Synthetic method of 3-(3-pyridyl)-5-ethyl formate-pyrazole

Abstract

The invention discloses a novel synthetic method of 3-(3-pyridyl)-5-ethyl formate-pyrazole. Easily available raw material 3-acetyl pyridine and sodium alkoxide as alkali react with diethyl oxalate to obtain a key intermediate sodium salt, which then reacts with hydrazine hydrate at 50 DEG C to prepare the 3-(3-pyridyl)-5-ethyl formate-pyrazole. The method has the advanategs of mild and simple reaction conditions, low cost, high yield and simple operation, and is suitable for industrial production.

Description

technical field

[0001] The invention relates to a synthesis process of 3-(3-pyridine)-5-ethyl carboxylate-pyrazole, which belongs to the technical fields of medicine and chemical industry. Background technique

[0002] Pyridine derivatives are important pharmaceutical intermediates with a wide range of uses.

[0003] 3-(3-pyridine)-5-ethyl carboxylate-pyrazole is a pyridine derivative, which can be used to synthesize antithrombotic drugs (BMCL2004, 14, 5263-5268); it can also synthesize antibacterial drugs (BMCL2000, 10, 1211 -1214).

[0004] The synthetic methods reported in the literature are as follows:

[0005] Route A (TL2010, 51, 5915-5918)

[0006]

[0007] Route B (US6506747)

[0008]

[0009] In Route A, the dangerous, explosive ethyl diazoacetate is required.

[0010] In route B, the first step needs to use a strong base LiHMDS at a low temperature of -78°C; the last step is to react with hydrazine hydrate overnight at 90°C.

[0011] Comparing the above...

Examples

Embodiment 1

[0021] Embodiment 1: synthetic compound 2

[0022] Sodium ethoxide (44g, 0.65 mol) was dissolved in absolute ethanol (500mL), under ice water cooling, slowly added dropwise a mixture of 3-acetylpyridine (79g, 0.65 mol) and diethyl oxalate (95g, 0.65 mol) solution, after addition, heated to 60°C and stirred for 5 hours, cooled, filtered with suction, washed with petroleum ether, and dried to obtain 145 g of light yellow solid compound (2), yield: 91.8%.

Embodiment 2

[0023] Example 2: Synthesis of 3-(3-pyridine)-5-ethyl formate-pyrazole (compound 3)

[0024] Compound (2) (64g, 0.26 mol) was added to glacial acetic acid (100mL) at room temperature, and then 85% hydrazine hydrate (15g, 0.26 mol) was added dropwise using a constant pressure dropping funnel, and stirred at 60°C for 4 hours after the addition was complete , cooled, neutralized to pH 7-8 with saturated sodium carbonate solution, extracted with ethyl acetate (300mL), washed with saturated brine, anhydrous Na 2 SO 4 Dry and concentrate to obtain 48 g of off-white solid 3-(3-pyridine)-5-ethyl carboxylate-pyrazole, yield: 85.1%.

[0025] HNMR (DMSO-d6, 300MHz): δ9.07(1H, s), 8.62(1H, d), 8.14(1H, d), 7.38(1H, m), 7.19(1H, s), 4.43(2H, q), 1.42 (3H, t).

technical field

[0001] The invention relates to a synthesis process of 3-(3-pyridine)-5-ethyl carboxylate-pyrazole, which belongs to the technical fields of medicine and chemical industry. Background technique

[0002] Pyridine derivatives are important pharmaceutical intermediates with a wide range of uses.

[0003] 3-(3-pyridine)-5-ethyl carboxylate-pyrazole is a pyridine derivative, which can be used to synthesize antithrombotic drugs (BMCL2004, 14, 5263-5268); it can also synthesize antibacterial drugs (BMCL2000, 10, 1211 -1214).

[0004] The synthetic methods reported in the literature are as follows:

[0005] Route A (TL2010, 51, 5915-5918)

[0006]

[0007] Route B (US6506747)

[0008]

[0009] In Route A, the dangerous, explosive ethyl diazoacetate is required.

[0010] In route B, the first step needs to use a strong base LiHMDS at a low temperature of -78°C; the last step is to react with hydrazine hydrate overnight at 90°C.

[0011] Comparing the above...

Examples

Embodiment 1

[0021] Embodiment 1: synthetic compound 2

[0022] Sodium ethoxide (44g, 0.65 mol) was dissolved in absolute ethanol (500mL), under ice water cooling, slowly added dropwise a mixture of 3-acetylpyridine (79g, 0.65 mol) and diethyl oxalate (95g, 0.65 mol) solution, after addition, heated to 60°C and stirred for 5 hours, cooled, filtered with suction, washed with petroleum ether, and dried to obtain 145 g of light yellow solid compound (2), yield: 91.8%.

Embodiment 2

[0023] Example 2: Synthesis of 3-(3-pyridine)-5-ethyl formate-pyrazole (compound 3)

[0024] Compound (2) (64g, 0.26 mol) was added to glacial acetic acid (100mL) at room temperature, and then 85% hydrazine hydrate (15g, 0.26 mol) was added dropwise using a constant pressure dropping funnel, and stirred at 60°C for 4 hours after the addition was complete , cooled, neutralized to pH 7-8 with saturated sodium carbonate solution, extracted with ethyl acetate (300mL), washed with saturated brine, anhydrous Na 2 SO 4 Dry and concentrate to obtain 48 g of off-white solid 3-(3-pyridine)-5-ethyl carboxylate-pyrazole, yield: 85.1%.

[0025] HNMR (DMSO-d6, 300MHz): δ9.07(1H, s), 8.62(1H, d), 8.14(1H, d), 7.38(1H, m), 7.19(1H, s), 4.43(2H, q), 1.42 (3H, t).

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