CN111205263A - Preparation method and application of bicyclol - Google Patents
Preparation method and application of bicyclol Download PDFInfo
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- CN111205263A CN111205263A CN202010319881.9A CN202010319881A CN111205263A CN 111205263 A CN111205263 A CN 111205263A CN 202010319881 A CN202010319881 A CN 202010319881A CN 111205263 A CN111205263 A CN 111205263A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
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Abstract
The invention belongs to the field of medicines, and particularly relates to a preparation method and application of bicyclol, wherein the preparation method comprises the following steps: adding bicycloalkylic alcohol acid and a base into a reaction solvent; adding methyl p-toluenesulfonate solution for reaction to obtain bicyclol. The preparation method of the bicyclol provided by the invention adopts the novel methyl p-toluenesulfonate methylating reagent, avoids the use of methylating reagent which is easy to prepare toxicity, easy to prepare explosion and not suitable for commercial purchase, and easily generates dangerous methylating reagent in the using process, thereby overcoming the defects of harsh post-treatment, low yield and the like caused by adopting methylating reagent which is easy to prepare toxicity and explosion, preparing the bulk drug meeting the quality requirement through simple process operation and mild experimental conditions at high yield, and having stable process yield, reproducibility and reliability and being suitable for industrial production.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a preparation method and application of bicyclol.
Background
The chemical name of Bicyclol (Bicyclol) is 4,4, -dimethoxy-5, 6,5,6, -bis (methylenedioxy) -2-hydroxymethyl-2-methoxycarbonyl biphenyl, the Bicyclol is a product developed by the medicines of Chinese medical academy of sciences and Chinese synergetic medical university, is the first anti-hepatitis innovative medicine with independent intellectual property rights in China, and has relatively obvious liver function protection effect on various clinical and experimental liver injuries, and the mechanism of the Bicyclol can be as follows: first, inhibition of lipid peroxidation induced by chemical poisons and drugs; secondly, the fluidity of the mitochondrial membrane is well maintained; third, increasing the level of antioxidant mercaptotransferase in the liver; fourthly, reducing the damage of liver cells, and inhibiting apoptosis to accelerate the decomposition of chemical poisons; fifthly, metabolism and elimination of carcinogens; sixth, regulating and controlling the gene expression of liver energy metabolism, cell apoptosis and other pathological and physiological processes.
However, in the current synthetic route for preparing bicyclol, the methylating reagents adopted in the methylation of the key steps are usually dimethyl sulfate and nitrosomethyl urea, wherein the dimethyl sulfate is a genotoxic impurity, belongs to a highly toxic chemical substance, and has a very complicated flow in the aspect of large-scale purchase; nitrosomethyl urea decomposes to diazomethane, which is very likely to cause explosion. Therefore, the method not only causes high standard established for the residual quantity of the methylating agent in the final product of the bicyclol, harsh refining process and waste of a large amount of manpower and material resources, but also causes production accidents easily due to high toxicity and easy explosion, and brings inconvenience to industrial production.
Disclosure of Invention
The invention aims to provide a preparation method and application of bicyclol, which avoid the adoption of dangerous and more toxic methylating reagents, have the advantages of simple operation, mild conditions, high product yield and high purity, have good reproducibility and feasibility and are suitable for industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a process for the preparation of bicyclol, comprising the steps of:
adding bicycloalkylic alcohol acid and a base into a reaction solvent;
adding a methyl p-toluenesulfonate solution for reaction to obtain bicyclol;
the equivalent ratio of the dicyclic alcohol acid to the methyl p-toluenesulfonate is 1.0-3.0;
adding a methyl p-toluenesulfonate solution for reaction to obtain bicyclol, wherein the reaction comprises the following steps:
dropwise adding a methyl p-toluenesulfonate solution dissolved by a reaction solvent for reaction;
after the reaction is finished, filtering, adding water into the filtrate to perform crystal approaching, and filtering again to obtain a crude product of the bicyclol;
and purifying the crude product of the bicyclol to obtain the bicyclol.
The preparation method of the bicyclol provided by the invention adopts the novel methyl p-toluenesulfonate methylating reagent, avoids the use of methylating reagent which is easy to prepare toxicity, easy to prepare explosion and not suitable for commercial purchase, and easily generates dangerous methylating reagent in the using process, thereby overcoming the defects of harsh post-treatment, low yield and the like caused by adopting methylating reagent which is easy to prepare toxicity and explosion, preparing the bulk drug meeting the quality requirement through simple process operation and mild experimental conditions at high yield, and having stable process yield, reproducibility and reliability and being suitable for industrial production.
