ASISCHEM A03574

Synthesis Example 29; Synthesis of Compound 167; Ethyl-2-(methylthio)-5-pyrimidine carboxylate (1 g, 5 mmol) was dissolved in MeOH (15 mL). 1N NaOH (6 mL) was added, and the reaction mixture stirred for 1 h. The MeOH was removed by rotary evaporator and conc. HCl (500 μl) was added. The resulting precipitate was filtered and washed with HEthyl-2-(methylthio)-5-pyrimidine carboxylate (1 g, 5 mmol) was dissolved in MeOH (15 mL). IN NaOH (6 mL)was added, and the reaction mixture stirred for 1 h. The MeOH was removed by rotary evaporator and conc. HCl (500ml) was added. The resulting precipitate was filtered and washed with H2O and dried in vacuo to yield 811 mg (95percent).The resulting pyrimidine carboxylic acid was coupled to 4-fluoroaniline using EEDQ (as in Synthesis Example 1) to yield911 mg (73percent) of the pyrimidine carboxamide intermediate. The thiomethyl ether moiety of the pyrimidine carboxamide(800 mg, 3.1 mmol) was oxidized with m-CPBA (530 mg, 3.1 mmol) in MeCN (150 mL) for 1 h at r. t., and the resultingprecipitate was filtered and dried in vacuo to yield 300 mg (35percent) of the oxidized material. The crude mixture (300 mg)was dissolved in anhydrous DMF (20 mL) and sodium hydrogen sulfide (124 mg, 2 mmol) was added. The reactionmixture was brought to gentle reflux for 2 h, then EtOAc (100 mL) was added, and the organic layer washed with H2O.The organic solvent was removed by rotary evaporator, and the 6-mercapto-pyrimidine carboxamide intermediate waspurified by preparative HPLC to yield 18 mg of product. The 6-mercapto-pyrimidine carboxamide was then alkylatedwith 2-bromomethyl-phenylboronic acid via Method B to yield 10 mg (36percent) of compound 163 as a white solid. ESI-MSm/z = 384.0 [M+H]+.To a solution of 112 (1.0 g, 5 mmoi) in MeOH (15 mL) is added IN NaOH solution (6 mL). After stirring at room temperature for 1 hour, the mixture is concentrated and concentrated HCI (0.5 mL) is added. The solid is collected by filtration, washed with water, and dry to give 133 as ayeilow solid (811 mg. 95percent). (MS: M+H[ 171.1)Ethyl 2-(methylthio)pyrimidine-5-carboxylate (4.500 g, 22.700 mmol) and sodium hydroxide (4.539 g, 113.499 mmol) was dissolved in methanol (20 mL)/water (5 mL) at room temperature and stirred at the same temperature for 1 hour. The reaction mixture was filtered through a pad of celite to remove the solid. The filtrate was poured into 1 N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and water was removed with anhydrous magnesium sulfate, followed by filtration and concentration under reduced pressure. The product was used without further purification (3.330 g, 86.2percent, white solid).The 2- (methylthio) pyrimidine-5-carboxylic acid used as starting material was prepared as follows:- To a solution of ethyl 2-(methylthio)-5-pyrinzidillecarboxylate (2. 68 g, 13.53 mmol) in ethanol (18.6 mL) was added potassium hydroxide (1.304 g, 23.28 mmol) and the resulting mixture stirred for 20 minutes at room temperature. The solvent was evaporated under reduced pressure and the residue partitioned between water and diethyl ether. The aqueous phase was then acidified with dilute aqueous hydrochloric acid and the resulting solid filtered off to give the title compound as a solid (1.96 g, 85. 2percent); NMR Spectrum : (DMSOd6) 2.58 (m, 3H), 9.01 (s, 2H), 13.54 (m, 1H).A mixture of 2- chloropyrimidine-5-carboxylic acid (50 mg, 0.31 mmol), sodium methanethiolate (43 mg, 0.62 mmol) and KTo a solution of To a solution of crude 19 (100 mg, 0.48 mmol ) in THF (5 mL) is added isobutyl chloroformate (0.05 mL, 0, 58 mmol) followed by NMM (0.06 mL, 0.58 mmol) at - 10 C. After stirring for 10 minutes, the mixture is filtered and sodium borohydride (37 mg, 0, 96 mmol) in water (0.2 mL) is added dropwise at 0 C. After stirring at room temperature for 20 minutes, the mixture is concentrated and the residue is partitioned between EA (20 mL) and water (10 mL). The organic layer is washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (MeOH:DCM = 1 : 100) to give A38 as a colorless oil (50 mg, 74% yield). (MS: i 1 · 1 11 194.1 ).Following the procedure for A38 using 133 (1.18 g, 6.9 mmoi), NMM (695 mg.6.9 mmoi), THF (20 mL), isohutyl chioroformate (1.13 g. 8.25 mmol), sodium borodeuteride(289 mg, 6.9 mmoi), and deueterate water (0.5 mL), then purii with silica gel columnchromatography (EA:PE == 1:5) to give i13d2 as a light yellow solid (290 rng, 25%). (MS:[M+H] 159.1)

Molecular Weight:170.19
XLogP3:0.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:2
Exact Mass:170.01499861
Monoisotopic Mass:170.01499861
Topological Polar Surface Area:88.4
Heavy Atom Count:11
Complexity:146
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes