Propanoic acid, 3-(chlorosulfonyl)-, methyl ester

Under ice-cooling, in a solution of methyl 3-mercaptopropionate (6.5 g, 54 mmol) and ice in dichloromethane, Chlorine gas is introduced until the reaction solution turns pale green.Continue to introduce chlorine for 0.5 hours, Nitrogen was purged to remove the chlorine in the reaction system.The reaction was extracted with dichloromethane and the combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give methyl 3-(chlorosulfonyl)propanoate (9.7 g, 96percent yield).Sulfuryl chloride (64.8 mL, 0.8 mol) was added dropwise under vigorous stirring to a mixture of finely ground potassium nitrate (84.14 g, 0.883 mol) and compound 1 (36.9 mL, 0.333 mol) at 0-10° C. (the temperature of the reaction mixture must not be higher than 0° C.). The reaction mixture was stirred for 1 hour at 0° C. The cooling was removed, and the mixture was stirred at room temperature for additional 16-18 hours. A saturated aqueous solution of NaHCOSynthesis of Benzyl (25, 4a5, 6a5, 6bR, 8aR, 1OS, 1 2a5, 1 2bR, 1 4bR)- 1 O-((3 -methoxy-3 -oxopropyl) sulfonamido)-2, 4a, 6a, 6b, 9, 9, 12a-heptamethyl-13-oxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 1 2b, 13, 1 4b-icosahydropicene-2-carboxylate (72-2). Into a 5 O-mL round-bottom flask, was placed 54-1 (300 mg, 1 equiv.), DCM (10 mL), [0217] A mixture of 2-chloro-3 -((3 , 4-dihydro-2H-pyrimido [1 , 2-cj quinazolin- 10- yl)oxy)aniline (100 mg, 0.31 mmol), To a 500 mL RBF was added Example 362.03 (8.44 g, 29.5 mmol) and TEA (20.50 mL, 147 mmol) in DCM (157 mL). At RT, 3-chlorosulfonyl-propionic acid methyl ester (6.60 mL, 35.4 mmol) in DCM (39.3 mL) was added dropwise with stirring. The reaction mixture was stirred at RT for 17 h. The reaction mixture was concentrated in vacuo and then diluted with 1 N HC1 and extracted with DCM. The combined organic layers were washed with brine and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the initial product as a light-yellow solid. The material thus obtained was triturated with DCM/ether to provide the title compound, Example 344.1 (9.4 g, 21.5 mmol, 73 % yield), as an off-white solid. The mother liquors were concentrated to afford another crop of Example 344.1 (2.0 g, 4.58 mmol, 16 %yield) as alight-yellow solid. LCMS-ESI (pos.), m/z: 437.0 (M+H)tTo a suspension of Example 311.01 (1.02 g, 3.37 mmol) in DCM (18 mL) in a 250 mL RBF at RT, was added TEA (2.35 mL, 16.9 mmol). To the mixture was added a solution of 3-chlorosulfonyl- propionic acid methyl ester (0.755 g, 4.05 mmol) in DCM (4 mL). The reaction mixture was stirred at RT for 3 h. Additional 3-chlorosulfonyl-propionic acid methyl ester (0.378g, 2.02 mmol) was added to the reaction mixture, and stirring was continued at RT for 16 h. Another portion of 3-chlorosulfonyl-propionic acid methyl ester (0.378g, 2.02 mmol) was then added, and the reaction was stirred for a further 24 h. The reaction mixture was then washed with 1.0 N HCl (aq), and then with saturated brine. The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo. The residue was trituated with MeOH/DCM/EtOAc/hexanes (5:2:2:91, 100 mL) and decanted. The solid was then further washed with 10% DCM/Et2O (200 mL) and dried under vacuum to provide the title compound, Example 361.01 (1.13 g, 74 % yield), as a tan powder which was used in the next step without further purification. LCMS-ESI (pos.) m/z: 452.9 (M+H)+.In the ice bath, To a solution of 2-chloroethylamine hydrochloride (5.0 g, 26.8 mmol) in dichloromethane was added triethylamine (18.7 mL, 134 mmol).Then

Molecular Weight:186.61
XLogP3:0.2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:185.9753576
Monoisotopic Mass:185.9753576
Topological Polar Surface Area:68.8
Heavy Atom Count:10
Complexity:202
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes