(E)-but-2-enoyl chloride

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

実験手順: At −70° C., a solution of tin tetrachloride (533 ml, 4.54 mol, 1.4 eq.) in dichloromethane (2.5 l) was treated with crotonyl chloride (350 ml, 90%, 3.24 mol, 1.0 eq.). The resulting solution was stirred for 30 min. and treated within 1.5 h with a solution of 1-isobutylcyclohex-1-ene (448 g, 3.24 mol) in dichloromethane (400 ml). The resulting mixture was stirred for 1 h at −70° C. and poured into ice/H2O. The org. phase was first washed with concentrated NaOH then with H2O, dried (MgSO4), and the solvent evaporated. Short-path Vigreux-distillation (0.15 mbar, bath temperature: 160° C.) of the crude product (592 g) gave a fraction (495 g, boiling range: 90-130° C.) that was redistilled using again a short-path Vigreux-column (0.11 mbar, bath temperature: 160° C.) to give (E)-1-(2-isobutylcyclohex-2-enyl)but-2-en-1-one (202 g, 30%). Boiling point: 120° C. (0.11 mbar). The resulting mixture was stirred for 1 h at −70° C. phase was first washed with concentrated NaOH with H2O, dried (MgSO4) the solvent evaporated Short-path Vigreux-distillation (0.15 mbar, bath temperature: 160° C.) of the crude product (592 g) gave a fraction (495 g, boiling range: 90-130° C.) that was redistilled a short-path Vigreux-column (0.11 mbar, bath temperature: 160° C.)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (S)-4-Benzyloxazolidin-2-one (35 g, 0.2 mol) was dissolved in THF (500 mL) and cooled to −78° C. A solution of nBuLi in hexane (80 mL, 0.2 mol) was added dropwise. The solution was stirred at this temperature for 30 min and then (E)-but-2-enoyl chloride (19 mL, 0.2 mol) was added slowly. The cold bath was removed and the reaction was allowed to stir at room temperature for 1 h, whereupon saturated NH4Cl solution (200 mL) was added. Most of the THF was removed under vacuum and the mixture was partitioned between ether and brine. After drying over Na2SO4, the organic layer was concentrated and the residue purified by silica gel chromatography (20% EtOAc in hexanes) to give the desired product (39 g, 79% yield) as a white solid. The cold bath was removed to stir at room temperature for 1 h, whereupon saturated NH4Cl solution (200 mL) was added Most of the THF was removed under vacuum the mixture was partitioned between ether and brine After drying over Na2SO4 the organic layer was concentrated the residue purified by silica gel chromatography (20% EtOAc in hexanes)

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

実験手順: To a solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (316 mg, 1.0 mmol) in THF (6 mL) stirred under N2 at 0° C. was added trans-crotonyl chloride. A yellow solid formed upon addition. The solid was collected by Buchner filtration after 2.5 hours and sonicated with EtOAc to give the title compound (216 mg, 52%), mp 279-281° C. A yellow solid formed upon addition The solid was collected by Buchner filtration after 2.5 hours sonicated with EtOAc

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

実験手順: To an ice cold solution of 0.158 g of 7-amino-4-(3-bromoanilino)-quinazoline (J Med Chem, 1985:3482) in 5 mL of tetrahydrofuran was added dropwise a solution of 0.105 g of crotonic acid chloride in 5 mL of tetrahydrofuran. When the addition was complete, the ice bath was removed and the reaction stirred at room temperature for 15 hours. The reaction was filtered to remove the yellow solid which was washed with tetrahydrofuran and recrystallized from 20 mL of boiling methanol to afford 0.060 g of the desired product, mp >250° C. When the addition the ice bath was removed The reaction was filtered to remove the yellow solid which was washed with tetrahydrofuran recrystallized from 20 mL of boiling methanol

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

実験手順: Using the general method of Example 92, crotonyl chloride (68 μL, 0.7 mmol) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.2 g, 0.7 mmol) to provide 0.2 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-(E)-2-butenamide as a white powder, m.p. 198-200° C. Analysis: Calculated for C19H24N6O: %C, 64.75; %H, 6.86; %N, 23.85; Found: %C, 64.25; %H, 6.68; %N, 23.99. HRMS (EI) calcd for C19H24N6O (M+) 352.2011 found 352.1996

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

実験手順: N-(3,5-di tert.butyl-4-hydroxyphenyl)crotonamide was prepared by adding a solution of 11.5 grams to crotonyl chloride in 50 milliliters of benzene to a solution of 2,6-di tert.butyl-4-aminophenol prepared as described in Example 2 to which had been added 6 grams of sodium carbonate. The addition was accomplished in 30 minutes at 25° C. to 38° C. The mixture was stirred for 11/4 hours and the solid product was filtered, washed thoroughly with 2% hydrochloric acid, and dried. The yield was 12.8 grams of product which melted at 211° C. to 214° C. prepared The addition the solid product was filtered washed thoroughly with 2% hydrochloric acid dried

