WO2016119270A1 - 由樟脑及其还原产物、冰片制备高纯度龙脑的方法 - Google Patents

由樟脑及其还原产物、冰片制备高纯度龙脑的方法 Download PDF

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WO2016119270A1
WO2016119270A1 PCT/CN2015/072066 CN2015072066W WO2016119270A1 WO 2016119270 A1 WO2016119270 A1 WO 2016119270A1 CN 2015072066 W CN2015072066 W CN 2015072066W WO 2016119270 A1 WO2016119270 A1 WO 2016119270A1
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borneol
camphor
aluminum
alcohol
handed
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French (fr)
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闻永举
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闻永举
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C07C1/20—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms
    • C07C1/24—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms by elimination of water
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
    • C07C13/39—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with a bicyclo ring system containing seven carbon atoms
    • C07C13/40—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with a bicyclo ring system containing seven carbon atoms with a bicycloheptane ring structure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
    • C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
    • C07C29/80—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment by distillation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
    • C07C35/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings
    • C07C35/28—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings the condensed ring system containing seven carbon atoms
    • C07C35/29—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings the condensed ring system containing seven carbon atoms being a (2.2.1) system
    • C07C35/30—Borneol; Isoborneol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C5/00—Preparation of hydrocarbons from hydrocarbons containing the same number of carbon atoms
    • C07C5/22—Preparation of hydrocarbons from hydrocarbons containing the same number of carbon atoms by isomerisation
    • C07C5/27—Rearrangement of carbon atoms in the hydrocarbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C7/00—Purification; Separation; Use of additives
    • C07C7/04—Purification; Separation; Use of additives by distillation

Definitions

  • the preparation method of high-purity borneol from camphor and its reduced products and borneol is in the fields of chemistry and medicine.
  • borneol has the effect of refreshing, clearing away heat and relieving pain. It is used for fever, fainting, convulsions, stroke, suffocation, stun, chest pain, chest pain, eye aches, Sore throat, ear canal and other symptoms. Borneol has many functions in Chinese patent medicine preparations and is widely used in the field of medicine. Briefly explain the pharmacological effects and main drugs of borneol from four aspects: (1) the effect on the central nervous system: borneol has a strong two-way regulation of central nervous system excitability, both sedative and tranquilizing effect, and has a refreshing effect.
  • the main products are Xueyile, Naotong Injection and Zhupo Qing Brain Tablets.
  • the role of the circulatory system it has a therapeutic effect on restoring blood flow in the infarct zone, slowing heart rate, and reducing myocardial oxygen consumption.
  • the main products are compound Danshen preparation, Suhexiang pill, Guanxin Suhe pill, Niuhuang Jiangya capsule, and Subing dripping pill.
  • Promote drug absorption Borneol can promote drug absorption, improve blood vessel wall permeability, open blood-cerebrospinal fluid barrier and blood-brain barrier, inhibit drug liver metabolism, thereby improving the therapeutic effect of other drugs.
  • the main products are sulfidin ice yellow tablets, Shuangqing injection, Angong Niuhuang Wan, Guyouling plaster, Jinyin Sanqi Capsule, Tongke Shuyu, Tonglingling Rubber Cream, Xuelian Pain, Gold Blue Aerosol .
  • borneol can go to saprophytic muscle, swelling and pain, so it is mostly used for mouth sores, carbuncles, modern medical tests prove that borneol has antibacterial, anti-inflammatory, analgesic effects.
  • the main products are Niuhuang Jiedu Pill, Huajing Zaizao Pill, Sore Tong Xiaoyan Pill, Bingbo Powder, Bingbo Lozenges, Wuling Zhitong Capsule, Boric Acid Borneol Ear Drops, Acetate Fluoride Essence Cream, Soothing and Itching Ice jade supper, pearl eyesight eye drops, musk hemorrhoids suppository, cytotoxic cream, musk sacral water.
  • Borneol has an irreplaceable pharmacological effect as an important raw material of Chinese patent medicine. With the continuous research of borneol and the continuous popularization of research results, the understanding of borneol is gradually deepened, and the clinical use of borneol will be gradually widened.
  • Borneol is an important spice widely used in the formulation of rosemary and lavender flavors. Because borneol has a unique cooling sensation to the human body, the fragrance and fragrance company has launched a series of borneol-based products, which are accepted by downstream consumers, especially in shower gels, shampoos and skin care products. The application is becoming more widespread, so the use of borneol in the field of synthetic fragrances will continue to grow.
  • the effective material basis and impurities of borneol The 2010 edition of the Pharmacopoeia stipulates that the quality standard of borneol should not be less than 55.0%, the camphor should not exceed 0.50%, the heavy metal should not exceed 5 parts per million, and the arsenic should not exceed one million. Second, non-volatile matter should not exceed 3.5mg per 10g. According to the Pharmacopoeia standards, the real effective substance of borneol is the borneol. The amount of borneol is not less than 55.0%, and the rest is impurities, which cannot exceed the standard.
  • the amount of iso-borne brain in the borneol should not exceed 44.50%. .
  • the borneol includes the left-handed dragon brain and the right-handed dinosaur, and the camphor includes the left-handed sacral brain and the right-handed sacral brain.
  • the allosaurus includes the left-handed dragon brain and the right-handed dragon brain, and the right-handed dragon brain such as the structure (1) and the left-handed dragon
  • the brain is like a structure (2), a right-handed iso-borne brain such as a structure (3), a left-handed iso-borne brain such as a structure (4), a right-handed brain such as a structure (5), and a left-handed brain such as a structure (6).
  • the nature of borneol and iso-borne brain and camphor the melting point of dextro-dragon brain is 208 ° C, the boiling point is 212 ° C, the melting point of L-dragon brain is 204 ° C, and the boiling point is 210 ° C.
  • the isomentia has a melting point of 208-214 ° C and a boiling point of 212 ° C.
  • Camphor has a melting point of 179 ° C and a boiling point of 204 ° C.
  • Dragon brain and isoborne brain are insoluble in water and soluble in ethanol, ether, chloroform and petroleum ether without turbidity.
  • Camphor is slightly soluble in water and soluble in ethanol, ether, chloroform and petroleum ether.
  • Heavy metals refer to metals with a relative density of 5 or higher, which can react with thioacetamide or sodium sulfide to develop metallic impurities under experimental conditions. Common heavy metals are lead, mercury, arsenic, cadmium, copper, etc. Since lead is easy to bring into medicines and is harmful to humans, lead is often represented by heavy metals. Heavy metals are highly toxic and easy to accumulate, causing irreversible degeneration of proteins, which can lead to serious symptoms of poisoning in the body. Arsenic salts, such as AsO 3 2- , As 2 O 3 , etc., in which the residual trivalent arsenic salt is extremely toxic, can cause serious poisoning and endanger life safety.
  • Camphor has the pharmacological effects of excitement, strong heart, anti-inflammatory, analgesic, antibacterial, antitussive, osmotic, and acaricidal, and interacts with other drugs. It is the earliest used in the world. One of the natural organic chemical ingredients. Camphor is widely used and has strong toxicity. It is manifested in obvious toxicity to ovary, testis, nerve, liver, heart, fetus, pregnant woman, potential toxicity to the kidney urinary system and less genotoxicity. The pharmacological action of isoborneol is similar to that of the borneol.
  • the borneol and allosaurus play a role in the body, they are combined with glucuronic acid and excreted.
  • the metabolic rate of the two is different in the body.
  • the hydroxyl group of the dragon brain is in the flat bond, which is beneficial to the binding of glucuronic acid.
  • the hydroxyl group of the isoborne brain is in the upright bond, and the glucuronic acid and its combination are subjected to 1,7,7-triple.
  • the steric hindrance of the base is relatively difficult to combine; after the combination, the upper end of the sugar ring in the glucuronide, 6-COOH and the isoborneol are large groups, especially the allosaurus erect 1,7,7-three
  • the methyl group causes the steric ring to have a large spatial tension, is unstable, and is easily hydrolyzed. The effect of the two makes it slow in metabolism, long in the body, and has a large effect on the body, which also leads to its prominent side effects.
  • LD natural lethal dose
  • borneol borneol
  • AI tablets the natural lethal dose (LD) of natural borneol, borneol and AI tablets is the largest in natural ice tablets, followed by synthetic borneol, and the smallest in eucalyptus.
  • the reason is that celery has the highest content of camphor and the most toxicity.
  • the high reproductive dose of synthetic borneol is higher than that of natural borneol in mice.
  • the reason is that the content of isoborneol in synthetic borneol is much higher, and the toxicity is greater.
  • the Pharmacopoeia stipulates that the dosage of natural borneol is 0.3g-0.9g, while the use of borneol and borneol can only be used in 0.15g-0.3g. Therefore, the higher the amount of positive dragon brain contained in the three kinds of borneol, the less harmful substances and the higher the safety.
  • Hg is basically insoluble in common solvents, and has a high density and often precipitates at the bottom of the container. Therefore, the separation of metallic mercury can be dissolved in an organic solvent, and the upper layer solution can be separated.
  • arsenic salts exist in an oxidized state, such as AsO 3 2- or As 2 O 3 , they are not volatile, and can also be separated by steam distillation to achieve separation of borneol and heavy metals; when arsenic is reduced, when AsH 3 is present Since AsH 3 is soluble in water (200 mL/L) and is a gas at normal temperature, and the borneol is insoluble in water and solid at normal temperature, borneol and AsH 3 are distilled off with water vapor by steam distillation.
  • the dragon brain is condensed and precipitated in the condensed water, and the AsH 3 flows away with the condensed water, and the effect of separating AsH 3 and the borneol is also achieved.
  • the dragon's brain has a high boiling point and the steam distillation rate is slow. The use of steam distillation alone to remove heavy metals will consume more energy.
  • Zhang Shuzheng and other boric acid are reacted with a mixture of borneol, isoborneol and camphor to obtain decyl borate and camphor.
  • the method can separate camphor and borneol (iso-borneol).
  • the iso-borne brain dehydrates to form terpenes, but the purity ratio of borneol and iso-borne brain does not change, indicating that the borneol and the iso-borne brain are not separated. it is good.
  • the solvent used is benzene or xylene, and its solvent toxicity is also large, and has no practical value. Therefore, the industrial separation technology of dragon brain and isoborne brain has not been solved yet.
  • Turpentine is a volatile oil obtained by distillation of turpentine secreted by Pinaceae, and is a liquid mixture composed of terpene compounds.
  • the main components are ⁇ -pinene and ⁇ -pinene.
  • turpentine oil can be divided into fat turpentine, sulphate turpentine, wood turpentine and dry turpentine, of which turpentine and sulphate can be used for large-scale industrial production.
  • the annual global output of turpentine is about 250,000-300,000 tons, including 15-18 million tons of sulfate turpentine and 10-15 thousand tons of turpentine.
  • China is the main producer of gum turpentine, with an annual output of 910,000 tons of fat turpentine.
  • Preparation of synthetic borneol and camphor (1) Preparation of synthetic borneol: ⁇ -pinene in light oil of turpentine is esterified with anhydrous oxalate to form a mixture of borneol oxalate, which is steam distilled to obtain volatile white light oil. And non-volatile borneol oxalate, the latter obtained by saponification and sodium hydroxide solution, and then separated and purified to obtain borneol.
  • the borneol prescribed by the Chinese Pharmacopoeia is prepared by this method, and the borneol contains a certain amount of isoborneol.
  • camphor selective reduction China's camphor and natural camphor production ranks first in the world, and camphor can be used to prepare borneol and iso-borne brain by hydrogenation reduction. Because the higher the content of the borneol, the better the quality of the borneol, so in the process of camphor reduction, the ratio of borneol/iso-borne brain is increased as much as possible.
  • Liu Tiancheng et al. studied the reaction of turpentine with oxalic acid, chloroacetic acid and trichloroacetic acid by MoO 3 /TiO 2 solid superacid catalyst.
  • the catalyst dosage is 5% of the mass of turpentine, and when the turpentine: chloroacetic acid is 100:25 (mass ratio), the borneol yield is 52.93%, and the selectivity of the borneol is 60.46% ([7] Liu Tiancheng, Ning Ping.
  • Liu Yonggen et al. used nanosolid superacid SO 4 2- /TiO 2 as a catalyst to synthesize exogenous borneol with chloroacetic acid and ⁇ -pinene at a certain temperature.
  • the traditional boric anhydride catalyzed a-decene esterification-saponification method has the disadvantages of easy filling, low safety, high corrosivity and serious pollution, and it is difficult to achieve industrialization ([8] Liu Yonggen, Deng Zhihong, etc.
  • the reduction method is 3g camphor, modified 3g D-tartaric acid modified RaneyNi catalyst, 500ml absolute ethanol, 1g sodium acetate, stirring speed 800r/min, reaction at 60 ° C for 10h, according to the preferred system, camphor conversion rate Not more than 21%, the brain is not more than 80%, does not have industrial production ([110] Jiao Guangxia. D-tartaric acid modified RaneyNi catalyzed asymmetric hydrogenation of camphor to synthesize borneol [D]. Huaqiao University, 2011). Ni-B/ ⁇ -Al 2 O 3 catalyzes the hydrogenation reduction of camphor.
  • the relative optical rotation was 69.2% of the right-handed product ([3]).
  • LiAlH 4 as a reducing agent the conversion rate of D-camphor can reach 80%, of which D-borne brain is about 90% and D-isocephalus is 10%.
  • the disadvantage of this method is that LiAlH 4 is expensive, and there are camphor and allosaurus in the product.
  • the brain is not well separated.
  • NaBH 4 acts as a reducing agent, and D-camphor is mainly converted into iso-borne brain, which has no value.
  • aluminum isopropoxide has a D-camphor conversion rate of 100%, of which D-long brain is 63% and D-isocephalus is 37%.
  • camphor Since camphor is several times more expensive than turpentine, the cost of preparing borneol with camphor is higher, and there is still a greater amount of isoborneol in the product.
  • the yield of borneol is higher, the preparation conditions are harsh, it is difficult to industrialize, or the reducing agent is too expensive and the cost is too high; on the other hand, the catalytic reduction selectivity of camphor is poor.
  • the post-treatment is cumbersome. Therefore, to date, there is no such a method that is very good, inexpensive, and can be industrially prepared to produce high-purity borneol.
  • borneol The effective substance of borneol is borneol.
  • the Chinese Pharmacopoeia stipulates that natural borneol should be no less than 96.0% in terms of right-handed dragon brain, and no more than 85.0% in the case of left-handed dragon brain.
  • Natural borneol and AI tablets are extracted from the cerebral palsy and Ayurveda respectively. On the one hand, the extract contains more camphor, and the camphor is repeatedly recrystallized by ethanol to remove the camphor. The process is complicated and the yield is low.
  • the invention aims at the problem that the above-mentioned borneol and isoflavone and camphor are close in nature, the boiling point is close, and it is difficult to separate, and a small amount of camphor is reduced to a borneol and an allosaurus by using a secondary alcohol-secondary alcohol aluminum, and the camphor is removed.
  • the lower boiling point secondary alcohol-secondary alcohol aluminum or tertiary alcohol-tertiary aluminum aluminum is replaced with borneol and isoborneol to form borneol aluminum and isomenta aluminum.
  • the thermal stability of the use of isobornol aluminum is much lower than that of the dragon brain aluminum.
  • the method can reduce camphor, isomental dehydration, recovery of secondary or tertiary alcohols, distill out borneol and terpenes, and remove heavy metals and arsenic salts, and the operation can be integrated, and the separation of borneol and terpenes Simple and efficient.
  • the whole process is low in cost, less in environmental pollution, and easy to industrialize.
  • Aluminum isopropoxide-isopropanol is used for the reduction and product of camphor as seen in (II).
  • Isopropanol acts as a solvent to dissolve camphor or borneol, and continuously evaporates the solvent containing acetone in isopropanol, and the camphor is continuously reduced.
  • the boiling point of isopropanol is 84 ° C
  • the boiling point of acetone is 56 ° C
  • the boiling point of camphor is 204 ° C
  • the boiling point of borneol and isoborneol is 208-214 ° C.
  • a reagent or compound having a low boiling point is preferentially volatilized;
  • Isopropanol and aluminum isopropoxide are used to replace dragon brain aluminum and isobornol aluminum (III), in which isopropanol is used as a solvent to dissolve the camphor reduction product or borneol to form a homogeneous solution, and then the isopropanol is continuously distilled to form a borneol.
  • isobornol aluminum Aluminum and isobornol aluminum;
  • the use of the boiling point of decene is 159 ° C, the boiling point of the borneol is 210-212 ° C, and the boiling point is greatly different.
  • the borneol and decene can be separated by distillation-sublimation method;
  • the terpene is insoluble in DMSO and DMF, and is easily soluble in saturated hydrocarbons such as petroleum ether, gasoline and cyclohexane.
  • the borneol has a large solubility in DMSO and DMF, and the borneol and decene can be separated by extraction;
  • the polar brain is more polar than decene, and the saturated hydrocarbons such as petroleum ether, cyclohexane and gasoline are used as eluents.
  • the alumina and silica gel chromatography can adsorb the borneol, and the adsorption of terpenes is weak, and can be utilized.
  • the borneol according to the present invention is mainly prepared from turpentine ⁇ -pinene, and mainly contains left-handed borneol and right-handed borneol, left-handed borneol, right-handed borneol, and still contains a small amount or a small amount of dextran,
  • a mixture of left-handed brains such as the structure of the right-handed dragon brain (1), the structure of the left-handed dragon brain (2), the structure of the right-handed dragon, such as the structure (3), the structure of the left-handed dragon, such as the structure (4), and the right-handed brain.
  • the invention relates to camphor, mainly to a synthetic camphor obtained from ⁇ -pinene, which is a mixture of right-handed camphor and left-handed camphor, such as structure (5) and left-handed brain as structure (6).
  • the invention relates to a camphor reduction product, which mainly comprises a synthetic camphor which is reduced by a reducing agent such as alcohol-Na, isopropanol-isopropoxide aluminum, H 2 -Pt, Raney nickel, etc., and mainly contains left-handed borneol and right-handed borneol.
  • a reducing agent such as alcohol-Na, isopropanol-isopropoxide aluminum, H 2 -Pt, Raney nickel, etc.
  • left-handed iso-borne brain right-handed iso-borne brain, still containing a small or a small mixture of right-handed camphor and left-handed brain, right-handed dragon brain such as structure (1), left-handed dragon brain such as structure (2), right-handed
  • the dragon brain is like a structure (3), a left-handed dragon brain such as a structure (4), a right-handed brain such as a structure (5), and a left-handed brain such as a structure (6).
  • the invention relates to a borneol, which refers to a mixture of a left-handed borneol and a right-handed borneol, such as a structure (1) and a left-handed borneol such as a structure (2).
  • the invention relates to a heterodragon brain, which refers to a mixture of a left-handed iso-long brain and a right-handed dragon brain, such as a structure (1) and a left-handed dragon brain such as a structure (2).
  • the terpene referred to in the present invention refers to a dehydration rearrangement of dextrorotol and levans, and the terpene purity is not less than 90.0%, and the terpene is as a structure (7).
  • the secondary alcohol in the present invention refers to a secondary alcohol having a boiling point lower than the boiling point of the camphor, including isopropanol, cyclohexanol, isobutanol, 2-pentanol, 3-pentanol, 2-hexanol, 3-hexanol, etc. Or a mixture of two or more of the above alcohols, preferably isopropanol.
  • the tertiary alcohol referred to in the present invention means a tertiary alcohol having a boiling point lower than the boiling point of the camphor, and includes tert-butanol, tert-amyl alcohol, 3-ethyl-3-pentanol and the like.
  • the aluminum secondary alcohol and the aluminum tertiary alcohol, the secondary aluminum alcohol and the aluminum powder are prepared by the AlCl 3 /HgCl 2 /I 2 catalyst to prepare the secondary aluminum alcohol, which also refers to the direct purchase of the secondary aluminum alcohol reagent;
  • the tertiary alcohol and the aluminum powder are prepared by using AlCl 3 , HgCl 2 , and I 2 catalysts to prepare the secondary aluminum alcohol, which also refers to the direct purchase of the secondary aluminum alcohol reagent.
  • the secondary alcohol-secondary alcohol aluminum acts to reduce camphor, and the amount of secondary alcohol is related to the content of camphor.
  • the ratio is 100:1-1:0.5.
  • the amount of secondary alcohol is preferably 2-3 times the amount of starting product (such as natural borneol for starting product, isopropanol for secondary alcohol, natural
  • starting product such as natural borneol for starting product, isopropanol for secondary alcohol, natural
  • the content of natural camphor in borneol is ⁇ 3%, 100g of natural borneol requires 200g-300g of isopropanol (AR)); when camphor is increased by 1% on the basis of 3%, the amount of secondary alcohol is increased by 0.5-1.
  • the starting material weight is multiplied.
  • the secondary alcohol-secondary alcohol aluminum interacts with the borneol and the isoborne brain to produce a borneol Aluminum and isophoraluminum, wherein the secondary alcohol is used as a solvent, preferably 2-3 times the weight of the starting material.
  • the tertiary alcohol-tertiary aluminum alkaloid interacts with the borneol and the iso-borne brain to form a camphor aluminum and isobornol aluminum, and the amount of the tertiary alcohol as a solvent is preferably 2-3 times the weight of the starting material. .
  • the secondary alcohol-secondary alcohol aluminum acts to reduce camphor
  • the molar amount of the secondary aluminum alcohol is related to the content of camphor.
  • the molar ratio of the product to the secondary aluminum alkoxide is 1:10-100:1.
  • the molar amount of the secondary aluminum alkoxide is preferably 1/5-1/3 times the molar amount of the starting product (eg, starting The product is selected from borneol, and the secondary aluminum is selected from isopropanol.
  • the secondary alcohol-secondary alcohol aluminum interacts with the borneol and the iso-borne brain to produce the dragon brain aluminum and the isobornol aluminum, and the amount of the secondary alcohol aluminum is related to the content of the isoborneol.
  • the more the content, the more the molar amount of the secondary aluminum alkoxide, and the ratio of the molar amount of the secondary aluminum alkoxide to the total molar amount of the borneol or camphor reduction product is 1/8 to 1/1, preferably 1/5 to 1/3.
  • the tertiary alcohol-tertiary aluminum alkaloid interacts with the borneol and the iso-borne brain to produce the dragon brain aluminum and the isobornol aluminum, and the amount of the tertiary alcohol aluminum is related to the content of the isoborneol, and the isoborneol
  • the ratio of the molar amount of tertiary aluminum alcohol to the total molar amount of borneol and isoborneol is 1/8-1/1, preferably 1/5-1/3. .
  • the secondary aluminum alcohol reduces camphor, preferably isopropanol, and has a reduction temperature of from 80 ° C to 130 ° C, preferably from 105 ° C to 115 ° C.
  • the secondary aluminum alkoxide and the borneol and the isoborne brain are subjected to a closed distillation to form a camphor aluminum and an isobornol aluminum, preferably isopropanol, and the substitution temperature is from 80 ° C to 150 ° C, preferably from 110 ° C to 130 ° C.
  • the temperature of the dipyridamole and the isobornol aluminum sealed dehydration rearrangement terpene is 130 ° C - 270 ° C, preferably the isobornasia aluminum dehydration rearrangement temperature is 140 ° C - 180 ° C.
  • the purification of borneol and decene is carried out by steam distillation, and the hydrolysis of borneol aluminum produces borneol and aluminum hydroxide, and the borneol is distilled together with decene to obtain a mixture of decene and borneol, and oxidizes. Aluminum does not volatilize.
  • the terpene and the borneol are separated by a distillation-sublimation method, and the distillation-sublimation is sublimed at 140 ° C to 210 ° C, preferably 160 ° C to 185 ° C.
  • polar solvents such as DMSO and DMF mainly refer to DMSO, DMF, glycerol, ethylene glycol, 1,3-propanediol, methylformamide, formamide, etc., and are used for extraction, polar solvent.
  • the ratio to the borneol is preferably not less than 3:1.
  • the saturated hydrocarbon mainly refers to a low-boiling saturated hydrocarbon and a mixture thereof, petroleum ether, gasoline, cyclohexane, n-hexane, cyclopentane, n-pentane, etc., in dissolving a mixture of borneol and terpene, in extraction It acts to dissolve the terpene; it elutes the terpene in the elution of column chromatography.
  • the column chromatography packing mainly refers to silica gel and alumina, and the ratio of the action to the borneol is 3:1-10:1, and preferably 4:1-5:1.
  • aluminum powder and borneol or camphor reduction are used to generate aluminum astrona and isoflavone aluminum, dehydration and rearrangement of isobornol aluminum, and the weight ratio of aluminum powder to borneol or camphor reduction is 1:1-1: 100, wherein when the content of camphor is small, the weight ratio of the aluminum powder to the borneol or camphor reduction is preferably 1:20-1:40.
  • the eluent is preferably a reagent having a large polarity, a low boiling point, and a soluble borneol, such as ethyl acetate or ethanol.
  • the conversion of isobornol in borneol and camphor reduction products to terpenes can be checked by TLC.
  • the specific method is high temperature dehydration of dragon brain aluminum and isobornol aluminum, dissolved with ethyl acetate and water, and borneol aluminum Longine aluminum) is hydrolyzed into cedar (isolons) and deuterated aluminum dehydrated terpenes, both of which are soluble in ethyl acetate.
  • cyclohexane-ethyl acetate (6:1) ) as a developing agent As a sample solution, cyclohexane-ethyl acetate (6:1) ) as a developing agent, a new preparation of 1% vanillin concentrated sulfuric acid as a color developer, borneol S / allosaurus S significantly increased (S: indicates the area of the spot), until the isoborne brain S is not obvious or not, but in the solvent There are terpenes in the front, borneol and allosaurus are bright red spots, and terpenes are purple-red spots. This method is more convenient to monitor than GC;
  • the borneol was subjected to hermetic distillation replacement with isopropanol-isopropanol Na, methanol-methanol magnesium, etc., and the isothermal brain wasomerized.
  • the results showed that the isobornol isomerized borneol product, but the borneol and allosaurus dehydration weight It is arranged in terpenes, and the reaction product is monitored by TLC.
  • the ratio of borneol S/isoterenol S is unchanged and it is not selective.
  • the high-purity borneol referred to in the present invention refers to the isobornol in the borneol or camphor reduction product by generating isobornol aluminum, dehydrating rearrangement of terpenes, borneol and decene by distillation-sublimation method, column chromatography,
  • the extraction method can be used alone or in combination to prepare the borneol, or the camphor can be used to prepare the camphor reduction product, and then the borneol prepared by the above method, the high-purity borneol contains no or a small amount of isoborneol, and the range thereof In 65.0%-100%, divided into three levels: the borneol content of the first grade superior product is not less than 96.0%; the borneol content of the second grade product is lower than the first grade superior product, but not less than 85.0%; the third grade borneol content Less than the second grade, but not less than 65.0%.
  • the invention discloses a method for preparing high-purity borneol from camphor, camphor reduction products and borneol.
  • Those skilled in the art can learn from the preparation of this article, the preparation of aluminum secondary alcohol, the preparation of aluminum tertiary alcohol, the temperature of different dehydration rearrangements of different secondary aluminum alkoxides, aluminum alkoxides and isobornol aluminum, and long-brain aluminum replacement, borneol and sputum
  • the separation method of the olefin is appropriately modified and optimized.
  • the separation of borneol and iso-borne brain is to transform the iso-borne brain into iso-long brain aluminum, and then dehydrated and rearranged into terpenes at high temperature. It is to be understood that the present invention is not limited by the modifications and changes and combinations of the methods and principles described herein.
  • the second-class and the third-grade products can be realized under the condition of the first-class superior products, shortening the time of the dehydration of the terpene by the iso-long brain aluminum or reducing the conversion temperature or reducing the amount of the secondary alcohol or reducing the amount of the aluminum powder.
  • Example 1 is an example of isopropanol.
  • the borneol crystal solid contains a small amount of terpenes.
  • the borneol of a small amount of terpene was heated and dissolved, and then sublimed at 170 ° C - 180 ° C to obtain 40.2 g.
  • the purity of the borneol was 96.8% by GC, and the borneol yield was 40.2%.
  • the borneol crystal solid contains a small amount of terpenes.
  • the lower layer solution was siphoned, diluted with water, filtered, and crystallized once in ethanol to obtain 36.8 g.
  • the purity of the borneol was 96.1% based on borneol.
  • the upper cyclohexane layer still contains a small amount of borneol, and the main contains terpene.
  • the cedar-containing silica gel in the column was eluted with ethyl acetate, and the ethyl acetate eluent was recovered to obtain 48.7 g of borneol, which was determined by GC purity to be 98.4%.
  • the main borneol crystal solid contains a small amount of borneol.
  • the borneol of a small amount of terpene was heated and dissolved, and then sublimed at 170 ° C - 180 ° C to obtain 38.5 g, the purity of the borneol was 96.5%, and the yield was 32.1% based on camphor.

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Abstract

由樟脑及其还原产物、冰片制备高纯度龙脑的方法，樟脑及其还原产物所含樟脑，冰片中所含樟脑采用异丙醇铝、钠－醇法、雷尼镍等还原法，生成龙脑和异龙脑。樟脑还原产物或冰片与低沸点仲醇－仲醇铝或叔醇－叔醇铝，通过密闭加热蒸出低沸点仲醇或叔醇，生成龙脑铝或异龙脑铝，继续密闭加热，异龙脑脱水重排生成莰烯，通过水蒸汽蒸馏，蒸出莰烯和龙脑。莰烯和龙脑通过蒸馏—升华法、萃取法、柱层析法单用或组合使用可实现分离。整个工艺流畅，操作简单，绿色环保，试剂低廉，成本低，易于工业生产，龙脑收率高。该法可除去冰片、樟脑还原产物中的樟脑、重金属、异龙脑，所得的龙脑含量较高，并提供了由冰片、樟脑还原产物制备莰烯的方法。

Description

由樟脑及其还原产物、冰片制备高纯度龙脑的方法 技术领域
由樟脑及其还原产物、冰片制备高纯度龙脑的制备方法，其领域为化学和医药。
背景技术
冰片的药理作用及临床应用：冰片具有开窍醒神、清热止痛之功效，用于热病神昏、惊厥、中风痰厥、气郁暴厥、中恶昏迷、胸痹心痛，目赤，口疮，咽喉肿痛，耳道流脓等病症。冰片在中成药制剂中发挥多种功效，在医药领域应用非常广泛。从4个方面简要阐冰片的药理作用及主要药品：(1)对中枢神经系统的作用：冰片对中枢神经兴奋性有较强的双向调节作用，既有镇静安神功效，又有醒脑作用。主要产品有雪抑乐、脑通注射液、珠珀清脑片。(2)对循环系统的作用：对恢复心梗死区血流量、减慢心率、降低心肌耗氧量有治疗效果。主要产品复方丹参制剂、苏合香丸、冠心苏合丸、牛黄降压胶囊、苏冰滴丸。(3)促进药物吸收作用：冰片能够促进药物吸收，提高血管壁通透性，开放血-脑脊液屏障及血脑屏障，抑制药物肝脏代谢，从而提高其他药物的治疗效果。主要产品有磺啶冰黄片、双清注射液、安宫牛黄丸、骨友灵贴膏、金银三七胶囊、痛可舒酊、透骨灵橡胶膏、雪莲痛贴、金蓝气雾剂。(4)抗菌、抗炎、镇痛作用：冰片可去腐生肌、消肿止痛，故多用于口疮、痈肿，现代医药学试验证明，冰片有抗菌、消炎、止痛作用。主要产品有牛黄解毒丸、华佗再造丸、喉痛消炎丸、冰硼散、冰硼含片、五灵止痛胶囊、硼酸冰片滴耳液、醋酸氟轻松冰片乳膏、舒肤止痒酊、冰玉栓、珍珠明目滴眼液、麝香痔疮栓、赛霉安乳膏、麝香正骨水。冰片作为一种重要的中成药原料具有不可替代的药理作用，随着冰片的研究不断深入，研究成果的不断普及，医药对冰片认识逐渐深入，冰片在临床上用途将逐渐扩宽。
香料和化妆品行业中的应用：冰片作为一种重要的香料，广泛用于配制迷迭香、熏衣草型香精。由于冰片对人体具有独特的清凉感，香精香料企业推出了一系列以冰片为主要成分的产品，并被下游终端消费者所接受，特别是在沐浴露、洗发露及护肤用品方面，冰片的应用日益广泛，因此冰片在合成香料领域的应用也将保持持续增长。
冰片的有效物质基础及杂质：2010版药典一部规定冰片的质量标准，含龙脑不得少于55.0％，樟脑不得过0.50％、重金属不得过百万分之五，砷量不得过百万分之二、不挥发物每10g不得过3.5mg。根据药典标准，冰片真正的有效物质是龙脑，龙脑的量不少于55.0％，其余为杂质，均不能超过标准。以百分比计算，重金属、砷盐、不挥发物忽略不计，其异龙脑量为100％-0.50％-55.0％＝44.50％，计冰片中异龙脑量不得超过44.50％，异龙脑也是杂质。其中，龙脑包括左旋龙脑和右旋龙脑，樟脑包括左旋樟脑和右旋樟脑，异龙脑包括左旋异龙脑和右旋异龙脑，右旋龙脑如结构(1)、左旋龙脑如结构(2)、右旋异龙脑如结构(3)、左旋异龙脑如结构(4)、右旋樟脑如结构(5)、左旋樟脑如结构(6)。
Figure PCTCN2015072066-appb-000001
龙脑与异龙脑、樟脑的性质：右旋龙脑熔点为208℃，沸点212℃，左旋龙脑熔点为204℃，沸点210℃。异龙脑熔点为208-214℃，沸点为212℃。樟脑的熔点179℃，沸点为204℃。龙脑、异龙脑不溶于水，溶于乙醇、乙醚、氯仿、石油醚而不浑浊。樟脑微溶于水，溶于乙醇、乙醚、氯仿、石油醚。在上述性质中，除旋光度外，龙脑与异龙脑在极性、沸点十分接近，龙脑与樟脑在极性、沸点有着很小差别。
重金属、砷盐的毒性及危害：重金属指相对密度在5以上的金属，在实验条件下能与硫代乙酰胺或硫化钠作用显色的金属杂质。常见的重金属有铅、汞、砷、镉、铜等，由于铅较易带入药品中，且对人体危害较大，故进行重金属检查时常以铅为代表。重金属毒性较大，易积蓄，使蛋白质产生不可逆转的变性，能导致机体严重中毒症状。砷盐，如AsO3 2-、As2O3等，其中残存的三价砷盐毒性极强，可引起严重的中毒症，危害生命安全。
樟脑、异龙脑的药理毒理：樟脑有兴奋、强心、消炎、镇痛、抗菌、止咳、促渗、杀螨等药理作用，并与其他药物间相互作用，是世界上最早被使用的天然有机化学成分之一。樟脑应用广泛，又具有较强毒性，表现在对卵巢、睾丸、神经、肝脏、心脏、胎儿、孕妇的明显毒性，对肾脏泌尿系统的潜在毒性和较小遗传毒性。异龙脑药理作用和龙脑类似，龙脑和异龙脑在体内发挥作用之后，与葡萄糖醛酸结合，排出体外。二者在体内代谢速率不一样，龙脑羟基处于平伏键，有利于和葡萄糖醛酸结合，而异龙脑的羟基处于直立键，葡萄糖醛酸和其结合，受到1,7,7-三甲基空间位阻，结合难度比较大；结合之后，葡萄糖醛酸苷中糖环的上端，6-COOH和异龙脑，均是大基团，特别是异龙脑直立1,7,7-三甲基，导致糖环的空间张力很大，很不稳定，易于水解。二者的作用，使其代谢速度慢，在体内停留时间长，作用影响大，也导致其副作用较为突出。
研究表明，天然冰片、冰片、艾片三者对小鼠的半数致死量(LD)，以天然冰片剂量最大，合成冰片次之，艾片最小，究其原因艾片樟脑含量最高，毒性最大。高剂量合成冰片对小鼠的一般生殖毒性高于天然冰片，究其原因，合成冰片中异龙脑含量很多，作用较强，毒性较大。如药典规定：入丸服用，天然冰片用量为0.3g-0.9g，而艾片、冰片只能用到0.15g-0.3g。故三种冰片所含正龙脑量越高，有害物质就越少，安全性就越高。
龙脑与重金属、砷盐的分离：重金属在氧化态、还原态以及单质(除汞外)，均不具备挥发性，故龙脑和重金属的分离，可以通过水蒸汽蒸馏。Hg基本不溶于常见的溶剂，而且密度大，常常沉淀在容器的底部，故金属汞的分离，可以用有机溶剂溶解，分取上层溶液即可。当砷盐以氧化态存在时，如AsO3 2-、As2O3也不具有挥发性，亦可通过水蒸汽蒸馏，达到龙脑和重金属的分离；当砷被还原，以AsH3存在时，由于AsH3可溶于水(200mL/L)，并且在常温下为气体，而龙脑不溶于水，常温下为固体，故通过水蒸汽蒸馏，龙脑、AsH3随水蒸汽被蒸出，龙脑遇冷凝水冷凝析出，AsH3随冷凝水流走，也达到分离AsH3和龙脑的效果。龙脑沸点高，水蒸气蒸馏速度慢。单独使用水蒸汽蒸馏除去离重金属，将耗费较多的能量。
龙脑与樟脑的分离及缺点：龙脑和樟脑在乙醇中溶解度略有不同，利用樟脑在乙醇溶解度大，在放冷的情况下，较龙脑析出速度慢，需反复多次乙醇重 结晶才能分离。其分离过程中，存在结晶次数多，损耗量大，产率低，成本高。该方法主要用于昂贵的天然冰片和天然樟脑的分离。
龙脑与异龙脑的分离及缺点：由于龙脑、异龙脑性质十分接近，就目前常规科学手段，难以规模化分离。科学家们进行诸多研究，人们采用衍生化、异构化分离，然条件苛刻，尚难以进行工业化生产。如异龙脑异构化正龙脑，以苯作溶剂，异龙脑和钠作用，于270℃高温下，异龙脑异构化正龙脑。由于苯沸点只有80.1℃，易燃、易挥发，且有剧毒，安全性极差。张淑娴等硼酸与龙脑、异龙脑和樟脑的混合物进行反应，得到硼酸莰酯和樟脑。该法能够分离出樟脑和龙脑(异龙脑)，当温度较高，异龙脑脱水形成莰烯，但龙脑和异龙脑的纯度比例不变，表明龙脑和异龙脑分离不好。同时所用到的溶剂为苯或二甲苯，其溶剂毒性也较大，无实用价值。故龙脑与异龙脑的工业化分离技术，至今尚没解决。
松节油主要化学成分及产量：松节油是松科松属植物分泌的松脂经过蒸馏得到的挥发油，是由萜烯类化合物组成的液体混合物，主要成分是α-蒎烯和β-蒎烯。根据制备方法的不同，松节油可划分为脂松节油、硫酸盐松节油、木松节油和干馏松节油，其中脂松节油和硫酸盐松节油能够应用于大规模工业化生产。近年来，全球松节油年产量约25-30万吨，其中硫酸盐松节油15-18万吨，脂松节油10-15万吨。中国为脂松节油主产国，年产脂松节油9-11万吨。
合成冰片及樟脑的制备方法：(1)合成冰片的制备：松节油中轻油中的α-蒎烯经过无水草酸酯化生成草酸龙脑酯混合物，经水蒸汽蒸馏，得挥发性白轻油和不挥发性草酸龙脑酯，后者经皂化和氢氧化钠溶液得水龙脑，再经分离和提纯即得冰片。中国药典所规定冰片，是通过该法制备，其冰片含有一定量的异龙脑。(2)合成樟脑的制备：松节油中轻油中的α-蒎烯经过钛等酸催化剂异构蒸馏，转变成莰烯。莰烯经冰醋酸酯化，生成乙酸异龙脑酯，再水解生成异龙脑，异龙脑再经过脱氢提纯，得到合成樟脑。
樟脑选择性还原现状及缺点：我国的樟脑及天然樟脑产量均居于世界第一，樟脑通过加氢还原，可以制备龙脑和异龙脑。由于龙脑含量越高，冰片的品质越佳，故在樟脑还原过程中，尽可能提高龙脑/异龙脑的比率。从七个方面对樟脑不对称还原龙脑的作一简要阐述：(一)使用硅烷制取：20世纪70年代有人研究用硅烷从樟脑制取龙脑，在RhCl(PPh3)4的催化下，樟脑与硅烷作用生 成硅醚，水解后即得龙脑。其异龙脑的含量高达73％～90％，龙脑含量较少。如在同样条件下，使用硅烷(CH3CH2)3SiH，则异龙脑的含量下降为35％([1]Ojima I,NihonyanagiM,Nagai Y.Stereoselective reduction of ketones with hydrosilane-rhod ium(I)complex combinations[J].Bull Chem Soc Jap,1972,45:3722)。(二)使用碱金属还原：樟脑不对称合成龙脑的研究，最成熟的是碱金属/NH3法。Huffman等报道了在液氨中用化学方法不对称还原樟脑，收率达到了95％,e.e值达到了85％。但须在超低温(-33～-78℃)的条件下进行，制备条件较苛刻，难以工业化生产([2]JohnW Huffman,WilliamW McWhorter.Dissolvingmetal reduction of cyclic ketones[J].J Org Chem,1979,44(4):594-599)。其次，碱金属/无水乙醇和碱金属/THF体系用于樟脑不对称还原时也取得了一定的成就。如王宁辉等人分别用以上两种方法进行的研究中，无水乙醇体系得到的右旋龙脑达80％，而THF体系得到的右旋龙脑比例较低72％([3]王宁辉,赵鹏,王维德,等.樟脑手性合成右旋龙脑.华侨大学学报:自然科学版,2006,27(1):89-91)。王维德等利用樟脑还原中间产物的分子热力学稳定性的差异，还原剂S/无水乙醇中进行樟脑的不对称还原,在该体系中还原樟脑的主产物为右旋龙脑，副产物为异龙脑，两者的比例几乎固定不变，反应所得樟脑最高转化率为78％,右旋龙脑最高产率为66％([4]王维德,黄颖芬,王宁辉,等.天然脑粉不对称还原制右旋龙脑[J].华侨大学学报(自然科学版)，2007.28(4)410-412)。黄颖芬等人用金属钠/无水乙醇体系对樟脑还原进行了详细的研究，研究表明樟脑的转化率可达到98.9％，龙脑产率81.7％([5]黄颖芬，王维德，王宁辉，等.天然脑粉二次还原精制右旋龙脑[J].化学工业与工程,2008,27(1))。(三)固体酸催化α-蒎烯和松节油：陈慧宗等人对CLY纳米催化剂催化α-蒎烯酯化-皂化法合成龙脑进行了研究([6]陈慧宗,刘永根.CLY纳米催化剂催化α-蒎烯合成龙脑[J].精细化工,2005,22(4):277-279)。刘天成等人研究了MoO3/TiO2固体超强酸催化剂催化松节油与草酸、氯乙酸、三氯乙酸反应的规律。催化剂用量为松节油质量的5％，松节油∶氯乙酸为100∶25(质量比)时，龙脑得率52.93％，正龙脑的选择性为60.46％([7]刘天成,宁平.MoO3/TiO2-固体超强酸催化松节油合成龙脑的研究[J].生物质化学工程，2007,41(3):27-30)。刘永根等采用纳米固体超强酸SO4 2-/TiO2为催化剂，用氯乙酸和α-蒎烯在一定温度下合成外型龙脑。但是传统硼酸酐催化a-蒎 烯酯化－皂化法中存在易冲料、安全性小、腐蚀性大、污染严重等缺点，难以实现工业化([8]刘永根,邓志红等.合成外型龙脑的新方法[J].江西师范大学学报，2004，28(3):193-195)。(四)使用格氏试剂：宋新鲁等人利用天然樟脑与β-2C上有活泼氢的格氏试剂反应时主要得到异冰片，冰片的产率很低。这是由于天然樟脑与β-2C上有活泼氢的格氏试剂反应时，由于樟脑分子外侧空阻大于内侧空阻，格氏试剂立体选择性地主要从空阻小的内侧进攻羰基，发生加氢反应，得到以外型为主的冰片(异冰片)([9]宋新鲁，杨义文.格氏试剂还原樟脑的立体选择性研究[J].江西师范大学学报，2007，31(2):141-143)。(五)电还原樟脑合成龙脑：以樟脑为原料用电化学方法合成了龙脑，在反应温度40℃下电解合成龙脑的收率为40.0％，其中正龙脑产率为31.3％，异龙脑产率为8.7％。，在樟脑与龙脑的分离上，采用利用邻苯二甲酸酐与龙脑成酯的分离，其方法繁琐，成本较高，在龙脑与异龙脑的分离上，采用硅胶H柱层析分离，由于龙脑和异龙脑在硅胶上，差异不大，要想获得良好的分离，其硅胶柱层析必须足够长，才可以获得良好的分离([10]杨国英.电化学合成苯甲酸、龙脑的研究[D].福建师范大学，2007：42-45)。故该方法工业化意义不大。(六)雷尼镍催化还原：采用D-酒石酸修饰RaneyNi，将天然脑粉中的樟脑不对称还原为龙脑。其还原方法为3g樟脑，修饰后的3g D-酒石酸修饰过的RaneyNi催化剂，500ml无水乙醇，1g乙酸钠，搅拌速度800r/min，在60℃反应10h，据文中优选的体系，樟脑转化率未超过21％，龙脑未超过80％，不具备工业化生产([110]焦广霞.D-酒石酸修饰RaneyNi催化樟脑不对称加氢合成龙脑[D].华侨大学，2011)。Ni-B/γ-Al2O3催化樟脑加氢还原，樟脑的转化率高达81.50％，异龙脑产率76.57％，e.e.值达87.87％，由于异龙脑过高，不具备应用价值([12]燕芳.Ni-B非晶合金制备及其对樟脑催化加氢性能研究杨[D].华侨大学，2011：51)。(七)其它方面：王宁辉等人，用右旋联萘酚改性过的氢化铝锂为手性试剂，把樟脑还原成右旋龙脑，得到转化率为82.4％、产率为24.55％、相对旋光度为69.2％的右旋产物([3])。LiAlH4作为还原剂，D-樟脑转化率可达80％，其中D-龙脑约90％、D-异龙脑10％，该法的缺点是LiAlH4价格昂贵，产物中有樟脑、异龙脑不好分离。NaBH4作为还原剂，D-樟脑主要转化为异龙脑，不具备价值。异丙醇铝作为还原剂，D-樟脑转化率可达100％，其中D-龙脑达63％，D-异龙脑达37％。由于樟脑较ɑ －松节油贵几倍，因此用樟脑制备冰片的成本较高，而且产物中尚有较多量的异龙脑。综上所述，一方面龙脑的产率虽较高的方法，但制备条件较苛刻，难以工业化生，或者还原剂过于昂贵，成本太高；另一方面，樟脑催化还原选择性差，在还原产物中均有一定量的异龙脑和占樟脑，后处理繁琐。因此，迄今为止，尚无一种很好，价格低廉，可产业化制备高纯度龙脑的一种方法。
冰片中龙脑纯度及发展趋势：冰片的有效物质为龙脑，龙脑纯度越高，冰片的品质越好，价格也越贵。中国药典规定天然冰片以右旋龙脑计，不得低于96.0％，艾片以左旋龙脑计，不得低于85.0％。天然冰片和艾片分别从龙脑樟和艾纳香中提取，一方面其提取物中含有较多樟脑，通过乙醇反复重结晶去除樟脑，其工艺复杂，收率低。另一方面右旋龙脑和左旋龙脑在植物中含量低，需要大规模化种植，也将占用大量耕地。两个方面导致天然冰片或艾片价格昂贵，每公斤高达上千元。与天然冰片或艾片相比，合成冰片只有几十元，因此现在大多数中成药制剂，采用合成冰片。由于合成冰片中含有较多异龙脑、尚残留微量樟脑、重金属及砷盐，美国已经禁止合成冰片入药，英国也将于2014年禁止重金属超标的中药销售，其他发达国家也可能会采用相应的政策。因此，就以后发展趋势而言，对冰片中异龙脑、樟脑、重金属的去除，提高龙脑的纯度，破在眉睫，利用樟脑，樟脑还原产物制备高纯度龙脑，也破在眉睫。
发明内容
本发明针对上述的龙脑与异龙脑、樟脑性质接近、沸点接近，难以分离的问题，采用仲醇－仲醇铝将少量樟脑还原成龙脑和异龙脑，除去樟脑。采用沸点较低的仲醇－仲醇铝或叔醇－叔醇铝与龙脑和异龙脑进行置换，生成龙脑铝和异龙脑铝。利用异龙脑铝的热稳定性远小于龙脑铝的热稳定性，在高温下在一定龙脑铝配比下，异龙脑铝脱水的速度远大于龙脑铝脱水的速度，生成龙脑铝和莰烯，通过水蒸汽蒸馏，蒸出龙脑和莰烯。利用莰烯在极性、沸点等方面，与龙脑有明显差异，通过蒸馏、柱层析、萃取等方法单用或组合均可以使龙脑和莰烯二者分离。因此，该方法将樟脑还原、异龙脑脱水、仲醇或叔醇的回收、蒸馏出龙脑和莰烯、并除掉重金属和砷盐，其操作可一体化，龙脑和莰烯的分离简单，效率较高。整个工艺成本低廉，环境污染较小，易于工业化生产。
为了进一步理解本发明和指导思想，以详细化学反应式说明。由于涉及 仲醇铝和叔醇铝较多，以异丙醇为例，详细化学反应式说明如下：异丙醇铝－异丙醇可以购买，也可以异丙醇和铝反应自制，自制见(I)；
Figure PCTCN2015072066-appb-000002
异丙醇铝－异丙醇用于樟脑的还原及产物见(II)，其中异丙醇起到溶剂，可以溶解樟脑或冰片，不断蒸出含有丙酮的异丙醇溶剂，樟脑不断被还原。其中异丙醇沸点为84℃，丙酮沸点为56℃，樟脑的沸点为204℃，龙脑、异龙脑沸点范围在208-214℃。沸点低的试剂或化合物优先挥发；
Figure PCTCN2015072066-appb-000003
异丙醇和异丙醇铝置换龙脑铝和异龙脑铝见(III)，其中异丙醇作为溶剂，溶解樟脑还原产物或冰片，形成均匀溶液，然后不断蒸出异丙醇，形成龙脑铝和异龙脑铝；
Figure PCTCN2015072066-appb-000004
当R1、R2均为异丙醇基时，龙脑铝和异龙脑铝在高热下脱水生成莰烯，异龙脑铝优先脱水重排生成莰烯，为莰烯主要生成物，见(IV)，其中当R1、R2任一为异丙醇基时，异龙脑铝优先脱水，龙脑铝脱水增多，当R1和R2均不为异丙醇时，龙脑铝和异龙脑铝均显著脱水重排，此法可用来制备莰烯，在较高温度下，也有一定量的龙脑或异龙脑脱水生成樟脑；
Figure PCTCN2015072066-appb-000005
龙脑铝和莰烯在水液中，经水蒸气蒸馏，龙脑铝水解生成龙脑，与莰烯一起可被蒸馏，见(V)；
Figure PCTCN2015072066-appb-000006
上述的五种化学反应式，可在同一反应器中，不需分离，连续进行，操作简单。
利用莰烯沸点为159℃，龙脑沸点210-212℃，利用沸点有较大差别，可用蒸馏法-升华法分离龙脑和莰烯；
利用莰烯难溶于DMSO、DMF，而易溶于石油醚、汽油、环己烷等饱和烃，龙脑在DMSO、DMF中具有较大溶解度，可以通过萃取法分离龙脑和莰烯；
利用龙脑极性大于莰烯，以石油醚、环己烷、汽油等饱和烃作为洗脱剂，氧化铝、硅胶层析剂能吸附龙脑，而对莰烯的吸附力很弱，可以利用柱层析法分离龙脑和莰烯；如莰烯的乙酸乙酯溶液、冰片的乙酸乙酯溶液、龙脑+莰烯的乙酸乙酯溶液作为样品液，点于羧甲基纤维素钠硅胶G薄层板，以环己烷为展开剂，新制的1％香草醛浓硫酸作显色剂，薄层喷雾显色。结果冰片、龙脑基本停留在原点，其Rf值小于0.1，而莰烯在展开剂前沿，其Rf值大于0.9。
本发明所涉及的冰片，主要指由松节油α-蒎烯制得，主含左旋龙脑和右旋龙脑、左旋异龙脑、右旋异龙脑、尚含少量或微量的右旋樟脑、左旋樟脑组成的混合物，右旋龙脑如结构(1)、左旋龙脑如结构(2)、右旋异龙脑如结构(3)、左旋异龙脑如结构(4)、右旋樟脑如结构(5)、左旋樟脑如结构(6)。
Figure PCTCN2015072066-appb-000007
本发明涉及樟脑，主要指由α-蒎烯制得的合成樟脑，为右旋樟脑和左旋樟脑的混合物，右旋樟脑如结构(5)、左旋樟脑如结构(6)。
Figure PCTCN2015072066-appb-000008
本发明涉及樟脑还原产物，主要指合成樟脑通过醇－Na、异丙醇－异丙醇铝、H2－Pt、雷尼镍等还原剂还原而成，主含左旋龙脑和右旋龙脑、左旋异龙脑、右旋异龙脑、尚含少量或微量的右旋樟脑、左旋樟脑组成的混合物，右旋龙脑如结构(1)、左旋龙脑如结构(2)、右旋异龙脑如结构(3)、左旋异龙脑如结构(4)、右旋樟脑如结构(5)、左旋樟脑如结构(6)。
Figure PCTCN2015072066-appb-000009
本发明涉及龙脑，指左旋龙脑和右旋龙脑的混合物，右旋龙脑如结构(1)、左旋龙脑如结构(2)。
Figure PCTCN2015072066-appb-000010
本发明涉及异龙脑，指左旋异龙脑和右旋异龙脑的混合物，右旋异龙脑如结构(1)、左旋异龙脑如结构(2)。
Figure PCTCN2015072066-appb-000011
本发明所说的莰烯，是指由右旋异龙脑和左旋异龙脑脱水重排而成，其莰烯纯度不低于90.0％，莰烯如结构(7)。
Figure PCTCN2015072066-appb-000012
本发明所说的仲醇指沸点低于樟脑沸点的仲醇，包括异丙醇、环己醇、异丁醇、2-戊醇、3-戊醇，2-己醇、3-己醇等，或上述两种及两种以上醇的混合物，优选异丙醇。
本发明所说的叔醇指沸点低于樟脑沸点的叔醇，包括叔丁醇、叔戊醇、3-乙基-3-戊醇等。
本发明所说的仲醇铝与叔醇铝，仲醇铝指仲醇与铝粉经AlCl3/HgCl2/I2催化剂制备仲醇铝，也指直接购买仲醇铝试剂；叔醇铝指叔醇与铝粉经AlCl3,HgCl2,I2催化剂制备仲醇铝，也指直接购买仲醇铝试剂。
本发明中，仲醇－仲醇铝起到还原樟脑的作用，其仲醇用量和樟脑的含量有关，樟脑含量越多，仲醇用量越多，仲醇与冰片或樟脑或樟脑还原产物的重量比例在100：1-1：0.5，当樟脑含量小于3％时，仲醇用量优选为2-3倍量起始产物重量(如起始产物选天然冰片，仲醇选异丙醇，当天然冰片中天然樟脑含量为≦3％时，100g天然冰片，需要200g-300g异丙醇(AR))；当樟脑在3％的基础上，其含量每增加1％，仲醇用量增加0.5-1倍量起始物重量。
本发明中，仲醇－仲醇铝与龙脑和异龙脑起到作用置换作用，生成龙脑 铝和异龙脑铝，其中仲醇作为溶剂的用量，优选起始物重量的2-3倍。
本发明中，叔醇－叔醇铝与龙脑和异龙脑起到作用置换作用，生成龙脑铝和异龙脑铝，其叔醇作为溶剂的用量优选起始物重量的2-3倍。
本发明中，仲醇－仲醇铝起到还原樟脑的作用，其仲醇铝的摩尔用量和樟脑的含量有关，樟脑含量越多，仲醇铝的摩尔用量也多，冰片、樟脑及其还原产物与仲醇铝的摩尔比例1：10-100：1，当樟脑含量小于3％时，仲醇铝的摩尔用量优选为1/5-1/3倍起始产物的摩尔用量(如起始产物选冰片，仲醇铝选异丙醇，当天然冰片中天然樟脑含量为≦3％时，100g天然冰片，需要35g异丙醇铝(AR))；当樟脑(天然樟脑)含量在3％的基础上，樟脑每增加1％，仲醇铝用量增加0.5％起始物的摩尔的重量。
本发明中，仲醇－仲醇铝与龙脑和异龙脑起到作用置换作用，生成龙脑铝和异龙脑铝，其仲醇铝的用量和异龙脑的含量有关，异龙脑含量越多，仲醇铝的摩尔用量也越多，仲醇铝的摩尔用量与冰片或樟脑还原产物总摩尔用量的比在1/8－1/1，其中优选1/5-1/3。
本发明中，叔醇－叔醇铝与龙脑和异龙脑起到作用置换作用，生成龙脑铝和异龙脑铝，其叔醇铝的用量和异龙脑的含量有关，异龙脑含量越多，叔醇铝的摩尔用量也越多，叔醇铝的摩尔用量与龙脑和异龙脑总摩尔用量的比在1/8－1/1，其中优选1/5-1/3。
在本发明中，仲醇铝还原樟脑，优选异丙醇，其还原温度80℃-130℃，优选105℃-115℃。
在本发明中，仲醇铝与龙脑和异龙脑密闭蒸馏置换生成龙脑铝和异龙脑铝，优选异丙醇，置换温度在80℃-150℃，其中优选110℃-130℃。
在本发明中，龙脑铝和异龙脑铝密闭蒸馏脱水重排莰烯的温度130℃-270℃，优选异龙脑铝脱水重排温度为140℃-180℃。
在本发明中，龙脑和莰烯的提纯，通过水蒸汽蒸馏，龙脑铝水解生成龙脑和氢氧化铝，龙脑与莰烯一起被蒸馏出来，得到莰烯和龙脑混合物，氢氧化铝不挥发。
在本发明中，通过蒸馏-升华法分离莰烯和龙脑，其蒸馏-升华在140℃-210℃升华，优选160℃-185℃。
在本发明中，DMSO、DMF等极性溶剂，主要指DMSO、DMF、丙三醇、乙二醇、1，3-丙二醇，甲基甲酰胺、甲酰胺等，用于萃取时，极性溶剂与龙脑的比例优选不低于3：1。
在本发明中，饱和烃主要指低沸点饱和烃及其混合物，石油醚、汽油、环己烷、正己烷、环戊烷、正戊烷等，在溶解龙脑和莰烯混合物，在萃取中，起到溶解莰烯；在柱层析的洗脱中起到洗脱莰烯。
在本发明中，柱层析填料主要指硅胶、氧化铝，启到吸附龙脑作用，与龙脑的比例3：1-10：1，其中优选4：1-5：1。
在本发明中，铝粉与冰片或樟脑还原物用于生成龙脑铝和异龙脑铝，异龙脑铝脱水重排作用，铝粉与冰片或樟脑还原物重量比1：1-1：100，其中当樟脑含量较少时，铝粉与与冰片或樟脑还原物重量比优选1：20-1：40。
在本发明中，通过氧化铝、硅胶等柱层析作为吸附剂，其洗脱剂优选极性较大大、沸点低、易溶解龙脑的试剂，如乙酸乙酯、乙醇等。
对冰片、樟脑还原产物中的异龙脑转变成莰烯，可以用TLC跟踪检查，具体方法为龙脑铝和异龙脑铝高温脱水物，用乙酸乙酯和水溶解，龙脑铝(异龙脑铝)经水解转变成龙脑(异龙脑)和异龙脑铝脱水成的莰烯，二者均溶于乙酸乙酯，作为样品液，以环己烷－乙酸乙酯(6：1)为展开剂，新制备1％香草醛浓硫酸为显色剂，龙脑S/异龙脑S显著增大(S：表示斑点面积)，直至异龙脑S不明显或没有，而在溶剂前沿有莰烯，龙脑、异龙脑呈鲜红色斑点，莰烯成紫红斑点，此法监控较GC方便；
用异丙醇-异丙醇Na、甲醇-甲醇镁等对冰片进行密闭蒸馏置换，高温化异构，结果未见异龙脑异构化龙脑产物，而是龙脑和异龙脑脱水重排成莰烯，反应产物中，以TLC监控，龙脑S/异龙脑S比例不变，不具备选择性。
本发明所说的高纯度龙脑，指冰片或樟脑还原产物中的异龙脑通过生成异龙脑铝，脱水重排莰烯，龙脑和莰烯通过蒸馏－升华法、柱层析法、萃取法单用或组合使用制备而成的龙脑，或将樟脑制备樟脑还原产物，再通过上述方法制备而成的龙脑，高纯度龙脑中不含或含少量的异龙脑，其范围在65.0％-100％，分三级：一级优等品龙脑含量不低于96.0％；二级品龙脑含量低于一级优等品，但不低于85.0％；三级品龙脑含量低于二级品，但不低于65.0％。
具体实施方式
本发明公开了樟脑、樟脑还原产物、冰片制备高纯度龙脑的方法。本领域技术人员可以借鉴本文内容，对仲醇铝的制备、叔醇铝的制备、不同仲醇铝、叔醇铝与异龙脑铝、龙脑铝置换脱水重排的温度、龙脑与莰烯的分离方法进行适当改进和优化。特别需要指出的在制备高纯度龙脑的方法中，龙脑和异龙脑的分离，是将异龙脑转变异龙脑铝，然后在高温下脱水重排成莰烯的。都将被视为本发明，相关人员明显不能在脱离本发明的内容、精神和范围对本文所述的方法、原理进行适当改动或变更与组合，来实现和应用本发明技术。
由于涉及的仲醇、叔醇的种类较多，不同还原剂对樟脑还原产物较多，冰片质量不低于55％规格较多。因此，不能对每一种醇类、每一种冰片类、每一种樟脑还原产物类进行举例说明，但为了进一步理解本发明，以樟脑被还原，异龙脑铝的制备、异龙脑铝脱水重排成莰烯，龙脑和莰烯的分离的过程，以异丙醇－异丙醇铝为例，制备一级优等品龙脑进一步说明本发明。其中，二级品、三级品可在一级优等品的条件下，缩短异龙脑铝脱水重排莰烯的时间或降低转化温度或减少仲醇铝或减少铝粉的用量等可实现。
实施例1异丙醇为例，
取4g铝粉(AR)，加入4g无水AlCl3(AR)，迅速混匀，加入异丙醇(AR)200ml，密闭下，于水浴回流反应12h，加入冰片100g，于水浴中至冰片溶解，摇匀，形成均相溶液。于气浴中120℃蒸馏异丙醇约170ml-180ml。密闭下，于气浴中150℃反应15h，加入水，温热2h后，通入蒸汽蒸馏，冷凝，馏出液先出来主含莰烯和少量龙脑的液体。后出来主含龙脑结晶固体，包含少量莰烯。将少量莰烯的龙脑加热溶解，然后于170℃-180℃升华，即得40.2g，经GC测定，龙脑纯度96.8％，以冰片计，龙脑收率40.2％。
实施例2
取4g铝粉(AR)，加入4g无水AlCl3(AR)，迅速混匀，加入异丙醇(AR)200ml，密闭下，于水浴回流反应12h，加入冰片100g，于水浴中至冰片溶解，摇匀，形成均相溶液。于气浴中120℃蒸馏异丙醇约170ml-180ml。密闭下，于气浴中150℃反应15h，加入水，温热2h后，通入蒸汽蒸馏，冷凝，馏出液先出来主含莰烯和少量龙脑的液体。后出来主含龙脑结晶固体，包含少量莰烯。将少量莰烯 的龙脑加入4倍量的环己烷溶解，分取上层溶液，以无水硫酸钠干燥，加入200mlDMSO(AR)，均匀，于10℃放置3-4h，分取下层溶液或虹吸下层溶液，加水稀释，滤过，在于乙醇中结晶1次，即得，36.8g，以冰片计，龙脑纯度为96.1％。其中上层环己烷层尚含少量龙脑，主含莰烯。
实施例3
取4g铝粉(AR)，加入4g无水AlCl3(AR)，迅速混匀，加入异丙醇(AR)200ml，密闭下，于水浴回流反应12h，加入冰片100g，于水浴中至冰片溶解，摇匀，形成均相溶液。于气浴中120℃蒸馏异丙醇约170ml-180ml。密闭下，于气浴中150℃反应15h，加入水，温热2h后，通入蒸汽蒸馏，冷凝，馏出液先出来主含莰烯和少量龙脑的液体，用4倍量的环己烷溶解，以无水硫酸钠干燥，得样品液(I)。后出来主含龙脑结晶固体，包含少量莰烯。将少量莰烯的龙脑加入4倍量的环己烷溶解，分取上层溶液，以无水硫酸钠干燥，得样品液(II)。取350g柱层析硅胶H(AR)，以内径为5cm的玻璃柱作为层析柱，装柱层析，先上样品液(I)，至层析柱上端样品液(I)很少，上样品液(II)，至层析柱上端样品液(II)很少时，用800ml环己烷洗脱，合并环己烷洗脱液，回收环己烷，得莰烯45g。层析柱中含龙脑的硅胶，再以乙酸乙酯洗脱，回收乙酸乙酯洗脱剂，得龙脑48.7g，经GC纯度测定，为98.4％。
实施例4
取17g铝粉(AR)，加入5g无水AlCl3，迅速混匀，再加入2.0gHgCl2(AR)，混匀，加入异丙醇(AR)1000ml，密闭下，约20min后，迅速反应，必要时用冷凝器冷凝。6h后，在于水浴中反应4h，加入樟脑120g，于气浴中110℃蒸馏出异丙醇。通入蒸汽，蒸馏，室温晾干，得樟脑还原产物(龙脑、异龙脑、少量樟脑混合物)100g。取4g铝粉，加入3.5g无水AlCl3，迅速混匀，加入异丙醇(AR)200ml，密闭下，于水浴回流反应12h，加入上述樟脑还原产物100g，于水浴中至樟脑还原产物溶解，摇匀，形成均相溶液。于气浴中120℃蒸馏异丙醇约170ml-180ml。密闭下，于气浴中150℃反应15h，加入水，温热2h后，通入蒸汽蒸馏，冷凝，馏出液先出来主含冰片烯和少量龙脑的液体。后出来主含龙脑结晶固体，包含少量冰片烯。将少量莰烯的龙脑加热溶解，然后于170℃-180℃升华，即得38.5g，龙脑纯度96.5％，以樟脑计，收率32.1％。
实施例5
取4g铝粉，置于1000ml三角烧瓶中，加入4g无水AlCl3，迅速混匀，混匀，加入异丙醇800ml，密闭下，在于水浴中反应8h，加入樟脑120g，于气浴中，瓶口接三叉蒸馏头，蒸馏头上端接一空气冷凝管，空气冷凝管上端接恒压漏斗。蒸馏头水平端接冷凝管，于110℃密闭蒸馏出异丙醇，每隔8h，用恒压漏斗加入异丙醇600ml，共加入异丙醇5000ml，共蒸出异丙醇5652ml。于150℃密闭蒸馏反应16h，加入水温2h后，通入蒸汽，蒸馏，冷凝，馏出液先出来主含莰烯和少量龙脑的液体。后出来主含龙脑结晶固体，包含少量冰片烯。将少量冰片烯的龙脑加热溶解，然后于170℃-180℃升华，即得30.4g，经GC测定龙脑纯度97.6％，以樟脑计，收率25.3％。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通人员来说，在不脱离本发明原理的前提下，还可以对异龙脑铝脱水转变莰烯、莰烯和龙脑的分离等，进行改进和优化，这些改进和优化也落入本发明权利要求保护范围之内。

Claims (27)

  1. 由樟脑及其还原产物、冰片制备高纯度龙脑的方法，其特征具体在于：以仲醇为溶剂，加入铝粉，以AlCl3/I2/HgCl2为催化剂，通过加热反应，制备仲醇－仲醇铝；
    采用低沸点的仲醇－仲醇铝溶液溶解樟脑或冰片或樟脑还原产物，在80℃-130℃蒸馏；
    用沸点较低的仲醇－仲醇铝或叔醇－叔醇铝溶液，溶解冰片或樟脑还原产物，在80℃-150℃通过密闭蒸馏低沸点溶剂，生成龙脑铝和异龙脑铝；
    龙脑铝和异龙脑铝在130℃-270℃下，继续密闭蒸馏，异龙脑铝脱水重排成莰烯；用水蒸汽蒸馏，冷却，得龙脑和莰烯混合物；
    龙脑、莰烯混合物，在140℃-220℃升华，分别得龙脑和莰烯；
    龙脑、莰烯混合物，经石油醚、环己烷、汽油等饱和烃溶解，用氧化铝、硅胶等层析柱，以石油醚、环己烷、汽油等饱和烃作为洗脱剂，回收洗脱剂，可得莰烯；用极性较大、沸点较低、冰片溶解度大的溶剂，如乙酸乙酯、乙醇等洗脱，回收洗脱剂，可得高纯度龙脑；
    龙脑、莰烯混合物，经石油醚、环己烷、汽油等饱和烃溶解，用DMF/DMSO等极性大溶剂萃取，分取下层，加水稀释可得高纯度龙脑；回收上层溶剂，可得莰烯。
  2. 如权利1要求所述，其特征在于：冰片，主要指由松节油α-蒎烯制得，主含左旋龙脑和右旋龙脑、左旋异龙脑、右旋异龙脑、尚含少量或微量的右旋樟脑、左旋樟脑组成的混合物，右旋龙脑如结构(1)、左旋龙脑如结构(2)、右旋异龙脑如结构(3)、左旋异龙脑如结构(4)、右旋樟脑如结构(5)、左旋樟脑如结构(6)。
    Figure PCTCN2015072066-appb-100001
  3. 如权利1要求所述，其特征在于：樟脑，主要指由α-蒎烯制得的合成樟脑，为右旋樟脑和左旋樟脑的混合物，右旋樟脑如结构(5)、左旋樟脑如结构(6)。
    Figure PCTCN2015072066-appb-100002
  4. 如权利1要求所述，其特征在于：樟脑还原产物，主要指合成樟脑通过醇－Na、异丙醇－异丙醇铝、H2－Pt、雷尼镍等还原剂还原而成，主含左旋龙脑和右旋龙脑、左旋异龙脑、右旋异龙脑、尚含少量或微量右旋樟脑、左旋樟脑，组成的混合物，右旋龙脑如结构(1)、左旋龙脑如结构(2)、右旋异龙脑如结构(3)、左旋异龙脑如结构(4)、右旋樟脑如结构(5)、左旋樟脑如结构(6)。
    Figure PCTCN2015072066-appb-100003
  5. 如权利1要求所述，其特征在于：龙脑，指左旋龙脑和右旋龙脑的混合物，右旋龙脑如结构(1)、左旋龙脑如结构(2)。
    Figure PCTCN2015072066-appb-100004
  6. 如权利1要求所述，其特征在于：莰烯，指由右旋异龙脑和左旋异龙脑脱水重排而成，莰烯如结构(7)。
    Figure PCTCN2015072066-appb-100005
  7. 如权利1要求所述，其特征在于：仲醇，指沸点低于樟脑沸点的仲醇，包括异丙醇、环己醇、异丁醇、2-戊醇、3-戊醇，2-己醇、3-己醇等，或上述两种及两种以上醇的混合物，优选异丙醇。
  8. 如权利1要求所述，其特征在于：叔醇，指沸点低于樟脑沸点的叔醇，包括叔丁醇、叔戊醇、3-乙基-3-戊醇等。
  9. 如权利1要求所述，其特征在于：仲醇铝与叔醇铝，仲醇铝指仲醇与铝粉经AlCl3/HgCl2/I2催化剂制备仲醇铝，也指直接购买仲醇铝试剂。
  10. 如权利1要求所述，其特征在于：叔醇铝指叔醇与铝粉经AlCl3,HgCl2,I2催化剂制备仲醇铝，也指直接购买仲醇铝试剂。
  11. 如权利1要求所述，其特征在于：仲醇－仲醇铝起到还原樟脑的作用，仲醇与冰片或樟脑或樟脑还原产物重量比例在100：1-1：0.5，当樟脑含量小于3％时，仲醇用量优选为2-3倍量起始产物重量；当樟脑在3％的基础上，其含量每增加1％，仲醇用量增加0.5-1倍量起始物重量。
  12. 如权利1要求所述，其特征在于：仲醇－仲醇铝与龙脑和异龙脑起到作用置换作用，生成龙脑铝和异龙脑铝，其仲醇作为溶剂的用量优选起始物重量的2-3倍。
  13. 如权利1要求所述，其特征在于：叔醇－叔醇铝与龙脑和异龙脑起到作用置换作用，生成龙脑铝和异龙脑铝，其叔醇作为溶剂的用量优选起始物重量的2-3倍。
  14. 如权利1要求所述，其特征在于：仲醇－仲醇铝起到还原樟脑的作用，其仲醇铝与冰片或樟脑或樟脑其还原产物与仲醇铝的摩尔比例1：10-100：1，当樟脑含量小于3％时，仲醇铝的摩尔用量优选为1/5-1/3倍起始产物的摩尔用量；当樟脑(天然樟脑)含量在3％的基础上，樟脑每增加1％，仲醇铝用量增加0.5％起始物的摩尔的重量。
  15. 如权利1要求所述，其特征在于：仲醇－仲醇铝与龙脑和异龙脑起到作用置换作用，生成龙脑铝和异龙脑铝，仲醇铝的摩尔用量与冰片或樟脑还原产物总摩尔用量的比在1/8－1/1，其中优选1/5-1/3。
  16. 如权利1要求所述，其特征在于：叔醇－叔醇铝与龙脑和异龙脑起到作用置换作用，生成龙脑铝和异龙脑铝，叔醇铝的摩尔用量也越多，叔醇铝的摩尔用量 与龙脑和异龙脑总摩尔用量的比在1/8－1/1，其中优选1/5-1/3。
  17. 如权利1要求所述，其特征在于：仲醇铝还原樟脑，优选异丙醇，其还原温度80℃-130℃，优选105℃-115℃。
  18. 如权利1要求所述，其特征在于：仲醇铝与龙脑和异龙脑密闭蒸馏置换生成龙脑铝和异龙脑铝，优选异丙醇，置换温度在80℃-150℃，其中优选110℃-130℃。
  19. 如权利1要求所述，其特征在于：龙脑铝和异龙脑铝密闭蒸馏脱水重排莰烯的温度130℃-270℃，优选异龙脑铝脱水重排温度为140℃-180℃。
  20. 如权利1要求所述，其特征在于：龙脑和莰烯的提纯，通过水蒸汽蒸馏，龙脑铝水解生成龙脑和氢氧化铝，龙脑与莰烯一起被蒸馏出来，得到莰烯和龙脑混合物。
  21. 如权利1要求所述，其特征在于：蒸馏-升华法分离莰烯和龙脑，其蒸馏-升华在140℃-210℃升华，优选160℃-185℃。
  22. 如权利1要求所述，其特征在于：萃取法所用的极性溶剂，主要指DMSO、DMF、丙三醇、乙二醇、1，3-丙二醇，甲基甲酰胺、甲酰胺等，用于萃取时，极性溶剂与龙脑的比例优选不低于3：1。
  23. 如权利1要求所述，其特征在于：柱层析法分离龙脑和莰烯，柱层析填料主要指硅胶、氧化铝，启到吸附龙脑作用，与龙脑的比例3：1-10：1，其中优选3：1-5：1。
  24. 如权利1要求所述，其特征在于：在萃取法和柱层析法所用的饱和烃，主要指低沸点饱和烃及其混合物，石油醚、汽油、环己烷、正己烷、环戊烷、正戊烷等，溶解龙脑和莰烯混合物，在萃取中，起到溶解莰烯；在柱层析的洗脱中起到洗脱莰烯。
  25. 如权利1要求所述，其特征在于：铝粉与冰片或樟脑还原物用于生成龙脑铝和异龙脑铝，异龙脑铝脱水重排作用，铝粉与冰片或樟脑还原物重量比1：1-1：100，其中当樟脑含量较少时，铝粉与与冰片或樟脑还原物重量比优选1：20-1：40。
  26. 如权利1,5要求所述，其特征在于：高纯度龙脑，指冰片或樟脑还原产物中的异龙脑通过生成异龙脑铝，脱水重排莰烯，龙脑和莰烯通过蒸馏－升华法、柱 层析法、萃取法单用或组合使用制备而成的龙脑，或将樟脑制备樟脑还原产物，再通过上述方法制备而成的龙脑，高纯度龙脑中不含或含少量的异龙脑，其范围在65.0％-100％，分三级：一级优等品龙脑含量不低于96.0％；二级品龙脑含量低于一级优等品，但不低于85.0％；三级品龙脑含量低于二级品，但不低于65.0％。
  27. 如权利1,6要求所述，其特征在于：莰烯，指龙脑铝或异龙脑铝脱水重排而成，经水蒸气蒸馏，通过蒸馏－升华法、柱层析法、萃取法单用或组合使用制备而成的莰烯，莰烯纯度不低于90.0％。
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111229255A (zh) * 2020-03-02 2020-06-05 昆明理工大学 镧改性的手性向列型介孔硅催化剂在合成正龙脑中的应用
CN113149050A (zh) * 2021-04-13 2021-07-23 新疆众和股份有限公司 一种高纯醇铝盐工业中固废的处理方法
CN115193454A (zh) * 2022-08-15 2022-10-18 台州学院 一种不对称选择加氢催化剂及其制备方法和应用
CN116497619A (zh) * 2023-05-17 2023-07-28 岳阳林纸股份有限公司 一种樟木氢氧化钠本色化学机械制浆工艺

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6238344B2 (zh) * 1985-07-17 1987-08-17 Yasuhara Yushi Kogyo Kk
CN102344343A (zh) * 2011-08-18 2012-02-08 福建青松股份有限公司 一种生产高纯度异龙脑的方法
CN103739448A (zh) * 2014-02-01 2014-04-23 闻永举 由樟脑及其还原产物、冰片制备高纯度龙脑的方法
CN103755527A (zh) * 2014-02-01 2014-04-30 闻永举 由樟科提取物或艾纳香提取物制备高纯度龙脑的方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6238344B2 (zh) * 1985-07-17 1987-08-17 Yasuhara Yushi Kogyo Kk
CN102344343A (zh) * 2011-08-18 2012-02-08 福建青松股份有限公司 一种生产高纯度异龙脑的方法
CN103739448A (zh) * 2014-02-01 2014-04-23 闻永举 由樟脑及其还原产物、冰片制备高纯度龙脑的方法
CN103755527A (zh) * 2014-02-01 2014-04-30 闻永举 由樟科提取物或艾纳香提取物制备高纯度龙脑的方法

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111229255A (zh) * 2020-03-02 2020-06-05 昆明理工大学 镧改性的手性向列型介孔硅催化剂在合成正龙脑中的应用
CN113149050A (zh) * 2021-04-13 2021-07-23 新疆众和股份有限公司 一种高纯醇铝盐工业中固废的处理方法
CN115193454A (zh) * 2022-08-15 2022-10-18 台州学院 一种不对称选择加氢催化剂及其制备方法和应用
CN115193454B (zh) * 2022-08-15 2023-09-05 台州学院 一种不对称选择加氢催化剂及其制备方法和应用
CN116497619A (zh) * 2023-05-17 2023-07-28 岳阳林纸股份有限公司 一种樟木氢氧化钠本色化学机械制浆工艺

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