CN117551094B - Preparation method of high-optical-purity rotundine - Google Patents

Preparation method of high-optical-purity rotundine Download PDF

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CN117551094B
CN117551094B CN202410044993.6A CN202410044993A CN117551094B CN 117551094 B CN117551094 B CN 117551094B CN 202410044993 A CN202410044993 A CN 202410044993A CN 117551094 B CN117551094 B CN 117551094B
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dimethoxy
rotundine
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dimethyl
acid
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CN117551094A (en
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杨冲生
杨志
徐红贵
陈雪江
赵沛月
孙敏
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YUNNAN INSTITUTE OF MATERIA MEDICA
Yunnan Baiyao Group Co Ltd
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Yunnan Baiyao Group Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to a preparation method of high optical purity rotundine. The invention takes cheap and easily available chemical raw materials of 3, 4-dimethoxy phenethylamine and 3, 4-dimethoxy phenylacetic acid as initial raw materials, N- (3, 4-dimethoxy phenethyl) -2- (3, 4-dimethoxy phenyl) acetamide is obtained by dehydration condensation under the action of condensing agent and acylation catalyst or activating agent, 1- (3, 4-dimethoxy benzyl) -6, 7-dimethyl-3, 4-dihydro isoquinoline is obtained by ring closure dehydration under the action of dehydrating agent, and 2,3,9, 10-tetramethoxy-5, 8,13 a-tetrahydro-6 is obtained by reduction and cyclizationH-isoquinolino [3,2-a ]]Isoquinoline, and then the target product rotundine is obtained through resolution of R-mandelic acid or S-mandelic acid. The process route has 5 steps of chemical reactions, the total yield is about 13%, the HPLC purity of the obtained target product is more than or equal to 99.5%, the enantiomeric excess percentage (ee percent) is more than or equal to 99.5%, the material cost of the process route is low, the optical purity of the obtained product is high, the operation is simple, the post treatment is convenient, and the process route is suitable for industrial production.

Description

Preparation method of high-optical-purity rotundine
Technical Field
The invention belongs to the technical field of medicines. In particular to a preparation method of high optical purity analgesic rotundine.
Background
Rotundine (Rotundine), also known as l-THP (levo-tetrahydropalmatine), l-tetrahydropalmatine, or craniodynidine, is an alkaloid extracted from the root or tuber of herbs such as corydalis genus of the Papaveraceae family or Stephania genus of the Fabricius family. The application history of the corydalis tuber in China has thousands of years, and the 'materia medica schema' has the description of the analgesic efficacy of the corydalis tuber for treating pain on the upper and lower sides of the body, in use, wonderful. The levo tetrahydropalmatine is the main active ingredient of corydalis tuber, has definite pharmacological action and small toxic and side effects, is approved to be applied to clinic in China in the last sixty years, is loaded into 1977 edition of Chinese pharmacopoeia, and is mainly used for treating pains of gastric ulcer and duodenal ulcer, menstrual pain, uterine contraction pain after delivery, tension insomnia and the like clinically in indication. Clinical practice for more than half century proves that rotundine has definite curative effect and clinical safety in aspects of analgesia, sedation and sleep aiding, and is a successful example of developing a patent medicine by using single effective components of traditional Chinese medicines.
Jin Guozhang the pharmacological actions of optical isomers are systematically researched by chemical resolution of the racemic tetrahydropalmatine, and the results show that the levotetrahydropalmatine has remarkable pharmacological actions of analgesia, sedation, hypnosis, central muscle relaxation and the like; the D-tetrahydropalmatine has no pharmacological effects of analgesia, sedation, hypnosis, central muscle relaxation and the like. Therefore, the levotetrahydropalmatine (rotundine) is clinically used for controlling the dextrorotatory tetrahydropalmatine. Related substances under the two text varieties rotundine items of Chinese pharmacopoeia (2020 edition) are measured by high performance liquid chromatography (general rule 0512), impurity peaks exist in a chromatogram of a sample solution, the sum of the peak areas of the impurities is not more than 0.5% of the main peak area of a control solution, and the method can not separate the levotetrahydropalmatine and the dextrorotatory tetrahydropalmatine. The optical purity of rotundine is checked by adopting a specific rotation measuring method, the method has poor precision and is greatly influenced by external factors such as environment and the like, and the application of the method in the accurate quality control of rotundine is limited.
In recent years, the analgesic market has grown rapidly, next to antitumor drugs. 35 drugs are received in the analgesic class of national basic medical insurance, industrial insurance and fertility insurance drug catalogue (2022 edition), and are classified into 3 classes of opioids (natural opioids, phenylpiperidine derivatives, morphinane derivatives, other opioids), other antipyretic analgesics (salicylic acid and its derivatives, pyrazolones, acylanilides and other antipyretic analgesics), and migraine drugs, of which rotundine (oral normal release dosage form, injection) and pregabalin (oral normal release dosage form) are classified into other antipyretic analgesic subclasses of the other antipyretic analgesic class. In 2016, FDA release guidelines decided to limit the use of opioid analgesics and stop abuse. The FDA requires that opioid analgesics be written in black box warnings of adverse drug reactions on the prescription drug specifications with serious risks including misuse, abuse, addiction, overdose, and death. In addition, it should be noted on the drug label that doctors can prescribe these opioid quick-acting analgesics to patients only when the non-addictive analgesic is insufficient to achieve the analgesic effect. Because of the problems of easy abuse and addiction of opioid drugs, the country has encouraged the research and development of non-opioid analgesic drugs, and rotundine is applied as an analgesic for many years, has definite curative effect and no addiction, and has great potential. The demand of rotundine bulk drug is increased year by year, most of bulk drug is mainly obtained by plant extraction, because plant resources containing tetrahydropalmatine such as stephania sinica diels of stephania of tetradaceae are extracted and dug in a transitional way, along with the increasing exhaustion of plant resources, the supply of rotundine bulk drug by a chemical synthesis method is a great trend in the long term, and if a chemical synthesis process route which is economical, practical and capable of producing rotundine bulk drug on a large scale can be developed, the method has great significance and urgent practical need.
At present, the rotundine bulk drug has two sources of plant extraction and chemical synthesis (including semi-synthesis and total synthesis). The national drug administration (NMPA) official network retrieves 8 rotundine bulk drug wholesale texts (including 1 KunYao group, 1 Yunnan Da Tang Hanfang pharmaceutical industry, 1 Xishuangbanna edition Napharmaceutical industry, 2 Chuxiong cloud plant pharmaceutical industry, 1 Chongqing Tiansheng pharmaceutical industry, 1 Chongqing Hill Anpharmaceutical industry, 1 Sichuan Yuxin pharmaceutical industry and 1 Sichuan Yoghurt pharmaceutical industry); the registration information of the primary and secondary packages of the drug evaluation Center (CDE) shows 18 cases of the rotundine drug substance records, wherein 17 cases and the existing commercial preparation association evaluation batch (the state is identified as an activated state "A"). The chemical synthesis manufacturer mainly comprises the Sichuan you Hua pharmaceutical industry, chongqing Hill an pharmaceutical industry and the like, and the plant extraction manufacturer mainly comprises the Chuxiong cloud plant pharmaceutical industry, sichuan Yuxin pharmaceutical industry and the like. The raw materials obtained by whatever source route are managed according to chemical drugs ("national standard H" beginning). The plant extraction source way is to extract rhizoma corydalis, herba corydalis Bungeanae, tortoise and the like as extraction raw materials, and the market demand is continuously increased, plant resources containing tetrahydropalmatine are greatly reduced, and the rotundine can not meet the market demand through the extraction way.
