4-methylsulfonyloxybutyl methanesulfonate

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 25 mL RB flask fitted with magnetic stirrer was charged 10 mL of methanol. To the stirred solvent was added 2-cyano-3-(4-hydroxy-phenyl)-propanoic acid (0.5 g, 2.62 mmol), followed by methanesulfonic aid (0.5 mL, 7.69 mmol). After addition, the RM was refluxed at 65° C. for 1 h. After 1 h, the solvent was evaporated, water (20 mL) was added and the organic layer was extracted with ethyl acetate (15 mL×2). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown liquid. (0.3 g, yield: 55.8%): MS (ESI, 120 eV): m/z=204.1 (M−H)+. To a 25 mL RB flask fitted with magnetic stirrer After addition the solvent was evaporated water (20 mL) was added the organic layer was extracted with ethyl acetate (15 mL×2) The organic layer was dried over anhydrous Na2SO4 the solvent was removed under reduced pressure The product was obtained as brown liquid

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 25 mL RB flask fitted with magnetic stirrer was charged 10 mL of methanol. To the stirred solvent was added 2-cyano-3-(4-hydroxy-phenyl)-propanoic acid (0.5 g, 2.62 mmol), followed by methanesulfonic aid (0.5 mL, 7.69 mmol). After addition, the RM was refluxed at 65° C. for 1 h. After 1 h, the solvent was evaporated, water (20 mL) was added and the organic layer was extracted with ethyl acetate (15 mL×2). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown liquid. (0.3 g, yield: 55.8%): MS (ESI, 120 eV): m/z=204.1 (M−H)+. To a 25 mL RB flask fitted with magnetic stirrer After addition the solvent was evaporated water (20 mL) was added the organic layer was extracted with ethyl acetate (15 mL×2) The organic layer was dried over anhydrous Na2SO4 the solvent was removed under reduced pressure The product was obtained as brown liquid

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Into a four-necked flask, fitted with a mechanical stirrer, condenser, thermometer and a Nitrogen inlet was added 665.53 g (1.40 moles) of PPG-4-N-Methyl-N,N-Diethanolamine Adipate oligomer, from Example 2, and 240.43 g (2.67 moles) of 1,3-Butanediol. With the reaction mixture at 30-35° C., 131.89 g (1.37 moles) of Methanesulfonic Acid (MSA) was slowly added to neutralize the amine. The reaction was monitored by measuring the Acid Value and Base Value of the reaction mixture over time. When Methanesulfonic salt of PPG-4-N-Methyl-N,N-Diethanolamine Adipate oligomer was formed, 120.51 g (1.30 moles) of Epichlorohydrin was charged. The reaction temperature was increased to 85-90° C. and kept under Nitrogen blanket while it stirred for the next 6 hours. Reaction was monitored by the drop in Acid Value. When the acid value stabilized, 541.63 g (1.6105 moles) of Cinnamidopropyldimethylamine was charged (Cinnamidopropyldimethylamine was prepared as disclosed in example 1 in U.S. Pat. No. 5,633,403). The reaction mixture was stirred for 6 hours at 85-90° C. and was monitored by a drop in Base Value. When the base value drop stabilized, the product was diluted with water to 64-68% actives to improve fluidity. The resulting product, [Poly(N-Hydroxypolyoxypropylethyl) N-Adipyl-Poly-Oxypropyl)-N-Methyl-N-(2,Hydroxy-3-Cinnamidopropyl Dimethyl Ammonium Chloride) Methane Sulfonate] was obtained as a viscous yellow liquid. Into a four-necked flask, fitted with a mechanical stirrer, condenser

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1.00 g (2.18 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10), 2.68 g (10.88 mmol) of busulfan, and 1.50 g (10.88 mmol) of potassium carbonate in 20 mL of acetone was stirred at reflux overnight. The mixture was concentrated in vacuo and the crude was dissolved in 30 mL of ethyl acetate. The insoluble solid was filtered off and the filtrate was concentrated in vacuo. The resulting white foam was chromatographed through silica gel column, and eluted with 30% ethyl acetate/hexane to give 1.02 g (77%) of butyl mesylate intermediate as a white solid: 1H NMR (CDCl3) δ0.90 (m, 6H), 1.20-1.67 (m, 12H), 1.98 (m, 4H), 2.22 (m, 1H), 2.83 (s, 6H), 3.04 (s, 3H), 3.08 (ABq, 2H), 4.05 (t, J=5.55 Hz, 2H), 4.11 (d, J=6.90 Hz, 1H), 4.35 (t, J=6.0 Hz, 2H), 5.49 (s, 1H), 6.00 (d, J=2.4 Hz, 1H), 6.52 (dd, J=9.0 Hz, 2.7 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.90 (d, J=9.0 Hz, 1H). at reflux overnight The mixture was concentrated in vacuo the crude was dissolved in 30 mL of ethyl acetate The insoluble solid was filtered off the filtrate was concentrated in vacuo The resulting white foam was chromatographed through silica gel column eluted with 30% ethyl acetate/hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1.00 g (2.18 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10), 2.68 g (10.88 mmol) of busulfan, and 1.50 g (10.88 mmol) of potassium carbonate in 20 mL of acetone was stirred at reflux overnight. The mixture was concentrated in vacuo and the crude was dissolved in 30 mL of ethyl acetate. The insoluble solid was filtered off and the filtrate was concentrated in vacuo. The resulting white foam was chromatographed through silica gel column, and eluted with 30% ethyl acetate/hexane to give 1.02 g (77%) of butyl mesylate intermediate as a white solid: 1H NMR (CDCl3) δ 0.90 (m, 6H), 1.20-1.67 (m, 12H), 1.98 (m, 4H), 2.22 (m, 1H), 2.83 (s, 6H), 3.04 (s, 3H), 3.08 (ABq, 2H), 4.05 (t, J=5.55 Hz, 2H), 4.11 (d, J=6.90 Hz, 1H), 4.35 (t, J=6.0 Hz, 2H), 5.49 (s, 1H), 6.00 (d, J=2.4 Hz, 1H), 6.52 (dd, J=9.0 Hz, 2.7 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.90 (d, J=9.0 Hz, 1H). at reflux overnight The mixture was concentrated in vacuo the crude was dissolved in 30 mL of ethyl acetate The insoluble solid was filtered off the filtrate was concentrated in vacuo The resulting white foam was chromatographed through silica gel column eluted with 30% ethyl acetate/hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1.00 g (2.18 mmol) of 5-(41-hydroxyphenyl)-7-(dimethylamino) tetrahydrobenzo-thiepine-1,1-dioxide (obtained from Example 1402, Step 10), 2.68 g (10.88 mmol) of busulfan, and 1.50 g (10.88 mmol) of potassium carbonate in 20 mL of acetone was stirred at reflux overnight. The mixture was concentrated in vacuo and the crude was dissolved in 30 mL of ethyl acetate. The insoluble solid was filtered off and the filtrate was concentrated in vacuo. The resulting white foam was chromatographed through silica gel column, and eluted with 30% ethyl acetate/hexane to give 1.02 g (77%) of butyl mesylate intermediate as a white solid: 1H NMR (CDCl3) δ 0.90 (m, 6H), 1.20-1.67 (m, 12H), 1.98 (m, 4H), 2.22 (m, 1H), 2.83 (s, 6H), 3.04 (s, 3H), 3.08 (ABq, 2H), 4.05 (t, J=5.55 Hz, 2H), 4.11 (d, J=6.90 Hz, 1H), 4.35 (t, J=6.0 Hz, 2H), 5.49 (s, 1H), 6.00 (d, J=2.4 Hz, 1H), 6.52 (dd, J=9.0 Hz, 2.7 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.90 (d, J=9.0 Hz, 1H). at reflux overnight The mixture was concentrated in vacuo the crude was dissolved in 30 mL of ethyl acetate The insoluble solid was filtered off the filtrate was concentrated in vacuo The resulting white foam was chromatographed through silica gel column eluted with 30% ethyl acetate/hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1.00 g (2.18 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzo-thiepine-1,1-dioxide (obtained from Example 1402, Step 10), 2.68 g (10.88 mmol) of busulfan, and 1.50 g (10.88 mmol) of potassium carbonate in 20 mL of acetone was stirred at reflux overnight. The mixture was concentrated in vacuo and the crude was dissolved in 30 mL of ethyl acetate. The insoluble solid was filtered off and the filtrate was concentrated in vacuo. The resulting white foam was chromatographed through silica gel column, and eluted with 30% ethyl acetate/hexane to give 1.02 g (77%) of butyl mesylate intermediate as a white solid: 1H NMR (CDCl3) δ 0.90 (m, 6H), 1.20-1.67 (m, 12H), 1.98 (m, 4H), 2.22 (m, 1H), 2.83 (s, 6H), 3.04 (s, 3H), 3.08 (ABq, 2H), 4.05 (t, J=5.55 Hz, 2H), 4.11 (d, J=6.90 Hz, 1H), 4.35 (t, J=6.0 Hz, 2H), 5.49 (s, 1H), 6.00 (d, J=2.4 Hz, 1H), 6.52 (dd, J=9.0 Hz, 2.7 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.90 (d, J=9.0 Hz, 1H) at reflux overnight The mixture was concentrated in vacuo the crude was dissolved in 30 mL of ethyl acetate The insoluble solid was filtered off the filtrate was concentrated in vacuo The resulting white foam was chromatographed through silica gel column eluted with 30% ethyl acetate/hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1.00 g (2.18 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzo-thiepine-1,1-dioxide (obtained from Example 1402, Step 10), 2.68 g (10.88 mmol) of busulfan, and 1.50 g (10.88 mmol) of potassium carbonate in 20 mL of acetone was stirred at reflux overnight. The mixture was concentrated in vacuo and the crude was dissolved in 30 mL of ethyl acetate. The insoluble solid was filtered off and the filtrate was concentrated in vacuo. The resulting white foam was chromatographed through silica gel column, and eluted with 30% ethyl acetate/hexane to give 1.02 g (77%) of butyl mesylate intermediate as a white solid: 1H NMR (CDCl3) δ 0.90 (m, 6H), 1.20-1.67 (m, 12H), 1.98 (m, 4H), 2.22 (m, 1H), 2.83 (s, 6H), 3.04 (s, 3H), 3.08 (ABq, 2H), 4.05 (t, J=5.55 Hz, 2H), 4.11 (d, J=6.90 Hz, 1H), 4.35 (t, J=6.0 Hz, 2H), 5.49 (s, 1H), 6.00 (d, J=2.4 Hz, 1H), 6.52 (dd, J=9.0 Hz, 2.7 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.90 (d, J=9.0 Hz, 1H). at reflux overnight The mixture was concentrated in vacuo the crude was dissolved in 30 mL of ethyl acetate The insoluble solid was filtered off the filtrate was concentrated in vacuo The resulting white foam was chromatographed through silica gel column eluted with 30% ethyl acetate/hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Into a four-necked flask, fitted with a mechanical stirrer, condenser, thermometer and a Nitrogen inlet was added 665.53 g (1.40 moles) of PPG-4-N-Methyl-N,N-Diethanolamine Adipate oligomer, from Example 2, and 240.43 g (2.67 moles) of 1,3-Butanediol. With the reaction mixture at 30-35° C., 131.89 g (1.37 moles) of Methanesulfonic Acid (MSA) was slowly added to neutralize the amine. The reaction was monitored by measuring the Acid Value and Base Value of the reaction mixture over time. When Methanesulfonic salt of PPG-4-N-Methyl-N,N-Diethanolamine Adipate oligomer was formed, 120.51 g (1.30 moles) of Epichlorohydrin was charged. The reaction temperature was increased to 85-90° C. and kept under Nitrogen blanket while it stirred for the next 6 hours. Reaction was monitored by the drop in Acid Value. When the acid value stabilized, 541.63 g (1.6105 moles) of