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

実験手順: N-(3,5-di tert.butyl-4-hydroxyphenyl)crotonamide was prepared by adding a solution of 11.5 grams to crotonyl chloride in 50 milliliters of benzene to a solution of 2,6-di tert.butyl-4-aminophenol prepared as described in Example 2 to which had been added 6 grams of sodium carbonate. The addition was accomplished in 30 minutes at 25° C. to 38° C. The mixture was stirred for 11/4 hours and the solid product was filtered, washed thoroughly with 2% hydrochloric acid, and dried. The yield was 12.8 grams of product which melted at 211° C. to 214° C. prepared The addition the solid product was filtered washed thoroughly with 2% hydrochloric acid dried

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

実験手順: Using the procedure of Step A of Example 1, 19.44 g of 2-acetylamino thiazole and 17.3 g of 2-(1-propenyl)-8-trifluoromethyl-4H-3,1-benzoxazin-4-one [prepared by Step A of Example 12 of European Pat. No. 40,573 from crotonyl chloride and 2-amino-trifluoromethyl benzoic acid] were reacted to obtain 19.03 g of β-oxo-2-[(1-oxo-2-butenyl)-amino]-N-(2-thiazolyl)-3-trifluoromethyl-benzene-proponamide melting at 206°-208° C. prepared by Step A of Example 12 of European Pat

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

実験手順: 71 g of 3,3,5-trimethylcyclohexanol having a cis content of 90% are placed in a 1-l reaction flask together with 60 g of pyridine in 300 ml of methyl tert-butyl ether and 63 g of crotonic acid chloride are added at 0 to 5° C. over 30 minutes. The reaction mixture is left to continue reacting for a further one hour at this temperature; it is then allowed to heat up to room temperature. After one hour it is heated for a further 30 min to 50° C. After cooling, it is fractionated with water, the organic phase is separated off and first washed with dilute hydrochloric acid and then stirred for a further 30 min with 5-percent sodium hydroxide solution. After washing until it is neutral, the solvent is drawn off and the residue distilled using a short column. 63 g of pure 3,3,5-trimethylcyclohexyl crotonate having a cis content of 90% are obtained at a boiling point of 121° C. under 20 mbar. MS: 210 (M*, 0,3), 195 (0,5), 141 (3), 124 (75), 109 (100), 95 (24), 87 (24), 82 (25), 69 (75), 55 (11), 41 (33). The cis-3,3,5-trimethylcyclohexyl esters of propionic acid, isobutyric acid and butyric acid can be prepared in an analogous manner. are added at 0 to 5° C. over 30 minutes The reaction mixture is left After one hour it is heated for a further 30 min to 50° C After cooling the organic phase is separated off first washed with dilute hydrochloric acid After washing until it the residue distilled

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

実験手順: 3.1 grams (0.021 mole) 4-ethyl-4-hydroxymethyl-2-oxazolidinone, prepared identically to that discussed in example 1, 2.3 grams (0.022 mole) trans-crotonyl chloride, and 25 milliliters chloroform were mixed in a one-necked round-bottom flask. The procedure employed was identical to that discussed in example 1. 4.20 grams (98 % of the yield theoretically expected) of pure product was obtained as a clear oil. The product exhibited the following spectral data: 1H NMR (CDCl3) δ0.90(t, 3H J=1.8 Hz), 1.48-1.67(m, 2H), 1.83(d, 3H J=3.6 Hz), 3.97-4.19(m, 4H), 5.79(d, 1H J=3.6 Hz), 6.90-6.99(m, 2H); 13C NMR (CDCl3) δ7.3, 18.1, 28.3, 60.2, 66.7, 70.9, 121.7, 146.3, 159.6, 166.0; IR (NaCl) 3229, 3020, 2960, 1780 cm-1 ; MS m/z 213. This monomer can be chlorinated or brominated by the same procedure as in example 1. were mixed in a one-necked round-bottom flask 4.20 grams (98 % of the yield theoretically was obtained as a clear oil

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

実験手順: Using the general method of Example 92, crotonyl chloride (68 μL, 0.7 mmol) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.2 g, 0.7 mmol) to provide 0.2 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-(E)-2-butenamide as a white powder, m.p. 198-200° C. Analysis: Calculated for C19H24N6O: %C, 64.75; %H, 6.86; %N, 23.85; Found: %C, 64.25; %H, 6.68; %N, 23.99. HRMS (EI) calcd for C19H24N6O (M+) 352.2011 found 352.1996

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

実験手順: Using the general method of Example 92, crotonyl chloride (68 μL, 0.7 mmol) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.2 g, 0.7 mmol) to provide 0.2 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-(E)-2-butenamide as a white powder, m.p. 198-200° C. Analysis: Calculated for C19H24N6O: %C, 64.75; %H, 6.86; %N, 23.85; Found: %C, 64.25; %H, 6.68; %N, 23.99. HRMS (EI) calcd for C19H24N6O (M+) 352.2011 found 352.1996