CN106636239B - Preparation method of chloramphenicol - Google Patents
Preparation method of chloramphenicol Download PDFInfo
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- CN106636239B CN106636239B CN201611007636.4A CN201611007636A CN106636239B CN 106636239 B CN106636239 B CN 106636239B CN 201611007636 A CN201611007636 A CN 201611007636A CN 106636239 B CN106636239 B CN 106636239B
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Abstract
The invention provides a method for preparing chloramphenicol, which comprises the following steps: the chloramphenicol is obtained by three reactions, namely dichloroacetylation, aldol condensation and asymmetric catalytic reduction, by taking an intermediate (p-nitro-alpha-aminoacetophenone hydrochloride) of the existing chloramphenicol production process as an initial raw material. The method for preparing the chloramphenicol avoids the steps of splitting, protecting and deprotecting, simplifies the production process of the chloramphenicol, improves the total yield, reduces the production cost, and solves the problems of long reaction steps, low atom economy and low product yield existing in the prior process for preparing the chloramphenicol.
Description
Technical Field
The invention relates to a preparation method of chloramphenicol, belonging to the technical field of biological pharmacy and biochemical engineering.
Background
Chloramphenicol is one of the most broad-spectrum antibiotic drugs in the current market, and the antibacterial action mechanism of chloramphenicol is that chloramphenicol binds with a ribosome 50S subunit to inhibit peptide acyltransferase, thereby inhibiting protein synthesis, and the structural formula is as follows:
chloramphenicol can effectively control most gram-negative and gram-positive bacteria, influenza bacillus, pertussis bacillus, dysentery bacillus, Escherichia coli, pneumonia bacillus, proteus, pseudomonas aeruginosa, rickettsia, chlamydia trachomatis, etc. Because the application of the chloramphenicol is very wide in the field of biological medicine, the discovery of a mild, efficient and economic method for preparing the chloramphenicol is concerned by wide chemical and biological workers.
The current industrial preparation method of chloramphenicol is as follows: the preparation method is characterized in that acetophenone is used as a starting material, and the preparation method comprises 8 steps of chemical reactions such as bromination, ammoniation, acetylation, aldol condensation, aluminum isopropoxide reduction, hydrolysis deprotection, chiral separation, dichloroacetylation and the like. The synthetic route is as follows:
this method has the following disadvantages:
(1) the route requires chiral resolution, and the theoretical yield of the resolution is only 50%, which leads to the yield of the whole route being below 30%; in addition, the splitting step is very complicated, which brings great inconvenience to industrial production;
(2) acetyl protection and deprotection are needed in the route, atom economy is poor, overall yield is reduced due to the increase of reaction steps, and difficulty is increased for industrial production.
(3) Aluminum isopropoxide is used in the reduction step of the route, a large amount of three wastes which are difficult to treat are generated in the process, and the damage to the environment is very large.
Therefore, the method for preparing chloramphenicol, which has mild preparation conditions, simple operation steps, efficient product yield, excellent atom economy and environmental friendliness, is urgently needed to be provided.
Disclosure of Invention
The technical problem to be solved by the invention is that the process for preparing chloramphenicol in the prior art has the problems of long reaction steps, complicated operation steps, harsh reaction conditions, low atom economy, low product yield and environmental friendliness, and further provides a method for preparing chloramphenicol, which has the advantages of low cost, easy preparation, high yield and environmental protection.
In order to solve the technical problems, the invention provides a method for preparing chloramphenicol, which comprises the following steps: the chloramphenicol is obtained by taking an intermediate (p-nitro-alpha-aminoacetophenone hydrochloride) of the existing chloramphenicol production process as an initial raw material and carrying out three reactions of dichloroacetylation, aldol condensation and asymmetric biocatalytic reduction.
The structural formula of the chloramphenicol is shown as follows:
preferably, the synthetic route of the chloramphenicol is as follows:
preferably, the dichloroacetylation reaction is specifically: mixing the p-nitro-alpha-aminoacetophenone hydrochloride, the solvent and dichloroacetyl chloride uniformly, adding an acid-binding agent, reacting at the temperature of 15-20 ℃, and obtaining a dichloroacetylation product after the reaction is finished.
It should be noted that the reaction solvent includes, but is not limited to, dichloromethane as long as it can perform a dissolving action. The acid-binding agent includes, but is not limited to, triethylamine, as long as the acid-binding agent can absorb acid generated in the reaction, and the components of the acid-binding agent can be adjusted by those skilled in the art according to actual needs.
Further preferably, the dichloroacetylation reaction further comprises filtering the reaction mixed solution after the dichloroacetylation reaction is finished, washing the filter cake with dichloromethane, collecting the filtrate, washing the filtrate with dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated saline solution in sequence, drying and desolventizing to obtain the dichloroacetylation product.
Preferably, the aldol condensation reaction is specifically: uniformly mixing the dichloro acetylation product with ethanol and formaldehyde, adjusting the pH value of the mixed solution to 7.2-7.5, reacting at the temperature of 32-35 ℃, and obtaining the p-nitro-alpha-dichloroacetamido-beta-hydroxy propiophenone after the reaction is finished.
Preferably, the catalytic reduction reaction is specifically: adding nitro-alpha-dichloroacetamido-beta-hydroxy propiophenone and ketoreductase into a buffer solution, reacting at the temperature of 20-40 ℃ and under the condition that the pH value is 6.0-8.0, and obtaining the chloramphenicol after the reaction is finished.
Preferably, the buffer solution is PBS buffer solution with pH value of 6.0-7.5 and concentration of 0.05-0.1 mol/L.
The buffer solution includes, but is not limited to, PBS buffer solution as long as it can perform a buffering action to maintain a salt balance and adjust a suitable pH in the enzyme-catalyzed reaction. The PBS buffer solution refers to phosphate buffer solution, and the components of the PBS buffer solution include but are not limited to Na2HPO4、KH2PO4NaCl and KCl, and the components of the compound can be adjusted by the technicians in the field according to actual requirements.
Preferably, NADP is also added to the buffer+And optionally adding one or more of isopropanol, glucose dehydrogenase, oxalate dehydrogenase, and lactate dehydrogenase.
Preferably, the p-nitro-alpha-aminoacetophenone hydrochloride is prepared by taking nitroacetophenone as a raw material and sequentially performing bromination reaction and ammoniation reaction.
Compared with the prior art, the invention has the following advantages:
(1) the preparation method of the chloramphenicol takes an intermediate (p-nitro-alpha-aminoacetophenone hydrochloride) of the existing chloramphenicol production process as a starting material, and can finally obtain the chloramphenicol with a total yield of up to 84 percent, Ee of >99 percent and Dr of >99/1 through three steps of dichloroacetylation, aldol condensation and asymmetric biocatalytic reduction. The method has the advantages that the method avoids the steps of splitting, protecting and deprotecting, simplifies the production process of the chloramphenicol, improves the total yield, reduces the production cost, and solves the problems of long reaction steps, low atom economy and low product yield existing in the prior process for preparing the chloramphenicol;
(2) the preparation method of chloramphenicol has the advantages of simple operation, mild conditions, simple post-treatment of the reaction, easy operation, less three wastes generation and environmental protection, solves the defects of complex operation, large pollution and the like of other preparation methods of chloramphenicol, and is suitable for large-scale industrial production.
Detailed Description
The present invention will be described in further detail with reference to examples, but is not limited thereto. The chloramphenicol is prepared by three steps of reactions, namely dichloroacetylation, aldol condensation and asymmetric biocatalytic reduction, by taking an intermediate (p-nitro-alpha-aminoacetophenone hydrochloride) of the existing chloramphenicol production process as a starting material. The synthetic route is as follows:
examples 1 to 6 are detailed for the dichloroacetylation reaction, the aldol condensation reaction, and the catalytic reduction reaction, respectively.
