4-AMINO-2-METHYLTHIO-PYRIMIDINE-5-CARBALDEHYDE

Method A: Add Mn0To a solution of (4-amino-2-(methylthio)pyrimidin-5-yl)methanol (11 g, 63 mmol, 1.0 equiv) in CHC13 (900 mL) was added Mn02 (43.85 g, 504 mmol, 8.0 equiv). The suspension was stirred overnight at rt. The resulting mixture was filtration and washing with CHC13. The filtrate was concentrated under vacuum to give 10 g (94percent) of 4-amino-2- (methylthio)pyrimidine-5 -carbaldehyde as a white solid.To a solution of (4-amino-2-(methylthio)pyrimidin-5-yl)methanol (11 g, 63 mmol, 1.0 equiv) in CHC1General procedure: The compound (3) (1 equiv.) was dissolved in chloroform to which Mn02 (6 equiv.) wasadded. The resulting suspension was stirred overnight, an additional portion of Mn02 (1.5 equiv.)was added and stirring was continued for a further 12 h. The solids were removed by filtration through a diatomaceous earth pad, which was washed with further chloroform. The chloroform was evaporated in vacuum to obtain the product (4).Starting from compound (3a), compound (4a) was obtained in 72percent yield using themethod described in General Procedure C. ‘H NMR (300 MHz, DMSO-d6), ö 2.55 (s, S-CH3, 3H), 5.74 (bs, NH, 1H), 8.20 (bs, NH, 1H), 8.45 (s, Ar-H, 1H), 9.80 (s, HC=O, 1H).Step 2: Intermediate 2 [00830j A mixture of Intermediate 1 (7.5 g, 44 mmol) and Mn02 (55 g, 630 mmol) in DCM (60 mL) was allowed to stir at room temperature overnight. The mixture was filtered, and the filtrate was concentrated. The resultant residue was purified by colunm chromatography (DCM:MeOH=20: 1) to afford the title compound as light yellow solid (3.85 g, 52percent). LCMS:170.2 [M+1]. ‘H NMR (400 MHz, CDC13): ö 2.55 (s, 3H), 8.42 (s, 1H), 9.78 (s, 1H).step 3: To a 3 L three-necked flask was added (4-amino-2-(methylthio)pyrimidin-5-yl)methanol (100 g, 0.58 mol), activated MnOc) To a solution of (4-amino-2-(methylthio)pyrimidin-5 -yl)methanol (11 g, 63 mmol, 1.0 equiv) in CHC13 (900 mL) was added Mn02 (43.85 g, 504 mmol, 8.0 equiv). The suspension was stirred overnight at rt. The resulting mixture was filtration and washing with CHC13. The filtrate was concentrated under vacuum to give 10 g (94percent) of 4-amino-2-(methylthio)pyrimidine-5- carbaldehyde as a white solid.To a solution [OF 4-AMINO-2-SULFANYL-PYRIMIDINE-5-CARBALDEHYDE (P-5B)] (100.00 g, 644.4 mmoles) and 325 mesh potassium carbonate (178.10 g, 1.29 moles) in acetone (1.5 L) was added iodomethane (128.10 g, 902.2 mmoles) dropwise over 20 minutes with mild cooling. The mixture was stirred at ambient temperature over the weekend. TLC showed remaining product (P-5B) from Step B, and then an additional aliquot of iodomethane was added (8 mL) and stirring continued overnight. TLC again showed some product from step B [(P-5B)] remaining and an addition portion of iodomethane was added (8 mL) and stirring was continued another 24 hour period. An HPLC showed 95.9percent S-alkylated product and 3.7percent of compound [(P-5B).] The reaction mixture was stripped to near dryness on a rotoevaporator. Water (1 L) was added to the residue and the product was collected via filtration and washed with water (200 mL). The product was dried overnight in a vacuum oven at [60°C.] Yield was 103.37 grams (94.8percent). HPLC showed 95.8percent Preparation 5 and 4.2percent of compound [(P-5B).]To a solution of 4-amino-2- (methylthio) pyrimidine-5-carbonitrile (3.0 g, 18.05 mmol) in THF (100 mL) is added diisobutylaluminum hydride (41.52 mL, 1.0 M in CH2C12, , 41.52 mmol) at 0°C. After the mixture is stirred for 2.5 hours at 0°C, hydrochloric acid (2N, 30mL) is added and stirring is continued for 20 minutes. To the reaction mixture is added saturated Na2CO3 until a pH of 8 is achieved. The suspended material is filtered through Celit pad and washed with K2CO3 solution. The solution is diluted with EtOAc and washed with saturated K2CO3, brine and dried, filtered and concentrated to give crude product, which is purified by flash silica gel column, eluting with hexane (100percent) gradient to hexane/ether (60/40 percent), to give the title intermediate as a solid (1.62 g, 53.1 percent).To a solution of 4-amino-2- (methylthio) pyrimidine-5-carbonitrile (3.0 g, 18.05 mmol) in THF (100 mL) is added diisobutylaluminum hydride (41.52 mL, 1.0 M in CH2C12, , 41.52 mmol) at 0°C. After the mixture is stirred for 2.5 hours at 0°C, hydrochloric acid (2N, 30mL) is added and stirring is continued for 20 minutes. To the reaction mixture is added saturated Na2CO3 until a pH of 8 is achieved. The suspended material is filtered through Celit pad and washed with K2CO3 solution. The solution is diluted with EtOAc and washed with saturated K2CO3, brine and dried, filtered and concentrated to give crude product, which is purified by flash silica gel column, eluting with hexane (100percent) gradient to hexane/ether (60/40 percent), to give the title intermediate as a solid (1.62 g, 53.1 percent).

Used for the preparation of pyridopyrimidines and naphthyridines as inhibitors of Akt kinase for the treatment of cancer.

Molecular Weight:169.21
XLogP3:0.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:2
Exact Mass:169.03098303
Monoisotopic Mass:169.03098303
Topological Polar Surface Area:94.2
Heavy Atom Count:11
Complexity:144
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes