PropylsulfaMide

A.i. Propane-1-sulfamide; Chlorosulfonyl isocyanate (12.3 mL; 0.14 mol; 1.0 eq.) was slowly added to a cold (- 35°C) solution of benzyl alcohol (14.7 mL; 0.14 mol; 1.0 eq.) in DCM (130 mL) over 30 min. A solution of n-propylamine (14 mL, 0.17 mol; 1.2 eq.) and triethylamine (29.5 mL; 0.21 mol; 1.5 eq.) in DCM (35 mL) was slowly added dropwise at -50°C. The mixture was warmed to 20°C for 2 h. It was washed with water, followed by aq. 33percent HCl and water. The mixture was warmed to 30°C and the layers were separated. The org. phase was washed with a mixture of EtGeneral procedure: The deprotection reaction of sulfonamide (1a–e) (1g) was carried out in distilled water (30 mL); the reaction mixture was refluxed for 15–30 min, then it was extracted with ethyl acetate (3 × 30 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to give sulfonamides (2a–e) in good yields.Under the protection of nitrogen, 155 g of the compound of formula III was added to the clean four-necked reaction flask, 300 ml of dichloromethane was added, Stir, Temperature control at about 20 , Slowly into the ammonia for about 1 hour, The reaction solution was concentrated under reduced pressure to obtain 132.5 g of the crude compound of formula V.The resulting crude compound was distilled to give 122.8 g of the compound of formula V as a colorless and transparent liquid. The total yield of the two steps was 88.8percent (based on the compound of formula I). GC purity was 99.5percent.General procedure: To a solution of Ex 3 (50 mg, 0.12 mmol) and TEA (51 uL, 0.36 mmol) in dioxane (2 mL) is added sulfamide (12 mg, 0.12 mmol). The reaction mixture is stirred at 100C for 18 h and is then evaporated. The crude compound is purified by prep. HPLC (Prep HPLC 2) to give the title compound Ex 15-5 as a white solid (35 mg, 63% yield).A mixture of 1 (100 g, 0.33 mol), K2CO3 (221 g, 1.6 mol), and acetonitrile (1.3 L) washeated to 50C and stirred for 20 min. The solution of 2 (43 g, 0.31 mol) in acetonitrile(200 mL) was added dropwise and maintained at 50C for 10 h. The reaction solvent wasreplaced with toluene (2 L) using a Dean-Stark apparatus. The precipitated solid was filteredand suspended in water (2 L). The pH was adjusted to 7 by using 6 N hydrochloricacid and stirred for 20 min. The resulting precipitate was filtered and dried in the oven at55C for 5 h. The crude product was recrystallized from ethyl acetate to acquire 106 g(85%) of 3 as a white solid, mp 236C-238C. IR (KBr): 3272, 2966, 1593, 1566, 1438.1H NMR (500 MHz, DMSO-d6): d 0.73-0.76 (t, JD6.9, Me); 1.30-1.36 (m, CH2), 2.52-2.56 (m, CH2), 5.68-5.71 (t, JD6.6, NH), 7.12-7.14 (d, 2 H, ArH), 7.50-7.51 (d, 2 H, ArH), 8.04 (s, 1 H, ArH). 13C NMR (125 MHz, DMSO): d 12.41, 21.63, 45.75, 120.26, 120.93, 131.50, 133.38, 136.21, 155.26, 156.73, 164.76.Under the protection of nitrogen, 155 g of the compound of formula III was added to the clean four-necked reaction flask, 300 ml of dichloromethane was added, Stir, Temperature control at about 20 , Slowly into the ammonia for about 1 hour, The reaction solution was concentrated under reduced pressure to obtain 132.5 g of the crude compound of formula V.The resulting crude compound was distilled to give 122.8 g of the compound of formula V as a colorless and transparent liquid. The total yield of the two steps was 88.8% (based on the compound of formula I). GC purity was 99.5%.1, 8 ml of