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Synthesis method of 3-oxocyclobutanecarboxylic acid

A technology of oxocyclobutane carboxylic acid and synthesis method, which is applied in the directions of organic chemistry, nitrile preparation, etc., can solve the problems of difficulty in large-scale production and high reaction temperature, and achieves low synthesis cost, high product purity and simple process route. Effect

Inactive Publication Date: 2013-08-07
LANZHOU WOJIN ENVIRONMENT PROTECTION SCI & TECH CO LTD
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Problems solved by technology

The biggest difficulty of this method is that in the ring-closing process, the reaction temperature is high, the reaction time is as long as 3 to 7 days, and the yield is only about 30%, which makes it difficult to achieve large-scale production

Method used

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  • Synthesis method of 3-oxocyclobutanecarboxylic acid

Examples

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Effect test

Embodiment 1

[0032] (1) Synthesis of 1, 3-dibromoacetal

[0033] Acetone (116 g, 2 mol) was added to absolute ethanol (2 L), bromine (640 g, 4 mol) was slowly added dropwise at room temperature, reacted at 20-30°C for 10 hours, and evaporated to dryness directly to obtain a white solid 1 , 493 g of 3-dibromoacetone, yield 85%;

[0034] (2) Synthesis of 3,3-dicyanoethyclobutanone

[0035] Dissolve malononitrile (66 g, 1 mol) in N, N-dimethylformamide (2 L), add potassium carbonate (276 g, 2 mol), sodium iodide (7.5 g, 50 mol) and tetrabutyl Ammonium bromide (16.1g, 50 mmol), stirred at room temperature for 0.5 hours, then heated to 60°C, slowly added dropwise 1,3-dibromoacetone (290 g, 1 mol) in DMF solution (1L), 60°C Stir for 24 hours. After the reaction, cool to room temperature, evaporate DMF under reduced pressure, add toluene (3 L) and water (1.5 L), stir and separate layers, wash the toluene layer with water, dry, filter, evaporate toluene under reduced pressure, and then 144....

Embodiment 2

[0039] (1) Synthesis of 1, 3-dibromoacetal

[0040] Acetone (116 g, 2 mol) was added to absolute ethanol (2 L), bromine (480 g, 3 mol) was slowly added dropwise at room temperature, reacted at 20-30°C for 10 hours, and evaporated to dryness directly to obtain a white solid 1 , 380 g of 3-dibromoacetone, yield 74.4%;

[0041] (2) Synthesis of 3,3-dicyanoethyclobutanone

[0042] Dissolve malononitrile (66 g, 1 mol) in N,N-dimethylformamide (2 L), add potassium carbonate (414 g, 3 mol), sodium iodide (7.5 g, 50 mol) and tetrabutyl ammonium bromide (16.1 g, 50 mmol), stirred at room temperature for 0.5 hours, then warmed up to 60°C, and slowly added dropwise a DMF solution (1 L) of 1,3-dibromoacetal (290 g, 1 mol), 60 Stir at ℃ for 24 hours. After the reaction, cool to room temperature, evaporate DMF under reduced pressure, add toluene (3L) and water (1.5L), stir and separate layers, wash the toluene layer with water, dry, filter, and evaporate toluene under reduced pressure. R...

Embodiment 3

[0046] (1) Synthesis of 1,3-dibromoacetal

[0047]Acetone (116 g, 2 mol) was added to absolute ethanol (2 L), bromine (640 g, 4 mol) was slowly added dropwise at room temperature, reacted at 20-30°C for 16 hours and directly evaporated to dryness to obtain a white solid 1 , 510.5 g of 3-dibromoacetone, yield 88%;

[0048] (2) Synthesis of 3,3-dicyanoethyclobutanone

[0049] Dissolve malononitrile (66 g, 1 mol) in N,N-dimethylformamide (2 L), add potassium carbonate (414 g, 3 mol), sodium iodide (7.5 g, 50 mol) and tetrabutyl ammonium bromide (16.1 g, 50 mmol), stirred at room temperature for 0.5 hours, then warmed up to 60°C, and slowly added dropwise a DMF solution (1 L) of 1,3-dibromoacetal (290 g, 1 mol), 60 Stir at ℃ for 24 hours. After the reaction, cool to room temperature, evaporate DMF under reduced pressure, add toluene (3L) and water (1.5L), stir and separate layers, wash the toluene layer with water, dry, filter, evaporate toluene under reduced pressure, Re-disti...

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Abstract

The invention provides a synthesis method of a medical intermediate 3-oxocyclobutanecarboxylic acid. A target product 3-oxocyclobutanecarboxylic acid is obtained by adopting acetone, bromine and malononitrile as raw materials, adopting ethanol, DMF (dimethyl formamide) and water as solvents, adopting sodium iodide as an activating agent and tetrabutylammonium bromide (TBAB) as a phase transfer catalyst through three-step reaction. By measurement of H-nuclear magnetic resonance, a mass spectrum, the high-efficiency gas chromatography and a melting point, the synthesized final product is proved to be the 3-oxocyclobutanecarboxylic acid, the purity of 3-oxocyclobutanecarboxylic acid is 99 to 99.2 percent, and the yield of 3-oxocyclobutanecarboxylic acid is 52 to 68 percent. The synthesis method is simple in process route, short in production period and low in synthesis cost; meanwhile, the application of highly toxic products such as osmium tetroxide and propadiene can be avoided, and the process is more moderate, more reliable and safer; and the solvents such as the ethanol, the DMF and the methylbenzene can be recycled in the reaction process, so that the emission and processing costs of toxic reagent can be reduced, the national environmental protection can be achieved, and a good industrialized production prospect can be realized.

Description

technical field [0001] The invention belongs to the technical field of organic chemical synthesis, and relates to a method for synthesizing pharmaceutical intermediate raw materials, in particular to a method for synthesizing 3-oxocyclobutanecarboxylic acid. Background technique [0002] 3-oxocyclobutane carboxylic acid is a very important pharmaceutical intermediate, which is widely used in the synthesis of dozens of APIs, such as ACK1 antibody, MDM2 antagonist, JAK inhibitor, CETP inhibitor, kinase inhibitor , PDE10 inhibitors, thrombin inhibitors and in autoimmune chronic inflammation and antineoplastic drugs are used. At present, the annual demand of the pharmaceutical intermediate is about 200~300Kg. However, there are few synthetic methods for this pharmaceutical intermediate, and the yield is very low, but the demand for this intermediate in the market is increasing day by day, so it is of great significance to develop a new process that can be scaled up in large qua...

Claims

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Application Information

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IPC IPC(8): C07C62/24C07C51/08
Inventor 王保祥
Owner LANZHOU WOJIN ENVIRONMENT PROTECTION SCI & TECH CO LTD
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