In a second aspect, the invention provides the use of the preparation method of the bicyclol, the bicyclol with better purity can be prepared by the preparation method, and the bicyclol can be used as a standard reference substance in the checking of related substances of the bicyclol.
Drawings
FIG. 1 shows a high performance liquid chromatography chromatogram of bicyclol obtained in example 1 of the present invention;
FIG. 2 shows a high performance liquid chromatography chromatogram of bicyclol obtained in example 2 of the present invention;
FIG. 3 shows a high performance liquid chromatography chromatogram of bicyclol obtained in example 3 according to the present invention;
FIG. 4 shows the HPLC chromatogram of bicyclol prepared in example 4 of the present invention.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In a first aspect, embodiments of the present invention provide a method for preparing bicyclol, including the following steps:
step S10, adding bicycloalkanol acid and alkali into a reaction solvent;
and step S20, adding methyl p-toluenesulfonate solution for reaction to obtain bicyclol.
In the preparation method of bicyclol provided by the embodiment, a new methylating reagent methyl p-toluenesulfonate is adopted, so that the defects of harsh post-treatment, low yield and the like caused by the adoption of methylating reagents which are easy to prepare poison and explode and are not suitable for commercial purchase are overcome, and the preparation method of bicyclol can prepare bulk drugs meeting quality requirements at high yield through simple process operation and mild experimental conditions, has stable process yield, has reproducibility and reliability and is suitable for industrial production.
It should be noted that the bicyclic alkyd used in this example can be prepared by the methods of the prior art, and the synthetic route is as follows:
further, in step S10, the feeding temperature is controlled to be 0 to 50 ℃, preferably 0 to 5 ℃.
Further, in step S10, the ratio of the mass of the bicycloalkyl acid to the volume of the reaction solvent includes 1 g: 2 ml-20 ml, for example, the ratio of the mass of the bicycloalkyl acid to the volume of the reaction solvent is 1 g: 2ml, 1 g: 12ml, 1 g: 15ml or 1 g: 20ml and the like. When the ratio of the mass of the bicycloalkyl acid to the volume of the reaction solvent is too large, the amount of the solvent is small, the reaction is violent, but the reaction is incomplete; when the ratio of the mass of the cyclic alcohol acid to the volume of the reaction solvent is too small, the solvent amount is large so that the concentration of the raw material is low and the reaction rate is slow. In this example, the ratio of the mass of the bicyclo-alkyd to the volume of the reaction solvent was controlled to be 1 g: 2 ml-20 ml, the reaction can be carried out mildly, and the reaction can be completed in a relatively short time. Preferably, the ratio of the mass of the bicyclic alkyd to the volume of reaction solvent comprises 1 g: 3 ml-10 ml, for example, the ratio of the mass of the bicycloalkyl acid to the volume of the reaction solvent is 1 g: 3ml, 1 g: 5ml, 1 g: 8ml or 1 g: 10ml, etc., and the yield of the product is good when the ratio is controlled within this range.
Further, in step S10, when the base is sodium hydride, the ratio of equivalents of bicycloalkyl acid to sodium hydride is 1.0-4.0, for example, the ratio of equivalents of bicycloalkyl acid to sodium hydride is 1, 2, 2.5, 3 or 4. The reaction rate can be influenced by the addition of sodium hydride, the reaction speed is low due to the addition of too little sodium hydride, the reaction is incomplete, and the reaction rate can be increased by increasing the proportion of sodium hydride. Preferably, the ratio of equivalents of the bicyclic alkyd to equivalents of sodium hydride is 1.5, at which the reaction is completed in a shorter time and the yield of the product is higher.
Further, in step S10, the reaction solvent includes one or more of acetonitrile, acetone, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, propyl acetate, butyl acetate, dichloromethane, and chloroform, and the reaction solvent has good solubility for the raw materials, can be effectively recycled, and is cheap, thereby reducing the production cost. Preferably, the reaction solvent is acetonitrile or acetone.
Further, in step S20, the reaction temperature is controlled to be 0 ℃ to 50 ℃, for example, the reaction temperature is 0 ℃ to 5 ℃, 10 ℃ to 20 ℃, 30 ℃ to 40 ℃ or 45 ℃ to 50 ℃, the reaction temperature is too low, the reaction rate is slow, and the reaction time is long; the reaction temperature is too high, the reaction rate is higher, but the side reaction is more. The reaction temperature is controlled to be 0-50 ℃, complete reaction can be carried out in a short time, and more side reactions are avoided. Preferably, the reaction temperature is controlled to be 0-5 ℃, and at the temperature, the reaction rate is high, and the yield of the product is high.
Further, in step S20, the equivalent ratio of the bicycloalkyl acid to the methyl p-toluenesulfonate includes 1.0 to 3.0, for example, the equivalent ratio of the bicycloalkyl acid to the methyl p-toluenesulfonate is 1, 1.5, 2, 2.5 or 3. The addition amount of the methylating agent is small, the reaction is incomplete, the addition amount is large, excessive side reactions can be caused, the equivalent ratio of the bicycloalkyl acid to the methyl p-toluenesulfonate is controlled within the range of 1.0-3.0, the side reactions can be reduced, and the yield of the product is properly improved. Preferably, the equivalent ratio of the bicyclic alkyd to methyl p-toluenesulfonate is 1.2.
Further, step S20 includes:
step S201, dropwise adding a methyl p-toluenesulfonate solution dissolved by a reaction solvent for reaction;
step S202, after the reaction is finished, filtering, adding water into the filtrate to perform crystal approaching, and filtering again to obtain a bicyclol crude product;
and step S203, purifying the crude product of the bicyclol to obtain the bicyclol.
In the above examples, the formation of excessive impurities due to an excessive temperature rise caused by a sudden exothermic reaction during heating was reduced by adding dropwise a methyl p-toluenesulfonate solution. In the reaction process, TLC is used for monitoring, when the reaction is finished, alkali is removed by simple filtration, crystal is forced by water after the reaction is finished, the reaction is filtered again to obtain a crude product of bicyclol, most of impurities with large polarity can be removed by crystal forced by water, and then the obtained crude product of bicyclol is purified to obtain bicyclol with high purity (99.8 percent, the maximum single impurity is less than 0.1 percent and is far higher than the standard of bicyclol in 2015 edition of Chinese pharmacopoeia).
Specifically, when the crude product of the bicyclol is purified, the crude product of the bicyclol can be firstly refluxed and dissolved by toluene, and activated carbon is added for decoloration, so that most of the methyl-etherified bicyclol impurities and the reaction raw material of the bicycloalkyl acid, namely the biphenyldicarboxylate, can be removed. Then hot filtering, stirring the filtrate at room temperature for crystallization, filtering again, decoloring the filter cake with active carbon, recrystallizing, filtering, and drying to obtain the bicyclol.
Further, in step S202, the volume ratio of the reaction solvent to the added water is 1:1 to 1:5, for example, the volume ratio of the reaction solvent to the added water is 1:1, 1:2, 1:3, 1:4, or 1:5, and the volume ratio of the reaction solvent to the added water is controlled within 1:1 to 1:5, so that a good crystal forcing effect can be obtained, and a good removal effect on impurities with large polarity is obtained. Preferably, the volume ratio of the reaction solvent to the added water is 1: 3.
Further, in step S203, when performing the recrystallization operation, the recrystallization solvent used includes one or more of ethyl acetate, n-heptane, toluene, dichloromethane, anhydrous ethanol, anhydrous methanol, isopropanol, acetonitrile, acetone, 1, 4-dioxane, petroleum ether, methyl tert-butyl ether, and anisole, and the solvent is used for recrystallization, so that a good crystallization effect can be obtained, the purity and yield of the product can be ensured, and the solvent is cheap and can be effectively recovered, thereby greatly reducing the production cost.
One preferable step of the preparation method of bicyclol provided by the embodiment of the invention is as follows:
step S1, adding bicycloalkanol acid and sodium hydride into acetonitrile at 0-5 ℃, wherein the ratio of the mass of bicycloalkanol acid to the volume of acetonitrile is 1 g: 3ml to 10ml, and the equivalent ratio of the bicycloalkyl acid to the sodium hydride is 1.5.
And step S2, dropwise adding methyl p-toluenesulfonate solution dissolved by acetonitrile to react, wherein the reaction temperature is 0-5 ℃, and the equivalent ratio of bicycloalkyl acid to methyl p-toluenesulfonate is 1.2.
And step S3, filtering after the reaction is finished, adding water into the filtrate to form crystals, and filtering again to obtain a crude bicyclol product, wherein the volume ratio of the reaction solvent to the added water is 1: 3.
And step S4, refluxing and dissolving the crude bicyclol product with toluene, adding activated carbon for decolorization, performing hot filtration, stirring and crystallizing the filtrate at room temperature, filtering, decolorizing the filter cake with activated carbon, recrystallizing toluene/acetonitrile, filtering, and drying to obtain bicyclol.
In a second aspect, the invention provides the use of the preparation method of the bicyclol, the bicyclol with better purity can be obtained by the preparation method, and the bicyclol can be used as a standard reference substance in the checking of related substances of the bicyclol.
The invention is described in further detail with reference to a number of tests performed in sequence, and a part of the test results are used as reference, and the following detailed description is given with reference to specific examples.
