Boron lactate synthesized from borneol, lactic acid and methyl lactate and method

Abstract

The invention belongs to the technical field of bornyl ester preparation, and discloses bornyl lactate synthesized from borneol, lactic acid and methyl lactate and a method. Adding borneol, lactic acid, methyl lactate, a catalyst and a water-carrying agent into a reaction kettle for reaction to obtain a liquid product; after the reaction is finished, cooling to room temperature, adding water, washing at room temperature, and collecting washing water; carrying out reduced pressure distillation on the collected oil layer, and recovering the solvent in the oil layer liquid; adding anhydrous MgSO4 into the oil layer liquid from which the solvent is removed, standing overnight and drying to obtain a bornyl lactate crude product; and carrying out fractionation on the obtained bornyl lactate crude product, and removing unreacted borneol and borneol dehydration byproducts to prepare refined bornyl lactate. The bornyl lactate prepared by the method disclosed by the invention is high in purity and easy to separate, and by chemically modifying borneol, the efficacy of a parent drug can be effectively enhanced, and the toxicity caused by the parent drug is reduced.

Description

Technical Field

[0001] The invention belongs to the technical field of borneol ester preparation, and particularly relates to borneol lactate synthesized from borneol, lactic acid and methyl lactate and a method thereof. Background Art

[0002] Borneol, also known as borneol, has been praised as a shining pearl in nature since ancient times. It is one of the earliest natural organic ingredients explored and successfully applied in the medical field. This precious medicinal material from the ancient East not only carries a profound cultural heritage, but also shines with unique brilliance in the fields of traditional Chinese medicine and modern medicine with its excellent anti-inflammatory and analgesic, anti-myocardial ischemia, brain protection and permeation-promoting effects.

[0003] In the vast number of prescriptions in traditional Chinese medicine, borneol is often cleverly incorporated as an "adjuvant drug". Although its role is not obvious, it is crucial. It is like a shrewd guide, which can enhance the leading role of the main and auxiliary drugs in the prescription, guide the efficacy of the drug to reach the lesion accurately, and maximize the therapeutic effect. However, the beauty of borneol also has its flaws. Its volatility and potential toxicity limit its single application in clinical practice and the possibility of long-term continuous use, which is undoubtedly a pity for its medicinal value.

[0004] In order to solve this problem, scientists embarked on a journey of exploration and innovation. They used chemical modification as the key to open a new chapter in the optimization of borneol's medicinal properties. The advent of new synthetic drugs such as tacrine-bornyl ester is the brilliant result of this effort. These innovative drugs not only retain the original pharmacological activity of borneol, but also effectively reduce toxicity through clever chemical structure modification, which has unprecedentedly improved the medicinal value of borneol. This breakthrough not only opens up a broader space for the application of borneol, but also provides new ideas and directions for research in the field of medicinal chemistry.

[0005] In the process of structural modification and modification of borneol, esterification has become the most commonly used technical means. Through this method, scientists have successfully synthesized a series of new borneol derivatives such as danshensu acyl alanyl proline borneol ester, danshensu borneol ester, and catechin borneol ester. These derivatives not only reduce the toxicity of borneol, but also significantly enhance its pharmacological effects, providing more options for clinical treatment. In addition, authoritative journals in the field of pharmaceutical research, such as the Journal of Pharmaceutical Research, Vol. 39, No. 4, 2020, have demonstrated to the world the great potential of the prodrug principle in the combination of borneol with natural active molecules or finished drugs with detailed experimental data and in-depth theoretical analysis, further confirming the scientificity and practicality of this method.

[0006] It is worth noting that due to the complex spatial structure of borneol and its derivatives, efficient condensation agents are often needed to overcome the challenge of steric hindrance during the synthesis process. For example, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 4-dimethylaminopyridine (DMAP) were used as condensation agents to successfully synthesize danshensu acyl-L-alanyl-L-proline bornyl ester; and 1,3-dicyclohexylcarbodiimide (DDC) played a key role in the synthesis of gallic acid bornyl ester in many studies. These sophisticated chemical operations not only demonstrate the wisdom and skills of scientists, but also lay a solid foundation for the future development of borneol drugs.

[0007] In addition, the research results disclosed in the Journal of Guangzhou University of Chinese Medicine in Volume 38, Issue 4, 2021 are also remarkable. The research team used 4-toluenesulfonic acid as a catalyst to successfully synthesize 3,5-dinitrobenzoyl bornyl with a yield of up to 62%. This achievement not only enriches the types of borneol derivatives, but also provides valuable reference and reference for the further development and application of related drugs. However, there is still a problem of low yield, which cannot meet higher requirements.

[0008] The background technology information mentioned above is mainly intended to assist readers to deeply understand the core concept and technical innovation path of the present invention, rather than directly constituting the scope of the prior art on which this patent application relies. In the absence of conclusive evidence that the background technology has been made public before the filing date of this patent application, these technical materials should not be regarded as a benchmark for judging the novelty or creativity of this application. Therefore, its role should be understood as an auxiliary reference rather than a decisive basis. Summary of the invention

[0009] The invention provides a borneol lactate synthesized from borneol, lactic acid and methyl lactate and a method thereof. The invention solves the problems that borneol is easy to volatilize in clinical medication and is easy to be lost during preparation production and storage, which affects the quality and efficacy of the preparation and has certain toxic and side effects. The method has the advantages of simple process, less discharge of three wastes, low cost, green environmental protection and the like.

[0010] In order to achieve the above technical objectives, the present invention adopts the following technical solutions:

[0011] A method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate, comprising the following steps:

[0012] (1) adding borneol, lactic acid, methyl lactate, catalyst and water-carrying agent in a molar ratio of 1:1-3:1-2:0.1-0.3:0.3-1.5 to a reaction kettle, stirring at a speed of 200-300 rpm, a reaction temperature of 65-125° C., and a reaction time of 3-8 h to obtain a liquid product; the catalyst comprises one or both of boric acid and boric oxide;

[0013] (2) After the reaction of step (1) is completed, the mixture is cooled to room temperature, 0.5-1.5 times of water is added to the product, and the mixture is washed 3-5 times at room temperature, and the washing water is collected;

[0014] (3) subjecting the oil layer collected in step (2) to reduced pressure distillation to recover the solvent in the oil layer liquid;

[0015] (4) adding anhydrous MgSO4 to the oil layer liquid after the solvent is removed and drying overnight to obtain a crude product of borneol lactate;

[0016] (5) fractionating the crude borneol lactate obtained in step (4) to remove unreacted borneol and borneol dehydration by-products to obtain refined borneol lactate.

[0017] Furthermore, the catalyst in step (1) also includes CaB6, wherein the mass ratio of boric acid or boron oxide to CaB6 is 1:0.5-1.

[0018] Furthermore, the catalyst described in step (1) is boric acid, boron oxide and CaB6, and the mass ratio thereof is 1:0.4-0.6:0.2-0.5.

[0019] Furthermore, the water-carrying agent in step (1) includes one or more of benzene, toluene, xylene, cyclohexane, and chloroform.

[0020] Furthermore, the water-carrying agent is used as an extraction solvent, an extractant of 0.2-3 times the mass of the washing water in step (2) is added, extraction is performed 2-3 times, and the extracts are combined; the extractant in the extract is removed by reduced pressure distillation, and the distillation substrate is used as a raw material for the next reaction.

[0021] Furthermore, the washing water after extraction is subjected to rotary evaporation to remove water at a vacuum degree of -0.1 MPa and a temperature of 80-85° C. to remove water until the mass concentration of lactic acid is 80-85%; and the concentrated lactic acid solution is used as a raw material for step (1).

[0022] Furthermore, after the reaction of step (1) is completed, the reaction mixture is cooled to room temperature, 0.5-1.5 times the amount of water as the product is added, and the mixture is washed 3-5 times at room temperature, and the washing water is collected.

[0023] Furthermore, the fractionation in step (5) is carried out in an oil bath with a vacuum degree of -0.09 to -0.1 MPa, and the distillate is collected when the fractionation port temperature is 145-150°C.

[0024] Furthermore, the content of borneol lactate described in step (5) is obtained from the gas chromatogram by area normalization method, and the gas chromatography analysis conditions are: carrier gas, high-purity nitrogen; programmed temperature: 70°C (2min), increased to 150°C at 50°C / min, stayed for 3min, increased to 230°C at 30°C / min, stayed for 30min; injection port temperature: 250°C, total flow rate 130.5mL / min, split ratio 50:1, septum purge 3mL / min; FID detection, detection port temperature: 250°C, hydrogen flow rate 40mL / min, air 450mL / min, nitrogen purge, 25mL / min, injection volume 0.2uL.

[0025] The present invention has the following beneficial effects:

[0026] 1. The present invention innovatively uses borneol and lactic acid as core starting materials, and pioneeringly catalyzes the fusion of the three (borneol, lactic acid and its methyl ester form), and successfully synthesizes borneol lactate. This process not only ensures the high yield and high purity of the product, but also greatly facilitates the subsequent separation and purification work.

[0027] 2. In order to further optimize the conversion efficiency, the present invention introduces a high-efficiency catalyst, which includes one or more of boric acid, boron oxide, and CaB6. These catalysts are like "accelerators" in the catalyst world, which significantly promote the conversion process of borneol to borneol lactate, thereby achieving a significant increase in product yield.

[0028] 3. The present invention incorporates a unique water-carrying agent strategy - adding a mixture of chloroform and toluene to the reaction raw materials. This innovation cleverly utilizes the "low azeotropic" characteristics formed by them with water, and efficiently carries the water generated in the reaction out of the reaction system in the form of an azeotrope. This effectively pushes the equilibrium of the esterification reaction to the right and greatly improves the equilibrium conversion rate of the reaction.

[0029] 4. It is worth mentioning that the method of the present invention can obtain the target product bornyl lactate with a relatively high purity. In particular, in a specific example (such as Example 9), we successfully prepared a fine product of bornyl lactate with a purity of up to 96.5%.

[0030] 5. The present invention also recycles excess lactic acid, methyl lactate and catalyst for repeated use twice, and the reuse effect is good. From a process perspective, the present invention, with its simple process design, low three waste emissions, cost control advantages and green environmental protection characteristics, shows a very high potential for industrial application, and provides strong support for promoting green production in related fields.

[0031] 6. The borneol lactate prepared by chemically modifying the borneol molecule in the present invention not only enhances the pharmacological efficacy of the original drug, but also effectively reduces its possible toxic side effects, bringing a new perspective and possibility to the field of drug research and development. DETAILED DESCRIPTION

[0032] To further explain the technical means and effects of the present invention, the technical solution of the present invention is further described below in conjunction with the embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.

[0033] In an embodiment of the present invention, a method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate comprises the following steps:

[0034] (1) adding borneol, lactic acid, methyl lactate, catalyst and water-carrying agent in a molar ratio of 1:1-3:1-2:0.1-0.3:0.3-1.5 to a reaction kettle, stirring at a speed of 200-300 rpm, a reaction temperature of 65-125° C., and a reaction time of 3-8 h to obtain a liquid product; the catalyst comprises one or both of boric acid and boric oxide;

[0035] (2) After the reaction of step (1) is completed, the mixture is cooled to room temperature, 0.5-1.5 times of water is added to the product, and the mixture is washed 3-5 times at room temperature, and the washing water is collected;

[0036] (3) subjecting the oil layer collected in step (2) to reduced pressure distillation to recover the solvent in the oil layer liquid;

[0037] (4) adding anhydrous MgSO4 to the oil layer liquid after the solvent is removed and drying overnight to obtain a crude product of borneol lactate;

[0038] (5) fractionating the crude borneol lactate obtained in step (4) to remove unreacted borneol and borneol dehydration by-products to obtain refined borneol lactate.

[0039] The catalyst in step (1) also includes CaB6, wherein the mass ratio of boric acid or boron oxide to CaB6 is 1:0.5-1.

[0040] The catalyst described in step (1) is boric acid, boron oxide and CaB6, and the mass ratio thereof is 1:0.4-0.6:0.2-0.5.

[0041] The water-carrying agent described in step (1) includes one or more of benzene, toluene, xylene, cyclohexane, and chloroform.

[0042] The water-carrying agent is used as the extraction solvent, and an extractant of 0.2-3 times the mass of the washing water in step (2) is added, and extraction is performed 2-3 times, and the extracts are combined; the extractant in the extract is removed by vacuum distillation, and the distillation substrate is used as the raw material for the next reaction.

[0043] The washing water after extraction is subjected to rotary evaporation at a vacuum degree of -0.1 MPa and a temperature of 80-85°C to remove water until the mass concentration of lactic acid is 80-85%; the concentrated lactic acid solution is used as the raw material of step (1).

[0044] The fractionation described in step (5) is carried out in an oil bath with a vacuum degree of -0.09 to -0.1 MPa, and the distillate is collected when the fractionation port temperature is 145-150°C.

[0045] Bornyl lactate sample analysis test:

[0046] Aglient7890A gas chromatograph, Agilent, USA; chromatographic column: AT-35, quartz capillary column (60m×0.25mm×0.25μm). GC analysis conditions: carrier gas, high-purity nitrogen; program temperature: 70℃ (2min), increase to 150℃ at 50℃ / min, stay for 3min, increase to 230℃ at 30℃ / min, stay for 30min; injection port temperature: 250℃, total flow rate 130.5mL / min, split ratio 50:1, septum purge 3mL / min; FID detection, detection port temperature: 250℃, hydrogen flow rate 40mL / min, air 450mL / min, nitrogen purge, 25mL / min. Injection volume 0.2uL.

[0047] The content of each component was obtained from the gas chromatogram using the area normalization method.

[0048] In order to make the disclosure of the present invention more complete, it is described below through more specific embodiments.

[0049] Example 1

[0050] A method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate, comprising the following steps:

[0051] (1) borneol, lactic acid, methyl lactate, boric acid, and toluene were added into a reaction kettle in a molar ratio of 1:1.5:1.0:0.1:0.3, with a stirring speed of 300 rpm, a reaction temperature of 122° C., and a reaction time of 6 h to obtain a liquid product;

[0052] (2) After the reaction of step (1) is completed, the mixture is cooled to room temperature, 1.5 times the amount of water as the product is added, and the mixture is washed three times at room temperature, and the washing water is collected;

[0053] (3) subjecting the oil layer collected in step (2) to reduced pressure distillation to recover the solvent in the oil layer liquid;

[0054] (4) adding anhydrous MgSO4 to the oil layer liquid after the solvent is removed and drying overnight to obtain a crude product of borneol lactate;

[0055] (5) fractionating the crude borneol lactate obtained in step (4) to remove unreacted borneol and borneol dehydration by-products to obtain refined borneol lactate.

[0056] The GC content of the crude bornyl lactate obtained in this example is 58.6%; the GC content of the purified bornyl lactate is 88.5%.

[0057] Example 2

[0058] A method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate, comprising the following steps:

[0059] (1) borneol, lactic acid, methyl lactate, boric acid, and chloroform were added into a reaction kettle in a molar ratio of 1:1.2:2.0:0.2:1.0, with a stirring speed of 250 rpm, a reaction temperature of 72° C., and a reaction time of 5 h to obtain a liquid product;

[0060] (2) After the reaction in step (1) is completed, the mixture is cooled to room temperature, and water 1 times the amount of the product is added, and the mixture is washed 4 times at room temperature, and the washing water is collected;

[0061] (3) subjecting the oil layer collected in step (2) to reduced pressure distillation to recover the solvent in the oil layer liquid;

[0062] (4) adding anhydrous MgSO4 to the oil layer liquid after the solvent is removed and drying overnight to obtain a crude product of borneol lactate;

[0063] (5) fractionating the crude borneol lactate obtained in step (4) to remove unreacted borneol and borneol dehydration by-products to obtain refined borneol lactate.

[0064] The GC content of the crude bornyl lactate obtained in this example is 55.5%; the GC content of the purified bornyl lactate is 85.7%.

[0065] Example 3

[0066] A method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate, comprising the following steps:

[0067] (1) borneol, lactic acid, methyl lactate, boric acid, and chloroform were added into a reaction kettle in a molar ratio of 1:2.0:1.5:0.3:0.8, with a stirring speed of 280 rpm, a reaction temperature of 72° C., and a reaction time of 4 h to obtain a liquid product;

[0068] (2) After the reaction of step (1) is completed, the mixture is cooled to room temperature, 0.8 times the amount of water as the product is added, and the mixture is washed 4 times at room temperature, and the washing water is collected;

[0069] (3) subjecting the oil layer collected in step (2) to reduced pressure distillation to recover the solvent in the oil layer liquid;

[0070] (4) adding anhydrous MgSO4 to the oil layer liquid after the solvent is removed and drying overnight to obtain a crude product of borneol lactate;

[0071] (5) fractionating the crude borneol lactate obtained in step (4) to remove unreacted borneol and borneol dehydration by-products to obtain refined borneol lactate.

[0072] The GC content of the crude bornyl lactate obtained in this example is 57.8%; the GC content of the purified bornyl lactate is 86.6%.

[0073] Example 4

[0074] A method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate, comprising the following steps:

[0075] (1) borneol, lactic acid, methyl lactate, boric acid, and toluene were added into a reaction kettle in a molar ratio of 1:2.0:2.0:0.25:1.5, with a stirring speed of 200 rpm, a reaction temperature of 125° C., and a reaction time of 8 h to obtain a liquid product;

[0076] (2) After the reaction in step (1) is completed, the mixture is cooled to room temperature, and water 1 times the amount of the product is added, and the mixture is washed 4 times at room temperature, and the washing water is collected;

[0077] (3) subjecting the oil layer collected in step (2) to reduced pressure distillation to recover the solvent in the oil layer liquid;

[0078] (4) adding anhydrous MgSO4 to the oil layer liquid after the solvent is removed and drying overnight to obtain a crude product of borneol lactate;

[0079] (5) fractionating the crude borneol lactate obtained in step (4) to remove unreacted borneol and borneol dehydration by-products to obtain refined borneol lactate.

[0080] The GC content of the crude bornyl lactate obtained in this example is 63.7%; the GC content of the purified bornyl lactate is 93.2%.

[0081] Example 5

[0082] A method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate, comprising the following steps:

[0083] (1) borneol, lactic acid, methyl lactate, boric acid, and chloroform were added into a reaction kettle in a molar ratio of 1:3.0:1.0:0.15:1.2, with a stirring speed of 280 rpm, a reaction temperature of 70° C., and a reaction time of 7 h to obtain a liquid product;

[0084] (2) After the reaction of step (1) is completed, the mixture is cooled to room temperature, 1.5 times the amount of water as the product is added, and the mixture is washed three times at room temperature, and the washing water is collected;

[0085] (3) subjecting the oil layer collected in step (2) to reduced pressure distillation to recover the solvent in the oil layer liquid;

[0086] (4) adding anhydrous MgSO4 to the oil layer liquid after the solvent is removed and drying overnight to obtain a crude product of borneol lactate;

[0087] (5) fractionating the crude borneol lactate obtained in step (4) to remove unreacted borneol and borneol dehydration by-products to obtain refined borneol lactate.

[0088] The GC content of the crude bornyl lactate obtained in this example is 60.4%; the GC content of the purified bornyl lactate is 89.9%.

[0089] Example 6

[0090] A method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate, comprising the following steps:

[0091] (1) borneol, lactic acid, methyl lactate, boric acid, and toluene were added into a reaction kettle in a molar ratio of 1:1.8:1.5:0.18:0.5, with a stirring speed of 250 rpm, a reaction temperature of 122° C., and a reaction time of 5 h to obtain a liquid product;

[0092] (2) After the reaction of step (1) is completed, the mixture is cooled to room temperature, 0.8 times the amount of water as the product is added, and the mixture is washed 5 times at room temperature, and the washing water is collected;

[0093] (3) subjecting the oil layer collected in step (2) to reduced pressure distillation to recover the solvent in the oil layer liquid;

[0094] (4) adding anhydrous MgSO4 to the oil layer liquid after the solvent is removed and drying overnight to obtain a crude product of borneol lactate;

[0095] (5) fractionating the crude borneol lactate obtained in step (4) to remove unreacted borneol and borneol dehydration by-products to obtain refined borneol lactate.

[0096] The GC content of the crude bornyl lactate obtained in this example is 56.3%; the GC content of the purified bornyl lactate is 87.4%.

[0097] Example 7

[0098] A method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate, comprising the following steps:

[0099] (1) borneol, lactic acid, methyl lactate, calcium boride, and chloroform were added into a reaction kettle at a molar ratio of 1:1.5:1.0:0.20:1.0, with a stirring speed of 300 rpm, a reaction temperature of 78° C., and a reaction time of 6 h to obtain a liquid product;

[0100] (2) After the reaction of step (1) is completed, the mixture is cooled to room temperature, 1.5 times the amount of water as the product is added, and the mixture is washed three times at room temperature, and the washing water is collected;

[0101] (3) subjecting the oil layer collected in step (2) to reduced pressure distillation to recover the solvent in the oil layer liquid;

[0102] (4) adding anhydrous MgSO4 to the oil layer liquid after the solvent is removed and drying overnight to obtain a crude product of borneol lactate;

[0103] (5) fractionating the crude borneol lactate obtained in step (4) to remove unreacted borneol and borneol dehydration by-products to obtain refined borneol lactate.

[0104] The GC content of the crude bornyl lactate obtained in this example is 40.5%; the GC content of the purified bornyl lactate is 82.9%.

[0105] Example 8

[0106] A method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate, comprising the following steps:

[0107] (1) borneol, lactic acid, methyl lactate, boric acid, calcium boride, and chloroform were added into a reaction kettle in a molar ratio of 1:1.5:1.0:0.10:0.02:1.0, stirred at 280 rpm, at a reaction temperature of 76° C., and for 6 h to obtain a liquid product;

[0108] (2) After the reaction of step (1) is completed, the mixture is cooled to room temperature, 1.5 times the amount of water as the product is added, and the mixture is washed 4 times at room temperature, and the washing water is collected;

[0109] (3) subjecting the oil layer collected in step (2) to reduced pressure distillation to recover the solvent in the oil layer liquid;

[0110] (4) adding anhydrous MgSO4 to the oil layer liquid after the solvent is removed and drying overnight to obtain a crude product of borneol lactate;

[0111] (5) fractionating the crude borneol lactate obtained in step (4) to remove unreacted borneol and borneol dehydration by-products to obtain refined borneol lactate.

[0112] The GC content of the crude bornyl lactate obtained in this example is 65.8%; the GC content of the purified bornyl lactate is 94.6%.

[0113] Example 9

[0114] A method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate, comprising the following steps:

[0115] (1) borneol, lactic acid, methyl lactate, boric acid, boric acid, boron oxide, calcium boride, and chloroform were added into a reaction kettle in a molar ratio of 1:1.5:1.0:0.10:0.02:0.02:1.0, stirred at 250 rpm, reacted at 77° C., and reacted for 7 h to obtain a liquid product;

[0116] (2) After the reaction of step (1) is completed, the mixture is cooled to room temperature, 0.8 times the amount of water as the product is added, and the mixture is washed 5 times at room temperature, and the washing water is collected;

[0117] (3) subjecting the oil layer collected in step (2) to reduced pressure distillation to recover the solvent in the oil layer liquid;

[0118] (4) adding anhydrous MgSO4 to the oil layer liquid after the solvent is removed and drying overnight to obtain a crude product of borneol lactate;

[0119] (5) fractionating the crude borneol lactate obtained in step (4) to remove unreacted borneol and borneol dehydration by-products to obtain refined borneol lactate.

[0120] The GC content of the crude bornyl lactate obtained in this example is 70.2%; the GC content of the purified bornyl lactate is 96.5%.

[0121] Comparative Example 1

[0122] (1) borneol, lactic acid, methyl lactate and toluene were added into a reaction kettle in a molar ratio of 1:2.0:1.0:1.0, stirred at 200 rpm, reacted at 122° C. and reacted for 7 h to obtain a liquid product;

[0123] (2) After the reaction of step (1) is completed, the mixture is cooled to room temperature, 1.5 times the amount of water as the product is added, and the mixture is washed 4 times at room temperature, and the washing water is collected;

[0124] (3) subjecting the oil layer collected in step (2) to reduced pressure distillation to recover the solvent in the oil layer liquid;

[0125] (4) adding anhydrous MgSO4 to the oil layer liquid after the solvent is removed and drying overnight to obtain a crude product of borneol lactate;

[0126] (5) fractionating the crude borneol lactate obtained in step (4) to remove unreacted borneol and borneol dehydration by-products to obtain refined borneol lactate.

[0127] The GC content of the purified bornyl lactate obtained in this comparative example was 0%.

[0128] Comparative Example 2

[0129] The operation steps are basically the same as those of Comparative Example 1, except that in step (1), borneol and boric acid are used in a mass ratio of 1:0.10, and the GC content of the purified borneol lactate obtained is 55.1%.

[0130] Comparative Example 3

[0131] The operation steps are basically the same as those of Comparative Example 1, except that in step (1), borneol and sulfuric acid are used in a mass ratio of 1:0.10, and the GC content of the purified borneol lactate obtained is 35.4%.

[0132] Table 1 shows the crude borneol lactate content and the borneol lactate fine product content prepared in Examples 1-9

[0133]

[0134] When we deeply explore the data shown in Table 1, it is not difficult to find that the synthesis process of borneol lactate shows remarkable efficiency and selectivity optimization characteristics under the synergistic effect of the three catalysts, which marks a significant technological advancement in the field of fine chemical synthesis. The careful design of Examples 1-9 not only verifies the applicability of the catalytic system for the efficient synthesis of borneol lactate, but also further reveals the important role of temperature control in accelerating reaction kinetics.

[0135] In Example 9, we have witnessed a great leap forward in the synthesis technology of borneol lactate. By finely regulating the reaction parameters, including borneol, lactic acid, methyl lactate in a molar ratio of 1: 1.5: 1.0, borneol and boric acid, boron oxide, calcium boride in a mass ratio of 1: 0.10: 0.02: 0.02, borneol and water-carrying agent toluene in a mass ratio of 1: 1.0, the rotating speed is 250rpm, the reaction temperature is controlled to be 77 ° C, the reaction time is 7h and other parameters, we successfully raised the fine product content of borneol lactate to an astonishing level of 96.5%. This achievement not only reflects a deep understanding of the reaction mechanism, but also reflects the exquisite control power in the synthesis process. The acquisition of high-purity products is of great significance for the purification, separation and application links of subsequent products, which reduces production costs, improves production efficiency, and also broadens the application prospects of borneol lactate in the fields of medicine, spices, cosmetics, etc.

