A method for the chemical preparation of pharmaceutical grade dextrohydrotalcid
By employing the Noyori asymmetric hydrogenation method and recrystallization technology, the problems of difficult raw material acquisition, high cost, severe pollution, and low purity in the synthesis of dexborneol have been solved, enabling the efficient preparation and industrial production of high-purity dexborneol.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- NANJING CORE TECH CO LTD
- Filing Date
- 2024-12-30
- Publication Date
- 2026-06-30
AI Technical Summary
Existing technologies for synthesizing dextroborneol suffer from problems such as difficulty in obtaining raw materials, high production costs, serious pollution, low yield, and low product purity, making it difficult to achieve industrial-scale production.
The Noyori asymmetric hydrogenation method was adopted, using ruthenium metal as a catalyst to asymmetricly reduce camphor in the presence of phosphine ligands. Subsequently, a silicon-oxygen bond was formed through trimethylchlorosilane, and the isomers were removed by recrystallization. Finally, high-purity dexborneol was prepared under hydrochloric acid conditions.
This method enables the efficient preparation of dextroborneol, improves product purity, simplifies separation steps, reduces production costs, minimizes environmental pollution, and is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical product synthesis, specifically relating to a chemical preparation method of pharmaceutical-grade dexborneol. Technical Background
[0002] Borneol, also known as camphor or borneol, is classified into natural and synthetic borneol based on its source. Natural borneol is currently available in commercially available perfumes. Borneol is further classified by its optical rotation into dextrorotatory borneol (borneol) and levorotatory borneol (borneol), while synthetic borneol is a mixture of borneol and isoborneol. Natural dextrorotatory borneol (d-Bormeol) has been a precious medicinal material and a valuable spice since ancient times, widely used in medicine, and research on its applications continues. Dextrorotatory borneol has superior anti-inflammatory and analgesic effects compared to levorotatory and racemic borneol, and its aroma rating in borneol aroma assessment is far higher than other borneol products. Currently, natural dextrorotatory borneol is extracted from plants, resulting in a single source and high price; therefore, finding new sources of dextrorotatory borneol is of great value.
[0003] 1. Camphor Synthesis Method
[0004]
[0005] The process for synthesizing borneol is relatively direct, starting directly from camphor material and using a reduction method. However, the raw materials are difficult to obtain, and the reducing agent is an easily explosive reagent, which restricts its use and cannot be effectively recycled, resulting in waste and pollution, and thus it has not been applied to production. Secondly, the product needs to be separated to obtain the desired dextrorotatory borneol, resulting in a low yield.
[0006] 2α-pinene direct hydration method
[0007]
[0008] Borneol can be produced by direct hydration of α-pinene. This method is relatively direct, but borneol often exists as a byproduct in the hydration reaction, with a content of only a few percent. At the same time, the byproducts produced by the reaction are numerous and difficult to separate and purify. There are also reports of using catalysts to improve the yield, but the yield improvement of borneol is still low, not exceeding 10%, and it is not suitable for industrialization.
[0009] 3. Decomposition method of organomagnesia
[0010]
[0011] The process is complex, involves lengthy synthesis steps, has high production costs, produces numerous byproducts, has poor quality, and is difficult to industrialize.
[0012] 4α-pinene esterification-saponification method
[0013]
[0014] Sodium hydroxide is used in the saponification process of this technology, which pollutes the environment, limits large-scale production, and is difficult to handle. 5 mol of sodium hydroxide needs to be treated for every 1 mol of borneol produced. In actual industrial production, 16 kg of wastewater is generated for every 1 kg of borneol produced. Raw material consumption is high and utilization rate is low. The use of acid can also cause equipment corrosion, which places high demands on the equipment and is often accompanied by the risk of material spillage and explosion. In addition, the quality of the borneol product is poor and contains many impurities.
[0015] 5. Solid strong acid catalyst method
[0016]
[0017] It requires calcination of the catalyst (600℃), has high catalytic efficiency, and is suitable for industrial mass production, but isomers still need to be separated.
[0018]
[0019] Using a self-made rare earth composite solid superacid SO42- / ZrO2-MoO3-Yb2O3 as a catalyst, camphene and acetic acid react to generate isoborneol acetate, which is then prepared under hydrolysis conditions to produce borneol.
[0020] Currently, the content of isoborneol in synthetic borneol on the market is between 35% and 45%. Through various purification methods (multiple extraction and crystallization, supercritical fluid extraction, etc.), synthetic borneol can achieve high purity, but the cost is high, making it unsuitable for raw pharmaceutical products. Synthetic borneol may contain the following four isomers, most of which are difficult to remove.
[0021] Summary of the Invention
[0022] To overcome the shortcomings of the above-mentioned routes, there is an urgent need to develop a method for the efficient preparation of dexborneol with high purity. Therefore, referring to the conventional asymmetric reduction method, the Noyori asymmetric hydrogenation was adopted to asymmetricly reduce camphor using ruthenium as a catalyst and phosphine ligands to prepare dexborneol and a small amount of the isomer isobathol. Then, under the action of trimethylchlorosilane, dexborneol can form a silicon-oxygen bond with TMS due to its spatial configuration, while isobathol cannot. Isobathol is removed by recrystallization to obtain the silyl ether protected compound of dexborneol. Dexborneol is then prepared under hydrochloric acid conditions and purified by recrystallization to obtain highly purified dexborneol. The route is shown in the following formula:
[0023]
[0024] This invention provides a method for preparing dextroborneol, the specific steps of which are as follows:
[0025] (1) Camphor is added to one of methanol, ethanol or isopropanol, stirred and dissolved, then ruthenium chloride and ligand R-BINAP are added, hydrogen is replaced, and the reaction is carried out under a certain pressure. After the reaction is completed, the insoluble matter is filtered out from the reaction solution, concentrated and then methyl ether is added. After cooling to a certain temperature, the solid is precipitated and dried to obtain a mixture of dextroborneol (a mixture of compounds 4 and 5).
[0026] (2) The first step reduction product (a mixture of compounds 4 and 5) was dissolved in dichloromethane, trimethylchlorosilane and triethylamine were added, and the mixture was stirred at room temperature. After the reaction was complete, the reaction solvent was concentrated to obtain a pale yellow oily substance. Isopropanol was added, the temperature was raised to 65-70℃, and the mixture was stirred to dissolve. The temperature was then gradually lowered to 0-5℃, and a certain amount of seed crystals (silyl ether camphor) was added to induce crystallization. The mixture was stirred at this temperature for 2 hours, the solid was filtered out and dried under vacuum to obtain silyl ether camphor (compound 3).
[0027] (3) Add methanol to silyl ether camphene (compound 3), heat to dissolve, add a certain amount of hydrochloric acid, stir for 30 minutes, concentrate the reaction solution to an oily substance, add n-heptane, raise the temperature to 75-85℃, stir for 30 minutes, then gradually lower the temperature to 10-15℃, a solid precipitates out, filter out the solid, and dry under vacuum to obtain crude dextroborneol.
[0028] (4) Add a certain amount of n-heptane to the crude dexborneol, heat to 80-90℃ until the solid is completely dissolved, then gradually cool down to 10-15℃ and stir at this temperature for 2 hours to obtain a white crystalline solid. Filter the obtained solid and dry it under vacuum at room temperature.
[0029] The method for preparing dextromethorphanol includes the following steps:
[0030] (1) Dissolve camphor in 8-12 times its volume of methanol, ethanol or isopropanol, add a catalyst of either [(R)-(-)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl][(1R,2R)-(+)-1,2-diphenylethylenediamine]ruthenium(II) or [(S)-(-)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl][(1R,2R)-(+)-1,2-diphenylethylenediamine]ruthenium(II), and react under hydrogen pressure of 0.2-1.0 MPa for 5-15 hours.
[0031] (2) The catalyst is prepared from dichlorophenylruthenium(II) dimer and R-(+)-1,1'-binaphthyl-2,2'-diphenylphosphine (R-BINAP). N,N-dimethylformamide is added to the dichlorophenylruthenium(II) dimer, and the mixture is heated to 90-110℃ and stirred for 1 h under nitrogen protection. After cooling to 30-40℃, R-(+)-1,1'-binaphthyl-2,2'-diphenylphosphine is added and stirred for 2 h. The mixture is then concentrated to a certain volume under reduced pressure and cooled to 10-15℃, resulting in the precipitation of a solid. The solid is filtered off and dried under vacuum. The catalyst is prepared by reacting a dichlorophenylruthenium(II) dimer with S-(+)-1,1'-binaphthyl-2,2'-diphenylphosphine (S-BINAP). N,N-dimethylformamide is added to the dichlorophenylruthenium(II) dimer, and the mixture is heated to 90-110°C and stirred for 1 hour under nitrogen protection. After cooling to 30-40°C, R-(+)-1,1'-binaphthyl-2,2'-diphenylphosphine is added, and the mixture is stirred for 2 hours. The mixture is then concentrated to a certain volume under reduced pressure and cooled to 10-15°C, resulting in solid precipitation. The solid is filtered off and dried under vacuum to obtain the catalyst.
[0032] (3) Preparation of silyl ether camphene
[0033] The reduction product is dissolved in one of dichloromethane, acetonitrile, tetrahydrofuran, acetone, or methyl tert-butyl ether, with a solvent ratio of 6-15 times. Trimethylchlorosilane, triisopropylsilyl, or tert-butyldiphenylsilyl is used, with an equivalent of 0.8-1.2. The organic base used is triethylamine, N,N-4-dimethylpyrimidine, or diisopropylethylamine, with an equivalent of 0.8-1.4.
[0034] (4) Preparation of crude dextroborneol (hydrolysis of silyl ether camphor):
[0035] Dissolve silyl ether camphor in 8-12 times its volume of methanol, ethanol or isopropanol, and hydrolyze it in 0.5-1.5 equivalents of hydrochloric acid, phosphoric acid or sulfuric acid at a temperature of 20-40°C.
[0036] (5) Preparation of dextroborneol purified product (recrystallization)
[0037] The solvent for crude camphor is one or two of n-heptane, n-hexane, methyl tert-butyl ether, or toluene, with a volume of 5-12 times that of crude dextroborneol. After heating and dissolving, the temperature for crystallization by gradient cooling is 0-15℃. Attached Figure Description
[0038] Figure 1 The reduction reaction formula for camphor and sodium borohydride
[0039] Figure 2 Direct hydration of α-pinene
[0040] Figure 3Decomposition of organomagnesia
[0041] Figure 4 α-pinene esterification-saponification method
[0042] Figure 5 Solid strong acid catalyst method
[0043] Figure 6 Rare earth composite solid superacid method Figure 7 Four configurations of synthetic borneol
[0044] Figure 8 This is a synthetic route diagram of the present invention. Figure 9 HPLC liquid chromatography spectrum of dextroborneol purified product Specific Implementation
[0045] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.
[0046] Example 1: Preparation of chiral reduction products
[0047] (1) In a 1000ml hydrogenation reactor, 50g (0.329mol) of camphor and 400mL of methanol were added, followed by dichloro[(R)-(-)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl][(1R,2R)-(+)-1,2-diphenylethylenediamine]ruthenium(II) (prepared from 0.50g of dichlorophenylruthenium(II) dimer and 0.62g of R-BINAP). After replacing the nitrogen gas, hydrogen gas was introduced at 0.3-0.6MPa, and the reaction was carried out at 50-55℃ for 12h. After the reaction was completed, the insoluble matter was filtered out from the reaction solution, concentrated, and methyl ether was added. After cooling to a certain temperature, the solid precipitated and dried to obtain 41.5g of dextroborneol mixture (a mixture of compounds 4 and 5).
[0048] (2) Preparation of silyl ether camphene
[0049] In a 1000 mL three-necked flask, 38.5 g (0.240 mol) of the first-step reduction product (a mixture of compounds 4 and 5) was dissolved in 380 mL of dichloromethane. 28.8 g (0.267 mol) of trimethylchlorosilane and 29.1 g (0.267 mol) of triethylamine were added, and the mixture was stirred at room temperature. After the reaction was complete, the reaction solvent was concentrated to obtain a pale yellow oil. Isopropanol was added, and the temperature was raised to 65-70 °C. After stirring to dissolve the product, the temperature was gradually lowered to 0-5 °C. A certain amount of seed crystals (silyl ether camphenol) was added to induce crystallization. The mixture was stirred at this temperature for 2 hours. The solid was filtered off and dried under vacuum to obtain 49.7 g of silyl ether camphenol (compound 3).
[0050] (3) Preparation of crude dextroborneol (hydrolysis of silyl ether camphor):
[0051] Add 46.5 g (0.240 mol) of silyl ether camphene alcohol (compound 3) to 500 mL of methanol, heat to dissolve, add 10 mL of hydrochloric acid, stir for 30 minutes, concentrate the reaction solution to an oily state, add 630 mL of n-heptane, raise the temperature to 75-85 °C, stir for 30 minutes, and then gradually lower the temperature to 10-15 °C. A solid precipitates out. Filter out the solid, and dry it under vacuum at room temperature to obtain 35.4 g of crude dextroborneol.
[0052] (4) Preparation of dextroborneol purified product (recrystallization)
[0053] (5) Add a certain amount of n-heptane to the obtained crude dexborneol 34.3g, heat to 80-90℃ until the solid is completely dissolved, then gradually cool down to 10-15℃ and stir at this temperature for 2 hours to obtain a white crystalline solid. Filter the obtained solid and vacuum dry at room temperature to obtain 29.5g of purified dexborneol.
[0054] Example 2:
[0055] Preparation of chiral reduction products
[0056] (1) In a 1000ml hydrogenation reactor, 55g (0.362mol) of camphor and 450mL of ethanol were added, followed by dichloro[(S)-(-)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl][(1R,2R)-(+)-1,2-diphenylethylenediamine]ruthenium(II) (prepared from 0.55g of dichlorophenylruthenium(II) dimer and 0.70g of S-BINAP). After replacing the nitrogen gas, hydrogen gas was introduced at 0.3-0.6MPa, and the reaction was carried out at 50-55℃ for 12h. After the reaction was completed, the insoluble matter was filtered out from the reaction solution, concentrated, and methyl ether was added. After cooling to a certain temperature, the solid precipitated and dried to obtain 46.0g of dextroborneol mixture (a mixture of compounds 4 and 5).
[0057] (2) Preparation of silyl ether camphene
[0058] In a 1000 mL three-necked flask, 40.5 g (0.263 mol) of the first-step reduction product (a mixture of compounds 4 and 5) was dissolved in 400 mL of dichloromethane. 25.6 g (0.237 mol) of trimethylchlorosilane and 23.9 g (0.237 mol) of triethylamine were added, and the mixture was stirred at room temperature. After the reaction was complete, the reaction solvent was concentrated to obtain a pale yellow oil. Isopropanol was added, and the temperature was raised to 65-70 °C. After stirring to dissolve the product, the temperature was gradually lowered to 0-5 °C. A certain amount of seed crystals (silyl ether camphenol) was added to induce crystallization. The mixture was stirred at this temperature for 2 hours. The solid was filtered off and dried under vacuum to obtain 54.5 g of silyl ether camphenol (compound 3).
[0059] (4) Preparation of crude dextroborneol (hydrolysis of silyl ether camphor):
[0060] Add 530 mL of methanol to 49.6 g (0.240 mol) of silyl ether camphene (compound 3), heat to dissolve, then add 11 mL of hydrochloric acid, stir for 30 minutes, concentrate the reaction solution to an oily state, add 630 mL of n-heptane, raise the temperature to 75-85 °C, stir for 30 minutes, then gradually lower the temperature to 10-15 °C, a solid precipitates out, filter out the solid, and dry under vacuum at room temperature to obtain 38.3 g of crude dextroborneol.
[0061] (4) Preparation of dextroborneol purified product (recrystallization)
[0062] (6) Add a certain amount of n-heptane to the obtained crude dexborneol 36.4g, heat to 80-90℃ until the solid is completely dissolved, then gradually cool down to 10-15℃ and stir at this temperature for 2 hours to obtain a white crystalline solid. Filter the obtained solid and vacuum dry at room temperature to obtain 30.6g of purified dexborneol.
Claims
1. (1) Dissolve camphor in 8-12 times the volume of methanol, ethanol or isopropanol, add catalyst [(R)-(-)-2,2'-bis(diphenylphosphine)-1,1'-binaphthylene][(1R,2R)-(+)-1,2-diphenylethylenediamine]ruthenium(II) or [(S)-(-)-2,2'-bis(diphenylphosphine)-1,1'-binaphthylene][(1R,2R)-(+)-1,2-diphenylethylenediamine]ruthenium(II), and react for 5-15 hours at a hydrogen pressure of 0.2-1.0 MPa. (2) The catalyst is prepared from dichlorophenylruthenium(II) dimer and R-(+)-1,1'-binaphthyl-2,2'-diphenylphosphine (R-BINAP). N,N-dimethylformamide is added to the dichlorophenylruthenium(II) dimer, and the mixture is heated to 90-110℃ and stirred for 1 h under nitrogen protection. After cooling to 30-40℃, R-(+)-1,1'-binaphthyl-2,2'-diphenylphosphine is added and stirred for 2 h. The mixture is then concentrated to a certain volume under reduced pressure and cooled to 10-15℃, resulting in the precipitation of a solid. The solid is filtered off and dried under vacuum. The catalyst is prepared by reacting dichlorophenylruthenium(II) dimer with S-(+)-1,1'-binaphthyl-2,2'-diphenylphosphine (S-BINAP). N,N-dimethylformamide is added to the dichlorophenylruthenium(II) dimer, and the mixture is heated to 90-110°C and stirred for 1 hour under nitrogen protection. After cooling to 30-40°C, R-(+)-1,1'-binaphthyl-2,2'-diphenylphosphine is added, and the mixture is stirred for 2 hours. The mixture is then concentrated to a certain volume under reduced pressure and cooled to 10-15°C, resulting in solid precipitation. The solid is filtered off and dried under vacuum to obtain the catalyst. (3) Preparation of silyl ether camphene The reduction product is dissolved in one of dichloromethane, acetonitrile, tetrahydrofuran, acetone, or methyl tert-butyl ether, with a solvent ratio of 6-15 times. Trimethylchlorosilane, triisopropylsilyl, or tert-butyldiphenylsilyl is used, with an equivalent of 0.8-1.
2. The organic base used is triethylamine, N,N-4-dimethylpyrimidine, or diisopropylethylamine, with an equivalent of 0.8-1.
4. (4) Preparation of crude dextroborneol (hydrolysis of silyl ether camphor): Dissolve silyl ether camphor in 8-12 times its volume of methanol, ethanol or isopropanol, and hydrolyze it in 0.5-1.5 equivalents of hydrochloric acid, phosphoric acid or sulfuric acid at a temperature of 20-40°C. (5) Preparation of dextroborneol purified product (recrystallization) The solvent for crude camphor is one or two of n-heptane, n-hexane, methyl tert-butyl ether, or toluene, with a volume of 5-12 times that of crude dextroborneol. After heating and dissolving, the temperature for crystallization by gradient cooling is 0-15℃.