(4-chlorophenyl)hydrazine;hydrochloride

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a slurry of methyl 3-oxy-2-dimethylphosphonoacrylate sodium salt (4.1 g, 0.017 mol) in anhydrous DMSO (25 mL) under nitrogen is added methyl iodide (4.5 g, 0.031 mol), and the reaction mixture stirred for 18 hours at ambient temperature. The mixture is poured into dilute sodium chloride solution and extracted with CH2Cl2 (6×75 mL). The extracts are washed with water (100 mL), dried (MgSO4), filtered and concentrated in vacuo to afford a brown oil (5.5 g). Partial separation by chromatography on silica gel (EtOAc) of half the crude product afforded pure E-isomer (0.27 g); a mixture of the E- and Z-isomers (0.75 g); and pure Z-isomer (0.14 g). The E- and Z-products are isolated in 52% overall yield. Methyl (E)-2-(dimethoxyphosphoryl)-3-methoxy-2-propenoate (E-isomer). 1H NMR (300 MHz, CDCl3): δ 7.55 (d, JH-P=10.8 Hz, 1H), 4.06 (s, 3H), 3.78 (d, JH-P=2.7 Hz, 6H), 3.75 (s, 3H). 31P NMR (121 MHz, CDCl3) δ 20.74. Methyl (Z)-2-(dimethoxyphosphoryl)-3-methoxy-2-propenoate (Z-isomer). 1H NMR (300 MHz, CDCl3) δ 7.90 (d, JH-P=31.8 Hz, 1H), 4.03 (s, 3H), 3.78 (d, JH-P=5.1 Hz, 6H), 3.75 (s, 3H). 31P NMR (121 MHz, CDCl3) δ 15.50. A mixture of crude methyl-2-(dimethoxyphosphoryl)-3-methoxy-2-propenoate (6.9 g, 0.030 mol), 4-chlorophenylhydrazine hydrochloride (5.4 g, 0.030 mol), and methanol (40 mL) is heated and held at reflux under nitrogen for one hour. TLC (EtOAc) of an aliquot shows that the methyl-2-(dimethoxyphosphoryl)-3-methoxy-2-propenoate is consumed. After cooling to 45° C., water (15 mL) is added, followed by potassium carbonate (4.1 g, 0.030 mol). This mixture is heated and held at 65° C. for one hour. TLC of an aliquot shows complete conversion to product. The reaction mixture is cooled to 25° C., and further worked up as described for Method A, to afford compound 3a as a red-amber solid (5.90 g, 65%). 1H and 31P NMR spectra indicated 90% assay product, which results in a net 58% yield. a mixture of the E- and Z-isomers (0.75 g) The E- and Z-products are isolated in 52% overall yield is heated at reflux under nitrogen for one hour is consumed water (15 mL) is added This mixture is heated The reaction mixture is cooled to 25° C.

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

実験手順: 2-Hydroxymethyl inden-1-one (Example 1(ii)(a) (4.0 g; 25.00 mmol), p-chlorophenylhydrazine hydrochloride (Aldrich) (4.52 g; 25.25 mmol), 10M hydrochloric acid (1 cm3) and ethanol (30 cm3) were heated under reflux for 22 hours. After cooling, the solvent was evaporated and the residual dissolved in dichloromethane and washed with 2M sodium hydroxide. The organic extracts were then dried (Na2SO4), filtered and concentrated in vacuo. Purification was by column chromatography (Eluant: dichloromethane] and recrystallisation (ethanol) gave off-white needle shaped crystals, m.p. 128-129° C.; b.p. 185° C.; 0.05 mmHg. under reflux for 22 hours After cooling the solvent was evaporated the residual dissolved in dichloromethane washed with 2M sodium hydroxide The organic extracts were then dried (Na2SO4) filtered concentrated in vacuo Purification dichloromethane] and recrystallisation (ethanol) gave off-white needle

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

実験手順: 14.8 g of 2-thiophenecarbaldehyde was added to a mixture of 25.2 g of p-chlorophenylhydrazine hydrochloride and 33.6 g of sodium acetate in 400 ml of 50% aqueous ethyl alcohol. The mixture was heated on a water bath for 30 minutes. After cooling, the precipitated solid was collected and crystallized from ethyl alcohol to give 1, as yellow needles, mp 137° C. The mixture was heated on a water bath for 30 minutes After cooling the precipitated solid was collected crystallized from ethyl alcohol to give 1

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

実験手順: 14.8 g of 2-thiophenecarbaldehyde was added to a mixture of 25.2 g of p-chlorophenylhydrazine hydrochloride and 33.6 g of sodium acetate in 400 ml of 50% aqueous ethyl alcohol. The mixture was heated on a water bath for 30 minutes. After cooling, the precipitated solid was collected and crystallized from ethyl alcohol to give 1, as yellow needles, mp 137° C. The mixture was heated on a water bath for 30 minutes After cooling the precipitated solid was collected crystallized from ethyl alcohol to give 1

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

実験手順: Substitution in the procedure of Example 4 for the 5-oxo-2,3,4,5-tetrahydro[1]benzothiepine-4-acetic acid and the 4-methoxyphenylhydrazine hydrochloride used therein of 7-chloro-5-oxo-2,3,4,5-tetrahydro[1]benzothiepine-4-acetic acid and 4-chlorophenylhydrazine hydrochloride, respectively, produces 10 chloro-2-(4-chlorophenyl)-4,4a,5,6-hexahydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one, melting at 141°-143° C.

