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A kind of 5-fluoro-1h-pyrazole-3-carboxylate intermediate and its synthetic method

A compound and selected technology, applied in the direction of organic chemistry, etc., can solve the problems of unstable diazonium salt, low yield, high activity, etc., and achieve the effects of easy purification, simple operation and short steps.

Active Publication Date: 2020-07-03
PHARMABLOCK SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The method of this report has the following deficiencies: the total yield of the synthetic route is 15.3%, and the yield is low; the hydrogenation reaction in the b step has certain danger; the diazotization reaction in the c step has a fire hazard, and the diazotization The diazonium salts produced by the reaction are easy to decompose under the action of slightly higher temperature or light, and some can even decompose at room temperature. In a dry state, some diazonium salts are unstable and have great vitality. , impact, can decompose and explode

Method used

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  • A kind of 5-fluoro-1h-pyrazole-3-carboxylate intermediate and its synthetic method
  • A kind of 5-fluoro-1h-pyrazole-3-carboxylate intermediate and its synthetic method
  • A kind of 5-fluoro-1h-pyrazole-3-carboxylate intermediate and its synthetic method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045]

[0046] Preparation of compound III from compound II:

[0047] Compound II (120.0g, 0.705mol, 1.0e.q.) was added to xylene (1200mL), and then trifluoroacetic acid (4.02g, 0.0353mol, 0.05e.q.) was added. After the addition, the temperature was raised to 140°C, reacted for 6 hours, and detected by GC After the raw material was reacted, it was washed with saturated aqueous sodium carbonate solution, extracted with ethyl acetate (3×900 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 108.0 g of compound III yellow liquid, with a yield of 90.0%.

[0048] Preparation of compound IV from compound III:

[0049] Compound III (70.0 g, 0.411 mol, 1.0 e.q.) was dissolved in THF (700 mL), and 2.5M n-butyllithium / n-hexane (197 mL, 0.494 mol, 1.2 e.q.) was added dropwise at -78°C under nitrogen protection, After dripping, keep it at -78°C for 20 minutes, slowly feed dry carbon dioxide gas for about 15 minutes, stop feed...

Embodiment 2

[0053]

[0054] Preparation of compound III from compound II:

[0055]Compound II (125.4g, 0.737mol, 1.0e.q.) was added to toluene (1200mL), and p-toluenesulfonic acid monohydrate (7.00g, 0.0369mol, 0.05e.q.) was added. After the addition, the temperature was raised to 110°C, and the reaction After 60 hours, GC detected that the reaction of the raw materials was complete, adding saturated aqueous sodium carbonate to wash, extracting with ethyl acetate (3×900 mL), drying with anhydrous magnesium sulfate, filtering, and concentrating the filtrate to dryness to obtain 117.0 g of compound III yellow liquid, with a yield of 93.3 %.

[0056] Preparation of compound IV from compound III:

[0057] Compound III (75.1 g, 0.441 mol, 1.0 e.q.) was dissolved in diethyl ether (650 mL), and under nitrogen protection, 1.3M tert-butyllithium / heptane (407 mL, 0.529 mol, 1.2 e.q.) was added dropwise at -78°C. Keep warm at -78°C for 35 minutes, then slowly inject dry carbon dioxide gas for a...

Embodiment 3

[0061]

[0062] Preparation of compound III from compound II:

[0063] Compound II (122.6g, 0.720mol, 1.0e.q.) was added to chlorobenzene (1200mL), then benzenesulfonic acid (5.69g, 0.0360mol, 0.05e.q.) was added, after the addition was completed, the temperature was raised to 130°C, reacted for 20 hours, and detected by GC After the raw materials were reacted, saturated aqueous sodium carbonate was added to wash, extracted with ethyl acetate (3×900 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 112.5 g of compound III yellow liquid, with a yield of 91.8%.

[0064] Preparation of compound IV from compound III:

[0065] Compound III (80.3g, 0.472mol, 1.0e.q.) was dissolved in 2-methyltetrahydrofuran (800mL), and under nitrogen protection, 2.0M LDA / n-hexane (283mL, 0.566mol, 1.2e.q.) was added dropwise at -60°C After dropping, keep it at -60°C for 60 minutes, slowly feed dry carbon dioxide gas for about 30 minute...

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Abstract

The invention discloses a compound shown as a structural formula IV and a synthesis method thereof as well as application of the compound IV to synthesis of 5-fluoro-1H-pyrazol-3-formate (a compound I), and belongs to the field of organic chemical synthesis. The synthesis method comprises the following steps: with N-substituted 5-fluoro-pyrazole (a compound II) as a raw material, rearranging underthe action of a catalyst to obtain a compound III, and smoothly synthesizing substituted 1H-pyrazol-3-formate through a carboxylation and esterification reaction. By the synthesis method, the operation is simple, the route is short and the obtained product is high in yield; the synthesis method is suitable for large-scale production.

Description

technical field [0001] The invention relates to the field of organic chemical synthesis, in particular to a synthetic 5-fluoro-1H-pyrazole-3-carboxylate intermediate and a synthetic method thereof. Background technique [0002] Halogen-substituted 1H-pyrazole-3-carboxylates have a wide range of applications in the field of medicine, for example, they can be used to prepare heterocyclic regulator compounds for lipid synthesis and pharmaceutically acceptable salts thereof, and to synthesize 11-beta hydroxy steroid Hydrogenase type 1 inhibitors and V1b receptor antagonists, etc. [0003] The route reported in CN 106061963 A is as follows: [0004] [0005] Reagents and yields: (a) MeOH, H 2 SO 4 , yield 70%; (b) Pd / C, H 2 , MeOH, yield: 73%; (c) NaNO 2 , KI, H 2 SO 4 , H 2 O, yield 30%. [0006] The method of this report has the following deficiencies: the total yield of the synthetic route is 15.3%, and the yield is low; the hydrogenation reaction in the b step has...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/04C07D231/16
CPCC07D231/16C07D405/04
Inventor 范海江管增东夏爱华李辉揭元萍
Owner PHARMABLOCK SCIENCES (NANJING) INC