CN101148407B

CN101148407B - Method for extracting ethyl acetate from ketoconazole production by continuous side line discharging method

Info

Publication number: CN101148407B
Application number: CN2007101338640A
Authority: CN
Inventors: 顾正桂; 林军
Original assignee: Nanjing Normal University
Current assignee: Nanjing Normal University
Priority date: 2007-10-16
Filing date: 2007-10-16
Publication date: 2010-04-14
Anticipated expiration: 2027-10-16
Also published as: CN101148407A

Abstract

The continuous side line ethyl acetate discharging process in ketoconazole production includes the following steps: 1. continuous intermediate feeding to the rectification tower cauldron, and beginning heating after reaching 1/3 liquid level; 2. side line discharging at tower top temperature of 71-73 deg.c, side line temperature of 76-78 deg.c, and bottom temperature of 84-86 deg.c; and 3. separating to obtain ethyl acetate of content 99.3 % in the yield of 94 %. The side line discharged ethyl acetate is collected with one side line collector connected through flange to the tower body. The present invention has short production period and lowered power consumption.

Description

Continuous lateral line discharging method is extracted the method for ethyl acetate in the KETOKONAZOL production

Technical field

The present invention relates to a kind of separating technology of chemical industry, particularly a kind of continuous lateral line discharging method is extracted the method for ethyl acetate in the KETOKONAZOL production.

Technical background

KETOKONAZOL is the active drug of treatment fungi.Mycosis is a kind of common multiple disease, and it is divided into superficial mycosis and deep mycosis.Superficial mycosis is meant by cure the disease fungi or condition pathomycete and infects human body skin, the first-class superficial tissues of hair and finger (toe) and one group of disease causing.Superficial mycosis is very common, and superficial mycosis accounts for all dermopathicly 1/4 according to statistics, and particularly foot fungus infection accounts for 46% of superficial skin fungus infected patient, and wherein tinea unguium just accounts for about 16%.Deep mycosis is that pathomycete infects subcutis and whole body system, and its primary lesion majority can involve all important organ and tissues, and can send out to skin and subcutaneous in lung.Deep mycosis was more rare in the past, but along with the widespread use of Broad spectrum antibiotics, cortin, antitumor drug, radiotherapy, chemotherapy and immunosuppressor and increasing of major surgery, destroyed the symbiotic relationship of normal flora, body is reduced the resistibility of fungi, and cause deep fungal infection increasing.According to incompletely statistics, during the nearly last ten years.The sickness rate of deep fungal infection has improved 3～5 times, simultaneously also causes deep fungal infection to be on the rise, and has become one of dead immediate cause such as the aids patient that lacks immunological competence, leukemia people.Have 1/3 to be accompanied with various mycosises and dead in the AIDS patient approximately, bibliographical information malignant tumor patient 1/2 is directly died from monilial infection, and 1/3 dies from aspergillosis or other fungi infestation.Therefore the antifungal drug needs clinically of various treatments mycotic medicine, particularly anti-deep infection also increase thereupon.KETOKONAZOL is the patent medicine that Belgian Janssen Pharmaceutica declares, but does not apply for a patent in China, so there is not Intellectual Property Rights in production and selling at home.

Though the present domestic manufacturer production that has, the continuous increase along with the KETOKONAZOL consumption has presented the situation that supply falls short of demand.There is data to show, the accumulative total consumption of present domestic KETOKONAZOL is approximately 50 tons/year, and the accumulative total supply of goods of domestic KETOKONAZOL manufacturer is only had an appointment 30 tons/year, add in the synthesis technique of existing KETOKONAZOL and exist some defectives, have very high economic worth so develop a production technique with low cost and simple to operate.

Relate to two very important intermediates in the synthesis technique of existing KETOKONAZOL; promptly suitable-[2-(2; the 4-dichlorophenyl)-2-(1H-imidazolyl-1-methyl)-1; 3 dioxolane-4-] p-toluenesulfonic esters (hereinafter to be referred as active ester) and 1-ethanoyl-4-(4-hydroxy phenyl) piperazine (hereinafter to be referred as side chain); KETOKONAZOL is obtained through the final step condensation by these two intermediates exactly, so the synthetic of intermediate activity ester and side chain is the synthetic key that obtains KETOKONAZOL.With active ester and side chain is the production process of the synthetic KETOKONAZOL of raw material, and adopting ethyl acetate, acetone and ethyl acetate respectively is solvent, through the processing of five steps, obtains qualified KETOKONAZOL crystal, and detailed process is seen shown in Figure 1.Be solvent with the ethyl acetate in the reaction process, ethyl acetate: the material ratio is 5: 1, NaOH: the ratio of (active ester+side chain) is 4～5: 100, the yield of ethyl acetate is bigger, the main gap distillation method that adopts is extracted ethyl acetate in producing at present, and there is long, problem such as energy consumption is high, purity and product recovery rate are low of cycle in leaching process; It is solvent that the final refining process adopts ethyl acetate, has same problem.

