive class-I PI3 kinases inhibitor, with IC50s of 0.5, 0.7, 3.7 and 6.4 nM for PI3Kα, PI3Kδ, PI3Kβ and PI3Kγ, respectively.

Copanlisib is an imidazoquinazoline that is 2,3-dihydroimidazo[1,2-c]quinazoline substituted by (2-aminopyrimidine-5-carbonyl)amino, methoxy, and 3-(morpholin-4-yl)propoxy groups at positions 5, 7 and 8, respectively. It is a intravenous pan-class I PI3K inhibitor used for the treatment of relapsed follicular lymphoma in patients who have received at least 2 prior systemic therapies. It has a role as an EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor, an antineoplastic agent and an apoptosis inducer. It is a member of morpholines, an aromatic ether, a diether, a tertiary amino compound, a secondary carboxamide, a pyrimidinecarboxamide, an aminopyrimidine and an imidazoquinazoline.|Copanlisib is a selective pan-Class I phosphoinositide 3-kinase (PI3K/Phosphatidylinositol-4,5-bisphosphate 3-kinase/phosphatidylinositide 3-kinase) inhibitor that was first developed by Bayer Healthcare Pharmaceuticals, Inc. The drug targets the enzyme that plays a role in regulating cell growth and survival. Copanlisib was granted accelerated approval on September 14, 2017 under the market name Aliqopa for the treatment of adult patients with relapsed follicular lymphoma and a treatment history of at least two prior systemic therapies. Follicular lymphoma is a slow-growing type of non-Hodgkin lymphoma that is caused by unregulated proliferation and growth of lymphocytes. The active ingredient in Aliquopa intravenous therapy is copanlisib dihydrochloride.|Copanlisib is a Kinase Inhibitor. The mechanism of action of copanlisib is as a Kinase Inhibitor.|Copanlisib is an intravenously administered phosphatidylinositol-3 kinase inhibitor that is used to treat relapsed and refractory follicular lymphoma. Copanlisib is associated with a high rate of minor serum enzyme elevations during therapy and has been reported to cause clinically apparent acute liver injury that can be severe and even fatal.|Copanlisib is a phosphoinositide 3-kinase (PI3K) inhibitor with potential antineoplastic activity. Copanlisib inhibits the activation of the PI3K signaling pathway, which may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis and dysregulated PI3K signaling may contribute to tumor resistance to a variety of antineoplastic agents.

Step A9 : preparation of copanlisib (10) A mixture of 1250 g of 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2, 3-dihydro- imidazo[1 , 2-c]quinazolin-5-amine, 20.3 kg of N, N-dimethylformamide, 531 g of 2-aminopyrimidine-5-carboxylic acid, 425 g of Ν, Ν-dimethylaminopyridine and 1000 g of N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride was stirred at r.t. for 17 h. The reaction mixture was filtered. The collected solids were washed with Ν, Ν-dimethylformamide, then ethanol, and dried at 50°C to yield 1 .6 kg (96percent). The isolated material was directly converted into the dihydrochloride.A mixture of 600 g of 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2, 3-dihydro- imidazo[1 , 2-c]quinazolin-5-amine, 306 g of 2-aminopyrimidine-5-carboxylic acid, 204 g of N, N-dimethyl-4-aminopyridine, 480 g of N-[3-(dimethylamino)propyl]-N'- ethylcarbodiimide hydrochloride and 1500 g of Ν, Ν-dimethylformamide was stirred at room temperature for 15 h. The mixture was filtered, the filter cake was washed with Ν, Ν-dimethylformamide then ethanol. The collected solids were dried in vacuum to yield 769 g of copansilib (96 percent).Step 6: Preparation of 2-amino-N-r7-methoxy-8-(3-morpholin-4-ylpropoxy)-2.3- dihvdroimidazori ^-clquinazolin-S-vnpyrimidine-δ-carboxamide.; 7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2, 3-dihydroimidazo[1 , 2-c]quinazolin-5-amine (100 mg, 0.22 mol) was dissolved in DMF (5 mL), and Intermediate B (46 mg, 0.33 mmol) was added. PYBOP (173 mg, 0.33 mmol) and diisopropylethylamine (0.16 mL, 0.89 mmol) were subsequently added, and the mixture was stirred at rt overnight. EtOAc was added, and the solids were isolated by vacuum filtration to give the title compound (42.7 mg, 40percent): HPLC MS RT = 1.09 min, MHIn a nitrogen atmosphere, Add in the reaction flask N- (7- morpholin-4-ylpropoxy) -8-methoxyquinazolin-4 (3H) -one-2-yl] -2-amino-5- pyrimidinecarboxamide ( IV) (2.28 g, 5 mmol) andPhosphorus oxychloride 10mL, Warmed to 80 ° C, Stirred for 2-3 hours, The temperature was lowered, 2-chloroethylamine hydrochloride (0.93 g, 8 mmol) was added, the temperature was raised again to 80-90 ° C., The reaction was stirred for 4-6 hours.Excess phosphorus oxychloride was removed by distillation under reduced pressure, the temperature was lowered to room temperature, and the remainder was added with ice water. The pH was adjusted to neutral by using 10percent sodium hydroxide by weight concentration at 0-5 ° C. The solid was precipitated, filtered, washed with water, Toluene recrystallization, Dry in vacuo to give a white solidPantokenis1.55 g, yield 64.6percent

Molecular Weight:480.5
XLogP3:0.3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:9
Rotatable Bond Count:7
Exact Mass:480.22335140
Monoisotopic Mass:480.22335140
Topological Polar Surface Area:140
Heavy Atom Count:35
Complexity:974
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes