| 59% |
|
Phosphorus oxychloride (6.92 g, 45.1 mmol, 1.50 equiv.) was cooled to 0 0C and then added drop-wise to anhydrous DMF (3.50 mL, 45.2 mmol, 1.50 equiv.) at 0 0C. The mixture was stirred 1 hour at room temperature and was then heated to 80 0C. The compound of formula VIII (2.50 mL, 30.2 mmol) was then added drop-wise to the reaction, and the resulting mixture was stirred 3 hours at 95 0C. The reaction was then quenched by slow addition to ice (40 g). The pH of the resulting solution was 2, and it was raised to 5 by slow addition of 12N aqueous sodium hydroxide solution (11.2 mL). The resulting aqueous solution was extracted with dichloromethane and/or ether (7 x 40 mL), and additional sodium hydroxide was added during extraction, as needed, to maintain a pH of 5. The extracts were then combined, dried over sodium sulfate, filtered and concentrated to yield a brown oil (3.79 g, 59% yield). |
| 50% |
|
A solution of POCl3 (2.61 mL, 28 mmol) in DMF (2.16 mL, 28 mmol)was stirred at 8 C for 2 h, and the resultant viscous solution waswarmed to 80 C. To this solution was added N-methylpyrazole (1 g,12 mmol), and it was stirred at 80 C for 1 h, at 100 C for 3 h, and at115 C for 1 h. The solution was then cooled to room temperature andquenched by addition of 60 mL of ice-cold water. The reaction mixturewas stirred for 24 h and then neutralized to pH 7 using 1 N NaOH andextracted with chloroform (3×30 mL). The combined organic layerwas washed with brine (30 mL) and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography to afford 5 (0.68 g, 50%), Rf=0.2 Hex/EA7:3. 1H NMR (400 MHz, CDCl3) delta 9.80 (s, 1H), 7.91 (s, 1H), 7.89 (s, 1H),3.93 (s, 3H). MS (ESI) m/z 110.8 [M+H]+. HRMS calcd for C5H6N2O[M+H]+ 111.0558, found 111.0556. |
| 40% |
|
Phosphorus oxychloride (181 g, 1.18 mol) was added dropwise to a stirred solution of 1- methylpyrazole (97 g, 1.18 mol) in dry DMF (240 ML) at 100 C. The reaction mixture was maintained at this temperature for 2 h, cooled to room temperature, poured onto ice water (1 L), and basified to pH 8 by the addition of 2 M aqueous sodium hydroxide solution. The mixture was then extracted with chloroform (4X500 mL), the organic phase dried over anhydrous sodium sulfate, filtered, concentrated in vacuo to a brown oil and the excess DMF distilled away. The crude product was purified (SIO2, diethyl ether) to provide the title compound as a pale yellow oil (52 g, 40%). |
|
With trichlorophosphate; at 90 - 100℃; for 3h; |
D7: l-Methyl-/H-pyrazole-4-carbaldehyde A solution of 1 -methyl -7H-pyrazole (20 g, 244 mmol) in dry DMF(50 ml) was heated to 90 C, then POCl3 (23.84 ml, 256 mmol) was added dropwise over lh, while the internal temperature was maintained between 95-100C. After heating for a further 2h, the mixture was cooled and poured onto ice (500g). It was extracted with DCM (300 mix 2), the collected organic parts were washed with brine (50 ml), dried over MgS04, and concentrated to give title compound as brown oil (18 g). LCMS: rt =0.90 min, [M+H+] =111 |
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Step 1) Method A: Phosphorus oxychloride (6.92 g, 45.1 mmol, 1.5 eq.) was cooled to 0C and then added drop- wise to anhydrous DMF (3.50 mL, 45.2 mmol, 1.5 eq.) at 0C. The colorless DMF solution soon becomes orange. The mixture was stirred for 1 hour at room temperature and then heated to 80C. 1 -Methyl- IH-pyrazole (2.5 mL, 30.2 mmol) is then added drop-wise to the reaction, and the resulting mixture was stirred 3 hours at 95C. The reaction was then quenched by slow addition to ice (40 g) via Pasteur pipette. The pH of the resulting solution was 2, and it was raised to 5 by slowly adding 12N aqueous sodium hydroxide solution (11.2 mL total). The resulting aqueous solution was extracted with dichloromethane (3 x 40 mL). At this point, the pH of the aqueous layer had dropped to 3, therefore additional 12 N NaOH solution (1 mL) was added to bring the pH to 6. The aqueous layer was then extracted further with ether (4 x 40 mL). The combined extracts were then dried over sodium sulfate, filtered and concentrated (at about 40-50C). After drying for 30 minutes under vacuum, a brown oil was recovered (3.79 g) which NMR indicated consisted of a mixture of product, starting material and DMF (52 wt %, 22 wt %, and 26 wt %, respectively). The calculated yield of was 59% and the calculated yield for recovery of unreacted starting material, was 34%. This crude material may be used without further purification in the next step. |
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Step 1: 1-methyl-IH-pyrazole-4-carbaldehydeA mixture of phosphoryl chloride (467 gm, 3.045 moles) and DMF was stirred for Ihour at 0-5C. The reaction is ?exothermic so temperature should be below 5C. To this,slowly added I-methyl-1H-pyrazole (50 gm, 0.6090 moles) and stirred for 30 mm at 0-5C. Then slowly raised the temperature to 20-30C and stirred for 30 mm. Further raised the temperature to 60-70C and stirred for 10-15 hours. Progress of the reaction was monitored by HPLC. The reaction mixture was cooled to 0-5C, to this added ethyl acetate (250 ml),DM water (I L) and aqueous ammonia solution (350 ml, pH-6 to 7). The reaction mixture was stirred for 1 hour at 20-30C. The inorganic salt obtained was filtered off, washed with ethyl acetate (250 ml). The filtrate was transferred in to a separating funnel. The reaction mixture was allowed to settle. The organic layer was separated and aqueous layer was extracted with ethyl acetate (250 ml). The entire organic layer was transferred to the reactionvessel, stirred for 10-15 mm and separated the final aqueous layer and organic layer. The combined organic layer having 1-methyl-IH-pyrazole-4-carbaldehyde and ethyl acetate was used as such for Step 2 without any purification or isolation at this step. |
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Step 1 : 1 -methyl- lH-pyrazole-4-carbaldehyde A mixture of phosphoryl chloride (467 gm, 3.045 moles) and DMF was stirred for 1 hour at 0-5C. The reaction is exothermic so temperature should be below 5C. To this slowly added 1 -methyl- lH-pyrazole (50 gm, 0.6090 moles) and stirred for 30 min at 0-5C. Then slowly raised the temperature from 20-30C to 60-70C and stirred for 10- 15 hours. Progress of the reaction was monitored by HPLC. The reaction mixture was cooled to 0-5C, to this added ethyl acetate (250 ml), DM water ( 1 L) and aqueous ammonia solution (350 ml, pH-6 to 7). The reaction mixture was stirred for 1 hour at 20-30C. The inorganic salt obtained was filtered off, washed with ethyl acetate (250 ml). The filtrate was transferred in to a separating funnel. The reaction mixture was allowed to settle. The organic layer was separated and aqueous layer was extracted with ethyl acetate (250 ml). The entire organic layer was transferred to the reaction vessel, stirred for 10-15 min and separated the final aqueous layer and organic layer. The combined organic layer having 1 -methyl- lH-pyrazole-4-carbaldehyde and ethyl acetate was used as such for Step 2 without any purification or isolation at this step. |
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Step 1) Method A: Phosphorus oxychloride (6.92 g, 45.1 mmol, 1.5 eq.) was cooled to 0C and then added drop-wise to anhydrous DMF (3.50 mL, 45.2 mmol, 1.5 eq.) at 0C. The colorless DMF solution soon becomes orange. The mixture was stirred for 1 hour at room temperature and then heated to 80C. 1 -Methyl- IH-pyrazole (2.5 mL, 30.2 mmol) is then added drop-wise to the reaction, and the resulting mixture was stirred 3 hours at 95C. The reaction was then quenched by slow addition to ice (40 g) via Pasteur pipette. The pH of the resulting solution was 2, and it was raised to 5 by slowly adding 12N aqueous sodium hydroxide solution (11.2 mL total). The resulting aqueous solution was extracted with dichloromethane (3 x 40 mL). At this point, the pH of the aqueous layer had dropped to 3, therefore additional 12 N NaOH solution (1 mL) was added to bring the pH to 6. The aqueous layer was then extracted further with ether (4 x 40 mL). The combined extracts were then dried over sodium sulfate, filtered and concentrated (at about 40-50C). After drying for 30 minutes under vacuum, a brown oil was recovered (3.79 g) which NMR indicated consisted of a mixture of product, starting material and DMF (52 wt %, 22 wt %, and 26 wt %, respectively). The calculated yield of was 59% and the calculated yield for recovery of unreacted starting material, was 34%. This crude material may be used without further purification in the next step. |
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With trichlorophosphate; at 90℃; for 3h; |
Methylpyrazole (4.1g, 50mmol, lequiv) and anhydrous DMF (11.6ml, 3equiv) were placed in a 100 ml of two-neck flask which was equipped with a Allihn condenser (a CaCl2 drying tube was connected thereto) and a constant-pressure dropping funnel, and the flask was placed in the oil bath of 90 C. Phosphorus oxychloride (5.6ml, 1.2equiv)) was added dropwise over a period of 1h. After the addition was completed, the mixture was stirred for a further 2h. Then the solution was cooled and poured into a lot of ice water. The resulting mixture was brought to pH 4~5 with a solution of 10% NaOH solution and then extracted with dichloromethane several times until the product in the aqueous phase is little. The combined organic phase was washed with a small amount of brine twice, dried over MgSO4, filtered and then evaporated in vacuo to give the crude product of <strong>[930-36-9]1-methyl-1H-pyrazole</strong>-4-carbaldehyde, which can be directly used in the next step without further separation. |
|
With trichlorophosphate; at 90℃; for 3h; |
Methylpyrazole (4.1 g, 50 mmol, 1 equiv) and anhydrous DMF (11.6 ml, 3 equiv) were placed in a 100 ml of two-neck flask which was equipped with a Allihn condenser (a CaC12 drying tube was connected thereto) and a constant- pressure dropping thnnel, and the flask was placed in the oil bath of 90 C. Phosphorus oxychloride (5.6 ml, 1.2 equiv) was added dropwise over a period of 1 h. After the addition was completed, the mixture was stirred for a further 2 h. Then the solution was cooled and poured into a lot of ice water. The resulting mixture was brought to pH 4-5 with a solution of 10% NaOH solution and then extracted with dichloromethane several times until the product in the aqueous phase is little. The combined organic phase was washed with a small amount of brine twice, dried over MgSO4, filtered and then evaporated in vacuo to give the crude product of 1-me- thyl-1H-pyrazole-4-carbaldehyde, which can be directly used in the next step without further separation. |
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A mixture of phosphoryl chloride (467 gm, 3.045 moles) and DMF was stirred for 1 hour at 0-5 C. The reaction is exothermic so temperature should be below 5 C. To this slowly added <strong>[930-36-9]1-methyl-1H-pyrazole</strong> (50 gm, 0.6090 moles) and stirred for 30 min at 0-5 C. Then slowly raised the temperature from 20-30 C. to 60-70 C. and stirred for 10-15 hours. Progress of the reaction was monitored by HPLC. The reaction mixture was cooled to 0-5 C., to this added ethyl acetate (250 ml), DM water (1 L) and aqueous ammonia solution (350 ml, pH-6 to 7). The reaction mixture was stirred for 1 hour at 20-30 C. The inorganic salt obtained was filtered off, washed with ethyl acetate (250 ml). The filtrate was transferred in to a separating funnel. The reaction mixture was allowed to settle. The organic layer was separated and aqueous layer was extracted with ethyl acetate (250 ml). The entire organic layer was transferred to the reaction vessel, stirred for 10-15 min and separated the final aqueous layer and organic layer. The combined organic layer having <strong>[930-36-9]1-methyl-1H-pyrazole</strong>-4-carbaldehyde and ethyl acetate was used as such for Step 2 without any purification or isolation at this step. |
| 600 mg |
With trichlorophosphate; at 90℃; for 3h; |
N-methylpyrazole (1.0 g, 1 eq.) was dissolved in N,N-dimethylformamide (2.8 ml, 3 eq.), phosphorus oxychloride (1.3ml, 1.2 eq.) was added dropwise at 90 C over about 1 h. The mixture was reacted for another 2 h and then cooled. The reaction liquid was poured into iced water and adjusted with 10% aqueous sodium hydroxide solution to PH 4?5, extracted four times with dichloromethane, rinsed with water twice, and separated by column chromatography to give 600 mg product |
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