EXAMPLE 1 Dichloroacetylation
This example is a dichloroacetylation reaction in the method for preparing chloramphenicol, which specifically includes the following steps:
uniformly mixing 21.6g of p-nitro-alpha-aminoacetophenone hydrochloride, 150ml of dichloromethane and 14.5g of dichloroacetyl chloride, adding 21g of triethylamine solution, reacting at the temperature of 20 ℃, and obtaining the dichloroacetylation product after the reaction is finished.
As a preferred embodiment of this embodiment, the dichloroacetylation reaction further comprises, after the dichloroacetylation reaction is completed, filtering the reaction mixture solution, washing the filter cake with dichloromethane, collecting the filtrate, washing the filtrate with dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine in sequence, drying, and desolventizing to obtain the dichloroacetylation product.
As an alternative to this embodiment, the reaction temperature may be replaced by any value in the range of 0-45 ℃ without affecting the achievement of the objects of the invention.
EXAMPLE 2 Dichloroacetylation
This example is a dichloroacetylation reaction in the method for preparing chloramphenicol, which specifically includes the following steps:
21.6g of p-nitro-alpha-aminoacetophenone hydrochloride and 150mL of dichloromethane are put into a 250mL four-necked bottle provided with a stirrer, a thermometer and a dropping funnel, the mixture is cooled to below 5 ℃ after being stirred uniformly, 14.5g of dichloroacetyl chloride is added into the bottle under stirring, 21g of triethylamine solution is taken, the solution is slowly dropped into the reaction solution at the temperature of 15 ℃ by the dropping funnel, the temperature is raised to 15 ℃, the mixture is stirred for 1h, after the reaction is finished, the solution is filtered, a filter cake is washed by dichloromethane, filtrate is collected, the filtrate is washed by dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated common salt solution in sequence, and the mixture is dried and desolventized to obtain 28.2g of dichloroacetylation product with the yield of 97%.
EXAMPLE 3 aldol condensation reaction
This example is an aldol condensation reaction in the method for preparing chloramphenicol, which specifically follows:
and (2) uniformly mixing 29.1g of the dichloroacetylation product prepared in the embodiment 2 with 200ml of ethanol and 11.4g of formaldehyde, adjusting the pH value of the mixed solution to 7.2, reacting at the temperature of 35 ℃, and obtaining the p-nitro-alpha-dichloroacetamido-beta-hydroxypropiophenone after the reaction is finished.
As a preferable embodiment of this embodiment, after the reaction is completed, the reaction mixture solution is cooled to 0 ℃, filtered, washed with ice water, filtered, and dried to obtain p-nitro- α -dichloroacetamido- β -hydroxypropiophenone.
As an alternative embodiment of this example, the reaction temperature of the aldol condensation reaction can be replaced by any value within the range of 32 to 35 ℃ and the pH can be replaced by any value within the range of 7.2 to 7.5 without affecting the achievement of the object of the present invention.
EXAMPLE 4 aldol condensation reaction
This example is an aldol condensation reaction in the method for preparing chloramphenicol, which specifically follows:
29.1g of the dichloroacetylation product prepared in example 2, 200mL of ethanol, and 11.4g of 37% by mass formaldehyde were put in a 250mL three-necked flask equipped with a stirrer and a thermometer, and mixed well with a small amount of NaHCO3And (3) regulating the pH value of the mixed solution to 7.5 by using a saturated solution, slowly heating to 32 ℃ under the condition of stirring, quickly cooling to 0 ℃ after the reaction is finished, filtering, washing by using ice water, carrying out suction filtration, and drying to obtain 29.35g of p-nitro-alpha-dichloroacetamido-beta-hydroxyphenylacetone with the yield of 92%.
