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Preparing method of 3-oxo-1-cyclobutane-carboxylic acid

A technology of cyclobutane carboxylic acid and oxo generation, which is applied in the field of preparation of pharmaceutical and chemical intermediates, can solve the problems of unsatisfactory product quality, expensive osmium tetroxide, and difficulty in large-scale production, and achieve easy control and control of production costs , cheap effect

Inactive Publication Date: 2009-10-14
ZHEJIANG GENEBEST PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] In known literature, the method for synthesizing this paper target compound mainly contains two kinds, and a kind of is to make product (Journal of the American Chemical Society, 1958,80,5837 -5840), but the osmium tetroxide used in this method is more expensive and toxic, and the raw material is difficult to obtain; another method needs to use 1,3-dibromoacetone as the main raw material (Journal of Organic Chemistry , 1988, 53(16), 3841-3843), the raw material is expensive and the purity is not high, so the quality of the product is not ideal, and it is difficult to produce on a large scale because of the cost

Method used

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Examples

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Embodiment 1

[0022] A. Preparation of 2,2-dichloromethyl-1,3-dioxolane

[0023] Add 1,3-dichloroacetone (12.7g, 0.1mol), toluene (100ml), ethylene glycol (7.5g, 0.12mol) and p-Toluenesulfonic acid (0.3g), heated up to 100°C and stirred to react, then refluxed at this temperature to divide water until the distillate was clear liquid, about 6 hours, then cooled to room temperature, filtered to remove insoluble matter, the filtrate Raise the temperature to 120°C to distill off toluene, and the obtained residue is crude 2,2-dichloromethyl-1,3-dioxolane, and collect the 88-92°C / 10mmHg fraction by distillation under reduced pressure, namely 2,2-dichloromethyl-1,3-dioxolane Chloromethyl-1,3-dioxolane (14.7 g), yield 86.0%.

[0024] B. Preparation of diisopropyl 5,8-dioxaspiro[3,4]octane-2,2-dicarboxylate

[0025] In a 500ml three-neck flask equipped with a reflux condenser, a thermometer and a magnetic stirring device, add DMF (N,N-dimethylformamide, 80ml), and add sodium hydride (5.5g, 0.24mol...

Embodiment 2

[0029] Other steps are identical with embodiment 1, just the 2 of A step, the preparation method of 2-dichloromethyl-1,3-dioxolane is as follows:

[0030] Add 1,3-dichloroacetone (12.7g, 0.1mol), toluene (35ml), ethylene glycol (6.8g, 0.11mol) and p-Toluenesulfonic acid (0.13g), heated up to 100°C and stirred to react, then refluxed at this temperature to divide water until the distillate was clear liquid, about 6 hours, then cooled to room temperature, filtered to remove insoluble matter, the filtrate Raise the temperature to 120°C to distill off toluene, and the obtained residue is crude 2,2-dichloromethyl-1,3-dioxolane, and collect the 88-92°C / 10mmHg fraction by distillation under reduced pressure, namely 2,2-dichloromethyl-1,3-dioxolane Chloromethyl-1,3-dioxolane (13.8 g), yield 80.7%.

Embodiment 3

[0032] Other steps are identical with embodiment 1, just the 2 of A step, the preparation method of 2-dichloromethyl-1,3-dioxolane is as follows:

[0033] Add 1,3-dichloroacetone (12.7g, 0.1mol), toluene (100ml), ethylene glycol (9.9g, 0.16mol) and p-Toluenesulfonic acid (0.3g), heated up to 100°C and stirred to react, then refluxed at this temperature to divide water until the distillate was clear liquid, about 6 hours, then cooled to room temperature, filtered to remove insoluble matter, the filtrate Raise the temperature to 120°C to distill off toluene, and the obtained residue is crude 2,2-dichloromethyl-1,3-dioxolane, and collect the 88-92°C / 10mmHg fraction by distillation under reduced pressure, namely 2,2-dichloromethyl-1,3-dioxolane Chloromethyl-1,3-dioxolane (14.9 g), yield 87.1%.

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Abstract

The invention discloses a preparing method of 3-oxo-1-cyclobutane-carboxylic acid. The method comprises the following steps: 1, 3-dichloroacetone is adopted as the raw material to generate ketol reaction with ethylene glycol, then generate cyclization reaction with methyl malonate, or ethyl malonate or diisopropyl malonate, and finally generate hydrolysis reaction under strong acid condition to prepare the 3-oxo-1-cyclobutane-carboxylic acid. The method provides a brand new synthetic route, the reaction condition of each step is mild, the process is simple, the reactions in all the steps are normal operations, the raw materials with high cost are effectively avoided, the cost of the product is reduced, and the scale application of the product can be possible.

Description

technical field [0001] The invention relates to a preparation method of medicine and chemical intermediates, in particular to a synthesis method of a four-membered ring. Background technique [0002] In the development of modern medicine and chemistry, there is a class of compounds that have attracted more and more attention as thrombin inhibitors. The key target structure in this class of compounds is the carboxylic acid functional group containing a four-membered ring, so in this class In the synthesis of compounds, the synthesis of four-membered rings is particularly critical. [0003] In known literature, the method for synthesizing this paper target compound mainly contains two kinds, and a kind of is to make product (Journal of the American Chemical Society, 1958,80,5837 -5840), but the osmium tetroxide used in this method is more expensive and toxic, and the raw material is difficult to obtain; another method needs to use 1,3-dibromoacetone as the main raw material (...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C62/24C07C51/373C07C51/09
Inventor 宋苗根
Owner ZHEJIANG GENEBEST PHARMA
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