CN103787971A - Preparation method of tert-butyl ester - Google Patents

Abstract

The invention discloses a preparation method of tert-butyl ester. The preparation method adopts methyl vinyl ketone, 4-formylpiperidine-1-tert-butyl formate and tris(dimethylamino methane) and the like as raw materials. By means of reaction, purification and other technological steps, 10-((dimethylamino)methylene)-9-oxo-3-azaspiro[5.5]undecyl-7-alkene-3-formic acid (E)-tert-butyl ester can be prepared. The tert-butyl ester is used for preparation of drugs treating high blood pressure and obesity, the yield is high, and no irritating odor pollution is generated in the preparation process.

Description

A kind of preparation method of the tert-butyl ester

Technical field

The present invention relates to a kind of preparation method of pharmaceutical intermediate, be specifically related to a kind of preparation method of the tert-butyl ester.

Background technology

So-called medicine intermediate, or pharmaceutical intermediate, be actually some some industrial chemicals or Chemicals for medicine synthesis process.This Chemicals, do not need the production licence of medicine, can produce in common chemical plant, as long as reach the rank of some, can be used for the synthetic of medicine.

CN 102115443A discloses a kind of by by carbonatoms being the olefin(e) compound of four reacts to make tert.-butyl acetate method with acetic acid.More particularly, the carbonatoms that use obtains from naphtha cracking technique is the alkene mixture of four, in said mixture, the percent by volume of iso-butylene is 30～60%, above-mentioned carbonatoms is to select iso-butylene to react in the reacting of olefin(e) compound and acetic acid of four, and object is to obtain highly purified tert.-butyl acetate.And, relate to that to improve carbonatoms be the concentration of the 1-butylene in the alkene mixture of four method that easily separates 1-butylene in ensuing technique.

CN 1850774A discloses a kind of novel synthesis of carboxylic acid tert-butyl ester, process and the step of described synthetic method are as follows: the tetrahydrofuran solution that adds a certain amount of samarium diodide under nitrogen protection, be heated to reflux, then add the trimethyl carbinol, under agitation add acyl chlorides, at 68 ℃, stir and make reaction; Then use NaHCO ₃saturated solution regulates pH value to be a bit larger tham 7, uses subsequently dichloromethane extraction three times, closes different organic phase; Then use anhydrous MgSO ₄dry, filtration, organic solvent is revolved in decompression, obtains crude product, then purifies by column chromatography, finally obtains pure carboxylic acid tert-butyl ester.

CN 1322708A discloses a kind of preparation method of tert-Butyl dicarbonate.It is an alkali metal salt of single-tert-butyl carbonate to be reacted with aromatic series or aliphatics sulfonic acid halide generate tert-Butyl dicarbonate.Above-mentioned basic metal is potassium or sodium, can make an alkali metal salt of single-tert-butyl carbonate and the reaction yield of aromatic series or aliphatics SULPHURYL CHLORIDE high, low cost of manufacture.

Summary of the invention

The object of the present invention is to provide a kind of preparation method of the tert-butyl ester, the described tert-butyl ester is for the preparation of the medicine for the treatment of hypertension, obesity.

For reaching this object, the present invention by the following technical solutions:

A preparation method for the tert-butyl ester, described method comprises:

(1) methyl vinyl ketone is added to the solution of 4-formyl piperidine-1-t-butyl formate in tetrahydrofuran (THF), reaction mixture is cooled to-10 ℃ following and in 10 minutes, dropwise add the ethanolic soln of potassium hydroxide, make reaction mixture rise again to room temperature and stir at least 12 hours, add hexanaphthene and use saturated sodium-chloride washing soln, organic layer is concentrated into oil, this oil is dissolved in 80:20 ~ 60:40 cyclohexane/ethyl acetate, after filtration to remove undissolved material, be oily product via hurried column chromatography purification filtrate to generate, this oil is ground in hexane to generate the solid that is white in color, obtain 9-oxo-3-azaspiro [5.5] 10 one-7-alkene-3-t-butyl formates,

(2) 9-oxo-3-azaspiro [5.5] 10 one-7-alkene-3-t-butyl formates of step (1) and three (dimethylamino methane) are dissolved in toluene and are heated to backflow, carry out at least 12 hours, reaction mixture is concentrated into minimum stirred volume and adds ethyl acetate, this mixture is heated to reflux and added heptane during 20 minutes, through 3-6 hour, hot solution is cooled to room temperature, solid utilizes coarse glass frit to filter and use heptane wash, produced solid is dry in vacuum drying oven, generation is yellow solid product, obtain 10-((dimethylamino) methylene radical)-9-oxo-3-azaspiro [5.5] 10 one-7-alkene-3-formic acid (E)-tert-butyl esters.

The described tert-butyl ester is for the preparation of the medicine for the treatment of hypertension, obesity, and its productive rate is high, and pollution has no irritating odor in preparation process.

Embodiment

For ease of understanding the present invention, it is as follows that the present invention enumerates embodiment.Those skilled in the art should understand, described embodiment only, for helping to understand the present invention, should not be considered as concrete restriction of the present invention.

Embodiment 1

The preparation method of a kind of 10-((dimethylamino) methylene radical)-9-oxo-3-azaspiro [5.5] 10 one-7-alkene-3-formic acid (E)-tert-butyl esters, described method comprises:

(1) 146 milliliters of methyl vinyl ketones are added to the solution of 375 grams of 4-formyl piperidine-1-t-butyl formates in 18 liters of tetrahydrofuran (THF)s, reaction mixture is cooled to-10 ℃ and in 10 minutes, dropwise add the ethanolic soln (3N of potassium hydroxide, 0.243 liter), make reaction mixture rise again to room temperature and stir 16 hours, add 10 liters of hexanaphthenes and use saturated sodium-chloride washing soln, organic layer is concentrated into oil, this oil is dissolved in the 80:20 cyclohexane/ethyl acetate of 2 liters and after filtration to remove undissolved material, be oily product via hurried column chromatography (70:30 hexane/ethyl acetate) purifying filtrate to generate, this oil is ground in hexane to generate the solid that is white in color, obtain 9-oxo-3-azaspiro [5.5] 10 one-7-alkene-3-t-butyl formates, its chemical formula is as follows:

(2) 9-oxo-3-azaspiro [5.5] 10 one-7-alkene-3-t-butyl formates of step (1) and 133 milliliter three (dimethylamino methane) are dissolved in 800 milliliters of toluene and are heated to backflow, carry out 17 hours, reaction mixture is concentrated into minimum stirred volume and adds 600 milliliters of ethyl acetate, this mixture is heated to reflux and during 20 minutes, add 1.2 liters of heptane, through 3 hours, hot solution is cooled to room temperature, solid utilizes coarse glass frit to filter and use heptane wash, produced solid is dried to 3 hours in vacuum drying oven at 40 ℃, generation is yellow solid product, the result is as follows:

1H?NMR（400MHz,CDCl3）δppm?7.48（s,1H）,6.57（d,J=9.97Hz,1H）,5.99（d,J=10.16Hz,1H）,3.32-3.51（m,4H）,3.06（s,6H）,2.72（s,2H）,1.57-1.66（m,2H）,1.41-1.53（m,11H）。

Described yellow solid product structural formula is:

Applicant's statement, the present invention illustrates detailed process composition and engineering flow process of the present invention by above-described embodiment, but the present invention is not limited to above-mentioned detailed process composition and engineering flow process, do not mean that the present invention must rely on above-mentioned detailed process composition and engineering flow process and could implement.Person of ordinary skill in the field should understand, any improvement in the present invention, and the selections of the equivalence replacement to the each raw material of product of the present invention and the interpolation of ancillary component, concrete mode etc., within all dropping on protection scope of the present invention and open scope.

Claims (1)

1. a preparation method for the tert-butyl ester, described method comprises:

(1) methyl vinyl ketone is added to the solution of 4-formyl piperidine-1-t-butyl formate in tetrahydrofuran (THF), reaction mixture is cooled to-10 ℃ following and in 10 minutes, dropwise add the ethanolic soln of potassium hydroxide, make reaction mixture rise again to room temperature and stir at least 12 hours, add hexanaphthene and use saturated sodium-chloride washing soln, organic layer is concentrated into oil, this oil is dissolved in 80:20 ~ 60:40 cyclohexane/ethyl acetate, after filtration to remove undissolved material, be oily product via hurried column chromatography purification filtrate to generate, this oil is ground in hexane to generate the solid that is white in color, obtain 9-oxo-3-azaspiro [5.5] 10 one-7-alkene-3-t-butyl formates,

(2) 9-oxo-3-azaspiro [5.5] 10 one-7-alkene-3-t-butyl formates of step (1) and three (dimethylamino methane) are dissolved in toluene and are heated to backflow, carry out at least 12 hours, reaction mixture is concentrated into minimum stirred volume and adds ethyl acetate, this mixture is heated to reflux and added heptane during 20 minutes, through 3-6 hour, hot solution is cooled to room temperature, solid utilizes coarse glass frit to filter and use heptane wash, produced solid is dry in vacuum drying oven, generation is yellow solid product, obtain 10-((dimethylamino) methylene radical)-9-oxo-3-azaspiro [5.5] 10 one-7-alkene-3-formic acid (E)-tert-butyl esters.