The following is an overview of the rotundine semisynthetic and total synthetic sources:
(1) Semisynthetic pathway
The fibrauretine is taken as a starting material, is reduced by a reducing agent to obtain the racemized tetrahydropalmatine, and is resolved by a chiral resolving agent to obtain the levotetrahydropalmatine (process route 1. Huo Li and the like (journal of Chinese medicine industry, 2012, 43 (5)): 323-325) reported potassium borohydride reduction method of fibrauretine: taking fibrauretine 20 g, placing the fibrauretine into a three-neck round bottom flask, adding 800 g methanol for dissolution, reducing potassium borohydride, removing most of solvent under reduced pressure after the reaction is finished, adding water for stirring, precipitating white crystals, filtering to obtain the racemic tetrahydropalmatine, and separating the racemic tetrahydropalmatine by D-dibenzoyltartaric acid to obtain the levotetrahydropalmatine, wherein the total yield is about 25%, the enantiomer excess percentage (ee%) is 99.6%, repeating the process operation, the total yield is about 11%, the enantiomer excess percentage (ee%) is about 77%, the yield is lower, the optical purity is poor, in addition, chloroform and other solvents with higher toxicity are used in the process, the environment is not friendly, the solvent residue is not easy to control, zhao Juan and the like (journal of Chinese medicinal chemistry, 2015, 25 (5): 378-381) report that fibrauretine 1 part, active nickel powder 0.01 part, sodium ethoxide 0.2 part, ethanol 10 parts are put into a high-pressure reaction kettle, hydrogen is introduced for replacement for 3 times, then hydrogen is introduced to 4.5 Mpa, the temperature in the kettle is controlled to be 85-90 ℃ and stirred for 2 h, materials in the kettle are pressed out after the reaction is finished, active nickel is filtered, filtrate is collected, filtrate is concentrated to recover ethanol, residues are added into distilled water for crystallization, the distilled water is filtered, racemic tetrahydropalmatine is obtained, then the L-tartaric acid chiral resolving agent is used for resolving to obtain the levotetrahydropalmatine, the total yield is 36.4%, the excessive enantiomer percentage (ee%), the target product levotetrahydropalmatine is not obtained.
The preparation of Sichuan blepharia (CN 106518864A, rejected after application publication) has proposed a method for synthesizing L-tetrahydropalmatine from berberine hydrochloride (process route 2). The route takes berberine hydrochloride as an initial raw material, and the ring opening is carried out to obtain the demethylene berberine hydrochloride; methylating to obtain fibrauretine; reducing fibrauretine to obtain the racemized tetrahydropalmatine; resolving rotundine by chiral resolving agent D-dibenzoyl tartaric acid. No yields and enantiomeric excess (ee) percentages are reported herein, and the highly toxic materials such as dimethyl sulfate used in the process are not environmentally friendly.
(2) Total synthesis route
Guangxi nan Ning pharmaceutical works (CN 1068113A, the patent application is regarded as withdrawal) proposed a method for preparing tetrahydropalmatine from guaiacol (process route 3): taking guaiacol as a starting material, and carrying out methylation, chloromethylation, cyanation, reduction and cyclization to obtain fibrauretine, and reducing the fibrauretine to obtain the racemized tetrahydropalmatine. The process route gives racemic tetrahydropalmatine in a total yield of about 14.3%. The resolution conditions and operation of the racemization tetrahydropalmatine are not reported, and reagents such as dimethyl sulfate, sodium cyanide and the like used in the process route are extremely toxic substances and are not friendly to the environment.
The Sichuan Eyew pharmaceutical industry (CN 108358913A, rejected after application publication) proposed a green synthesis process of rotundine sulfate (process route 4): using catechol as a starting material, and obtaining 3, 4-dimethoxy phenethylamine through esterification, acylation, nitrosation and reduction; condensing with 2, 3-dimethoxy benzaldehyde to obtain a key intermediate, cyclizing, reducing to obtain racemic tetrahydropalmatine, and acidifying with sulfuric acid to obtain the final product. The tetrahydropalmatine sulfate obtained in the process route is not further resolved and rotundine is prepared.
The pharmaceutical factory of Sichuan blessing (CN 109293654A, rejected after application disclosure) provides a rotundine production process (process route 5): 3, 4-dimethoxy phenethylamine is used as a starting material, is subjected to condensation hydrogenation with ortho-vanillin, is subjected to cyclization with glyoxal, is reduced to obtain racemic tetrahydropalmatine, and is resolved by a chiral resolving agent to obtain rotundine. No specific chiral resolving agent is reported herein nor is there any yield or percent enantiomeric excess (ee%). The process route is not obviously innovative and is basically the same as the route.
Jiangsu Bai Aoshikang medicine (CN 113896728A, substantial examination) provides a preparation method of rotundine (process route 6): 3, 4-dimethoxy phenethylamine is used as a starting material, is subjected to condensation hydrogenation with orthovanillin, and is then subjected to cyclization with glyoxal to obtain fibrauretine, and the fibrauretine is subjected to asymmetric hydrogenation reduction under the catalysis of a biphosphine-nickel complex to obtain rotundine. The overall yield is reported here to be about 58.3% and the enantiomeric excess is about 99.6%. The biphosphine-nickel complex used in the process route is expensive, needs to be customized and is not suitable for technological production.
In the above-mentioned rotundine preparation patent application route, whether berberine hydrochloride or fibrauretine is used as a starting material in the semisynthetic route or guaiacol or catechol is used as a starting material in the fully synthetic route, the above-mentioned rotundine is finally converted into fibrauretine, and two modes exist for further converting the fibrauretine into rotundine: one is the use of chiral catalysts to effect asymmetric hydrogenation reduction; the other is to obtain the racemized tetrahydropalmatine after reduction and then split the racemized tetrahydropalmatine by using a chiral splitting agent. The method for preparing rotundine by reducing fibrauretine by using asymmetric chiral catalyst has high yield, but the asymmetric catalyst has high price, needs customization and is not suitable for industrial production; the method for preparing rotundine by using chiral resolving agent after the fibrauretine is reduced has the problems of rising the price of fibrauretine year by year, few resolving agent types reported in literature, unsatisfactory resolving effect, low yield, poor optical purity and the like.
Disclosure of Invention
The invention aims to provide a preparation method of high-optical-purity rotundine. The preparation method has the advantages of cheap and easily available starting materials, no use of highly toxic reagents, simple operation, convenient post-treatment, high optical purity of the obtained product and suitability for industrial production.
In order to achieve the purpose of the invention, the preparation method of the high optical purity rotundine comprises the following steps:
the preparation method of the high optical purity rotundine is characterized by comprising the following 5 steps:
(1) Dissolving 3, 4-dimethoxy phenethylamine and 3, 4-dimethoxy phenylacetic acid with solvent, dehydrating and condensing under the action of condensing agent and acylation catalyst or activator to obtain N- (3, 4-dimethoxy phenethyl) -2- (3, 4-dimethoxy phenyl) acetamide, purifying with recrystallization solvent to obtain N- (3, 4-dimethoxy phenethyl) -2- (3, 4-dimethoxy phenyl) acetamide pure product;
(2) Dissolving N- (3, 4-dimethoxy phenethyl) -2- (3, 4-dimethoxy phenyl) acetamide with a solvent, and carrying out Bischler-Napieralski reaction under the action of a dehydrating agent to obtain 1- (3, 4-dimethoxy benzyl) -6, 7-dimethyl-3, 4-dihydro isoquinoline;
(3) Reducing the 1- (3, 4-dimethoxy benzyl) -6, 7-dimethyl-3, 4-dihydro-isoquinoline by using a reducing agent to obtain 1- (3, 4-dimethoxy benzyl) -6, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline;
(4) Performing Pictet-Spengler reaction on 1- (3, 4-dimethoxybenzyl) -6, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline and formaldehyde or paraformaldehyde under the acid condition of formic acid to obtain 2,3,9, 10-tetramethoxy-5, 8,13 a-tetrahydro-6H-isoquinolin [3,2-a ] isoquinoline;
(5) 2,3,9, 10-tetramethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline is dissolved by a solvent, and is resolved by a chiral resolving agent under the action of a heat stabilizer to obtain the target compound rotundine.
The synthetic route related to the invention is as follows:
the solvent in the step (1) is one of dichloromethane, chloroform, carbon tetrachloride, toluene, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, toluene, tetrahydrofuran, acetonitrile, ethyl acetate, xylene, diethyl ether and methyl tertiary butyl ether; condensing agents are dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 4-N, N-dimethylpyridine, 1-hydroxybenzotriazole, O- (7-azabenzotriazol-1-yl) -bis (dimethylamino) carbohexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbohexafluorophosphate, O- (5-chlorobenzotriazol-1-yl) -bis (dimethylamino) carbohexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbotetrafluoroborate, O- (N-succinimidyl) -bis (dimethylamino) carbotetrafluoroborate, benzotriazol-1-yloxy-tris (dimethylamino) phosphate, benzotriazol-1-yloxy-tris (tetrahydropyrrolyl) hexafluorophosphate, diphenylphosphoryl chloride, diethyl cyanophosphate, diphenylphosphorothioate, phosphorothioate and bis (2-azido-phosphoryl) 2-phosphoryl-2-phosphoryl chloride; the acylation catalyst or activator is one of sodium bicarbonate, sodium carbonate, ammonia water, potassium carbonate, potassium bicarbonate, triethylamine, N-diisopropylethylamine, trimethylamine, pyridine and 4-N, N-lutidine; the recrystallization solvent is one or two of methanol, ethanol, dichloromethane, ethyl acetate, butyl acetate, petroleum ether, heptane, n-hexane, cyclohexane, xylene, acetonitrile, tetrahydrofuran, acetonitrile, diethyl ether and methyl tertiary butyl ether.
The solvent in the step (2) is one of acetonitrile, ethanol, acetic acid, toluene, dimethylbenzene, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, diethyl ether and acetone; the dehydrating agent is one or two of phosphorus oxychloride, phosphorus oxybromide, thionyl chloride phosphorus pentoxide, polyphosphoric acid, trifluoroacetic anhydride, trifluoromethanesulfonic anhydride, phosphorus trichloride and boron trifluoride diethyl ether.
The reducing agent in the step (3) is one of sodium borohydride, potassium borohydride, lithium aluminum hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, zinc powder, iron powder, palladium carbon/hydrogen, nickel/hydrogen and boron trifluoride diethyl ether.
1- (3, 4-dimethoxybenzyl) -6, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline in said step (4): formic acid: the weight ratio of formaldehyde or paraformaldehyde is 1 (1-25) to 0.5-5.
The solvent in the step (5) is one or two of methanol, ethanol, isopropanol, N-butanol, tertiary butanol, acetone, N-dimethylformamide and acetonitrile; the heat stabilizer is one or two of pyridine dimethyl borate, tetrahydroxy diboron, triisopropyl borate, tri-n-octyl borate, bis-pinacolato borate, trimethyl borate and boric acid; the resolving agent is R-mandelic acid or S-mandelic acid.
2,3,9, 10-tetramethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline in said step (5): solvent: heat stabilizer: the weight ratio of the resolving agent is 1 (5-30): 0.1-5.
The invention is characterized in that the chemical synthesis preparation method comprises the following steps: the method comprises the steps of taking cheap and easily available chemical raw materials of 3, 4-dimethoxy phenethylamine (compound 1) and 3, 4-dimethoxy phenylacetic acid (compound 2) as starting materials, and carrying out dehydration condensation amidation reaction under the action of a condensing agent of 1- (3-dimethyl propyl) -3-ethyl carbodiimide and 1-hydroxybenzotriazole to obtain N- (3, 4-dimethoxy phenethyl) -2- (3, 4-dimethoxy phenyl) acetamide (compound 3); the compound 3 is subjected to Bischler-Napieralski reaction under the action of a dehydrating agent phosphorus oxychloride to obtain 1- (3, 4-dimethoxy benzyl) -6, 7-dimethyl-3, 4-dihydro isoquinoline (compound 4); reducing the compound 4 by sodium borohydride to obtain 1- (3, 4-dimethoxy benzyl) -6, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline (compound 5); performing Pictet-Spengler reaction on the compound 5 and formaldehyde under the condition of formic acid acidity to obtain 2,3,9, 10-tetramethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline (compound 6); the compound 6 is resolved by chiral resolving agent R-mandelic acid to obtain the target compound rotundine (compound 7).
Compared with the prior art, the rotundine preparation method adopts cheap and easily available chemical raw materials as starting materials, and the sources are not limited by natural conditions and resources; compared with the existing semi-synthesis and total synthesis processes, the method does not need to be converted into fibrauretine for re-reduction; the selected chiral resolving agent is cheap and easy to obtain; the optical purity of the product obtained after resolution is high; the material cost is low; the use of reagents without extremely toxic agents; most of the solvent can be recycled; the operation is simple; the post-treatment is convenient; is suitable for industrial production.
Drawings
Figure 1 is a chromatogram of compound 6 (i.e., racemic tetrahydropalmatine without resolution): the product is measured by adopting a high performance liquid chromatography, and chromatographic conditions are as follows: cellophane (Daicel) CHIRALCEL OJ-H chiral chromatography column (4.6 mm ×250 mm, 5 μm); mobile phase: ethanol (100%); flow rate: 0.8 ml/min; column temperature: 25 ℃; detection wavelength 280 nm; sample injection volume: 10. mu.l. In the figure, 14.806 min is a chromatographic peak of the dextrorotatory tetrahydropalmatine, and 17.139 min is a chromatographic peak of the levotetrahydropalmatine (namely rotundine).
Fig. 2 is a chromatogram of the rotundine control: the reference substance is purchased from a middle inspection institute (product batch LY 0601), and the high performance liquid chromatography is adopted to measure the reference substance, and the chromatographic conditions are as follows: cellophane (Daicel) CHIRALCEL OJ-H chiral chromatography column (4.6 mm ×250 mm, 5 μm); mobile phase: ethanol (100%); flow rate: 0.8 ml/min; column temperature: 25 ℃; detection wavelength 280 nm; sample injection volume: 10. mu.l. 17.089 min is the chromatographic peak of levotetrahydropalmatine (i.e., rotundine).
Fig. 3 is a rotunding chromatogram prepared as in example 1: the product is measured by adopting a high performance liquid chromatography, and chromatographic conditions are as follows: cellophane (Daicel) CHIRALCEL OJ-H chiral chromatography column (4.6 mm ×250 mm, 5 μm); mobile phase: ethanol (100%); flow rate: 0.8 ml/min; column temperature: 25 ℃; detection wavelength 280 nm; sample injection volume: 10. mu.l. After resolution, the content of D-tetrahydropalmatine (i.e., rotundine) was 0.05%, the content of L-tetrahydropalmatine (i.e., rotundine) was 99.95%, and the percent enantiomeric excess (ee%) was 99.9%.
Fig. 4 is a rotunding chromatogram prepared as in example 2: the product is measured by adopting a high performance liquid chromatography, and chromatographic conditions are as follows: cellophane (Daicel) CHIRALCEL OJ-H chiral chromatography column (4.6 mm ×250 mm, 5 μm); mobile phase: ethanol (100%); flow rate: 0.8 ml/min; column temperature: 25 ℃; detection wavelength 280 nm; sample injection volume: 10. mu.l. After resolution, the content of D-tetrahydropalmatine (i.e., rotundine) was 0.15%, the content of L-tetrahydropalmatine (i.e., rotundine) was 99.85%, and the percent enantiomeric excess (ee%) was 99.7%.
Fig. 5 is a chromatogram of d-tetrahydropalmatine prepared as in example 3: the spectrum is a dextrorotatory tetrahydropalmatine chromatogram obtained after partial operation in rotundine preparation according to example 3, specifically a product obtained by refluxing and stirring compound 6, S-mandelic acid, tetrahydroxy diboron and 95% ethanol, standing and crystallizing at room temperature for 12-24 h, filtering, collecting a filter cake, adjusting the filter cake to be alkaline with sodium hydroxide solution, extracting with dichloromethane, concentrating, and recrystallizing with ethanol. The product is measured by adopting a high performance liquid chromatography, and chromatographic conditions are as follows: cellophane (Daicel) CHIRALCEL OJ-H chiral chromatography column (4.6 mm ×250 mm, 5 μm); mobile phase: ethanol (100%); flow rate: 0.8 ml/min; column temperature: 25 ℃; detection wavelength 280 nm; sample injection volume: 10. mu.l. After resolution, the levotetrahydropalmatine was 98.27%, the levotetrahydropalmatine (i.e., rotundine) was 1.73%, and the percent enantiomeric excess (ee%) was 96.54%.
Detailed Description
The present invention will be further understood by those skilled in the art by reference to the following detailed description of the specific embodiments, which are not intended to limit the invention in any way, but rather to make various modifications or improvements to the present invention without departing from the spirit of the invention.
Example 1
Step (1) preparation of N- (3, 4-Dimethoxyphenylethyl) -2- (3, 4-dimethoxyphenyl) acetamide (Compound 3)
3, 4-Dimethoxyphenylethylamine (200 g, 1.1 mol, 1.0 eq), 3, 4-dimethoxyphenylacetic acid (216.3 g, 1.1 mol, 1.0 eq), 1- (3-dimethylpropyl) -3-ethylcarbodiimide (232 g, 1.2 mol, 1.1 eq), 1-hydroxybenzotriazole (163.5 g, 1.2 mol, 1.1 eq) and dichloromethane 1.5L were charged into a 3L three-necked round bottom flask equipped with a thermometer, a dropping funnel and a stirrer, the ice bath was cooled to 0 ℃, triethylamine (222.6 g, 2.2 mol, 2.0 eq) was added dropwise thereto, the time was controlled to be 0.5-1 h, the temperature was slowly raised to room temperature after the addition, and stirring was continued for 5 h. TLC (dichloromethane: methanol=8:1) detection was performed with the disappearance of the starting material in the reaction solution as the reaction end point. Pure water 2L was added, 0.5 h was stirred, the organic phase was collected, the aqueous phase was extracted with dichloromethane 1.5L, the organic phases were combined, the organic phase was washed with 5% citric acid solution 2.5L, saturated sodium bicarbonate solution 2.5L, saturated brine 1.5L, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give a white solid. The resulting solid was transferred to a single port reaction flask and methyl t-butyl ether 1L was added and triturated to make a slurry of 4 h. Filtering, washing the filter cake with a small amount of methyl tertiary butyl ether, and collecting the filter cake. Drying under reduced pressure at 60℃4 h afforded 321 g of compound 3 as a white solid with an HPLC purity of 99% and a yield of about 81.3%.
HR-ESI-MS m/z 360.17837 [M+H ] + (Calcd. for C 20 H 26 NO 5 360.17436).
1 H-NMR(400 MHz, CDCl 3 ): δ 6.80-6.75(m, 1H), 6.72-6.64(m, 3H), 6.63-6.57(m, 1H), 6.54-6.46(m, 1H), 5.46(s, 1H), 3.88(s, 3H), 3.82(s, 3H), 3.79(s, 6H), 3.48-3.38(m, 4H), 2.69-2.62(d, J = 6.5 Hz, 2H).
13 C-NMR(100 MHz, CDCl 3 ): δ 171.29, 149.31, 149.08, 148.35, 147.70, 131.12, 127.30, 121.65, 120.64, 112.47, 111.78, 111.51, 111.22, 55.96, 55.92, 55.90, 55.88, 43.50, 40.75, 35.05.
Step (2) preparation of 1- (3, 4-dimethoxybenzyl) -6, 7-dimethyl-3, 4-dihydroisoquinoline (Compound 4)
Compound 3 (200 g, 0.56 mol, 1.0 eq), phosphorus oxychloride (173.9 g, 1.12 mol, 2.0 eq) and toluene 1.8L were charged to a 3L three-necked round bottom flask equipped with a thermometer, reflux tube and stirrer, heated to 90 ℃ and stirred for 1.5 h. TLC (dichloromethane: methanol=6:1) detection was performed with the disappearance of the starting material in the reaction solution as the reaction end point. The toluene solvent was removed by concentration, saturated sodium bicarbonate solution 2L was added to the residue, dichloromethane 1.2 was L was used for extraction, the organic phase was collected, the aqueous phase was extracted with dichloromethane 1.2L, the organic phases were combined, washed with saturated brine 1.2L, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give a white solid. The resulting solid was transferred to a single port reaction flask and slurried with methanol 800 ml grind 4 h. The mixture was filtered, the filter cake was washed with a small amount of methanol, and the filter cake was collected and dried under reduced pressure at 55℃for 4 h to give 149.3 g of a white solid of Compound 4 with a HPLC purity of 98% and a yield of about 78.6%.
HR-ESI-MS m/z 342.16606 [M+H ] + (Calcd. for C 20 H 24 NO 4 342.16271).
1 H-NMR(400 MHz, CDCl 3 ): δ 7.66(d, J = 1.5 Hz, 1H), 7.59(dd, J = 8.4, 1.8 Hz, 1H), 6.92-6.85(m, 2H), 6.74(s, 1H), 4.02(s, 3H), 3.95(s, 3H), 3.83(s, 6H), 3.78(m, 4H), 2.86-2.76(s, 2H).
13 C-NMR(100 MHz, CDCl 3 ): δ 164.75, 154.29, 151.79, 149.30, 147.79, 131.19, 128.76, 126.72, 119.67, 111.38, 110.63, 110.15, 109.77, 56.28, 56.25, 56.14, 56.16, 47.41, 46.72, 25.57.
Step (3) preparation of 1- (3, 4-dimethoxybenzyl) -6, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline (Compound 5)
Compound 4 (140 g, 0.41 mol, 1.0 eq) and methanol 1.4L were added to a 3L three-necked round bottom flask equipped with a thermometer, reflux tube and stirrer, heated to complete dissolution, sodium borohydride (31 g, 0.82 mol, 2.0 eq) was added in portions, heated to reflux after the addition was completed, and stirred for 2 h. TLC (dichloromethane: methanol=6:1) detection was performed with the disappearance of the starting material in the reaction solution as the reaction end point. The methanol solvent was removed by concentration, the residue was added with 5% hydrochloric acid solution to adjust the pH to 3-5, dichloromethane 1.5 was L extracted, the organic phase was discarded, the aqueous phase was collected, the aqueous phase was adjusted to pH 12 with 10% sodium hydroxide solution, dichloromethane 1.5L extracted, the organic phase was collected, the aqueous phase was extracted with dichloromethane 1L, the organic phases were combined, washed with saturated brine 1L, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give a white solid. Without further purification, drying under reduced pressure at 55deg.C 4.4 h afforded 106.2 g of compound 5 as a white solid with 97.1% HPLC purity in about 75.4% yield.
HR-ESI-MS m/z 344.18171 [M+H ] + (Calcd. for C 20 H 26 NO 4 344.17836).
1 H-NMR(400 MHz, CDCl 3 ): δ 7.64(d, J = 1.9 Hz, 1H), 7.57(dd, J = 8.4, 1.9 Hz, 1H), 6.90-6.83(m, 2H), 6.72(s, 1H), 4.29(m, 1H), 3.97(s, 3H), 3.91(s, 3H), 3.85(s, 6H), 3.75-3.61(m,4H), 2.83-2.73(m, 2H), 1.72(s, 1H).
13 C-NMR(100 MHz, CDCl 3 ): δ 154.19, 151.70, 149.18, 147.67, 131.10, 128.62, 126.61, 119.53, 111.26, 110.54, 110.06, 109.66, 61.06, 56.16, 56.13, 56.05, 56.03, 47.28, 25.44.
Preparation of step (4) 2,3,9, 10-tetramethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline (Compound 6)
Compound 5 (100 g, 0.29 mol, 1.0 eq), 40% aqueous formaldehyde (130.5 g, 1.74 mol, 6.0 eq) and formic acid 800 ml were charged to a 2L three-necked round bottom flask equipped with a thermometer, reflux and stirrer, and stirred at reflux for 4 h. TLC (dichloromethane: methanol=5:1) detection was performed, with the disappearance of the starting material in the reaction solution as the reaction end point. Cooling to room temperature, adding pure water 800 ml and dichloromethane 800 ml, extracting, discarding the organic phase, collecting the aqueous phase, adjusting the pH of the aqueous phase to 10-12 with 10% sodium hydroxide solution, adding dichloromethane 800 ml for extraction, collecting the organic phase, extracting the aqueous phase with dichloromethane 800 ml, combining the organic phases, washing with saturated brine 500 ml, drying with anhydrous magnesium sulfate, filtering, and concentrating the filtrate to obtain pale yellow solid. Transferring the obtained solid into a single-port reaction bottle, adding absolute ethyl alcohol 500 ml, heating to dissolve completely, filtering while hot, collecting filtrate, cooling the filtrate to-10deg.C, standing for crystallization 5 h. The filter cake was washed with a small amount of 95% ethanol (pre-cooled to-10 ℃) and collected. Drying under reduced pressure at 55deg.C 4.4 h afforded compound 6 as a white solid 66.7 g with HPLC purity of 99.5% and yield of about 64.4%.
HR-ESI-MS m/z 356.18171 [M+H ] + (Calcd. for C 21 H 26 NO 4 356.17436).
1 H-NMR(400 MHz, CDCl 3 ): δ 6.87(d, J = 8.4 Hz, 1H), 6.78(d, J = 8.3 Hz, 1H), 6.73(s, 1H), 6.61(s, 1H), 4.24(d, J = 15.8 Hz, 1H), 3.92(s, 3H), 3.89(s, 3H), 3.75(s, 6H), 3.53(d, J = 14.5 Hz, 2H), 3.30-3.08(m, 4H), 2.82(dd, J = 15.1, 12.0 Hz, 1H), 2.71-2.57(m, 2H).
13 C-NMR(100 MHz, CDCl 3 ): δ 150.34, 147.55, 147.50, 145.14, 129.79, 128.78, 127.82, 126.88, 123.95, 111.42, 111.01, 108.68, 60.24, 59.40, 56.15, 55.94, 55.92, 54.09, 51.60, 36.43, 29.20.
Step (5) preparation of the target compound rotundine (Compound 7)
Compound 6 (50 g, 0.14 mol, 1.0 eq), R-mandelic acid (63.9 g, 0.42 mol, 3.0 eq), boric acid (13 g, 0.21 mol, 1.5 eq) and 95% ethanol 500 ml were placed in a 500 ml three-necked round bottom flask equipped with a thermometer, a reflux tube and a stirrer, and stirred under reflux for 2 h. Standing at room temperature for crystallizing 12-24 h, filtering, eluting the filter cake with a small amount of 95% ethanol, collecting the filter cake, transferring to a beaker, adjusting the pH to 11 with 5% sodium hydroxide solution, adding dichloromethane 400 ml for extraction, collecting an organic phase, extracting an aqueous phase with dichloromethane 300 ml, combining the organic phases, washing the organic phase with pure water 400 ml, washing with saturated saline 400 ml, drying with anhydrous magnesium sulfate, filtering, and concentrating the filtrate to obtain an off-white solid. Transferring the obtained solid into a single-port reaction bottle, adding ethanol 50 and ml, heating to dissolve completely, filtering while hot, collecting filtrate, standing at room temperature, and crystallizing 12: 12 h. The filter cake was washed with a small amount of ethanol, and the filter cake was collected and dried under reduced pressure at 55℃for 4 h to give a white rotundine solid 18.5 g in a yield of 37.1%, with an HPLC purity of 100% and an enantiomeric excess percentage (ee%) of 99.9% (see FIG. 3 of the specification).
m.p. 141-142 ℃, and the melting point (general rule 0612) of the rotundine item of the second part of Chinese pharmacopoeia (2020 edition) is m.p. 141-144 ℃.
The specific rotation is measured to be-293 degrees (c=0.1 g/ml, chloroform), and the specific rotation is measured to be-290 degrees to-300 degrees under the rotundine item (general rule 0621) of the second part of the Chinese pharmacopoeia.
HR-ESI-MS m/z 356.17836 [M+H ] + (Calcd. for C 21 H 26 NO 4 356.18436).
1 H-NMR(400 MHz, CDCl 3 ): δ 6.87(dd, J = 8.3, 2.1 Hz, 1H), 6.78(dd, J = 8.3, 2.9 Hz, 1H), 6.73(s, 1H), 6.61(d, J = 2.0 Hz, 1H), 4.23(dd, J = 15.8, 1.9 Hz, 1H), 3.93-3.79(m, 12H), 3.58-3.49(m, 2H), 3.29-3.07(m, 3H), 2.89-2.77(m, 1H), 2.72-2.56(m, 2H).
13 C-NMR(100 MHz, CDCl 3 ): δ 150.39, 147.62, 147.56, 145.19, 129.81, 128.75, 127.85, 126.91, 123.98, 111.50, 111.10, 108.76, 60.28, 59.43, 56.20, 55.99, 55.96, 54.11, 51.63, 36.40, 29.19.
Example 2
Step (1) preparation of N- (3, 4-Dimethoxyphenylethyl) -2- (3, 4-dimethoxyphenyl) acetamide (Compound 3)
3, 4-Dimethoxyphenylethylamine (200 g, 1.1 mol, 1.0 eq), 3, 4-dimethoxyphenylacetic acid (216.3 g, 1.1 mol, 1.0 eq), O- (benzotriazol-1-yl) -bis (dimethylamino) tetrafluoroborate (353.2 g, 1.2 mol, 1.1 eq) and dichloromethane 1.5L were charged into a 3L three-necked round bottom flask equipped with a thermometer, a dropping funnel and a stirrer, the ice bath was cooled to 0 ℃, N-diisopropylethylamine (327 g, 2.5 mol, 2.3 eq) was added dropwise thereto under the control of 0.5 to 1 h, the temperature was slowly raised to room temperature after the addition, and stirring was continued for 3 h. TLC (dichloromethane: methanol=8:1) detection was performed with the disappearance of the starting material in the reaction solution as the reaction end point. Pure water 2L was added, 0.5 h was stirred, the organic phase was collected, the aqueous phase was extracted with dichloromethane 1.5L, the organic phases were combined, the organic phase was washed with 5% citric acid solution 2.5L, saturated sodium bicarbonate solution 2.5L, saturated brine 1.5L, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give a white solid. Transferring the obtained solid into a single-port reaction bottle, adding ethyl acetate 400 ml, stirring until the solid is completely dissolved, cooling to 0 ℃ in an ice bath, dropwise adding petroleum ether 1.2L into the solution, precipitating a large amount of solid, continuously stirring for 2 h, filtering, and collecting a filter cake. Drying under reduced pressure at 60℃4 h afforded 329 g of compound 3 as a white solid with an HPLC purity of 99.2% and a yield of about 83.3%.
HR-ESI-MS m/z 360.17588 [M+H ] + (Calcd. for C 20 H 26 NO 5 360.17436).
Step (2) preparation of 1- (3, 4-dimethoxybenzyl) -6, 7-dimethyl-3, 4-dihydroisoquinoline (Compound 4)
Compound 3 (250 g, 0.69 mol, 1.0 eq), phosphorus pentoxide (244.8 g, 1.73 mol, 2.5 eq) and acetonitrile 2L were charged to a 3L three-necked round bottom flask equipped with a thermometer, reflux tube and stirrer, and stirred at reflux for 2 h. TLC (dichloromethane: methanol=6:1) detection was performed with the disappearance of the starting material in the reaction solution as the reaction end point. The acetonitrile solvent was removed by concentration, saturated sodium bicarbonate solution 2.5. 2.5L, dichloromethane 2.5. 2.5L were added to the residue and the organic phase was collected, the aqueous phase was extracted with dichloromethane 2.2. 2.2L, the organic phases were combined, washed with saturated brine 1.5. 1.5L, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated to give a white solid. Transferring the obtained solid into a single-port reaction bottle, adding absolute ethyl alcohol 1.5, L, heating to dissolve completely, filtering while the solid is hot, collecting filtrate, cooling the filtrate to-10 ℃, standing for 4, h, and precipitating a large amount of solid. The mixture was filtered, the filter cake was collected, and dried under reduced pressure at 55℃for 4.4 h to give 179.1 g of a white solid of Compound 4 with a HPLC purity of 99.1% and a yield of about 75.4%.
HR-ESI-MS m/z 342.17101 [M+H ] + (Calcd. for C 20 H 24 NO 4 342.16271).
Step (3) preparation of 1- (3, 4-dimethoxybenzyl) -6, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline (Compound 5)
Compound 4 (150 g, 0.44 mol, 1.0 eq) and 95% ethanol 1.5L, a palladium-carbon catalyst (wet product, palladium content 10%) 10 g, hydrogen substitution 3 times, hydrogen pressurization to 0.5 Mpa, start stirring and temperature rise to 70 ℃. Introducing hydrogen to carry out hydrogenation reaction, controlling the pressure of the hydrogen in the kettle to be 0.5 Mpa until the reaction does not absorb hydrogen, and detecting by TLC (dichloromethane: methanol=7:1), wherein the disappearance of raw materials in the reaction liquid is taken as the reaction end point. The mixture was filtered through celite, and the filtrate was concentrated to give a white solid, which was dried under reduced pressure at 55℃for 4.4 h to give 130.5 g of compound 5 as a white solid with an HPLC purity of 96.1% and a yield of about 86.5%.
HR-ESI-MS m/z 344.18171 [M+H ] + (Calcd. for C 20 H 26 NO 4 344.17836).
Preparation of step (4) 2,3,9, 10-tetramethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline (Compound 6)
Compound 5 (130 g, 0.38 mol, 1.0 eq), 40% aqueous formaldehyde (285 g, 3.8 mol, 10.0 eq) and formic acid 1.3L were charged to a 3L three-necked round bottom flask equipped with a thermometer, reflux and stirrer, and stirred at reflux 4 h. TLC (dichloromethane: methanol=5:1) detection was performed, with the disappearance of the starting material in the reaction solution as the reaction end point. Cooling to room temperature, adding pure water 1.5L, extracting with dichloromethane 1.5L, discarding the organic phase, collecting the aqueous phase, adjusting the pH of the aqueous phase to 10-12 with 10% sodium hydroxide solution, adding dichloromethane 1.5L for extraction, collecting the organic phase, extracting the aqueous phase with dichloromethane 1.5L, mixing the organic phases, washing with saturated saline water 1L, drying with anhydrous magnesium sulfate, filtering, and concentrating the filtrate to obtain pale yellow solid. Transferring the obtained solid into a single-port reaction bottle, adding absolute ethyl alcohol 700 and ml, heating to dissolve completely, filtering while the solid is hot, collecting filtrate, cooling the filtrate to-10 ℃, and standing for crystallization 5 h. The filter cake was washed with a small amount of 95% ethanol (pre-cooled to-10 ℃) and collected. Drying under reduced pressure at 55deg.C 4.4 h gives 86.6 g of compound 6 as a white solid with an HPLC purity of 99.7% and a yield of about 64.4%.
HR-ESI-MS m/z 356.18171 [M+H ] + (Calcd. for C 21 H 26 NO 4 356.17436).
Step (5) preparation of the target compound rotundine (Compound 7)
Into a 500 ml three-necked round bottom flask equipped with a thermometer, a reflux tube and a stirrer were charged compound 6 (50 g, 0.14 mol, 1.0 eq), R-mandelic acid (42.6 g, 0.28 mol, 2.0 eq), triisopropyl borate (26.3 g, 0.14 mol, 1.0 eq) and 95% ethanol 500 ml, followed by stirring under reflux for 2 h. Standing at room temperature for crystallization of 12-24 h, filtering, eluting filter cake with a small amount of ethanol, collecting filter cake, transferring to a beaker, adjusting pH to 11 with 5% sodium hydroxide solution, adding dichloromethane 400 ml for extraction, collecting an organic phase, extracting an aqueous phase with dichloromethane 400 ml, combining the organic phases, washing the organic phase with pure water 400 ml, washing with saturated saline 400 ml, drying with anhydrous magnesium sulfate, filtering, and concentrating the filtrate to obtain a light yellow solid. Transferring the obtained solid into a single-port reaction bottle, adding ethanol 50 ml, heating to dissolve completely, adding 3 g active carbon, stirring for 0.5 h, adding diatomite while hot, filtering, collecting filtrate, standing at room temperature, and crystallizing for 12 h. The filter cake was washed with a small amount of ethanol and dried under reduced pressure at 55℃to give a white rotundine solid 17.2 g in a yield of about 34.4%, with an HPLC purity of 100% and an enantiomeric excess percentage (ee%) of 99.7% (see FIG. 4 of the specification).
HR-ESI-MS m/z 356.18816 [M+H ] + (Calcd. for C 21 H 26 NO 4 356.18436).
Example 3
Step (1) preparation of N- (3, 4-Dimethoxyphenylethyl) -2- (3, 4-dimethoxyphenyl) acetamide (Compound 3)
3, 4-Dimethoxyphenylethylamine (200 g, 1.1 mol, 1.0 eq), 3, 4-dimethoxyphenylacetic acid (216.3 g, 1.1 mol, 1.0 eq), 1- (3-dimethylpropyl) -3-ethylcarbodiimide (232 g, 1.2 mol, 1.1 eq), 4-N, N-dimethylpyridine (268.7 g, 2.2 mol, 2.0 eq) and N, N-dimethylformamide (1.2L) were charged to a 3L-neck round-bottom flask equipped with a thermometer, a dropping funnel and a stirrer, and stirring was continued at room temperature for 10 h. TLC (dichloromethane: methanol=8:1) detection was performed with the disappearance of the starting material in the reaction solution as the reaction end point. Pure water 2L, ethyl acetate 2L and stirring 1 h are added, the liquid is separated, the organic phase is collected, the aqueous phase is extracted with ethyl acetate 1.5L, the organic phase is collected, the aqueous phase is extracted with ethyl acetate 1L, the organic phases are combined, the organic phase is washed with 5% citric acid solution 2.5L, saturated sodium bicarbonate solution 2.5L, saturated saline solution 1.5L, dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated to give a white solid. The resulting solid was transferred to a single port reaction flask and methyl t-butyl ether 1L was added and triturated to a slurry of 6 h. Filtering, washing the filter cake with a small amount of methyl tertiary butyl ether, and collecting the filter cake. Drying under reduced pressure at 60deg.C 4.4 h afforded 306.7 g of compound 3 as a white solid with an HPLC purity of 98.5% and a yield of about 77.6%.
HR-ESI-MS m/z 360.17109 [M+H ] + (Calcd. for C 20 H 26 NO 5 360.17436).
Step (2) preparation of 1- (3, 4-dimethoxybenzyl) -6, 7-dimethyl-3, 4-dihydroisoquinoline (Compound 4)
Into a 3L three-necked round bottom flask equipped with a thermometer, a reflux tube and a stirrer were charged compound 3 (200 g, 0.56 mol, 1.0 eq), phosphorus oxychloride (86.8 g, 0.56 mol, 1.0 eq), phosphorus pentoxide (79.2 g, 0.56 mol, 1.0 eq) and toluene 1.2L, heated to 90℃and stirred for 1.5 h. TLC (dichloromethane: methanol=6:1) detection was performed with the disappearance of the starting material in the reaction solution as the reaction end point. The toluene solvent was removed by concentration, saturated sodium bicarbonate solution 2L was added to the residue, dichloromethane 1.5 was L was used for extraction, the organic phase was collected, the aqueous phase was extracted with dichloromethane 1.5L, the organic phases were combined, washed with saturated brine 1.5L, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give a white solid. The resulting solid was transferred to a single port reaction flask, and methanol 600 ml was added and triturated for 4 h. The mixture was filtered, the filter cake was washed with a small amount of methanol, and the filter cake was collected and dried under reduced pressure at 55℃for 4.4 h to give 151.6 g of an off-white solid of Compound 4 having an HPLC purity of 98.1% and a yield of about 79.3%.
HR-ESI-MS m/z 342.16001 [M+H ] + (Calcd. for C 20 H 24 NO 4 342.16271).
Step (3) preparation of 1- (3, 4-dimethoxybenzyl) -6, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline (Compound 5)
Compound 4 (150 g, 0.44 mol, 1.0 eq) and methanol 1.6L were added to a 3L three-necked round bottom flask equipped with a thermometer, reflux tube and stirrer, heated to complete dissolution, sodium cyanoborohydride (57.9 g, 0.92 mol, 2.1 eq) was added in portions, heated to reflux after the addition was completed, and stirring was continued for 2 h. TLC (dichloromethane: methanol=6:1) detection was performed with the disappearance of the starting material in the reaction solution as the reaction end point. Concentrating to remove methanol solvent, adding 5% hydrochloric acid solution to the residue to adjust pH to 3-5, extracting with dichloromethane 1.5L, discarding organic phase, collecting water phase, adjusting pH of the water phase to 12 with 10% sodium hydroxide solution, adding dichloromethane 1.5L, extracting, collecting organic phase, extracting water phase with dichloromethane 1.5L, mixing organic phases, washing with saturated saline 1.2L, drying with anhydrous magnesium sulfate, filtering, concentrating filtrate to obtain white solid. Without further purification, drying 4.4 h under reduced pressure at 55deg.C afforded 116.2 g of compound 5 as a white solid with 97.5% HPLC purity in about 76.9% yield.
HR-ESI-MS m/z 344.17122 [M+H ] + (Calcd. for C 20 H 26 NO 4 344.17836).
Preparation of step (4) 2,3,9, 10-tetramethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline (Compound 6)
Compound 5 (110 g, 0.32 mol, 1.0 eq), trioxymethylene (86.4 g, 0.96 mol, 3.0 eq) and formic acid 1.5L were charged to a 3L three-necked round bottom flask equipped with a thermometer, reflux and stirrer, and stirred at reflux for 4 h. TLC (dichloromethane: methanol=5:1) detection was performed, with the disappearance of the starting material in the reaction solution as the reaction end point. Cooling to room temperature, adding pure water 1.2L, extracting with dichloromethane 1.2L, discarding the organic phase, collecting the aqueous phase, adjusting the pH of the aqueous phase to 10-12 with 10% sodium hydroxide solution, adding dichloromethane 1.2L for extraction, collecting the organic phase, extracting the aqueous phase with dichloromethane 1.2L, mixing the organic phases, washing with saturated saline water 1L, drying with anhydrous magnesium sulfate, filtering, and concentrating the filtrate to obtain pale yellow solid. Transferring the obtained solid into a single-port reaction bottle, adding methanol 500 and ml, heating to dissolve completely, filtering while hot, collecting filtrate, cooling the filtrate to-10deg.C, standing for crystallization 5 h. Filtering and collecting filter cakes. Drying under reduced pressure at 55deg.C 4.4 h afforded compound 6 as a white solid 68.5 g with HPLC purity of 99.9% and yield of about 60.2%.
HR-ESI-MS m/z 356.17174 [M+H ] + (Calcd. for C 21 H 26 NO 4 356.17436).
Step (5) preparation of the target compound rotundine (Compound 7)
Into a 500 ml three-necked round bottom flask equipped with a thermometer, a reflux tube and a stirrer were charged compound 6 (50 g, 0.14 mol, 1.0 eq), S-mandelic acid (31.9 g, 0.21 mol, 1.5 eq), tetrahydroxydiboron (6.3 g, 0.07 mol, 0.5 eq) and 95% ethanol 500 ml, followed by stirring under reflux for 2 h. Standing at room temperature for crystallization of 12-24 h, filtering, leaching the filter cake with a small amount of 95% ethanol, and collecting the filter cake (No. 1) and the filtrate (No. 2) respectively.
The filter cake (No. 1) was transferred to a beaker, the pH was adjusted to 11 with 5% sodium hydroxide solution, dichloromethane 400 ml was added for extraction, the organic phase was collected, the aqueous phase was extracted with dichloromethane 400 ml, the organic phases were combined, the organic phase was washed with pure water 400 ml, washed with saturated brine 400 ml, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give a pale yellow solid. Transferring the obtained solid into a single-port reaction bottle, adding ethanol 50 ml, heating to dissolve completely, adding 3 g active carbon, stirring for 0.5 h, adding diatomite while hot, filtering, collecting filtrate, standing at room temperature, and crystallizing for 12 h. The filter cake is filtered, washed by a small amount of ethanol, and the filter cake is collected and dried under reduced pressure at 55 ℃ for 4.4 h to obtain pale yellow acicular dextro tetrahydropalmatine solid 17.1 g with a yield of about 36.2 percent, an HPLC purity of 100 percent and an enantiomeric excess percentage (ee%) of 96.54 percent (see figure 5 of the specification).
The filtrate (No. 2) was concentrated to remove the solvent, the residue was adjusted to pH 12 with 5% sodium hydroxide solution, dichloromethane 500 ml was added for extraction, the organic phase was collected, the aqueous phase was extracted with dichloromethane 300 ml, the organic phases were combined, the organic phase was washed with pure water 400 ml, saturated brine 400 ml, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give an off-white solid. Transferring the obtained solid into a single-port reaction bottle, adding 95% ethanol 50 ml, heating to dissolve completely, filtering while hot, collecting filtrate, standing at room temperature, and crystallizing 12 h. Filtering, collecting filter cake, transferring the filter cake to a single-mouth bottle, adding 95% ethanol 40 ml again, heating to dissolve completely, filtering while hot, collecting filtrate, standing at room temperature, and crystallizing 12 h. The filter cake was collected and dried under reduced pressure at 55 ℃ for 4 h to give a white rotundine solid 14.1 g in a yield of 28.2%, HPLC purity 100% and an enantiomeric excess percentage (ee%) of 99.8%.
HR-ESI-MS m/z 356.185443 [M+H ] + (Calcd. for C 21 H 26 NO 4 356.18436).

Claims (5)

1. The preparation method of the high optical purity rotundine is characterized by comprising the following 5 steps:
(1) Dissolving 3, 4-dimethoxy phenethylamine and 3, 4-dimethoxy phenylacetic acid with solvent, dehydrating and condensing under the action of condensing agent and acylation catalyst or activator to obtain N- (3, 4-dimethoxy phenethyl) -2- (3, 4-dimethoxy phenyl) acetamide, purifying with recrystallization solvent to obtain N- (3, 4-dimethoxy phenethyl) -2- (3, 4-dimethoxy phenyl) acetamide pure product;
(2) Dissolving N- (3, 4-dimethoxy phenethyl) -2- (3, 4-dimethoxy phenyl) acetamide with a solvent, and carrying out Bischler-Napieralski reaction under the action of a dehydrating agent to obtain 1- (3, 4-dimethoxy benzyl) -6, 7-dimethyl-3, 4-dihydro isoquinoline;
(3) Reducing the 1- (3, 4-dimethoxy benzyl) -6, 7-dimethyl-3, 4-dihydro-isoquinoline by using a reducing agent to obtain 1- (3, 4-dimethoxy benzyl) -6, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline;
(4) Performing Pictet-Spengler reaction on 1- (3, 4-dimethoxybenzyl) -6, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline and formaldehyde or paraformaldehyde under the acid condition of formic acid to obtain 2,3,9, 10-tetramethoxy-5, 8,13 a-tetrahydro-6H-isoquinolin [3,2-a ] isoquinoline;
(5) 2,3,9, 10-tetramethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline is dissolved by a solvent, and is resolved by a chiral resolving agent under the action of a heat stabilizer to obtain a target compound rotundine;
the solvent in the step (1) is one of dichloromethane, chloroform, carbon tetrachloride, toluene, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, dimethylbenzene, diethyl ether and methyl tertiary butyl ether; condensing agents are dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 4-N, N-lutidine, 1-hydroxybenzotriazole, O- (7-azabenzotriazol-1-yl) -bis (dimethylamino) carbohexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbohexafluorophosphate, O- (5-chlorobenzotriazol-1-yl) -bis (dimethylamino) carbohexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbotetrafluoroborate, O- (N-succinimidyl) -bis (dimethylamino) carbotetrafluoroborate, benzotriazol-1-yloxy-tris (dimethylamino), hexafluorophosphate, benzotriazol-1-yloxy-tris (tetrahydropyrrolyl), diphenylphosphoryl chloride, diethyl cyanophosphate, diphenylphosphoroazide, phosphorothioate and bis (2-chloro-2-azido-alkyl) phosphoryl; the acylation catalyst or activator is one of sodium bicarbonate, sodium carbonate, ammonia water, potassium carbonate, potassium bicarbonate, triethylamine, N diisopropylethylamine, trimethylamine, pyridine and 4-N, N-lutidine; the recrystallization solvent is one or two of methanol, ethanol, dichloromethane, ethyl acetate, butyl acetate, petroleum ether, heptane, n-hexane, cyclohexane, xylene, acetonitrile, tetrahydrofuran, diethyl ether and methyl tertiary butyl ether;
the solvent in the step (5) is one or two of methanol, ethanol, isopropanol, N-butanol, tertiary butanol, acetone, N-dimethylformamide and acetonitrile; the heat stabilizer is one or two of pyridine dimethyl borate, tetrahydroxy diboron, triisopropyl borate, tri-n-octyl borate, bis-pinacolato borate, trimethyl borate and boric acid; the resolving agent is R-mandelic acid or S-mandelic acid.
2. The method for preparing high optical purity rotundine according to claim 1, wherein the method comprises the following steps: the solvent in the step (2) is one of acetonitrile, ethanol, acetic acid, toluene, dimethylbenzene, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, diethyl ether and acetone; the dehydrating agent is one or two of phosphorus oxychloride, phosphorus oxybromide, thionyl chloride, phosphorus pentoxide, polyphosphoric acid, trifluoroacetic anhydride, trifluoromethanesulfonic anhydride, phosphorus trichloride and boron trifluoride diethyl ether.
3. The method for preparing high optical purity rotundine according to claim 1, wherein the method comprises the following steps: the reducing agent in the step (3) is one of sodium borohydride, potassium borohydride, lithium aluminum hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, zinc powder, iron powder, palladium carbon/hydrogen, nickel/hydrogen and boron trifluoride diethyl ether.
4. The method for preparing high optical purity rotundine according to claim 1, wherein the method comprises the following steps: 1- (3, 4-dimethoxybenzyl) -6, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline in step (4): formic acid: the weight ratio of formaldehyde or paraformaldehyde is 1 (1-25) to 0.5-5.
5. The method for preparing high optical purity rotundine according to claim 1, wherein the method comprises the following steps: 2,3,9, 10-tetramethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline in step (5): solvent: heat stabilizer: the weight ratio of the resolving agent is 1 (5-30): 0.1-5.
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