[0136] In summary, the experimental data shown in Table 1 not only verify the feasibility and efficiency of the synthesis of bornyl lactate under this system, but also demonstrate the profound understanding of the technical principles and the significant progress of process innovation through the excellent performance of the best example 9. This series of research results provides an important reference for the efficient and green synthesis of fine chemicals, and also injects new vitality into the sustainable development of related industries.

[0137] In order to investigate the catalytic effect of different catalysts on the synthesis of borneol lactate, the commonly used sulfuric acid catalyst was used to catalyze the synthesis of borneol lactate, and the results were compared with the blank test. The test results are shown in Table 2.

[0138] Table 2 is a comparison of the experimental results of different catalysts in Comparative Examples 1-3

[0139]

[0140] From the detailed data in Table 2, we can deeply analyze the chemical inertness of the interaction between lactic acid and borneol in a catalyst-free environment. This discovery not only reveals the inherent mechanism of the lack of direct conversion between the two under natural conditions, but also emphasizes the key role of catalysts in promoting such organic reactions. In the absence of catalysts, the carboxyl group of lactic acid and the hydroxyl group of borneol failed to effectively activate and form a stable ester bond, which highlights the limitations of intermolecular interactions in the absence of external energy or electron transfer media.

[0141] Further comparison of the effects of the traditional and widely used sulfuric acid catalyst with the three emerging mixed catalysts of boric acid, boric oxide and calcium boride revealed a significant technological advancement. Sulfuric acid, as a strong acid catalyst, can effectively promote many esterification reactions, but its strong corrosiveness not only increases the difficulty of operation and safety risks, but may also have an adverse effect on the purity and color of the target product. In this study, the borneol lactate product generated under sulfuric acid catalysis is darker in color. This phenomenon is likely due to the coloring effect of the by-products or residues produced during the sulfuric acid catalysis on the product, which directly affects the market acceptance and subsequent application value of the product.

[0142] In comparison, the three mixed catalysts of boric acid, boron oxide and calcium boride showed more superior performance. The mixed catalyst is known for its relatively mild catalytic activity and environmental friendliness. When promoting the esterification reaction of lactic acid and borneol, it not only effectively reduces the occurrence of side reactions, but also significantly increases the yield of the target product borneol lactate. Specifically, the content of borneol lactate obtained under boric acid catalysis is 19.7% higher than that under sulfuric acid catalysis. This data is not only a direct quantification of the catalyst efficiency, but also a high recognition of the potential application value of boric acid in the field of fine chemical synthesis.

[0143] In addition, this significant advancement of the mixed catalyst catalytic system is also reflected in its improvement of product quality. The purer and lighter-colored borneol lactate not only meets the strict purity requirements of high-end chemical products, but also broadens its application range in industries such as medicine, fragrances and cosmetics. Therefore, from the perspective of technical principles and practical application effects, boric acid as a catalyst for the esterification reaction of lactic acid and borneol undoubtedly represents an important direction of technological innovation, providing new ideas and options for research and development in related fields.

[0144] Catalyst reuse test adopted in Example 4:

[0145] A process for synthesizing borneol lactate from borneol, recycled lactic acid, methyl lactate and a catalyst comprises the following steps:

[0146] (1) Add borneol and lactic acid in a ratio of 1:1, the recovered lactic acid, methyl lactate and catalyst, and toluene with water into a reaction kettle and stir (the amount of borneol and water with water is consistent with the amount added in Example 4), the speed is 200 rpm, the reaction temperature is controlled to be 125 ° C, the reaction time is 8 h, and a liquid product is obtained;

[0147] (2) After the reaction in step (1) is completed, the mixture is cooled to room temperature, and water 1 times the amount of the product is added, and the mixture is washed 4 times at room temperature, and the washing water is collected;

[0148] (3) subjecting the oil layer collected in step (2) to reduced pressure distillation to recover the solvent in the oil layer liquid;

[0149] (4) adding anhydrous MgSO4 to the oil layer liquid after the solvent is removed and drying overnight to obtain a crude product of borneol lactate;

[0150] (5) fractionating the crude borneol lactate obtained in step (4) to remove unreacted borneol and borneol dehydration by-products to obtain refined borneol lactate.