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

実験手順: 4-chlorophenylhydrazine hydrochloride (5.24 g, 29.27 mmol), 2-fluoro-5-iodobenzaldehyde (7.5 g, 30.00 mmol) and cesium carbonate (22.8 g, 69.98 mmol) was suspended in NMP (120 mL) and stirred at ambient temperature for 45 min. The temperature was raised to +160° C. and the reaction mixture was stirred for 1 h, the now black suspension was allowed to reach r.t. Water was added, the slurry was extracted with EtOAc (500 mL. The organic phase was washed with brine (2×). The brine fractions and waterphase was combined and back extracted once with EtOAc. This second EtOAc phase was washed with brine (2×) before combined with the previous EtOAc phase. The organic phases were dried over Na2SO4, filtered and evaporated. The black residue were dissolved in DCM/Heptane (=1/1) and filtered through a silica column, and the column was then further eluted with DCM/Heptane (=1/1) solvent mixture. The fractions containing product was evaporated, residue was dissolved in EtOAc and Heptane was added, evaporation and diluting with Heptane afforded a slurry, the solid material was collected by filtration and washed with Heptane. Yield 2.82 g (27%) The temperature was raised to +160° C. the reaction mixture was stirred for 1 h to reach r.t the slurry was extracted with EtOAc (500 mL The organic phase was washed with brine (2×) back extracted once with EtOAc This second EtOAc phase was washed with brine (2×) The organic phases were dried over Na2SO4 filtered evaporated The black residue were dissolved in DCM/Heptane (=1/1) filtered through a silica column the column was then further eluted with DCM/Heptane (=1/1) solvent mixture The fractions containing product was evaporated residue was dissolved in EtOAc Heptane was added evaporation diluting with Heptane afforded a slurry the solid material was collected by filtration washed with Heptane

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

実験手順: To a solution of ethyl 6-difluoromethoxy-4-oxo-3,4-dihydrobenzo[4,5]furo[2,3-d]pyridazine-9-carboxylate (from step 6 of example 4) (168 mg, 0.4 mmol) in ethanol (20 ml), p-chloro phenylhydrazine hydrochloride (72 mg, 0.4 mol) and sodium carbonate (43 mg, 0.4 mmol) was added at room temp. The reaction mixture was stirred at room temp. for 4 hrs. Ethanol was distilled out under vacuum. The concentrated mass was heated to reflux temperature in acetic acid. Progress of reaction was monitored by TLC. At the end, water was added, the solid obtained was filtered and suck dried. The solid was dried in oven. White colored solid (160 mg) was obtained. Ethanol was distilled out under vacuum The concentrated mass was heated to reflux temperature in acetic acid Progress of reaction the solid obtained was filtered suck dried The solid was dried in oven

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

実験手順: To a solution of 12.1 g. of 4-chlorophenylhydrazine hydrochloride in a mixture of 13.5 ml. of 5 N sodium hydroxide, 100 ml. of 30% aqueous acetic acid and 50 ml. of p-dioxane is added 10.0 g. of N-(dimethylaminomethylene pyrazinecarboxamide. The procedure of Example 2 is then followed giving 3.8 g. of the desired product as tan crystals, mp. 129°-131° C. The procedure of Example 2 is then followed giving 3.8 g

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

実験手順: Prepared from 4-chloro-δ-oxobenzenepentanoic acid and (4-chlorophenyl)hydrazine hydrochloride according to the method of Description 7. 1H NMR (250 MHz, DMSO-d6) δ2.55-2.61 (2H, m), 3.07-3.13 (2H, m), 7.16 (2H, d, J 12.6 Hz), 7.41 (2H, d, J 12.6 Hz), 7.62-7.71 (3H, m), 11.52 (1H, br s), and 12.19 (1H, br s). m/z (ES+) 331, 333 (M+1).

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

実験手順: Prepared from 4-chloro-δ-oxobenzenepentanoic acid and (4-chlorophenyl)hydrazine hydrochloride according to the method of Description 7. 1H NMR (250 MHz, DMSO-d6) δ2.55-2.61 (2H, m), 3.07-3.13 (2H, m), 7.16 (2H, d, J 12.6 Hz), 7.41 (2H, d, J 12.6 Hz), 7.62-7.71 (3H, m), 11.52 (1H, br s), and 12.19 (1H, br s). m/z (ES+) 331, 333 (M+1).

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

実験手順: Prepared from δ-oxobenzenepentanoic acid and (4-chlorophenyl)hydrazine hydrochloride according to the method of Description 7. 1H NMR (360 MHz, CDCl3) (Contains 20% δ-oxobenzenepentanoic acid) δ8.02 (1H, s), 7.52-7.33 (6H, m), 7.23-7.18 (1H, m), 7.10-7.07 (1H, m), 3.16-3.11 (2H, m), and 2.65-2.60 (2H, m).

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

実験手順: Prepared from δ-oxobenzenepentanoic acid and (4-chlorophenyl)hydrazine hydrochloride according to the method of Description 7. 1H NMR (360 MHz, CDCl3) (Contains 20% δ-oxobenzenepentanoic acid) δ8.02 (1H, s), 7.52-7.33 (6H, m), 7.23-7.18 (1H, m), 7.10-7.07 (1H, m), 3.16-3.11 (2H, m), and 2.65-2.60 (2H, m).