The final step that KETOKONAZOL is produced is acetone, miconazole and the fibrous material that adopts in the ethyl acetate washing crystal, improves the quality of KETOKONAZOL.All adopt at present the gap method to handle the ethyl acetate mother liquor of KETOKONAZOL in producing in the industrial production, detailed process as shown in Figure 1, production technique is as shown in Figure 2.This method cycle is long, energy consumption is high, purity and product recovery rate are low.Adopt condition shown in the table 1, obtain result shown in the table 2.

Table 1 gap water distilling apparatus condition

Table 2 separating resulting

Adopt the gap method to reclaim ethyl acetate, the rate of recovery of ethyl acetate only is 39.1%, and removal process produces a large amount of light constituents, and light constituent accounts for 57.8%, and every processing is (1900kg) once, needs 14 hours.

Summary of the invention

Above-mentioned deficiency at prior art, the purpose of this invention is to provide a kind of continuous lateral line discharging method and extract the method for ethyl acetate in the KETOKONAZOL production, this method improvement technology mainly comprises the innovative approach of three aspects, the one, adopt continuous intermediate feed, the 2nd, the side line discharging, the 3rd, designed side line discharging collector.After the separation, ethyl acetate content reaches 99.3%, and yield reaches 94%, and the production cycle obviously shortens, and the production cycle shortened to 6 hours in 14 hours by the gap distillation, and energy consumption can reduce by 53%.

The scheme of finishing the foregoing invention task is, continuous lateral line discharging method extract KETOKONAZOL produce in the method for ethyl acetate, step is as follows:

(1), adopt continuous intermediate feed mode, raw material is squeezed in the rectifying tower still, when liquid level reaches 1/3, begin heating;

(2), when rectifying tower top, end temperature-stable, beginning side line discharging, the top temperature is that 71～73 ℃, side line drop temperature are 84～86 ℃ of 76～78 ℃, end temperature;

(3), separate after, the ethyl acetate content of side line discharging reaches 99.3%, yield reaches 94%.

Side line discharging of the present invention, can adopt the side line discharging collector of following structure to carry out: to connect in the receiving tank bottom and get the material pipe, collector adopts flange plate to be connected with tower body up and down, is evenly distributed with some steam guiding tubes and some upflow tubes in the described receiving tank.

The concrete structure of above-described " steam guiding tube " is: be evenly distributed on the bottom of collector, be arranged in parallel with tower body; Gas below the collector can flow into the collector top smoothly by steam guiding tube.

The concrete structure of described upflow tube is: be evenly distributed on the bottom of collector, be arranged in parallel with tower body.The a little higher than upflow tube of steam guiding tube length.When liquid level was higher than upflow tube, tower joint below liquid flows into by upflow tube was guaranteed the highly stable of liquid level in the collector.

The length of described steam guiding tube is 31～35mm, and diameter is

Can amplify in proportion with tower diameter as required; The length of described upflow tube is 25～30mm, is slightly smaller than the diameter of steam guiding tube, and diameter is

Or amplify in proportion with tower diameter.

Advantage of the present invention: adopt aforesaid operations method and technology, under table 3 condition, can obtain result shown in the table 4, adopt this method, after the separation, ethyl acetate content reaches 99.3%, yield reaches 94%, production cycle obviously shortens, and the production cycle shortened to 6 hours in 14 hours by the gap distillation, and energy consumption can reduce by 53%.

Table 3 continuous lateral line discharging rectifier unit condition

Table 4 separating resulting

Description of drawings

Fig. 1 is a KETOKONAZOL production process synoptic diagram;

Fig. 2 is that prior art gap method reclaims ethyl acetate process synoptic diagram;

Fig. 3 extracts the schema of ethyl acetate for continuous lateral line discharging rectification method of the present invention;

Fig. 4 extracts the equipment synoptic diagram of ethyl acetate for continuous lateral line discharging of the present invention.

Embodiment:

Embodiment 1, continuous lateral line discharging method is extracted the method for ethyl acetate in the KETOKONAZOL production, adopt equipment shown in Figure 4 and technical process shown in Figure 3, adopt processing condition shown in the table 3, step is as follows: (1), the continuous intermediate feed mode of employing, raw material is squeezed in the rectifying tower still, when liquid level reaches 1/3, begun heating; (2), when rectifying tower top, end temperature-stable, beginning side line discharging, the top temperature is that 71～73 ℃, side line drop temperature are 84～86 ℃ of 76～78 ℃, end temperature.

The result is as shown in table 4.Adopt this method, after the separation, ethyl acetate content reaches 99.3%, and yield reaches 94%, and the production cycle shortened to 6 hours by 14 hours, and energy consumption reduces by 53%.

Claims

1. the method for ethyl acetate during a continuous lateral line discharging method extraction KETOKONAZOL is produced, step is as follows:

(3), separate after, side line discharging ethyl acetate content reaches 99.3%, yield reaches 94%;

Described side line discharging, adopt the side line discharging collector of following structure to carry out: connect in the receiving tank bottom and get the material pipe, collector adopts flange plate to be connected with tower body up and down, is evenly distributed with some steam guiding tubes and some upflow tubes in the described receiving tank;

The concrete structure of described steam guiding tube is: be evenly distributed on the bottom of collector, be arranged in parallel with tower body;

The concrete structure of described upflow tube is: be evenly distributed on the bottom of collector, be arranged in parallel with tower body; The a little higher than upflow tube of steam guiding tube length.