A method for synthesizing borneol

Abstract

The present invention provides a method for synthesizing borneol, belonging to the field of drug synthesis. It is based on natural camphor as a starting material, (R) 2-methyl-CBS-oxazaborolidine as a chiral catalyst, borane dimethyl sulfide tetrahydrofuran as a reducing agent, and reacts and synthesizes borneol in an organic solvent, wherein the molar ratio of camphor, (R) 2-methyl-CBS-oxazaborolidine, and borane dimethyl sulfide tetrahydrofuran is: 328.44 parts of camphor, 16.42-295.59 parts of (R) 2-methyl-CBS-oxazaborolidine, and 328.44-591.18 parts of borane dimethyl sulfide tetrahydrofuran. The synthetic method of the present invention is based on the premise of using a small amount of chiral catalyst, and the reaction time is significantly shortened, the method has high reproducibility, strong scalability, stable yield and product quality is significantly better than the natural borneol quality standard.

Description

Technical Field

[0001] The invention relates to a method for synthesizing borneol, and belongs to the field of drug synthesis. Background Art

[0002] Borneol (also known as: borneol, orange slices, moxa slices, camphor, plum blossom borneol, kabu Luoxiang, plum blossom brain, borneol brain, plum ice, camphor, etc.), according to its different sources, is divided into natural borneol (D-borneol) and synthetic borneol. Borneol tastes pungent, bitter, and slightly cold; it enters the heart, liver, and lung meridians; it is fragrant and dispersing, and has the effects of opening the orifices and refreshing the mind, clearing away heat and dispersing toxins, and clearing the eyes and removing cataracts. It is mainly used to treat fever, high fever, coma, stroke, phlegm, convulsions, epilepsy, summer heat and dampness obstructing the orifices, throat paralysis and deafness, mouth sores and swollen teeth, sores, carbuncles, malnutrition, hemorrhoids, red and swollen eyes, and cataracts covering the eyes. For those with phlegm and fire stagnation, throat paralysis and hoarseness, or fire and heat stagnation, mouth sores and swollen teeth, borneol can be combined with cinnabar, borax, and Xuanming powder to blow and apply to the affected area to disperse fire and detoxify. For patients with heat-retention and coma, borneol can be used in combination with Chinese medicines such as musk, bezoar, coptis root, and curcuma to clear away heat and open the mind. In addition to being used in combination with Chinese medicines, borneol can also be used in combination with the chemical drug edaravone to form edaravone dexamethasone injection concentrated solution, etc., which is used to improve neurological symptoms, daily living activities, and functional disorders caused by acute ischemic stroke. Compared with single-ingredient edaravone injection, edaravone dexamethasone injection concentrated solution shows clear efficacy advantages, similar clinical safety, and the treatment time window is extended from 24h to 48h, which is of great significance for stroke treatment.

[0003] However, natural borneol raw materials are relatively difficult to obtain and expensive, which greatly increases the burden on patients; synthetic borneol starting materials are abundant, highly accessible, and inexpensive, but the technical difficulty of synthesizing high-quality borneol is very high (low conversion rate and low product purity, etc.), which can be seen from the Chinese Pharmacopoeia that synthetic borneol content ≥55% can meet medicinal use. The existing methods for synthesizing borneol mainly include camphor reduction method, a-pinene acidification saponification method, and hydration method.

[0004] Wang Helin [Journal of Materials Science and Engineering, 2017, 31 (11): 43-49 and Chemical Engineering, 2017, 45 (11): 7-11.] et al. discussed the solid superacid SO4 2- / Preparation of TiO2-Al2O3 catalyst and its catalytic synthesis of borneol. The results showed that the conversion rate of α-pinene was as high as 100%, the yield of borneol was only 59.74%, and SO4 2- / TiO2-Al2O3 cannot be obtained commercially, which limits its industrial application.

[0005] CN118239823A uses camphor as raw material, and obtains high-purity d-borneol after sulfonation reaction, reduction reaction, dehydration oxidation treatment, column purification treatment, splitting reaction, desulfonation reaction and hydrolysis reaction. The content of left-handed product in d-borneol is less than 1.0%, and isoborneol is not detected. This method involves multi-step derivatization, de-derivation, chiral splitting and column chromatography, etc., which is cumbersome to operate and the overall yield is not high, affecting its overall cost.

[0006]

[0007] Zhao Peng et al. from Huaqiao University [Journal of Huaqiao University (Natural Science Edition), 2010, 31 (6): 671-673] reported on the asymmetric reduction of camphor in an alkali metal / THF (tetrahydrofuran) system. After a series of process optimizations, the camphor conversion rate was about 93%, and the yield of dextrorotatory borneol was only about 72%. The quality of the product was not mentioned in the article.

[0008]

[0009] Huang Yingfen of Huaqiao University used a secondary reduction process of metal sodium / anhydrous ethanol system in her master's thesis "Synthesis of dextrorotatory borneol by asymmetric reduction of natural camphor powder". After secondary reduction, the camphor conversion rate and borneol yield were greatly improved, among which the camphor conversion rate can reach about 98% and the borneol yield can reach about 81%. However, the whole operation process is relatively complicated, and there are certain limitations for industrial application, and high-quality synthetic borneol has not been obtained. In the article, Huang Yingfen discussed in detail the method of asymmetric reduction of ketones to alcohols, pointing out that the asymmetric catalytic reduction of carbonyl compounds using oxazaboridine is one of the most effective means of similar reactions. Among them, a series of catalysts studied by Corey et al. [J.Am.Chem.Soc.1987, 109,5551-5553], Marthre DJ et al. [Journal of Organic Chemistry. 1991, 56(2): 751-762.], Midland MM et al. [Journal of Organic Chemistry. 1992, 57(10): 2953-2956.] and Jiang YZ et al. [Tetrahedron Asymmetry. 1994, 5(7): 1211-1214.] are highlighted, including:

[0010]

[0011] CN 119039104A introduces a method for reducing right-rotating camphor in the presence of (R)-2-methyl-CBS-oxazaborol; wherein the reducing agent for reducing right-rotating camphor is a negative hydrogen compound of boron, and a product with a DR value of ≥98.5% is prepared, and then right-borneol with a purity of ≥98.5% can be obtained by recrystallization. The enantiomer in the product prepared by this method, i.e., left-rotating borneol>0.5%, and the amount of expensive chiral catalyst is large, and the price of (R)-2-methyl-CBS-oxazaborol is expensive, about 2,600 yuan / 500g. Summary of the invention

[0012] The invention provides a method for synthesizing borneol. The method mainly uses natural camphor as a starting material and reduces it in the presence of a chiral catalyst to obtain a crude borneol product, and the crude product is further recrystallized to prepare a synthetic borneol.

[0013] The invention provides a method for synthesizing borneol, which uses natural camphor as a starting material, (R)-2-methyl-CBS-oxazaborolidine as a chiral catalyst, and borane dimethyl sulfide tetrahydrofuran as a reducing agent to react and synthesize borneol in an organic solvent, wherein the molar ratio of camphor, (R)-2-methyl-CBS-oxazaborolidine, and borane dimethyl sulfide tetrahydrofuran is:

[0014] 328.44 parts of camphor, 16.42-295.59 parts of (R)-2-methyl-CBS-oxazaborolidine, and 328.44-591.18 parts of borane dimethyl sulfide tetrahydrofuran.

[0015] Preferably, the molar ratio of camphor, (R)-2-methyl-CBS-oxazaborolidine, and borane dimethyl sulfide tetrahydrofuran is:

[0016] 328.44 parts of camphor, 65.69 parts of (R)-2-methyl-CBS-oxazaborolidine, and 394.12 parts of borane dimethyl sulfide tetrahydrofuran.

[0017] The synthesis method of the present invention comprises the following steps:

[0018] a. Weigh the starting materials, chiral catalysts and reducing agents in various molar ratios;

[0019] b. Add toluene to (R)-2-methyl-CBS-oxazaborolidine, place at -20°C, and add borane dimethyl sulfide tetrahydrofuran solution under nitrogen protection;

[0020] c. Add camphor-containing toluene solution at -20°C and keep the temperature to react for 30 minutes;

[0021] d. quenching reaction;

[0022] e. Purification: After quenching, adjust the pH of the reaction solution to 1-2 with hydrogen chloride ethyl acetate solution at 0°C to precipitate solid, stir at room temperature and filter, concentrate the filtrate to obtain a dry product; then add an alkane solvent, heat until the solution is clear, stir at room temperature to crystallize, filter, and dry the filter cake under reduced pressure; then add ethanol or acetone to the dry product at room temperature to dissolve it, then add pure water, pulp, filter, and vacuum dry the filter cake to obtain borneol.

[0023] Wherein, in step b, 4.55-81.93 g of (R)-2-methyl-CBS-oxazaborolidine is added to every 500 mL of toluene; in step c, 50 g of camphor is added to every 500 mL of toluene.

[0024] Wherein, the alkane solvent described in step e is cyclohexane or methylcyclopentane, 2-methylpentane, or 3-methylpentane.

[0025] Beneficial effects of the present invention:

[0026] a: The product quality is significantly higher than that reported in the literature, i.e., the relevant substances are all less than 0.1%, and the enantiomers are less than 0.1%.

[0027] b: The amount of chiral catalyst used is small and the reaction time is short, the overall cost is lower, and it is more patient-friendly.

[0028] c: This method is easy to operate, has strong process reproducibility, high yield, low overall cost, and stable and reliable product quality.

[0029] The borneol prepared by the synthesis method of the present invention can have a purity of more than 99.9%, and the product quality (DR value ≥ 99.5%, purity ≥ 99.5% and single impurity less than 0.1%, enantiomer ≤ 0.1% (natural borneol pharmacopoeia standard ≤ 0.5%)) is significantly better than natural borneol. The synthesis method of the present invention, under the premise of using a small amount of chiral catalyst, significantly shortens the reaction time, has high reproducibility, strong scalability, stable yield and the product quality is significantly better than the quality standard of natural borneol. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 GC spectrum of related substances in the borneol synthesized in Example 1;

[0031] Figure 2 GC spectrum of the isomers of borneol synthesized in Example 1;

[0032] Figure 3 GC spectrum of related substances in borneol synthesized in Example 2;

[0033] Figure 4 GC spectrum of the isomers of borneol synthesized in Example 2;

[0034] Figure 5 This is the GC spectrum of related substances in the borneol synthesized in Example 3;

[0035] Figure 6 This is the GC spectrum of the isomers of borneol synthesized in Example 3;

[0036] Figure 7 This is the GC spectrum of related substances in the borneol synthesized in Example 4;

[0037] Figure 8 GC spectrum of the isomers of borneol synthesized in Example 4;

[0038] Fig. 9 This is the GC spectrum of related substances in the borneol synthesized in Example 5;

[0039] Fig.10 This is the GC spectrum of the isomers of borneol synthesized in Example 5;

[0040] Fig.11 The GC spectrum of related substances in the borneol synthesized in Comparative Example 1;

[0041] Fig.12 The GC spectrum of the isomers of borneol synthesized in Comparative Example 1;

[0042] Fig.13 GC spectrum of related substances in borneol synthesized in Comparative Example 2;

[0043] Fig.14 This is the GC spectrum of the isomers in borneol synthesized in Comparative Example 2. DETAILED DESCRIPTION

[0044] Example 1 Synthesis method of borneol of the present invention

[0045]

[0046] Add 18.21 g (65.69 mmol, 0.20 equiv.) of (R)-2-methyl-CBS-oxazaborolidine to a reaction bottle, add 500 mL of toluene (10 V / m), place at -20°C, add 197.06 mL (394.12 mmol, 1.20 equiv.) of borane dimethyl sulfide tetrahydrofuran solution (2M) under nitrogen protection, add 500 mL (10 V / m) of toluene solution of 50.00 g camphor (328.44 mmol, 1.00 equiv.) at -20°C, keep the temperature for reaction for 30 min, monitor the reaction by TLC, and add 100 mL of methanol to quench the reaction (control the reaction temperature <-15°C during quenching). After quenching, the pH of the reaction solution was adjusted to 1-2 with a hydrogen chloride ethyl acetate solution (2M) at 0°C to precipitate a solid. The solid was stirred at room temperature for 1 h and then filtered. The filtrate was concentrated to obtain a dry product. Then, 200 mL (4V / m) of cyclohexane was added and the mixture was heated until the solution was clear. The mixture was stirred at room temperature for 2 h and filtered. The filter cake was dried under reduced pressure. 50 mL of ethanol (1V / m) was added to the dry product at room temperature to dissolve it. Then, 200 mL of pure water (4V / m) was added and the mixture was slurried at room temperature and filtered. The filter cake was dried under vacuum at 40°C to obtain 48.21 g of the product (yield 95.16%) with a purity of 99.984% (see Table 1, Figure 1 , isoborneol 0.016%), L-borneol 0.012% (see Table 2, Figure 2 ).

[0047] Reference for the purity of the product of the present invention and the determination of the contents of isoborneol and borneol therein: Gao Wenfen et al., Separation and content determination of borneol enantiomers in Xingnaojing injection by gas chromatography, Journal of Pharmaceutical Analysis, 2012, 32 (5).

[0048] Test results:

[0049] 1 H NMR (400 MHz, DMSO- d 6) δ 4.46 (d, J = 4.8 Hz, 1H), 3.87 – 3.75 (m,1H), 2.17 – 2.06 (m, 1H), 2.00 – 1.88 (m, 1H), 1.69 – 1.59 (m, 1H), 1.54 (t, J = 4.6 Hz, 1H), 1.20 – 1.04 (m, 2H), 0.88 – 0.80 (m, 7H), 0.77 (s, 3H). 13 C NMR (101 MHz, DMSO- d6) δ 75.27, 49.48, 47.76, 45.05, 38.95, 28.47, 26.21, 20.58,19.06, 13.92.

[0050] Table 1 GC spectrum characteristic peak information of related substances in borneol

[0051]

[0052] Table 2 Characteristic peak information of GC spectrum of isomers in borneol obtained by the method of this embodiment

[0053]

[0054] Example 2 Synthesis method of borneol of the present invention

[0055] 4.55 g (16.42 mmol, 0.05 equiv.) of (R)-2-methyl-CBS-oxazaborolidine was added to the reaction bottle, and 500 mL of toluene (10 V / m) was added. The reaction was placed at -20°C, and 295.59 mL (591.18 mmol, 1.80 equiv.) of borane dimethyl sulfide tetrahydrofuran solution (2M) was added under nitrogen protection. At -20°C, 500 mL (10 V / m) of toluene solution of 50.00 g camphor (328.44 mmol, 1.00 equiv.) was added. The temperature was maintained for 45 min. The reaction was completed by TLC monitoring, and 100 mL of methanol was added to quench the reaction (the reaction temperature was controlled to be <-15°C during quenching). After quenching, the pH of the reaction solution was adjusted to 1-2 with hydrogen chloride ethyl acetate solution (2M) at 0°C to precipitate solids. The solids were stirred at room temperature for 1 h and then filtered. The filtrate was concentrated to obtain a dry product. Then, 200 mL of methylcyclopentane (4V / m) was heated until the solution was clear, and the mixture was stirred at room temperature for 2 h for crystallization and filtered. The filter cake was dried under reduced pressure. 50 mL of ethanol (1V / m) was added to the dry product at room temperature to dissolve it. Then, 200 mL of pure water (4V / m) was added, and the mixture was slurried at room temperature and filtered. The filter cake was dried under vacuum at 40°C to obtain 46.95 g of the product (yield 92.67%) with a purity of 99.957% (see Table 3, Figure 3 , isoborneol 0.043%), L-borneol 0.013% (see Table 4, Figure 4 ).

[0056] Table 3 GC spectrum characteristic peak information of related substances in borneol

[0057]

[0058] Table 4 Characteristic peak information of GC spectrum of isomers in borneol

[0059]

[0060] Example 3 Synthesis method of borneol of the present invention

[0061] 9.10 g (32.84 mmol, 0.10 equiv.) of (R)-2-methyl-CBS-oxazaborolidine was added to a reaction bottle, and 500 mL of toluene (10 V / m) was added. The reaction was placed at -20°C, and 295.59 mL (591.18 mmol, 1.80 equiv.) of borane dimethyl sulfide tetrahydrofuran solution (2M) was added under nitrogen protection. At -20°C, 500 mL (10 V / m) of toluene solution of 50.00 g camphor (328.44 mmol, 1.00 equiv.) was added. The temperature was maintained for 45 min. The reaction was completed by TLC monitoring, and 100 mL of methanol was added to quench the reaction (the reaction temperature was controlled to be <-15°C during quenching). After quenching, the pH of the reaction solution was adjusted to 1-2 with hydrogen chloride ethyl acetate solution (2M) at 0°C to precipitate solids. The solids were stirred at room temperature for 1 h and then filtered. The filtrate was concentrated to obtain a dry product. Then, 200 mL of 2-methylpentane (4V / m) was added and heated until the solution was clear. The mixture was stirred at room temperature for 2 h and filtered. The filter cake was dried under reduced pressure. 50 mL of acetone (1V / m) was added to the dry product at room temperature to dissolve it. Then, 200 mL of pure water (4V / m) was added, and the mixture was slurried at room temperature and filtered. The filter cake was dried under vacuum at 40°C to obtain 46.88 g of the product (yield 92.53%) with a purity of 99.953% (see Table 5, Figure 5 , isoborneol 0.047%), L-borneol 0.035% (see Table 6, Figure 6 ).

[0062] Table 5 GC spectrum characteristic peak information of related substances in borneol

[0063]

[0064] Table 6 Characteristic peak information of GC spectrum of isomers in borneol

[0065]

[0066] Example 4 Synthesis method of borneol of the present invention

[0067] Add 36.41 g (32.84 mmol, 0.40 equiv.) of (R)-2-methyl-CBS-oxazaborolidine to a reaction bottle, add 500 mL of toluene (10 V / m), place at -20°C, add 164.22 mL (328.44 mmol, 1.00 equiv.) of borane dimethyl sulfide tetrahydrofuran solution (2M) under nitrogen protection, add 500 mL (10 V / m) of toluene solution of 50.00 g camphor (328.44 mmol, 1.00 equiv.) at -20°C, keep the temperature for 15 min, monitor the reaction by TLC, and add 100 mL of methanol to quench the reaction (control the reaction temperature <-15°C during quenching). After quenching, the pH of the reaction solution was adjusted to 1-2 with hydrogen chloride ethyl acetate solution (2M) at 0°C to precipitate solids. The solids were stirred at room temperature for 1 h and then filtered. The filtrate was concentrated to obtain a dry product. Then 300 mL of 3-methylpentane (6V / m) was added and heated until the solution was clear. The mixture was stirred at room temperature for 2 h and filtered. The filter cake was dried under reduced pressure. 50 mL of ethanol (1V / m) was added to the dry product at room temperature to dissolve it. Then 200 mL of pure water (4V / m) was added and the mixture was slurried at room temperature and filtered. The filter cake was dried under vacuum at 40°C to obtain 48.00 g of the product (yield 94.75%) with a purity of 99.954% (see Table 7, Figure 7 , isoborneol 0.046%), L-borneol 0.015% (see Table 8, Figure 8 ).

[0068] Table 7 GC spectrum characteristic peak information of related substances in borneol

[0069]

[0070] Table 8 Characteristic peak information of GC spectrum of isomers in borneol

[0071]

[0072] Example 5 Synthesis method of borneol of the present invention

[0073] 81.93 g (295.59 mmol, 0.90 equiv.) of (R)-2-methyl-CBS-oxazaborolidine was added to a reaction bottle, and 500 mL of toluene (10 V / m) was added. The reaction was placed at -20°C, and 164.22 mL (328.44 mmol, 1.00 equiv.) of borane dimethyl sulfide tetrahydrofuran solution (2M) was added under nitrogen protection. At -20°C, 500 mL (10 V / m) of toluene solution of 50.00 g camphor (328.44 mmol, 1.00 equiv.) was added. The temperature was maintained for 15 min. The reaction was completed by TLC monitoring, and 100 mL of methanol was added to quench the reaction (the reaction temperature was controlled to be <-15°C during quenching). After quenching, the pH of the reaction solution was adjusted to 1-2 with hydrogen chloride ethyl acetate solution (2M) at 0°C to precipitate solids. The solids were stirred at room temperature for 1 h and then filtered. The filtrate was concentrated to obtain a dry product. Then, 100 mL of cyclohexane (2V / m) was added and heated until the solution was clear. The mixture was stirred at room temperature for 2 h and filtered. The filter cake was dried under reduced pressure. 50 mL of acetone (1V / m) was added to the dry product at room temperature to dissolve it. Then, 200 mL of pure water (4V / m) was added, and the mixture was slurried at room temperature and filtered. The filter cake was dried under vacuum at 40°C to obtain 47.41 g of the product (yield 93.58%) with a purity of 99.974% (see Table 9, Fig. 9 , isoborneol 0.026%), L-borneol 0% (see Table 10, Fig.10 ).

[0074] Table 9 GC spectrum characteristic peak information of related substances in borneol

[0075]

[0076] Table 10 Characteristic peak information of GC spectrum of isomers in Borneol

[0077]

[0078] Comparative Example 1

[0079] 50.00 g (328.44 mmol, 1.00 equiv.) of camphor was added to the reaction flask, and 1000 mL of toluene (20 V / m) was added under nitrogen protection. 18.21 g (65.69 mmol, 0.20 equiv.) of (R)-2-methyl-CBS-oxazaborolidine was added to the reaction flask at -20°C, and then 197.06 mL (394.12 mmol, 1.20 equiv.) of borane dimethyl sulfide tetrahydrofuran solution (2M) was added, and the temperature was maintained for 30 min. The reaction was monitored by TLC. If there was camphor raw material remaining, the reaction was continued for 2 h. The reaction was completed by TLC monitoring, and 100 mL of methanol was added to quench the reaction (the reaction temperature was controlled to be <-15°C during quenching). After quenching, the pH of the reaction solution was adjusted to 1-2 with hydrogen chloride ethyl acetate solution (2M) at 0°C to precipitate solids. The solids were stirred at room temperature for 1 h and then filtered. The filtrate was concentrated to obtain a dry product. Then, 200 mL of cyclohexane (4V / m) was added and heated until the solution was clear. The mixture was stirred at room temperature for 2 h and filtered. The filter cake was dried under reduced pressure. 50 mL of ethanol (1V / m) was added to the dry product at room temperature to dissolve it. Then, 200 mL of pure water (4V / m) was added and the mixture was slurried at room temperature and filtered. The filter cake was dried under vacuum at 40°C to obtain 43.33 g of the product (yield 85.83%) with a purity of 95.325% (see Table 11, Fig.11 , isoborneol 4.546%), L-borneol 0% (see Table 12, Fig.12 ).

[0080] Experiments have shown that changing the order of adding camphor and the catalyst reducing agent will affect the purity of the final product.

[0081] Table 11 GC spectrum characteristic peak information of related substances in borneol

[0082]

[0083] Table 12 Characteristic peak information of GC spectrum of isomers in borneol

[0084]

[0085] Comparative Example 2

[0086] Add 91.03 g (328.44 mmol, 1.00 equiv.) of (R)-2-methyl-CBS-oxazaborolidine into a reaction bottle, add 500 mL of toluene (10 V / m), place at -20°C, add 197.06 mL (394.12 mmol, 1.20 equiv.) of borane dimethyl sulfide tetrahydrofuran solution (2M) under nitrogen protection, add 500 mL (10 V / m) of toluene solution of 50.00 g camphor (328.44 mmol, 1.00 equiv.) at -20°C, keep the temperature for reaction for 30 min, monitor the reaction by TLC, and add 100 mL of methanol to quench the reaction (control the reaction temperature <-15°C during quenching). After quenching, the pH of the reaction solution was adjusted to 1-2 with hydrogen chloride ethyl acetate solution (2M) at 0°C to precipitate solids. The solids were stirred at room temperature for 1 h and then filtered. The filtrate was concentrated to obtain a dry product. Then, 200 mL (4V / m) of cyclohexane was added and the mixture was heated until the solution was clear. The mixture was stirred at room temperature for 2 h and filtered. The filter cake was dried under reduced pressure. 50 mL of ethanol (1V / m) was added to the dry product at room temperature to dissolve it. Then, 200 mL of pure water (4V / m) was added and the mixture was slurried at room temperature and filtered. The filter cake was dried under vacuum at 40°C to obtain 45.02 g of the product (yield 88.86%) with a purity of 99.670% (see Table 13, Fig.13 , isoborneol 0.043%), L-borneol 0.160% (see Table 14, Fig.14 ).

[0087] Experiments have shown that when the amount of chiral catalyst used exceeds the scope of the present invention, and when the post-treatment is consistent with the embodiment after half an hour of reaction, the product obtained will have a low yield.

[0088] Table 13 GC spectrum characteristic peak information of related substances in borneol

[0089]

[0090] Table 14 Characteristic peak information of GC spectrum of isomers in borneol

[0091]

Claims

1. A method for synthesizing borneol, characterized in that: The method uses natural camphor as a starting material, (R)-2-methyl-CBS-oxazaborolidine as a chiral catalyst, and borane dimethyl sulfide tetrahydrofuran as a reducing agent, and reacts in an organic solvent to synthesize borneol, wherein the molar ratio of camphor, (R)-2-methyl-CBS-oxazaborolidine, and borane dimethyl sulfide tetrahydrofuran is: 328.44 parts of camphor, 16.42-295.59 parts of (R)-2-methyl-CBS-oxazaborolidine, and 328.44-591.18 parts of borane dimethyl sulfide tetrahydrofuran; It includes the following steps: a. Weigh the starting materials, chiral catalysts and reducing agents in various molar ratios; b. Add toluene to (R)-2-methyl-CBS-oxazaborolidine, place at -20°C, and add borane dimethyl sulfide tetrahydrofuran solution under nitrogen protection; c. Add camphor-containing toluene solution at -20°C and keep the temperature to react for 30 minutes; d. quenching reaction; e. Purification: After quenching, adjust the pH of the reaction solution to 1-2 with hydrogen chloride ethyl acetate solution at 0°C to precipitate solid, stir at room temperature and filter, concentrate the filtrate to obtain a dry product; then add an alkane solvent, heat until the solution is clear, stir at room temperature to crystallize, filter, and dry the filter cake under reduced pressure; then add ethanol or acetone to the dry product at room temperature to dissolve it, then add pure water, pulp, filter, and vacuum dry the filter cake to obtain borneol.

2. The method for synthesizing borneol according to claim 1, characterized in that: The molar ratio of camphor, (R)-2-methyl-CBS-oxazaborolidine and borane dimethyl sulfide tetrahydrofuran is: 328.44 parts of camphor, 65.69 parts of (R)-2-methyl-CBS-oxazaborolidine, and 394.12 parts of borane dimethyl sulfide tetrahydrofuran.

3. The method for synthesizing borneol according to claim 1 or 2, characterized in that: The method comprises the following steps: in step b, 4.55-81.93 g of (R)-2-methyl-CBS-oxazaborolidine is added to every 500 mL of toluene; and in step c, 50 g of camphor is added to every 500 mL of toluene.

4. The method for synthesizing borneol according to claim 1 or 2, characterized in that: The method comprises the following steps: the alkane solvent described in step e is cyclohexane or methylcyclopentane, 2-methylpentane or 3-methylpentane.

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