Preparation method of high-purity d-borneol

Abstract

The invention belongs to the technical field of d-borneol, and particularly relates to a preparation method of high-purity d-borneol, which comprises the following steps: S1, separating and purifying a primary d-borneol product by a molecular eutectic method to obtain d-borneol I; s2, recrystallizing the D-borneol I to obtain the D-borneol II; and S3, re-crystallizing the D-borneol No.2 again to obtain the D-borneol No.3. The preparation method of the high-purity D-borneol mainly comprises the combination of a molecular eutectic technology and a re-crystallization technology, and is simple, convenient, efficient, low in cost and easy to industrialize. The purity of the prepared high-purity d-borneol can reach 99.9% or above, the yield can reach 95% or above, and the high-purity d-borneol is a high-quality raw material for preparing high-quality downstream products. The requirement of modern pharmacy on the high purity of the d-borneol is met. The dual purposes of greatly improving the purity and the yield of the d-borneol are achieved.

Description

Technical Field

[0001] The invention belongs to the technical field of d-borneol, and particularly relates to a method for preparing high-purity d-borneol. Background Art

[0002] Borneol is a natural product obtained by distilling the resin from the trunk of the borneol tree. Borneol can open all the orifices, dissipate stagnation, remove cataracts and improve eyesight, reduce swelling and relieve pain, open the mind, clear away heat and detoxify. It is mainly used to treat diseases such as lockjaw caused by stroke, coma caused by fever, deafness caused by qi stagnation, throat paralysis, carbuncle, etc. In spices, it is a precious fixative and an important raw material for preparing high-end perfumes. In addition, borneol has the effect of removing rot, preserving and repelling insects. It can also be used as a cooling additive in the beverage industry. It has a wide range of uses.

[0003] At present, the content of borneol raw materials on the market is not high (Chinese Pharmacopoeia): synthetic borneol (commonly known as synthetic borneol), borneol (C 10 H 18 O) shall not be less than 55.0%, camphor shall not exceed 0.5%; L-borneol of natural borneol, L-borneol (C 10 H 18 O) shall not be less than 85%, L-camphor shall not exceed 10%, and isoborneol shall not exceed 5%; D-borneol of natural borneol, D-borneol (C 10 H 18 O) should not be less than 96%, and L-camphor should not exceed 3%. It can be seen that no raw material content reaches more than 99.9%. On the other hand, according to the requirements of drugs (monomer components, chemical drugs), impurities with a content greater than 0.1% all need to understand their pharmacology and toxicology, etc., which is costly. Therefore, controlling the content of active ingredients to exceed 99.9% is a general requirement for chemical drugs. It is very important to develop high-purity borneol to meet the needs of modern pharmacy.

[0004] There are some studies on the preparation technology of high-purity borneol: "A method for preparing high-purity d-borneol" (CN201610164899.X), including the following process steps: 1) taking commercially available crude d-borneol and dissolving it in reagent A; 2) adding reagent B to the solution obtained in step 1); 3) adding reagent C to the solution obtained in step 2); 4) adding the solution obtained in step 3) to reagent D; 5) cooling and recrystallizing the solution obtained in step 4), filtering and drying, and obtaining high-purity d-borneol. The present invention avoids the use of flammable and explosive organic reagents with very low flash points, improves the safety of the present invention in actual operation, and has good application value; however, the technical operation steps are very complicated, the recycling of solvents is difficult to handle, and environmental protection issues are difficult to solve. "A refining process of natural borneol" (application number 201911023354.7), including: 1) collecting the branches and leaves of camphor camphor, washing and drying, and then crushing and sieving to obtain camphor camphor branch and leaf powder; 2) adding water to soak and co-distilling, condensing and crystallizing the fraction to obtain a crude extract of natural borneol; 3) adding methyl tert-butyl ether, stirring and dissolving to obtain a mixed solution A; 4) distilling to obtain anhydrous natural borneol; 5) adding petroleum ether, ultrasonically dissolving to obtain a mixed solution B; 6) sealing, refrigerating, recrystallizing, filtering, vacuum drying, and obtaining a pure natural borneol. The content of the refined right-handed camphor in the present invention is above 98.46%, and the recovery rate of methyl tert-butyl ether is above 86.7%; however, the purity of the product obtained by this technology still does not meet the requirements of modern pharmacy, and the purity and solvent recovery rate of the product are still not ideal. "A natural borneol extraction and refining process" (application number 202011195165.0), including the following steps: 1) take the crude brain raw material for cleaning, dehydration and drying; 2) place the raw material after cleaning in step 1) into a vacuum tank, evacuate the vacuum tank, and put the vacuum tank in a vacuum state; 3) fill the vacuum tank in step 2) with inert gas, and control the pressure in the vacuum tank, the range value is 0.005 to 0.02MPa; 4) computer controls the temperature in the vacuum tank, so that the tank top temperature in the vacuum tank is maintained at 50-90℃, the air pressure in the tank is controlled within 0.15MPa, and the time is controlled to 1-3h; 5) cool down, the temperature is maintained at 40-50℃, the vacuum tank is aired, reaches normal air pressure, opens the tank, and extracts the finished product. This method can obtain high-purity natural borneol (99%), but due to high vacuum and high temperature, the equipment requirements are very high, and the equipment investment is large; and the purity of the product is more than 95%, not reaching 99.9%. "Study on the preparation of high-purity natural d-borneol" (Song Yongfang, Luo Jialiang. Chemistry and Industry of Forest Products, 23(3):11, 2003) reported a process in which 70% to 80% crude d-borneol was obtained by steam distillation and sublimation using camphor tree branches and leaves as raw materials; and then recrystallization of borneol with a purity of more than 99% was achieved using different solvents (petroleum ether, ethyl acetate, ethanol, etc.).

[0005] The existing technologies are either complicated and have high solvent consumption; or the obtained products are not pure enough, especially it is difficult to separate L-borneol or D-borneol, and it is difficult to obtain high-purity (99.9%) L-borneol or D-borneol; or the investment is high; or there are environmental problems, the yield is not high, etc. Summary of the invention

[0006] In order to solve the problems in the prior art, the present invention provides a method for preparing high-purity d-borneol, which achieves the purpose of preparing high-purity d-borneol by combining "molecular eutectic technology" + "solvent recrystallization".

[0007] The present invention solves the technical problem by adopting the following technical solutions:

[0008] The present invention aims to provide a method for preparing high-purity d-borneol, comprising the following steps:

[0009] S1: The primary product of d-borneol is separated and purified by molecular eutectic method to obtain d-borneol No. 1;

[0010] S2: recrystallizing d-borneol No. 1 to obtain d-borneol No. 2;

[0011] S3: Recrystallize d-Borneol No. 2 again to obtain d-Borneol No. 3.

[0012] Further, the molecular eutectic method in S1 includes the following steps:

[0013] 1) Add eutectic material to the primary product of d-borneol, raise the temperature until the eutectic material is dissolved, and stir and mix thoroughly;

[0014] 2) Add n-octane, stir thoroughly, cool to precipitate crystals, and filter to separate the crystals;

[0015] 3) adding water and an organic solvent to the crystals, stirring thoroughly, standing for stratification, and recovering the solvent from the upper organic phase to obtain d-borneol No. 1.

[0016] Furthermore, the eutectic material is one of urea, malonic acid or piperazine.

[0017] Furthermore, the amount of the primary product of dextrorotatory borneol added is 1 part, the amount of the eutectic material added is 1 part, and the amount of n-octane added is 1-10 parts.

[0018] Further, the molecular eutectic method in S1 includes the following steps:

[0019] 1) Add 1 part of d-borneol primary product (d-borneol content less than 80%) obtained by steam distillation of borneol camphor tree branches and leaves to 1 part of eutectic material, heat until the eutectic material is dissolved, and stir and mix thoroughly for 1-10 hours;

[0020] 2) Add 1-10 parts of n-octane, stir thoroughly, cool to below 5°C to precipitate crystals for 1-10 hours, and filter and separate the crystals;

[0021] 3) Add 1-10 times of water to the crystals, add 1-10 times of organic solvent, stir thoroughly, let stand for 1-10 hours, recover the solvent from the upper organic phase, and obtain D-borneol No. 1. D-borneol No. 1 contains more than 90%; the yield of D-borneol is more than 95%.

[0022] Furthermore, the organic solvent is one or two of petroleum ether, n-hexane, n-octane and n-decane.

[0023] Further, the recrystallization of d-borneol No. 1 in S2 comprises the following steps:

[0024] 1) D-borneol No. 1 is mixed with 1-10 times the amount of solvent, heated to fully dissolve; filtered, the filtrate is cooled to below 5°C, and crystallized for 1-3 days; filtered to obtain D-borneol No. 2; No. 2 contains more than 99% D-borneol; the yield of D-borneol is more than 100% (the residue will not take away D-borneol and cause loss)

[0025] 2) After the remaining mother liquor is solvent recovered, the residue is used for the molecular eutectic method in S1 to recover d-borneol.

[0026] Further, the recrystallization of d-borneol No. 2 in S3 comprises the following steps:

[0027] 1) D-borneol No. 2 is mixed with 1-10 times the amount of solvent, heated to fully dissolve; filtered, the filtrate is cooled to below 5° C., and crystallized for 1-3 days; filtered to obtain D-borneol No. 3; No. 3 contains more than 99.9% of D-borneol; the yield of D-borneol is more than 100% (the residue will not take away the D-borneol and cause loss).

[0028] 2) The remaining mother liquor, after recovering the solvent, the residue is used for the recrystallization of d-borneol in S2 to recover d-borneol.

[0029] Furthermore, the solvents in S2 and S3 are one or two of ethanol, isopropanol, ethyl acetate, petroleum ether, n-hexane, n-octane, n-decane, and ethyl isobutyl ether.

[0030] Compared with the prior art, the beneficial technical effects of the present invention are:

[0031] 1. Impurities in d-borneol include "l-camphor" and "isoborneol", which have similar molecular weights, boiling points, and various physical and chemical parameters, but different spatial conformations. The present invention utilizes "molecular eutectic technology" to selectively extract and recycle d-borneol, thereby ensuring the extraction purity and yield of d-borneol. The purity of No. 1 d-borneol is greater than 90%; the yield of No. 1 d-borneol is more than 95%.

[0032] 2. The method for preparing high-purity d-borneol of the present invention mainly comprises the combination of molecular eutectic technology and recrystallization technology, and the method is simple, efficient, low-cost and easy to industrialize. The purity of the high-purity d-borneol prepared by the present invention can reach more than 99.9%, and the yield can reach more than 95%, which is a high-quality raw material for preparing high-quality downstream products. It meets the requirements of modern pharmacy for high-purity d-borneol. The dual purpose of greatly improving the purity and yield of d-borneol is achieved.

[0033] 3. The mother liquor residue from the third crystallization is used for the second recrystallization, and the mother liquor residue from the second crystallization is used for molecular eutectic, which is recycled to ensure the recovery rate of d-borneol and greatly reduce the cost of high-purity d-borneol.

[0034] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention, it can be implemented in accordance with the contents of the specification. In order to make the above contents of the present invention and its objectives, features and advantages more obvious and easy to understand, the specific implementation methods of the present invention are listed below. DETAILED DESCRIPTION

[0035] The technical solution of the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary illustrations and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0036] In addition, unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0037] Example 1: Preparation of high-purity d-borneol

[0038] The specific steps are as follows:

[0039] 1. Preparation of D-Borneol No. 1:

[0040] 1 kg of commercially available d-borneol primary product (d-borneol content 50%) was added with 1 kg of urea, heated to liquid phase, and fully stirred and mixed for 1 hour; 1 kg of n-octane was added, fully stirred and mixed, cooled to 5 ° C, left to stand for 1 hour, and 0.771 kg of precipitation was separated; 0.771 kg of water was added, 0.771 kg of petroleum ether was added, fully mixed, left to stand for 1 hour, and the upper organic phase was separated; the organic solvent was recovered to obtain 527.4 g of d-borneol No. 1. Gas chromatography analysis showed that No. 1 contained 91.10% d-borneol; the yield of d-borneol was 96.0%.

[0041] 2. Preparation of D-Borneol No. 2:

[0042] 100 mL of n-octane was added to 100 g of d-borneol No. 1, fully dissolved, filtered, the filtrate was cooled to 5 ° C, and crystallized for 1 day; filtered, the crystals were dried at 80 ° C, and 78.6 g of d-borneol No. 2 was obtained; after the mother liquor recovered the solvent, it was used to return to the previous step to prepare d-borneol No. 1. Gas chromatography analysis showed that No. 2 contained more than 99.10% d-borneol; the yield of d-borneol was 85.5% (because the residue was returned to the previous step for reuse, the actual yield was 100%).

[0043] 3. Preparation of D-Borneol No. 3:

[0044] 1000mL of ethyl isobutyl ether was added to 100g of d-borneol No. 2, and the temperature was raised to fully dissolve; filtered, the filtrate was cooled to 0°C, and crystallized for 3 days; filtered, the product was dried at 60°C, and 87.3g of d-borneol No. 3 was obtained; after the mother liquor recovered the solvent, the residue was used for "d-borneol recrystallization" to recover d-borneol. Gas chromatography analysis showed that No. 3 contained 99.91% d-borneol; the yield of d-borneol was 88.0% (because the residue was returned to the previous step for reuse, the actual yield was 100%).

[0045] Example 2: Preparation of high-purity d-borneol

[0046] The specific steps are as follows:

[0047] 1. Preparation of D-Borneol Product No. 1:

[0048] 1 kg of commercially available d-borneol primary product (d-borneol content 70%) was added with 1 kg of malonic acid, heated to liquid phase, and fully stirred and mixed for 10 hours; 10 kg of n-octane was added, fully stirred and mixed, cooled to -10 ° C, left stand for 10 hours, and 1.303 kg of precipitation was separated; 13.03 kg of water was added, 13.03 kg of n-hexane was added, fully mixed, left stand for 10 hours, and the upper organic phase was separated; the organic solvent was recovered to obtain 745.0 g of d-borneol No. 1. Gas chromatography analysis showed that No. 1 contained 91.23% d-borneol; the yield of d-borneol was 97.1%.

[0049] 2. Preparation of D-Borneol No. 2:

[0050] 1000 mL of ethyl acetate was added to 100 g of d-borneol No. 1, fully dissolved, filtered, and the filtrate was cooled to 0 ° C and crystallized for 3 days; filtered, the crystals were dried at 60 ° C to obtain 83.9 g of d-borneol No. 2; after the mother liquor recovered the solvent, it was used to return to the previous step to prepare d-borneol No. 1. Gas chromatography analysis showed that No. 2 contained more than 99.02% d-borneol; the yield of d-borneol was 91.1% (because the residue was returned to the previous step for reuse, the actual yield was 100%).

[0051] 3. Preparation of D-Borneol No. 3:

[0052] 100 mL of n-decaned alkane was added to 100 g of d-borneol No. 2, and the temperature was raised to fully dissolve; filtered, the filtrate was cooled to 5 ° C, and crystallized for 2 days; filtered, the product was dried at 60 ° C, and 86.7 g of d-borneol No. 3 was obtained; after the mother liquor recovered the solvent, the residue was used for "d-borneol recrystallization" to recover d-borneol. Gas chromatography analysis showed that No. 3 contained 99.92% d-borneol; the yield of d-borneol was 87.5% (because the residue was returned to the previous step for reuse, the actual yield was 100%).

[0053] Example 3: Preparation of high-purity d-borneol

[0054] The specific steps are as follows:

[0055] 1. Preparation of D-Borneol Product No. 1:

[0056] 1 kg of commercially available d-borneol primary product (d-borneol content 30%) was added with 1 kg of piperazine, heated to liquid phase, and stirred for 4 hours; 4 kg of n-octane was added, stirred for 5 hours, cooled to 0°C, and precipitated for 0.519 kg; 2.5 kg of water was added, 2.5 kg of n-octane was added, mixed thoroughly, and the upper organic phase was separated; the organic solvent was recovered to obtain 317.0 g of d-borneol No. 1. Gas chromatography analysis showed that No. 1 contained 90.01% d-borneol; the yield of d-borneol was 95.12%.

[0057] 2. Preparation of D-Borneol No. 2:

[0058] 100g of d-borneol No. 1 was added with 300mL of ethanol, fully dissolved, filtered, and the filtrate was cooled to 3°C and crystallized for 2 days; filtered, and the crystals were dried at 60°C to obtain 76.8g of d-borneol No. 2; after the mother liquor recovered the solvent, it was used to return to the previous step to prepare d-borneol No. 1. Gas chromatography analysis showed that No. 2 contained more than 99.03% d-borneol; the yield of d-borneol was 84.5% (because the residue was returned to the previous step for reuse, the actual yield was 100%).

[0059] 3. Preparation of D-Borneol No. 3:

[0060] 300mL of isopropanol was added to 100g of d-borneol No. 2, and the temperature was raised to fully dissolve; filtered, the filtrate was cooled to 4°C, and crystallized for 2 days; filtered, the product was dried at 60°C to obtain 89.1g of d-borneol No. 3; after the mother liquor recovered the solvent, the residue was used for "d-borneol recrystallization" to recover d-borneol. Gas chromatography analysis showed that No. 3 contained 99.90% d-borneol; the yield of d-borneol was 89.9% (because the residue was returned to the previous step for reuse, the actual yield was 100%).

[0061] Comparative Example 1 (Patent Technology: CN201610164899.X): A method for preparing high-purity d-borneol

[0062] Take 100g of commercially available crude d-borneol (purity 85%), and dissolve it in a mixed solution of 500g times the mass of p-methyl anisole and 2-chloroanisole; add 5g mass (the mass of crude d-borneol) of sodium borohydride to the above mixed solution, shake and mix, and let stand for 5 hours at 10°C; add 200 volumes of 2-ethylhexanoic acid to the reaction solution of step 2, shake and mix for half an hour, let stand for 1 hour, and extract the lower liquid phase; shake and mix the liquid phase separated in step 3 with 4 times the volume of n-heptanol for half an hour, let stand for 2 hours, and divide the lower liquid phase; the solution obtained in step 4 is cooled to -20°C, a large amount of flaky crystals are obtained, filtered, and dried to obtain high-purity d-borneol white crystals with a purity of 99.9%. Analyze the content and yield of d-borneol by gas chromatography.

[0063] Comparative Example 2 (Application No. 201911023354.7): A refining process of natural borneol

[0064] 10 kg of fresh borneol camphor leaves were collected and dried, and then crushed through a 20-mesh sieve to obtain borneol camphor leaf powder; 100 g of the borneol camphor leaf powder obtained in step (1) was added to 800 mL of water and soaked for 0.8 h, then placed in a distillation flask, and distilled at 95° C. for 2 h. The fraction was condensed and crystallized to obtain a crude extract of natural borneol (repeated multiple times to collect 10 g of the crude extract of natural borneol); 10 g of the crude extract of natural borneol obtained in step (2) was placed in a conical flask, 30 mL of methyl tert-butyl ether was added, and the mixture was stirred to dissolve to obtain a mixed solution A; the borneol obtained in step (3) was added to the flask, and the mixture was stirred to obtain a mixed solution A. The obtained mixed solution A is placed in a distillation flask, and distilled for 1.5 hours under a 60° C. water bath heating condition to recover methyl tert-butyl ether to obtain anhydrous natural borneol; 5 g of anhydrous natural borneol obtained in step (4) is added with 5 mL of petroleum ether, and 300 W ultrasonic treatment is performed for 8 minutes to assist in dissolution to obtain a mixed solution B; the mixed solution B obtained in step (5) is sealed and placed in a refrigerator, refrigerated at -4° C. for 20 hours, and filtered after recrystallization. The obtained crystalline product is placed in a vacuum drying oven, the vacuum degree is adjusted to 95 KPa, and the temperature is dried at 60° C. for 5 hours to obtain pure natural borneol.

[0065] Comparative Example 3:

[0066] 4 kg of n-octane was added to 1 kg of commercially available primary d-borneol product (d-borneol content 30%), and after sufficient stirring and mixing, it was cooled to 0°C, left to stand for 5 hours, filtered, and precipitated and dried at 60°C to obtain 222.8 g of d-borneol No. 1. Gas chromatography analysis showed that No. 1 contained 73.5% d-borneol; the yield of d-borneol was 54.6%. The preparation of d-borneol products No. 2 and No. 3 was the same as in Example 3.

[0067] Comparative Example 4:

[0068] 4 kg of n-octane was added to 1 kg of commercially available primary d-borneol product (d-borneol content 70%), and after sufficient stirring and mixing, it was cooled to 0°C, allowed to stand for 5 hours, filtered, and the precipitate was dried at 60°C to obtain 222.8 g of d-borneol No. 1. Gas chromatography analysis showed that No. 1 contained 86.45% d-borneol; the yield of d-borneol was 71.3%. The preparation of d-borneol products No. 2 and No. 3 was the same as in Example 3.

[0069] Comparative Example 5:

[0070] All operations were the same as in Example 3, and the eutectic material was 1 kg of oxalic acid.

[0071] Comparative Example 6:

[0072] All operations were the same as in Example 3, and the eutectic material was 1 kg of imidazole.

[0073] Comparative Example 7:

[0074] 1. Preparation of D-Borneol Product No. 1:

[0075] 1 kg of commercially available d-borneol primary product (d-borneol content 30%) was added with 1 kg of piperazine, heated to liquid phase, and stirred for 4 hours; 0.5 kg of n-octane was added, stirred for 5 hours, cooled to 10°C, and precipitated for 0.617 kg; 2.5 kg of water was added, 2.5 kg of n-octane was added, mixed thoroughly, and the upper organic phase was separated; the organic solvent was recovered to obtain 367.3 g of d-borneol No. 1. Gas chromatography analysis showed that No. 1 contained 78.85% d-borneol; the yield of d-borneol was 96.5%. The preparation of d-borneol No. 2 and No. 3 was exactly the same as in Example 3.

[0076] Comparative Example 8:

[0077] 1. Preparation of D-Borneol Product No. 1:

[0078] 1 kg of commercially available d-borneol primary product (d-borneol content 30%) was added with 1 kg of piperazine, heated to liquid phase, and fully stirred for 4 hours; then 20 kg of n-octane was added, fully stirred and mixed, cooled to 10°C, allowed to stand for 5 hours, and 0.501 kg of precipitate was separated; 2.5 kg of water was added, 2.5 kg of n-octane was added, fully mixed, allowed to stand for 5 hours, and the upper organic phase was separated; the organic solvent was recovered to obtain 303 g of d-borneol No. 1. Gas chromatography analysis showed that No. 1 contained 92.3% d-borneol; the yield of d-borneol was 93.2%. The preparation of d-borneol No. 2 and No. 3 was exactly the same as in Example 3.

[0079] Test Example 1: Preparation of d-borneol purity and recovery test

[0080] 1. Experimental Materials

[0081] Test drug 1: d-Borneol (No. 1, No. 2, No. 3) prepared according to the conditions of Example 1.

[0082] Test drug 2: d-Borneol (No. 1, No. 2, No. 3) prepared according to the conditions of Example 2.

[0083] Test drug 3: d-Borneol (No. 1, No. 2, No. 3) prepared according to the conditions of Example 3.

[0084] Control drug 1: Dextrorotatory borneol prepared according to patented technology (CN201610164899.X) according to comparative example 1.

[0085] Control drug 2: Patented technology (application number 201911023354.7) Dextrorotatory borneol prepared according to comparative example 2.

[0086] Control drug 3: a product prepared according to Comparative Example 3.

[0087] Control drug 4: a product prepared according to Comparative Example 4.

[0088] Control drug 5: a product prepared according to Comparative Example 5.

[0089] Control drug 6: a product prepared according to Comparative Example 6.

[0090] Control drug 7: a product prepared according to Comparative Example 7.

[0091] Control drug 8: a product prepared according to Comparative Example 8.

[0092] 2. Content analysis (Chinese Pharmacopoeia)

[0093]

Content determination

[0094] Chromatographic conditions and system suitability test: polyethylene glycol 20000 (PEG-20M) was used as the stationary phase, the coating concentration was 10%; the column temperature was 170° C. The theoretical plate number calculated based on the dextrorotatory borneol peak should not be less than 2000.

[0095] Preparation of reference solution: Take an appropriate amount of borneol reference, weigh accurately, and add ethyl acetate to make a solution containing 0.5 mg per ml.

[0096] Preparation of test solution: Take about 12.5 mg of the product, accurately weigh it, put it in a 25 ml volumetric flask, add ethyl acetate to dissolve and dilute to the scale, shake well, and you have it.

[0097] Determination method: Accurately pipette 1 μl of reference solution and test solution respectively, inject into gas chromatograph, and determine.

[0098] The changes of d-borneol content and yield of samples were detected by gas chromatography.

[0099] The effects of different preparation processes on the content of d-borneol were studied. The test results are shown in Table 1.

[0100] Table 1

[0101]

[0102]

[0103] As can be seen from the table, no matter how much the content of d-borneol in the starting material is, the d-borneol No. 1 obtained according to this preparation process has a content of about 90%; d-borneol No. 2 reaches about 99%; d-borneol No. 3 reaches more than 99.9% (experimental drugs 1, 2, 3); the yield of d-borneol exceeds 95%. The high-purity d-borneol obtained by the patented technology (CN201610164899.X) has a content of 99.9%, but the yield is significantly lower (comparative drug 1); the d-borneol obtained by the patented technology (application number 201911023354.7) has a content of 99.63%, which cannot reach more than 99.9% (comparative drug 2); the conventional technology is used to purify d-borneol, especially the d-borneol with a low content, not only the product purity is low, but also the yield is very low (comparative drug 3); for raw materials with a high content of d-borneol, the product purity and yield obtained by traditional crystallization technology are There has been some improvement, but there is still a big gap compared with the product purity and yield obtained by the "molecular co-crystal technology" (Comparative drug 4); using other co-crystal materials such as oxalic acid and imidazole, the increase in product purity is very small, which is basically consistent with the traditional crystallization method (Comparative drugs 5 and 6 compared with comparative drugs 3 and 4); when the amount of diluent (n-octane) added to the co-crystal system is too small, the yield of the product increases, but the purity is not enough (Comparative drug 7); when the amount of diluent (n-octane) added to the co-crystal system is too much, the purity of the product increases, but the yield is low (Comparative drug 8).

[0104] In summary, the technology of the present invention is obviously superior to other technologies.

[0105] Test Example 2: Safety Evaluation of D-Borneol

[0106] 1. Test materials

[0107] Test drug 1: d-borneol (No. 3) prepared according to the conditions of Example 1;

[0108] Test drug 2: d-borneol (No. 3) prepared according to the conditions of Example 2;

[0109] Test drug 3: d-borneol (No. 3) prepared according to the conditions of Example 3;

[0110] Control drug 1: Dextrorotatory borneol prepared according to comparative example 1 using patented technology (CN201610164899.X);

[0111] Control drug 2: patented technology (application number 201911023354.7) prepared according to comparative example 2;

[0112] 2. Experimental methods

[0113] Test method (according to the national new drug application test method): 60 Kunming mice, half male and half female, were randomly divided into six groups; after balanced feeding for 6 days, they were set aside; the drug was prepared with 1% Tween 80 aqueous solution as a 10% solution and gavaged: 1.0mL / mouse; the control group was gavaged with the same volume of distilled water. The toxic reactions and deaths of the animals were observed and recorded once every morning, and the weight gain was recorded after the drug was administered every day; the animals were killed on d14, and the tissues and organs were observed with the naked eye. The relevant tissues of those with obvious lesions were taken for pathological examination. The weight and diarrhea test results of the mice after oral administration of the drug are shown in Table 2.

[0114] Table 2

[0115] Group Dosage (g / Kg) 3-day weight (g) 14-day weight (g) Diarrhea rate (%) Blank group 0 23.53±2.11 28.34±3.44 0 Trial drug 1 10 23.21±2.71 28.42±3.51 0 Trial drug 2 10 23.24±2.73 28.45±3.57 0 Trial drug 3 10 23.31±2.72 28.43±3.52 0 Control drug 1 10 22.86±3.51 27.71±3.93 10 Comparative drug 2 10 22.71±3.61 27.11±3.32 20

[0116] The results showed that when the mice were given a dose of 10g / kg, no death was observed in any group of mice, and the activity of the mice was different, indicating that the safety was relatively high. Compared with the normal group, within 3 days after intragastric administration, the weight of the mice in the d-borneol group prepared by the present invention decreased slightly; after 14 days, the weight of the mice was exactly the same as that of the normal group (experimental drugs 1, 2, and 3). Compared with the normal group, within 3 days after intragastric administration, the weight of the mice in the d-borneol group prepared by the patented technology (CN201610164899.X) decreased slightly, but did not reach a significant level; after 14 days, the weight of the mice decreased slightly from the normal group, and one mouse had diarrhea (control drug 1); indicating that its safety is lower than that of the product prepared by this patented technology. Compared with the normal group, within 3 days after intragastric administration, the weight of mice in the d-borneol group prepared by the patented technology (application number 201911023354.7) decreased slightly, but not significantly; after 14 days, the weight of mice decreased more significantly than that of the normal group, and 2 mice also had diarrhea (control drug 2), indicating that its safety is significantly lower than that of the product prepared by this patented technology. It can be seen that the d-borneol prepared by this technology has higher purity and higher safety.

[0117] The serial numbers of the above embodiments of the present invention are only for description and do not represent the advantages or disadvantages of the embodiments.

[0118] The embodiments of the present invention are described above, but the present invention is not limited to the above-mentioned specific implementation modes. The above-mentioned specific implementation modes are merely illustrative and not restrictive. Under the guidance of the present invention, ordinary technicians in this field can also make many forms without departing from the scope of protection of the purpose of the present invention and the claims, which are all within the protection of the present invention.

Claims

1. A method for preparing high-purity d-borneol, characterized in that: The following steps are involved: S1: The primary product of d-borneol is separated and purified by molecular eutectic method to obtain d-borneol No. 1; S2: recrystallizing d-borneol No. 1 to obtain d-borneol No. 2; S3: Recrystallize d-Borneol No. 2 again to obtain d-Borneol No.

3.

2. A method for preparing high-purity d-borneol as claimed in claim 1, characterized in that: The molecular eutectic method in S1 includes the following steps: 1) Add eutectic material to the primary product of d-borneol, raise the temperature until the eutectic material is dissolved, and stir and mix thoroughly; 2) Add n-octane, stir thoroughly, cool to precipitate crystals, and filter to separate the crystals; 3) adding water and an organic solvent to the crystals, stirring thoroughly, standing for stratification, and recovering the solvent from the upper organic phase to obtain d-borneol No.

1.

3. A method for preparing high-purity d-borneol as claimed in claim 2, characterized in that: The eutectic material is one of urea, malonic acid or piperazine.

4. A method for preparing high-purity d-borneol as claimed in claim 2, characterized in that: The amount of the primary product of d-borneol added is 1 part, the amount of the eutectic material added is 1 part, and the amount of n-octane added is 1-10 parts.

5. A method for preparing high-purity d-borneol as claimed in claim 2, characterized in that: The molecular eutectic method in S1 includes the following steps: 1) Add 1 part of eutectic material to 1 part of commercially available or borneol primary product obtained by steam distillation of borneol camphor tree branches and leaves, heat until the eutectic material is dissolved, and stir and mix thoroughly for 1-10 hours; 2) Add 1-10 parts of n-octane, stir thoroughly, cool to below 5°C to precipitate crystals for 1-10 hours, and filter and separate the crystals; 3) Add 1-10 times of water to the crystals, add 1-10 times of organic solvent, stir thoroughly, let stand for 1-10 hours, recover the solvent from the upper organic phase, and obtain d-borneol No.

1.

6. A method for preparing high-purity d-borneol as claimed in claim 5, characterized in that: The organic solvent is one or two of petroleum ether, n-hexane, n-octane and n-decane.

7. A method for preparing high-purity d-borneol as claimed in claim 1, characterized in that: The recrystallization of d-borneol No. 1 in S2 comprises the following steps: 1) Mix d-borneol No. 1 with 1-10 times the amount of solvent, heat it up to fully dissolve it; filter, cool the filtrate to below 5° C., and crystallize it for 1-3 days; filter to obtain d-borneol No. 2; 2) After the remaining mother liquor is solvent recovered, the residue is used for the molecular eutectic method in S1 to recover d-borneol.

8. A method for preparing high-purity d-borneol as claimed in claim 7, characterized in that: The recrystallization of d-borneol No. 2 in S3 comprises the following steps: 1) Mix d-borneol No. 2 with 1-10 times the amount of solvent, heat it up to fully dissolve it; filter, cool the filtrate to below 5°C, and crystallize it for 1-3 days; filter to obtain d-borneol No. 3; 2) The remaining mother liquor, after recovering the solvent, the residue is used for the recrystallization of d-borneol in S2 to recover d-borneol.

9. A method for preparing high-purity d-borneol as claimed in claim 8, characterized in that: The solvents in S2 and S3 are one or two of ethanol, isopropanol, ethyl acetate, petroleum ether, n-hexane, n-octane, n-decane, and ethyl isobutyl ether.

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