N, N-dimethylformamide, 100 g (724 mmol) of General procedure: Under nitrogen atmosphere, a mixture of sulfonamide 2a-h (1 mmol), maleic anhydride derivatives (2 mmol), and H6P2W18O62 catalyst (2 mmol%) in acetonitrile (2 mL), was stirred at reflux. Reaction was monitored by TLC. After achieving the reaction, dichloromethane (2 ×10 mL) was added and the catalyst was filtered; water (10 mL) was then added. The organic layers were combined and dried over anhydrous sodium sulfate and removed under reduced pressure. The residue obtained was purified by flash chromatography (Merck silica gel 60H, CH2Cl2/MeOH, 9:1) to afford the corresponding sulfonyl maleimide derivatives.General procedure: Under nitrogen atmosphere, a mixture of sulfonamide 2a-h (1 mmol), maleic anhydride derivatives (2 mmol), and H6P2W18O62 catalyst (2 mmol%) in acetonitrile (2 mL), was stirred at reflux. Reaction was monitored by TLC. After achieving the reaction, dichloromethane (2 ×10 mL) was added and the catalyst was filtered; water (10 mL) was then added.The organic layers were combined and dried over anhydrous sodium sulfate and removed under reduced pressure. The residue obtained was purified by flash chromatography (Merck silica gel 60H, CH2Cl2/MeOH, 9:1) to afford the corresponding sulfonyl maleimide derivatives.The compound of (2 g; 4.25 mmol), propylsulfamide (735 mg; 5.32 mmol; 1.2 eq.; prepared as described in Bolli et al, J. Med. Chem. (2012), 55, 7849-7861), cesium fluoride (2.0 g; 12.8 mmol; 3 eq.) and potassium carbonate (1.7 g; 12.8 mmol; 3 eq.) were suspended in DMSO (20 mL) at 20-25C. The mixture was heated to 70-75C for 15 h. Water (20 mL) and DCM (20 mL) were added. The layers were separated and the org. phase was washed with 30% aq. citric acid (20 mL) before being concentrated to dryness. The residue was recrystallized from toluene to yield the title compound as a white powder (600 mg; 24% yield). (0325) The product had MS and NMR data equivalent to those reported in Bolli et al, J. Med. (0326) Chem. (2012), 55, 7849-7861. (0327) LC-MS (method 1): tR = 1.83 min; 96.7% a/aThe compound of (10 g; 20.6 mmol), propylsulfamide (3.1 g; 22.6 mmol; 1.1 eq.; prepared as described in Bolli et al, J. Med. Chem. (2012), 55, 7849-7861), TBAF.3H20 (19.5 g; 61.7 mmol; 3 eq.) and potassium carbonate (8.5 g; 61.7 mmol; 3 eq.) were suspended in DMSO (100 mL). The mixture was heated to 100C for 1 h and then cooled to 20-25C. Water (100 mL) and DCM (100 mL) were added. The org. layer was washed 3 times with water (100 mL each time), 20% aq. citric acid (100 mL) and water (100 mL) before being concentrated under reduced pressure to dryness. The residue was suspended in EA (15 mL) and heated to reflux. Hept (30 mL) was added. The mixture was allowed to cool to 20-25C on its own. The precipitate was filtered off and rinsed with Hept (10 mL). The beige solid thus collected (11.0 g) was recrystallized from EA (30 mL) and Hept (25 mL) to afford the title compound as a white solid (6.4 g; 53% yield). (0323) The product had MS and NMR data equivalent to those reported in Bolli et al, J. Med. Chem. (2012), 55, 7849-7861. LC-MS (method 1): tR = 1.89 min; 100% a/a.

Molecular Weight:138.19
XLogP3:-0.4
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:138.04629874
Monoisotopic Mass:138.04629874
Topological Polar Surface Area:80.6
Heavy Atom Count:8
Complexity:134
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes