N-methylidenehydroxylamine

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

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

Procedure: A mixture of 3.0 g of 4-cyano-3-fluorobenzaldehyde obtainable from 2-fluoro-4-nitrotoluene by oxidation to the corresponding benzoic acid, conversion into the corresponding nitrile, reduction to 2-fluoro-4-aminobenzonitrile and conversion of the corresponding diazonium salt with formaldoxime into the aldehyde in accordance with the method of Beech (J. Chem. Soc. 1297 (1954)); the target product is also obtainable from 2-fluoro-4-aminotoluene by conversion into 3-fluoro-4-methylbenzonitrile by the Sandmeyer method, hydrolysis of the nitrile, bromination of the side chain of the ethyl 3-fluoro-4-methylbenzoate obtainable, conversion into the aldehyde by the Sommelet method, conversion of the resulting oxime into ethyl 3-fluoro-4-cyanobenzoate, reduction to 3-fluoro-4-cyanobenzyl alcohol and subsequent oxidation to the target product) and 3.5 g of 2-n-heptylpropane-1,3-diol is heated together with 1 g of strongly acid cation exchanger in 100 ml of toluene for 8 hours using a water separator. The catalyst is then filtered off and the toluene is removed. After customary working-up, 2-(4-cyano-3-fluorophenyl)-5-n-heptyl-1,3-dioxane is obtained. The catalyst is then filtered off the toluene is removed

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

Procedure: A mixture of 3.0 g of 4-cyano-3-fluorobenzaldehyde obtainable from 2-fluoro-4-nitrotoluene by oxidation to the corresponding benzoic acid, conversion into the corresponding nitrile, reduction to 2-fluoro-4-aminobenzonitrile and conversion of the corresponding diazonium salt with formaldoxime into the aldehyde in accordance with the method of Beech (J. Chem. Soc. 1297 (1954)); the target product is also obtainable from 2-fluoro-4-aminotoluene by conversion into 3-fluoro-4-methylbenzonitrile by the Sandmeyer method, hydrolysis of the nitrile, bromination of the side chain of the ethyl 3-fluoro-4-methylbenzoate obtainable, conversion into the aldehyde by the Sommelet method, conversion of the resulting oxime into ethyl 3-fluoro-4-cyanobenzoate, reduction to 3-fluoro-4-cyanobenzyl alcohol and subsequent oxidation to the target product) and 3.5 g of 2-n-heptylpropane-1,3-diol is heated together with 1 g of strongly acid cation exchanger in 100 ml of toluene for 8 hours using a water separator. The catalyst is then filtered off and the toluene is removed. After customary working-up, 2-(4-cyano-3-fluorophenyl)-5-n-heptyl-1,3-dioxane is obtained. The catalyst is then filtered off the toluene is removed

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

Procedure: A mixture of paraformaldehyde (11.5 g, 0.38 mol) and hydroxylamine hydrochloride (26.3 g, 0.38 mol) in water (170 mL) was heated until a clear solution was obtained. Then there was added hydrated sodium acetate (51 g, 0.38 mol), and the mixture was boiled gently under reflux for 15 minutes to give a 10% solution of formaldoxime. A mixture of 2-choro-4-methylaniline (35.5 g, 0.25 mol) and water (50 mL) was stirred, and concentrated hydrochloric acid (57 mL) was added slowly. The mixture was cooled to room temperature, 100 g of ice was added, and the temperature of the mixture was maintained at −5° C. to +5° C. by means of an ice-salt bath. To the stirred mixture there was added a solution of sodium nitrite (17.5 g, 0.25 mol) in water (25 mL). After completion of the addition, the stirring was continued for a period of 15 minutes. The stirred solution of the diazonium salt was made neutral to Congo red by the addition of a solution of hydrated sodium acetate in water (35 mL). The aqueous 10% formaldoxime was added hydrated cupric sulfate (6.5 g, 0.026 mol), sodium sulfite (1.0 g, 0.0079 mole), and a solution of hydrated sodium acetate (160 g) in water (180 mL). The solution was maintained at 10-15° C. by means of a cold-water bath and stirred vigorously. The neutral diazonium salt solution was slowly introduced below the surface of the formaldoxime. After the addition of the diazonium salt solution was complete, the stirring was continued for an additional hour and then the mixture was treated with concentrated hydrochloric acid (230 mL). The mixture was gently heated under reflux for 2 hours. The mixture was extracted with three portions of ether (150 mL), and the ethereal extracts were washed with a saturated NaCl solution, Then the organic layer was dried over anhydrous Na2SO4 and concentrated to obtain yellow solid (Yield: 21 g, 36%). the temperature of the mixture was maintained at −5° C. to +5° C. by means of an ice-salt bath After completion of the addition The solution was maintained at 10-15° C. by means of a cold-water bath stirred vigorously the stirring was continued for an additional hour The mixture was gently heated under reflux for 2 hours The mixture was extracted with three portions of ether (150 mL) the ethereal extracts were washed with a saturated NaCl solution the organic layer was dried over anhydrous Na2SO4 concentrated

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

Procedure: A mixture of paraformaldehyde (11.5 g, 0.38 mol) and hydroxylamine hydrochloride (26.3 g, 0.38 mol) in water (170 mL) was heated until a clear solution was obtained. Then there was added hydrated sodium acetate (51 g, 0.38 mol), and the mixture was boiled gently under reflux for 15 minutes to give a 10% solution of formaldoxime. A mixture of 2-choro-4-methylaniline (35.5 g, 0.25 mol) and water (50 mL) was stirred, and concentrated hydrochloric acid (57 mL) was added slowly. The mixture was cooled to room temperature, 100 g of ice was added, and the temperature of the mixture was maintained at −5° C. to +5° C. by means of an ice-salt bath. To the stirred mixture there was added a solution of sodium nitrite (17.5 g, 0.25 mol) in water (25 mL). After completion of the addition, the stirring was continued for a period of 15 minutes. The stirred solution of the diazonium salt was made neutral to Congo red by the addition of a solution of hydrated sodium acetate in water (35 mL). The aqueous 10% formaldoxime was added hydrated cupric sulfate (6.5 g, 0.026 mol), sodium sulfite (1.0 g, 0.0079 mole), and a solution of hydrated sodium acetate (160 g) in water (180 mL). The solution was maintained at 10-15° C. by means of a cold-water bath and stirred vigorously. The neutral diazonium salt solution was slowly introduced below the surface of the formaldoxime. After the addition of the diazonium salt solution was complete, the stirring was continued for an additional hour and then the mixture was treated with concentrated hydrochloric acid (230 mL). The mixture was gently heated under reflux for 2 hours. The mixture was extracted with three portions of ether (150 mL), and the ethereal extracts were washed with a saturated NaCl solution, Then the organic layer was dried over anhydrous Na2SO4 and concentrated to obtain yellow solid (Yield: 21 g, 36%). the temperature of the mixture was maintained at −5° C. to +5° C. by means of an ice-salt bath After completion of the addition The solution was maintained at 10-15° C. by means of a cold-water bath stirred vigorously the stirring was continued for an additional hour The mixture was gently heated under reflux for 2 hours The mixture was extracted with three portions of ether (150 mL) the ethereal extracts were washed with a saturated NaCl solution the organic layer was dried over anhydrous Na2SO4 concentrated

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

Procedure: A mixture of 3.0 g of 4-cyano-3-fluorobenzaldehyde obtainable from 2-fluoro-4-nitrotoluene by oxidation to the corresponding benzoic acid, conversion into the corresponding nitrile, reduction to 2-fluoro-4-aminobenzonitrile and conversion of the corresponding diazonium salt with formaldoxime into the aldehyde in accordance with the method of Beech (J. Chem. Soc. 1297 (1954)); the target product is also obtainable from 2-fluoro-4-aminotoluene by conversion into 3-fluoro-4-methylbenzonitrile by the Sandmeyer method, hydrolysis of the nitrile, bromination of the side chain of the ethyl 3-fluoro-4-methylbenzoate obtainable, conversion into the aldehyde by the Sommelet method, conversion of the resulting oxime into ethyl 3-fluoro-4-cyanobenzoate, reduction to 3-fluoro-4-cyanobenzyl alcohol and subsequent oxidation to the target product) and 3.5 g of 2-n-heptylpropane-1,3-diol is heated together with 1 g of strongly acid cation exchanger in 100 ml of toluene for 8 hours using a water separator. The catalyst is then filtered off and the toluene is removed. After customary working-up, 2-(4-cyano-3-fluorophenyl)-5-n-heptyl-1,3-dioxane is obtained. The catalyst is then filtered off the toluene is removed

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

Procedure: The key intermediate for pyrrolo[2,3-d]pyrimidines with phenoxymethylene, alkoxymethylene or oxime ether moieties at C-6 is the bromide 7, which is prepared in 6 steps from methyl cyanoacetate and chloroacetone (scheme 4). The monoalkylation product 2 is protected as 1,3-dioxolane, then the pyrimidine ring is formed by reaction with a benzamidine. Cyclization of the pyrrole ring occurs on reaction with aqueous HCl, and refluxing with POCl3 yields the chloride 5. Boc-protection of the pyrrole followed by radical bromination with NBS gives the bromide 7.

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

Procedure: 4-Cyano-2-ethylbenzaldehyde oxime was prepared by the procedure of Jolad et al., Org. Syntheses, Coll. Vol. V, 139 (1973). A mixture of paraformaldehyde (2.8 g, 93 mmol) and hydroxylamine hydrochloride (6 g, 86 mmol) in water (39 mL) was heated in a 500 mL 3-necked flask. When a clear, colorless solution was obtained, sodium acetate trihydrate (11.8 g, 87 mmol) was added. The solution was heated for 15 minutes, then cooled in an ice-salt bath to approximately 5°-10° C. To this solution was added copper sulfate (0.97 g, 6.08 mmol), sodium sulfite (0.23 g, 1.82 mmol) and sodium acetate trihydrate (37 g, 272 mmol) in water (42 mL). The resulting green solution was cooled to an internal temperature of approximately 5°-10° C. A diazonium salt solution of 4-amino-3-ethylbenzonitrile was previously prepared as follows: A mixture of 4-amino-3-ethylbenzonitrile (8.32 g, 57 mmol), concentrated hydrochloric acid (13.2 mL), ice (23 g), and water (11.6 mL) was cooled in an ice-salt bath. While maintaining the internal temperature below 10° C., a solution of sodium nitrite (4.2 g, 61 mmol) in water (5.8 mL) was added dropwise. The resulting slurry was stirred at 5°-10° C. for an additional 15 minutes. Then a solution of sodium acetate trihydrate (5.1 g, 37 mmol) in water (8.1 mL) was added. This solution of the diazonium salt was siphoned under the surface of the 10% formaldoxime solution. The reaction mixture was stirred vigorously and allowed to slowly warm to room temperature as the ice-salt bath melted. After 2 hours the reaction mixture was diluted with brine (100 mL), extracted with dichloromethane (2×400 mL), and dried (Na2 SO4). Purification by chromatography (silica gel, hexane:ethyl acetate (7:1)) gave 2.97 g (30%) of a solid: 1H NMR (DMSO-d6) δ11.80 (s, 1H), 8.45 (s, 1H), 8.00-7.60 (m, 3H), 2.90 (m, 2H), 1.20 (m, 3H). was heated in a 500 mL 3-necked flask When a clear, colorless solution was obtained The solution was heated for 15 minutes cooled in an ice-salt bath to approximately 5°-10° C The resulting green solution was cooled to an internal temperature of approximately 5°-10° C was cooled in an ice-salt bath While maintaining the internal temperature below 10° C. The reaction mixture was stirred vigorously extracted with dichloromethane (2×400 mL) dried (Na2 SO4) Purification by chromatography (silica gel, hexane:ethyl acetate (7:1))