[0151] The test results of using the recovered lactic acid, methyl lactate and catalyst twice in succession in Example 4 are shown in Table 3.

[0152] Table 3 Test results of two consecutive uses of the recovered lactic acid, methyl lactate and catalyst used in Example 4

[0153]

[0154] As can be seen from Table 3, after the catalyst used in Example 4 was reused twice, the crude content of bornyl lactate only dropped from 63.7% to 55.8%, which shows that the catalyst still has a relatively high catalytic activity.

[0155] The above-mentioned embodiments are intended to demonstrate a preferred execution path of the present invention, however, the implementation scope of the present invention is not limited to these specific examples. Without departing from the core concept and basic principle of the present invention, any form of adjustment, polishing, replacement, fusion or simplification shall be regarded as an equivalent form of transformation and shall naturally be included in the protection scope of the present invention.

Claims

1. A method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate, characterized in that: The steps include: (1) adding borneol, lactic acid, methyl lactate, catalyst and water-carrying agent in a molar ratio of 1:1-3:1-2:0.1-0.3:0.3-1.5 to a reaction kettle, stirring at a speed of 200-300 rpm, a reaction temperature of 65-125° C., and a reaction time of 3-8 h to obtain a liquid product; the catalyst comprises one or both of boric acid and boric oxide; (2) After the reaction of step (1) is completed, the mixture is cooled to room temperature, water is added, and washing is performed at room temperature, and the washing water is collected; (3) subjecting the oil layer collected in step (2) to reduced pressure distillation to recover the solvent in the oil layer liquid; (4) adding anhydrous MgSO4 to the oil layer liquid after the solvent is removed and drying overnight to obtain a crude product of borneol lactate; (5) fractionating the crude borneol lactate obtained in step (4) to remove unreacted borneol and borneol dehydration by-products to obtain refined borneol lactate.

2. The method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate according to claim 1, characterized in that: The catalyst in step (1) also includes CaB6, wherein the mass ratio of boric acid or boron oxide to CaB6 is 1:0.5-1.

3. The method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate according to claim 1, characterized in that: The catalyst described in step (1) is boric acid, boron oxide and CaB6, and the mass ratio thereof is 1:0.4-0.6:0.2-0.

5.

4. The method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate according to claim 1, characterized in that: The water-carrying agent described in step (1) includes one or more of benzene, toluene, xylene, cyclohexane, and chloroform.

5. The method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate according to claim 1, characterized in that: The water-carrying agent is used as the extraction solvent, and an extractant of 0.2-3 times the mass of the washing water in step (2) is added, and extraction is performed 2-3 times, and the extracts are combined; the extractant in the extract is removed by vacuum distillation, and the distillation substrate is used as the raw material for the next reaction.

6. The method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate according to claim 5, characterized in that: The washing water after extraction is subjected to rotary evaporation at a vacuum degree of -0.1 MPa and a temperature of 80-85°C to remove water until the mass concentration of lactic acid is 80-85%; the concentrated lactic acid solution is used as the raw material of step (1).

7. The method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate according to claim 1, characterized in that: After the reaction in step (1) is completed, the mixture is cooled to room temperature, 0.5-1.5 times of water as much as the product is added, and the mixture is washed 3-5 times at room temperature, and the washing water is collected.

8. The method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate according to claim 1, characterized in that: The fractionation described in step (5) is carried out in an oil bath with a vacuum degree of -0.09 to -0.1 MPa, and the distillate is collected when the fractionation port temperature is 145-150°C.

9. The method for synthesizing borneol lactate from borneol, lactic acid and methyl lactate according to claim 1, characterized in that: The content of bornyl lactate described in step (5) is obtained from the gas chromatogram by area normalization method, and the gas chromatography analysis conditions are: carrier gas, high-purity nitrogen; program Heating: 70℃ (2min), increased to 150℃ at 50℃ / min, stayed for 3min, increased to 230℃ at 30℃ / min, stayed for 30min; Injection port temperature: 250℃, total flow rate 130.5mL / min, split ratio 50:1, septum purge 3mL / min; FID detection, detection port temperature: 250℃, hydrogen flow rate 40mL / min, air 450mL / min, nitrogen purge, 25mL / min, injection volume 0.2uL.

10. Bornyl lactate synthesized according to the method according to any one of claims 1 to 9.

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