Example 5 catalytic reduction reaction
This example is a catalytic reduction reaction in the method for preparing chloramphenicol, and specifically includes the following steps:
50g of the nitro- α -dichloroacetamido- β -hydroxyphenylacetone prepared in example 4 and 1g of ketoreductase (purchased from Suzhou navigation Biotechnology Co., Ltd.: trade name YH2069, only one of which is shown here to illustrate the effects of the present invention, and the commercial products are different from each other in terms of achieving the objects of the present invention, hereinafter, not described in detail) were added to a buffer solution, and the buffer solution was reacted at 40 ℃ and a pH of 8.0 to obtain chloramphenicol.
Preferred as the present embodimentIn one embodiment, the buffer further comprises glucose, glucose dehydrogenase and NADP+As a specific embodiment of this preferred embodiment, the glucose, glucose dehydrogenase and NADP+The amounts used were 62.5g, 1g and 50mg, respectively.
In this example, the buffer solution is a PBS buffer solution, and the PBS buffer solution may be replaced with other buffer solutions as long as it can perform a buffering action of maintaining a salt balance and adjusting an appropriate pH in the enzyme-catalyzed reaction.
As an alternative implementation manner of this embodiment, the reaction temperature of the catalytic reduction reaction may be replaced by any value within a range of 20 to 40 ℃, and the pH value of the reaction solution may be replaced by any value within a range of 6.0 to 8.0, which does not affect the implementation of the object of the present invention, and hereinafter, the following description is omitted.
Example 6 catalytic reduction reaction
This example is a catalytic reduction reaction in the method for preparing chloramphenicol, and specifically includes the following steps: 50g of the nitro-alpha-dichloroacetamido-beta-hydroxyphenylacetone and 62.5g of glucose, which are prepared in example 4, are placed in a 1000mL three-neck flask, 500mL of PBS buffer solution with the pH value of 6.5 and the concentration of 0.05mol/L are added into the flask, then the three-neck flask is placed in a reaction pot, the rotating speed is set to 850rpm, the temperature is set to 30 ℃, and 50mg of NADP is added into the three-neck flask respectively+1g of glucose dehydrogenase (purchased from Suzhou navigation Biotechnology Co., Ltd.: product No. YH1901, only one type of product is shown here to illustrate the effect of the present invention, and there is no difference between the commercially available types of products for achieving the object of the present invention), and 1g of ketoreductase powder (purchased from Suzhou navigation Biotechnology Co., Ltd.: product No. YH2069), obtaining a mixed solution, maintaining the pH of the mixed solution at 6.5 with a NaOH solution having a concentration of 2mol/L, reacting for 3 hours to obtain the chloramphenicol, and measuring the conversion rate>99％,>99％Ee,>99:1Dr, (where Ee ═ (R, R)/[ (R, R) + (S, S)]；Dr＝[(R,R)+(S,S)]/[(R,S)+(S,R)])。
As a preferred embodiment of this example, HPLC is used to monitor the reaction and the reaction time is prolonged so that the conversion rate does not increase, i.e., the reaction is judged to be complete.
As a preferred embodiment of this embodiment, after the catalytic reduction reaction is completed, the solution after the reaction is extracted with dichloromethane, and the organic phases are combined, dried and desolventized to obtain the chloramphenicol. In this example, the above preferred embodiment was employed to obtain 47 g of the chloramphenicol in 94% yield, 98% purity, Ee > 99%, and Dr >99: 1.
It should be noted that the pH value of the PBS buffer solution can be replaced by any value from 6.0 to 7.5, and the concentration can be replaced by any value from 0.05 to 0.1mol/L, which does not affect the achievement of the object of the invention.
It is to be understood that the above examples are illustrative only for the purpose of clarity of description and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. It is not necessary or necessary to exhaustively enumerate all embodiments herein, and obvious variations or modifications can be made without departing from the scope of the invention.
Claims (9)
1. A method for preparing chloramphenicol is characterized by comprising the following steps: the chloramphenicol is obtained by three steps of dichloroacetylation, aldol condensation and asymmetric enzymatic reduction of p-nitro-alpha-aminoacetophenone hydrochloride by using ketoreductase, which is purchased from Suzhou pilotage biotechnology limited and has the product number YH 2069.
