A preparation method of D-(-)-formylmandelic acid chloride

Abstract

The present invention adopts D mandelic acid, dichloromethane under the catalysis of activated carbon, with slightly excessive anhydrous formic acid, with solid light as dehydrating agent, formylation reaction occurs, obtains colorless viscous thing D (-) formyl mandelic acid, without purification, is directly used in next step reaction. Dichloromethane is added to colorless viscous thing D (-) formyl mandelic acid and dissolved, adds activated carbon catalyst, drips solid light solution, insulation reaction, reacts complete, and distillation reclaims dichloromethane, and obtaining colorless transparent liquid is D (-) formyl mandelic acid chloride. Add solid light as dehydrating agent in the reaction, the use of formaldehyde can be saved, reaction is gentle, environmental protection, reaction conversion rate and product purity can be effectively improved, production cost is effectively reduced, and easy to operate, is more conducive to industrialized production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemicals and relates to a method for preparing D-(-)-O-formylmandelic acid chloride. Background Art

[0002] D-(-)-O-Formylmandelic acid chloride (D-FMC) is an important raw material for the synthesis of the cephalosporin drugs cefuroxime sodium and cefotaxime sodium, and is also a chemical raw material. Currently, the traditional domestic preparation of D-(-)-O-formylmandelic acid chloride widely uses the methylacetic anhydride method. This method uses sodium formate as a raw material, but it produces acetylmandelic acid chloride as an impurity. This is not conducive to obtaining high-purity D-(-)-O-formylmandelic acid chloride.

[0003] Existing patent CN103319335A mentions the use of thionyl chloride as a dehydrating agent to react formic acid with mandelic acid to produce formylmandelic acid, which is then chlorinated with thionyl chloride to produce formylmandelic acid chloride. This reaction uses a large amount of thionyl chloride, which severely corrodes equipment, makes tail gas treatment difficult, and produces insufficient industrial-grade sodium sulfite.

[0004] While CN01704746A uses a large amount of formic acid as a formylation agent, avoiding the safety issues associated with using thionyl chloride, the invention's recycling of the formic acid contains a large amount of water and cannot be reused, resulting in no cost savings and significant waste of the raw formic acid. Summary of the Invention

[0005] The purpose of this section is to summarize some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of this application to avoid obscuring the purpose of this section, the abstract and the title of the invention, and such simplifications or omissions should not be used to limit the scope of the present invention.

[0006] In view of the above problems and the problems existing in the prior art, the present invention is proposed.

[0007] Therefore, the object of the present invention is to provide a method for preparing D-(-)-O-formylmandelic acid chloride based on the deficiencies in the prior art.

[0008] To solve the above technical problems, according to one aspect of the present invention, the present invention provides the following technical solution: a method for preparing D-(-)-formylmandelic acid chloride, comprising:

[0009] Dissolve D-mandelic acid and anhydrous formic acid in a solvent, add catalyst 1, and then dropwise add a dehydrating agent to cause a formylation reaction to obtain a colorless viscous substance, D(-)formylmandelic acid, which can be directly used in the next reaction;

[0010] Dissolve the colorless viscous D(-)formylmandelic acid, add catalyst 2, and add the light-fixing solution dropwise. After the addition is completed, keep the mixture warm for reaction. After the reaction is completed, raise the temperature to reflux, distill off dichloromethane, cool the temperature, filter out the activated carbon, and then evaporate the residue to obtain colorless and transparent D(-)formylmandelic acid chloride.

[0011] As a preferred embodiment of the method for preparing the bismuth oxyhalide / graphene nanocomposite material of the present invention, D-mandelic acid and anhydrous formic acid are dissolved in a solvent, wherein the molar ratio of D-mandelic acid to anhydrous formic acid is 1:1 to 1.2; the solvent includes dichloromethane, and the amount of the solvent is 300 ml.

[0012] As a preferred embodiment of the method for preparing D-(-)-formylmandelic acid chloride of the present invention, the catalyst 1 is activated carbon, and the addition amount is 5 g; the dehydrating agent is added dropwise, wherein the dehydrating agent is a mixture of solid light and dichloromethane, the addition temperature is 0-10°C, and the addition time is 2-4 hours.

[0013] As a preferred embodiment of the method for preparing D-(-)-formylmandelic acid chloride of the present invention, the dehydrating agent comprises 300 g of dichloromethane and solid light, wherein the molar ratio of the added solid light to D-mandelic acid is 1-1.2:1.97.

[0014] As a preferred embodiment of the method for preparing D-(-)-formylmandelic acid chloride of the present invention, the method comprises dissolving the colorless viscous D(-)formylmandelic acid, wherein the amount of D(-)formylmandelic acid is 350-360 g, and the solvent is dichloromethane, and the amount of the solvent is 300 ml.

[0015] As a preferred embodiment of the method for preparing D-(-)-formylmandelic acid chloride according to the present invention, the catalyst 2 is activated carbon, and the added amount is 5 g; the light-fixing solution is added dropwise, wherein the solution includes 300 g of dichloromethane and light-fixing, the molar ratio of the added light-fixing to D-formylmandelic acid is 0.74:1.97, the dropping temperature is 10-20°C, and the dropping time is 4-6 hours.

[0016] As a preferred embodiment of the method for preparing D-(-)-formylmandelic acid chloride of the present invention, the heat preservation reaction is carried out at a temperature of 15 to 20° C. and a heat preservation time of 0.5 to 1.5 h.

[0017] As a preferred embodiment of the method for preparing D-(-)-formylmandelic acid chloride of the present invention, the temperature is raised to reflux, wherein the reflux time is 5 hours.

[0018] As a preferred embodiment of the method for preparing D-(-)-formylmandelic acid chloride of the present invention, the residue is distilled again, wherein the distillation method is distillation under a vacuum of 1 mHg using a mechanical pump.

[0019] As a preferred embodiment of the method for preparing D-(-)-formylmandelic acid chloride of the present invention, the content of D-(-)-formylmandelic acid chloride prepared by the method for preparing D-(-)-formylmandelic acid chloride according to any one of claims 1 to 9 is greater than 99%.

[0020] The present invention aims to overcome the deficiencies of the prior art and provide a method for preparing D-(-)-O-formylmandelic acid chloride, thereby reducing formaldehyde waste during the reaction process. The obtained product has a formaldehyde content of greater than 99%, a chirality of more than 99.3%, and tail gas is easily absorbed, thereby achieving green and environmentally friendly production.

[0021] Beneficial effects of the present invention:

[0022] The object of the present invention is to provide a method for preparing D-(-)-O-formylmandelic acid chloride in response to the deficiencies in the prior art. The prepared D-(-)-O-formylmandelic acid chloride has a content of 99% and a chirality of more than 99.3%. Its tail gas is easily absorbed, thereby achieving green and environmentally friendly production.

[0023] The invention adds a dehydrating agent to fix light during the formylation reaction process, which not only saves formic acid but also greatly improves the reaction conversion rate, effectively reduces production costs, is simple to operate, and is more conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. Those skilled in the art can also derive other drawings based on these drawings without inventive effort. Among them:

[0025] Figure 1 Flow chart of the synthesis of formylmandelic acid.

[0026] Figure 2 Flow chart of the synthesis of D-formylmandelic acid chloride. DETAILED DESCRIPTION

[0027] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with specific embodiments.

[0028] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein. Those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0029] Secondly, the term "one embodiment" or "embodiment" herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in various places throughout this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive of other embodiments.

[0030] The method comprises dissolving D-mandelic acid and anhydrous formic acid, adding a catalyst, and then dripping a dehydrating agent to carry out a formylation reaction to obtain a colorless viscous substance, D(-)formylmandelic acid, which is directly used for the next reaction.

[0031] Dissolve the colorless, viscous D(-)formylmandelic acid, add a catalyst, and dropwise add the light-consolidating solution. Allow to react at room temperature. After the reaction is complete, raise the temperature to reflux, cool, filter out the activated carbon, distill off the dichloromethane, and then evaporate the residue to obtain colorless, transparent D(-)formylmandelic acid chloride.

[0032] Example 1:

[0033] Table 1 Feed ratio for synthesis of formylmandelic acid

[0034]

[0035] Add 300 g of D-mandelic acid, 100 g of formic acid, and 300 g of dichloromethane into a 2000 ml four-necked flask and stir at room temperature for half an hour to dissolve them.

[0036] After dissolution, add 5g of activated carbon, cool to 0-10℃, and then add a mixed solution of 195g of Guguang and 300g of dichloromethane dropwise at a temperature of 0-10℃. Hydrogen chloride gas is occasionally precipitated and the addition time is 3h.

[0037] After the addition is complete, the temperature is maintained at 10-20°C for 5 hours, the activated carbon is filtered, and the dichloromethane and excess formic acid are recovered under normal pressure to obtain 350-360 g of colorless viscous D(-)formylmandelic acid liquid.

[0038] Example 2:

[0039] Table 2 Synthesis of D-formylmandelic acid chloride feed ratio

[0040]

[0041] The crude D(-)formylmandelic acid obtained by distillation in the first step was added to a 2000ml four-necked flask. 300g of dichloromethane and 5g of activated carbon were then added dropwise to the flask. 220g of a light-fixed dichloromethane solution was added dropwise at 10-20°C for 5 hours, with hydrogen chloride gas evolving. After the addition was complete, the mixture was incubated at 15-20°C for 1 hour, then slowly heated to reflux. After reflux for 5 hours, the temperature was lowered, the activated carbon was filtered out, and the dichloromethane was recovered. The residue was then placed under a mechanical pump and vacuumed at 1mHg to obtain the colorless, transparent D(-)formylmandelic acid chloride. The resulting D(-)formylmandelic acid chloride yielded 380-390g, with a detected content exceeding 99% and an ee of 99%.