Cinnamidopropyldimethylamine was charged (Cinnamidopropyldimethylamine was prepared as disclosed in example 1 in U.S. Pat. No. 5,633,403). The reaction mixture was stirred for 6 hours at 85-90° C. and was monitored by a drop in Base Value. When the base value drop stabilized, the product was diluted with water to 64-68% actives to improve fluidity. The resulting product, [Poly(N-Hydroxypolyoxypropylethyl) N-Adipyl-Poly-Oxypropyl)-N-Methyl-N-(2,Hydroxy-3-Cinnamidopropyl Dimethyl Ammonium Chloride) Methane Sulfonate] was obtained as a viscous yellow liquid. Into a four-necked flask, fitted with a mechanical stirrer, condenser

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1.00 g (2.18 mmol) of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzo-thiepine-1,1-dioxide (obtained from Example 1402, Step 10), 2.68 g (10.88 mmol) of busulfan, and 1.50 g (10.88 mmol) of potassium carbonate in 20 mL of acetone was stirred at reflux overnight. The mixture was concentrated in vacuo and the crude was dissolved in 30 mL of ethyl acetate. The insoluble solid was filtered off and the filtrate was concentrated in vacuo. The resulting white foam was chromatographed through silica gel column, and eluted with 30% ethyl acetate/hexane to give 1.02 g (77%) of butyl mesylate intermediate as a white solid: 1H NMR (CDCl3) δ0.90 (m, 6H), 1.20-1.67 (m, 12H), 1.98 (m, 4H), 2.22 (m, 1H), 2.83 (s, 6H), 3.04 (s, 3H), 3.08 (ABq, 2H), 4.05 (t, J=5.55 Hz, 2H), 4.11 (d, J=6.90 Hz, 1H), 4.35 (t, J=6.0 Hz, 2H), 5.49 (s, 1H), 6.00 (d, J=2.4 Hz, 1H), 6.52 (dd, J=9.0 Hz, 2.7 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.90 (d, J=9.0 Hz, 1H) at reflux overnight The mixture was concentrated in vacuo the crude was dissolved in 30 mL of ethyl acetate The insoluble solid was filtered off the filtrate was concentrated in vacuo The resulting white foam was chromatographed through silica gel column eluted with 30% ethyl acetate/hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 7-Bromo-1,2-dihydrobenzofuran (64 mg, 0.3 mmol; Intermediate 77) and para-toluenesulfonic acid monohydrate (62 mg, 0.3 mmol) were mixed and then a 1:10 mixture (by weight) of methanesulfonic and phosphorous pentoxide (1 mL) was added. The resultant mixture was stirred over night at room temperature and was then poured onto ice/water. The obtained crystalline material was filtered and dried to give 120 mg of the title product. 1H NMR (400 MHz, CDCl3) δ 2.40 (s, 3H), 3.33 (t, 2H), 4.73 (t, 2H), 7.29 (d, 2H), 7.65 (d, 1H), 7.79 (d, 2H), 7.89 (d, 1H); GC-MS (EI+) for C15H13BrSO3 m/z 354 (M+H)+. was then poured onto ice/water The obtained crystalline material was filtered dried

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 25 mL RB flask fitted with magnetic stirrer was charged 10 mL of methanol. To the stirred solvent was added 2-cyano-3-(4-hydroxy-phenyl)-propanoic acid (0.5 g, 2.62 mmol), followed by methanesulfonic aid (0.5 mL, 7.69 mmol). After addition, the RM was refluxed at 65° C. for 1 h. After 1 h, the solvent was evaporated, water (20 mL) was added and the organic layer was extracted with ethyl acetate (15 mL×2). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown liquid. (0.3 g, yield: 55.8%): MS (ESI, 120 eV): m/z=204.1 (M−H)+. To a 25 mL RB flask fitted with magnetic stirrer After addition the solvent was evaporated water (20 mL) was added the organic layer was extracted with ethyl acetate (15 mL×2) The organic layer was dried over anhydrous Na2SO4 the solvent was removed under reduced pressure The product was obtained as brown liquid