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

Procedure: 3-Fluoro-4-iodoaniline (15.36 g, 0.069 M) and concentrated hydrochloric acid (18.51 g) were dissolved in a mixture of water (30 ml) and ice (30 g). The solution was treated at 0–5° with a solution of sodium nitrite (4.81 g, 0.07 M) in water (15 ml). The pH of the resulting red-brown solution was adjusted to 5–6 by the addition of sodium acetate (6.05 g, 0.044 M). To the solution of formaldoxime was added sodium acetate (45.38 g, 0.333 M), hydrated copper sulfate (1.72 g, 6.9 mM) and sodium sulfite (0.275 g, 2.18 mM), giving a deep green solution, which was cooled to 10–15°. The solution of the diazonium salt was then slowly introduced with vigorous stirring, and stirring continued for 1 hour. The mixture was extracted with diethyl ether (3×100 ml), the combined extracts washed with water (100 ml), and dried (magnesium sulfate). The residue after filtration and evaporation was chromatographed in four portions on 50 g silica Mega Bond Elut® columns, eluting with a gradient from dichloromethane to 5% methanol in dichloromethane. Relevant fractions were combined to give the desired product (3.52 g). giving a deep green solution, which was cooled to 10–15° The mixture was extracted with diethyl ether (3×100 ml) the combined extracts washed with water (100 ml) dried (magnesium sulfate) The residue after filtration and evaporation was chromatographed in four portions on 50 g silica Mega Bond Elut® columns eluting with a gradient from dichloromethane to 5% methanol in dichloromethane

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

Procedure: Prepared as in Example 48, via the following four-step sequence: 2-(2,5-dimethylpyrrolyl)-6-[4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridine was first alkylated with 2-chlorocyclohexanone, using potassium carbonate as the base and a catalytic amount of sodium iodide, in dimethylformamide at 80° C. for 24 hours, in 92% yield. The resulting ketone was converted to the oxime methyl ether using O-methylhydroxylamine hydrochloride and triethylamine in methanol at reflux for 16 h in 81% yield. The oxime ether was then reduced to the amine using borane methyl sulfide in tetrahydrofuran at reflux for 2 days, followed by refluxing in ethanol with sodium carbonate and cesium fluoride for 16 hours, in 12% yield. The amine was then deblocked with hydroxylamine hydrochloride in refluxing aqueous ethanol to afford the desired final product in 89% yield as a tan solid after conversion to the hydrochloride salt. Prepared as in Example 48 at reflux for 16 h in 81% yield at reflux for 2 days

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 3-acetylamino-4-(2', 4'-dibromo-6'-methylphenylazo)-N,N-diethylaniline (4.8 parts), copper (I) iodide (2.0 parts), formaldoxime trimer (1.8 parts), triethylamine (1.5 parts), and nitrobenzene (100 parts) was heated to 90° C. for 11/2 hours when thin layer chromatography showed reaction to be complete. Isolation by the method of Example 3 gave 3-acetylamino-4-(2'-cyano-4'-bromo-6'-methylphenylazo)-N,N-diethylaniline, infra red spectrum identical with that of authentic material. reaction

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 3-acetylamino-4-(2',4'-dibromo-6'-nitrophenylazo)-N,N-diethylaniline (5.3 parts), copper (I) iodide (1.9 parts), formaldoxime trimer (1.8 parts), 2,6-lutidine (2.15 parts), and nitrobenzene (100 parts), was heated to 90° C. for 10 hours when thin layer chromatography showed reaction to be effectively complete. The mixture was filtered, cooled, and the solvent was removed by steam distillation. Crystallisation of the solid product from ethanol gave 3-acetylamino-4-(2'-cyano-4'-bromo-6'-nitrophenylazo)-N,N-diethylaniline (Found; C, 49.5; H, 4.3; Br, 17.7; N, 18.3. C19H19BrN6O3 requires C, 49.65; H, 4.15; Br, 17.4; N, 18.3%) reaction The mixture was filtered cooled the solvent was removed by steam distillation Crystallisation of the solid product from ethanol