1,1,3,3-tetraethoxypropane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring suspension of (4-bromophenyl)hydrazine hydrochloride (3.28 g, 14.7 mmol) in EtOH (25 mL) was added concentrated HCl (0.147 mL, 1.47 mmol) and 1,1,3,3-tetraethoxypropane (3.87 mL, 16.1 mmol). The reaction mixture was heated at reflux for 2 h then cooled to room temperature. The reaction mixture was poured onto water (150 mL) and hexanes (20 mL) and stirred for 1 h. A brown precipitate was collected by filtration and washed with water (2×10 mL) and hexanes (10 mL). The resultant solid was dried in air then washed with toluene (10 mL) to afford 2 g (61%) of 1-(4-bromophenyl)-1H-pyrazole INT-84 as a light brown powder. LCMS-ESI (m/z) calculated for C9H7BrN2: 223; found 223/225 [M+H]+, tR=2.14 min (Method 10). The reaction mixture was heated at reflux for 2 h A brown precipitate was collected by filtration washed with water (2×10 mL) and hexanes (10 mL) The resultant solid was dried in air then washed with toluene (10 mL)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring suspension of (4-bromophenyl)hydrazine hydrochloride (3.28 g, 14.7 mmol) in EtOH (25 mL) was added concentrated HCl (0.147 mL, 1.47 mmol) and 1,1,3,3-tetraethoxypropane (3.87 mL, 16.1 mmol). The reaction mixture was heated at reflux for 2 h then cooled to room temperature. The reaction mixture was poured onto water (150 mL) and hexanes (20 mL) and stirred for 1 h. A brown precipitate was collected by filtration and washed with water (2×10 mL) and hexanes (10 mL). The resultant solid was dried in air then washed with toluene (10 mL) to afford 2 g (61%) of 1-(4-bromophenyl)-1H-pyrazole INT-84 as a light brown powder. LCMS-ESI (m/z) calculated for C9H7BrN2: 223; found 223/225 [M+H]+, tR=2.14 min (Method 10). The reaction mixture was heated at reflux for 2 h A brown precipitate was collected by filtration washed with water (2×10 mL) and hexanes (10 mL) The resultant solid was dried in air then washed with toluene (10 mL)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of (2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-butyramidine (0.33 g, 0.82 mmol) in 1,1,3,3-tetraethoxy-propane (7 ml) and DMF (1.5 ml) was heated for 1 h at 150° C. Evaporation and purification by column chromatography on silica gel (dichloromethane/MeOH 98:2) yielded the title compound (73 mg, 20%) as a light brown oil, MS: m/e=440.2 (M+H+). Evaporation and purification by column chromatography on silica gel (dichloromethane/MeOH 98:2)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a vigorously stirred mixture of 2-nitrothiophene (J-1) (13 g, 0.1 mol) and concentrated hydrochloric acid (195 mL) was added tin (25 g) at 0° C. After most of the tin was dissolved, EtOH (70 mL) and anhydrous ZnCl2 (6 g) were added. The mixture was heated to 85° C., and then treated with malonaldehyde bis(diethyl acetal) (17.2 g, 0.078 mol) in EtOH (30 mL). The resulting reaction was maintained at 85° C. for 1 h, then poured onto ice (100 g), basified with NH3.H2O, and extracted with DCM (75 mL×3). The combined organic layers were concentrated and purified by chromatography on silica gel to give the title compound. MS (m/z): 135 (M)+. The resulting reaction was maintained at 85° C. for 1 h poured onto ice (100 g) extracted with DCM (75 mL×3) The combined organic layers were concentrated purified by chromatography on silica gel

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a vigorously stirred mixture of 2-nitrothiophene (J-1) (13 g, 0.1 mol) and concentrated hydrochloric acid (195 mL) was added tin (25 g) at 0° C. After most of the tin was dissolved, EtOH (70 mL) and anhydrous ZnCl2 (6 g) were added. The mixture was heated to 85° C., and then treated with malonaldehyde bis(diethyl acetal) (17.2 g, 0.078 mol) in EtOH (30 mL). The resulting reaction was maintained at 85° C. for 1 h, then poured onto ice (100 g), basified with NH3.H2O, and extracted with DCM (75 mL×3). The combined organic layers were concentrated and purified by chromatography on silica gel to give the title compound. MS (m/z): 135 (M)+. The resulting reaction was maintained at 85° C. for 1 h poured onto ice (100 g) extracted with DCM (75 mL×3) The combined organic layers were concentrated purified by chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into the same reactor as used in the previous step were poured 30 g (0.1 mol) of bis (isopropylguanidine) sulphate, 120 ml of water, 75 ml of pure hydrochloric acid solution (s.g. 1.18) and slowly (over 11/2 hours), at room temperature, 44 g (0.2 mol) of 1,1,3,3-tetraethoxy propane. The mixture was then heated to 50°-55° C. under stirring for two hours, then cooled and neutralized by an excess of pure sodium hydroxide solution. The mixture was extracted using 300 ml of diethyl ether. The extracts were washed with a saturated solution of sodium chloride, then dried and the diethyl ether was evacuated off. There was obtained 25 g (yield 91%) of a yellowish oil boiling at 91°-91.5° C. under 11 mm of Hg, the analysis of which showed good correspondence with the formula C7H11N3. at room temperature The mixture was then heated to 50°-55° C. cooled The mixture was extracted The extracts were washed with a saturated solution of sodium chloride dried the diethyl ether was evacuated off

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred, refluxing solution of 1.0 g. of freshly fused zinc chloride in 220 g. (1.0 mole) of 1,1,3,3-tetraethoxypropane and 200 g. (1.96 moles) of acetic anhydride is added dropwise during 3 hr. 10 min. 91 g. (0.57 mole) of diethyl malonate. After addition is complete, the reaction mixture is refluxed for one-half hour after which time the lower boiling components of the reaction mixture are removed by distillation up to a vapor temperature of 120° C. (pot 130° C.). An additional 50 ml. of acetic anhydride are added and reflux is continued for 16 hr. Again, low boilers are removed and the desired product is isolated from the residue by vacuum distillation. There is obtained 120 g. (87%) of product as a yellow oil: b.p. 110°-128°/0.1-1.7 mm. ν (film) 1720 (C=O) and 1610 cm.-1 (C=O); δ(TMS,CDCL3) 7.47, 7.13, 6.25 (s, s, t, 1 H each, olefinic protons), 3.84-4.6 (m, 6H, ethyl methylene) and 1.35 (overlapping triplets, 9H, ethyl methyls). To a stirred, refluxing solution of 1.0 g 10 min After addition the reaction mixture is refluxed for one-half hour after which time the are removed by distillation up to a vapor temperature of 120° C. (pot 130° C.) of acetic anhydride are added reflux Again, low boilers are removed

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a vigorously stirred mixture of 2-nitrothiophene (J-1) (13 g, 0.1 mol) and concentrated hydrochloric acid (195 mL) was added tin (25 g) at 0° C. After most of the tin was dissolved, EtOH (70 mL) and anhydrous ZnCl2 (6 g) were added. The mixture was heated to 85° C., and then treated with malonaldehyde bis(diethyl acetal) (17.2 g, 0.078 mol) in EtOH (30 mL). The resulting reaction was maintained at 85° C. for 1 h, then poured onto ice (100 g), basified with NH3.H2O, and extracted with DCM (75 mL×3). The combined organic layers were concentrated and purified by chromatography on silica gel to give the title compound. MS (m/z): 135 (M)+. The resulting reaction was maintained at 85° C. for 1 h poured onto ice (100 g) extracted with DCM (75 mL×3) The combined organic layers were concentrated purified by chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared according to the experimentals described for Example 23 above from 3-{[2-(4-chlorophenoxy)ethyl]sulfanyl}-1H-1,2,4-triazol-5-amine and malonaldehyde bis(diethyl acetal) in 42% yield; EM (calc.): 306.0; MS (ESI) m/e: 307.0 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 9.33 (dd, 1H), 8.81 (dd, 1H), 7.31 (m, 3H), 7.02 (dt, 2H), 4.33 (t, 2H), 3.62 (t, 2H).

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 44.5 g (0.164 mole) of 4-acetamido-3-bromophenylacetic acid and 131 ml of 6 N hydrochloric acid are heated to 100° C. for 2 hours. The solution of 4-amino-3-bromophenylacetic acid (which is thus formed) is cooled to -6° C. in an ice-sodium chloride bath, and a solution of 11.7 g (0.17 mole) of sodium nitrite in 130 ml of water is added dropwise thereto at -6° C. Stirring is continued for a further hour at the same temperature, and the thus-prepared solution of the diazonium salt is poured slowly into a solution (which is cooled to -10° C.) of 100 g (0.443 mole) of tin(II) chloride dihydrate in 100 ml of concentrated hydrochloric acid to form 3-bromo-4-hydraziniumphenylacetic acid chloride. Dilution of the latter with 300 ml of water is effected, and 36 ml (0.163 mole) of 1,1,3,3-tetraethoxypropane are added dropwise thereto; stirring is then effected for 4 hours at room temperature. The resulting reaction mixture is rendered alkaline with 35% strength solution of sodium hydroxide and is heated to 100° C. for one hour in order to hydrolyze 3-bromo-4-(pyrazol-1-yl)phenylacetic acid ethyl ester, which is formed simultaneously along with the corresponding free acid. The produced ethanol is distilled off, and clarification is effected with activated charcoal. This is followed by acidification with hydrochloric acid and extraction with chloroform. The organic phase is dried. Concentration to dryness is effected in a vacuum, and the residue is recrystallized from benzene to obtain 38.5 g (83.5% of theory) of 3-bromo-4-(pyrazol-1-yl)phenylacetic acid (m.p. 100° to 101° C.). The resulting reaction mixture which is formed simultaneously along with the corresponding free acid The produced ethanol is distilled off This is followed by acidification with hydrochloric acid and extraction with chloroform The organic phase is dried Concentration to dryness the residue is recrystallized from benzene

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 20 g (100 mmoles) of 2-(4-amino-3-chlorophenyl) propionic acid are dissolved in 20 ml of concentrated hydrochloric acid and diazotized with 6.9 g of sodium nitrite in 20 ml of water at from -2° to -6° C. The solution is thereafter stirred for a further hour and subsequently stirred into 100 ml of a freshly-prepared, ice-cold, 5.5 N solution of sodium hydrogen sulfite. Heating is then effected slowly to a temperature of from 60° to 70° C. After one hour, acidification is effected with concentrated hydrochloric acid, and the resulting reaction mixture is left at 70° C. for a further 12 hours. 2-(3-chloro-4-hydrazinophenyl)propionic acid forms therein. 22 g (100 mmoles) of 1,1,3,3-tetraethoxypropane are then added thereto. After three hours' heating to 100° C., the reaction mixture is cooled, rendered alkaline with 35% strength sodium hydroxide solution and, in order to saponify the 2-[3-chloro-4-(pyrazol-1-yl)phenyl]propionic acid ethyl ester which is formed in addition to the acid, reheated for one hour. After cooling, impurities are extracted by shaking with benzene; the aqueous phase is acidified with concentrated hydrochloric acid; the product is extracted with diethyl ether; and the ether phase is washed with water, dried and concentrated in a vacuum. 24 g (96% of theory) of 2-[3-chloro-4-(pyrazol-1-yl)phenyl]propionic acid, m.p. 83° to 85° C., are thus obtained. Heating is then effected slowly to a temperature of from 60° to 70° C the resulting reaction mixture is left at 70° C. for a further 12 hours the reaction mixture is cooled is formed in addition to the acid reheated for one hour After cooling impurities are extracted by shaking with benzene the product is extracted with diethyl ether and the ether phase is washed with water dried concentrated in a vacuum