[0042] Example 3:

[0043] In a 2000 ml four-necked flask, 300 g (1.97 mol) of D-mandelic acid, 100 g (2.17 mol) of formic acid, and 300 g of dichloromethane were added and stirred at room temperature for half an hour to dissolve them.

[0044] After dissolution, add 5g of activated carbon, cool to 0-10℃, and then add the dichloromethane solution of Guguang to the solution dropwise. The amount of Guguang added is shown in Table 3. The addition temperature is 0-10℃, hydrogen chloride gas is occasionally precipitated, and the addition time is 3h.

[0045] After the addition is completed, the temperature is controlled at 10-20°C and kept warm for 5 hours, the activated carbon is filtered, and the dichloromethane and excess formic acid are recovered under normal pressure to obtain a colorless viscous liquid of D(-)formylmandelic acid.

[0046] Calculations show that the conversion rates of D-mandelic acid reached 99.9%, 99.9%, 99.8%, and 95.2%, respectively, when the added amounts of Guguang were 1.2 mol, 1 mol, 0.6 mol, and 0.4 mol. Considering production costs, the best effect was achieved when the added amount of Guguang was 1 mol, i.e., the molar ratio of Guguang to D-mandelic acid was 1:1.97.

[0047] Table 3 Solidification feeding amount and corresponding D-mandelic acid conversion rate

[0048]

[0049] Example 4:

[0050] Into a 2000 ml four-necked flask, 300 g (1.97 mol) of D-mandelic acid, formic acid, and 300 g of dichloromethane were added. The amount of formic acid added was as shown in Table 4. The mixture was stirred at room temperature for half an hour to dissolve the mixture.

[0051] After dissolution, add 5 g of activated carbon, cool to 0-10°C, and then maintain at 10-20°C for 5 hours. Filter the activated carbon and recover dichloromethane and excess formic acid at atmospheric pressure to obtain a colorless, viscous liquid of D(-)formylmandelic acid.

[0052] Calculations show that without adding light-fixing agent, when the added amount of formic acid is 2.17 mol, 10 mol, 20 mol, 30 mol, and 50 mol, the conversion rate of D-mandelic acid reaches 50%, 65%, 75%, 85%, and 92%, respectively.

[0053] Table 4 Formic acid feed amount and corresponding mandelic acid conversion rate without adding light fixation

[0054]

[0055]

[0056] In summary, the present invention addresses the deficiencies of the prior art and provides a method for preparing D-(-)-O-formylmandelic acid chloride. Examples illustrate that the present invention can prepare high-purity D(-)-formylmandelic acid chloride. Furthermore, adding a certain amount of solid light during the synthesis of formylmandelic acid can save formic acid and improve conversion efficiency. A molar ratio of solid light to D-mandelic acid of 1:1.97 achieves high conversion efficiency and is the most economical and environmentally friendly.

[0057] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for preparing D-(-)-formylmandelic acid chloride, characterized in that: include, Dissolve D-mandelic acid and anhydrous formic acid in a solvent, add catalyst 1, and then dropwise add a dehydrating agent to cause a formylation reaction to obtain a colorless viscous substance, D (-) formylmandelic acid, which can be directly used in the next reaction; Dissolve the colorless viscous D(-)formylmandelic acid, add catalyst 2, and dropwise add the light-fixing solution. After the addition is complete, heat and react. After the reaction is complete, raise the temperature to reflux, distill off the dichloromethane, cool the temperature, filter out the activated carbon, and then evaporate the residue to obtain colorless and transparent D(-)formylmandelic acid chloride. Dissolving D-mandelic acid and anhydrous formic acid in a solvent, wherein the mass ratio of D-mandelic acid to anhydrous formic acid is 300g:100g, the solvent is dichloromethane, and the amount of the solvent is 300ml; The catalyst 1 is activated carbon, and the addition amount is 5g; the dehydrating agent is added dropwise, wherein the dehydrating agent is a mixture of 300g of dichloromethane and Guguang, wherein the molar ratio of the added Guguang to D-mandelic acid is 1-1.2:1.97; the dropping temperature is 0-10°C, and the dropping time is 2-4h; The colorless viscous substance D(-) formylmandelic acid is dissolved, wherein 350-360 g of D(-) formylmandelic acid is dissolved in 300 ml of dichloromethane; The catalyst 2 is activated carbon, and the added amount is 5g; the added light-consolidating solution, wherein the solution is 300g of dichloromethane and light-consolidating, the molar ratio of the added light-consolidating to D-formylmandelic acid is 0.74:1.97, the dropping temperature is 10~20℃, and the dropping time is 4~6h.

2. The method for preparing D-(-)-formylmandelic acid chloride according to claim 1, wherein: The insulation reaction has a temperature of 15-20° C. and a time of 0.5-1.5 h.

3. The method for preparing D-(-)-formylmandelic acid chloride according to claim 1, wherein: The temperature is raised to reflux, wherein the reflux time is 5 hours.

4. The method for preparing D-(-)-formylmandelic acid chloride according to claim 1, wherein: The re-distillation residue is distilled by a mechanical pump under a vacuum of 1 mHg.

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