2. The process for the preparation of chloramphenicol as described in claim 1, characterized in that the chloramphenicol is synthesized by the following route:。
3. the process for the preparation of chloramphenicol according to any of the claims 1-2, characterized in that the dichloroacetylation is in particular: mixing the p-nitro-alpha-aminoacetophenone hydrochloride and dichloroacetyl chloride in a solvent uniformly, adding an acid-binding agent, reacting at the temperature of 15-20 ℃, and obtaining a dichloroacetylation product after the reaction is finished.
4. The method for preparing chloramphenicol according to claim 3, wherein the solvent is selected from one or more of dichloromethane, chloroform, ethyl acetate, N-dimethylformamide, and tetrahydrofuran, and the acid-binding agent is selected from one or more of triethylamine, pyridine, N-dimethylformamide, sodium phosphate, and sodium carbonate.
5. The method for preparing chloramphenicol according to claim 3, wherein the dichloroacetylation further comprises, after the dichloroacetylation is completed, filtering the reaction mixture, washing the filter cake with dichloromethane, collecting the filtrate, washing the filtrate with dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine in this order, and drying and desolventizing to obtain the dichloroacetylation product.
6. The process for the preparation of chloramphenicol according to any of the claims 1-2, characterized in that the aldol condensation reaction is in particular: uniformly mixing the dichloro acetylation product with ethanol and formaldehyde, adjusting the pH value of the mixed solution to 7.2-7.5, reacting at the temperature of 32-35 ℃, and obtaining the p-nitro-alpha-dichloroacetamido-beta-hydroxy propiophenone after the reaction is finished.
7. The process for the preparation of chloramphenicol according to any of claims 1-2, characterized in that the catalytic reduction reaction is in particular: adding nitro-alpha-dichloroacetamido-beta-hydroxy propiophenone and ketoreductase into a buffer solution, reacting at the temperature of 20-40 ℃ and the pH value of 6.0-8.0, and obtaining the chloramphenicol after the reaction is finished.
8. The method of claim 7, wherein the buffer further comprises NADP + and optionally one or more of isopropanol, glucose dehydrogenase, oxalate dehydrogenase, and lactate dehydrogenase.
9. The method for preparing chloramphenicol according to any one of claims 1-2, characterized in that the p-nitro- α -aminoacetophenone hydrochloride is prepared by using nitroacetophenone as a raw material, and sequentially performing bromination reaction and amination reaction.
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| CN201611007636.4A CN106636239B (en) | 2016-11-16 | 2016-11-16 | Preparation method of chloramphenicol |
| PCT/CN2017/076528 WO2018086287A1 (en) | 2016-11-11 | 2017-03-14 | Method for preparing chloramphenicol compound |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010025238A2 (en) * | 2008-08-27 | 2010-03-04 | Codexis, Inc. | Ketoreductase polypeptides for the production of a 3-aryl-3-hydroxypropanamine from a 3-aryl-3-ketopropanamine |
| WO2011022548A2 (en) * | 2009-08-19 | 2011-02-24 | Codexis, Inc. | Ketoreductase polypeptides for the preparation of phenylephrine |
| CN102399161A (en) * | 2011-12-21 | 2012-04-04 | 武汉武药科技有限公司 | Preparation method of chloramphenicol |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010025238A2 (en) * | 2008-08-27 | 2010-03-04 | Codexis, Inc. | Ketoreductase polypeptides for the production of a 3-aryl-3-hydroxypropanamine from a 3-aryl-3-ketopropanamine |
| WO2011022548A2 (en) * | 2009-08-19 | 2011-02-24 | Codexis, Inc. | Ketoreductase polypeptides for the preparation of phenylephrine |
| CN102399161A (en) * | 2011-12-21 | 2012-04-04 | 武汉武药科技有限公司 | Preparation method of chloramphenicol |
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