Example 1
Step S1, adding 10.0g (26.6 mmol) of bicycloalkyl acid and 0.96g (39.9 mmol, 1.5 eq) of sodium hydride into 80ml of acetonitrile at 0-5 ℃, and stirring for about 20 min.
Step S2, 20ml of acetonitrile solution dissolved with 5.9g (31.9 mmol, 1.2 eq) of methyl p-toluenesulfonate is added dropwise for about 30min, and the mixture is stirred and reacted at 0-5 ℃ for about 6 h.
And step S3, monitoring the reaction by TLC, filtering, collecting filtrate, dropwise adding 300ml of water under stirring at 0-5 ℃, keeping the room temperature for stirring for 2 hours after dropwise adding, filtering, and drying a filter cake to obtain 7.9g of crude bicyclol, wherein the yield of the crude bicyclol is 76.2%.
And step S4, refluxing and dissolving the crude bicyclol product with 80ml of toluene, adding 0.5g of activated carbon for decoloring for 30min, carrying out hot filtration, stirring the filtrate at room temperature for 1h, separating out a solid, filtering, recrystallizing the filter cake with toluene/acetonitrile (4: 1), filtering, and drying to obtain 6.2g of bicyclol, wherein the yield of the bicyclol is 78.5%.
The obtained bicyclol is subjected to high performance liquid chromatography detection, fig. 1 shows a high performance liquid chromatography spectrogram of the bicyclol prepared in the embodiment, a table in fig. 1 shows peak results of the high performance liquid chromatography spectrogram, including retention time, peak area percentage and the like, and according to fig. 1, the purity of the bicyclol prepared by the embodiment is 99.966%, and each single impurity is less than 0.1%.
Example 2
Step S1, adding 10.0g (26.6 mmol) of bicycloalkyl acid and 0.64g (26.6 mmol, 1.0 eq) of sodium hydride into 15ml of dichloromethane at 45-50 ℃, and stirring for about 20 min.
Step S2, 5ml of methylene chloride solution dissolved with 5.0g (26.6 mmol, 1.0 eq) of methyl p-toluenesulfonate is added dropwise for about 30min, and the mixture is stirred and reacted at 45-50 ℃ for about 3 h.
And step S3, monitoring the reaction by TLC, filtering, collecting filtrate, dropwise adding 100ml of water under stirring at 45-50 ℃, keeping the room temperature for stirring for 2 hours after dropwise adding, filtering, and drying a filter cake to obtain 7.8g of crude bicyclol, wherein the yield of the crude bicyclol is 75.2%.
And step S4, refluxing and dissolving the crude bicyclol product with 80ml of toluene, adding 0.5g of activated carbon for decoloring for 30min, carrying out hot filtration, stirring the filtrate at room temperature for 1h, separating out a solid, filtering, recrystallizing the filter cake with toluene/acetonitrile (4: 1), filtering, and drying to obtain 6.1g of bicyclol, wherein the yield of the bicyclol is 78.2%.
The obtained bicyclol is subjected to high performance liquid chromatography detection, fig. 2 shows a high performance liquid chromatography spectrogram of the bicyclol prepared in the embodiment, a table in fig. 2 shows peak results of the high performance liquid chromatography spectrogram, including retention time, peak area percentage and the like, according to fig. 2, the bicyclol prepared in the embodiment has the purity of 99.819% and each single impurity is less than 0.1%.
Example 3
Step S1, adding 10.0g (26.6 mmol) of bicycloalkyl acid and 1.92g (79.8 mmol, 4.0 eq) of sodium hydride into 160ml of acetone at 30-40 ℃, and stirring for about 20 min.
Step S2, 40ml of acetone solution dissolved with 14.9g (79.8 mmol, 3.0 eq) of methyl p-toluenesulfonate is added dropwise for about 30min, and the mixture is stirred and reacted for about 3h at 30-40 ℃.
And step S3, after TLC monitoring reaction is finished, filtering, collecting filtrate, dropwise adding 200ml of water under stirring at 30-40 ℃, keeping room temperature for stirring for 2 hours after dropwise adding, filtering, and drying a filter cake to obtain 7.6g of crude bicyclol, wherein the yield of the crude bicyclol is 73.2%.
And step S4, refluxing and dissolving the crude bicyclol product with 80ml of toluene, adding 0.5g of activated carbon for decoloring for 30min, carrying out hot filtration, stirring the filtrate at room temperature for 1h, separating out a solid, filtering, recrystallizing the filter cake with toluene/acetonitrile (4: 1), filtering, and drying to obtain 6.0g of bicyclol, wherein the yield of the bicyclol is 78.9%.
The obtained bicyclol is subjected to high performance liquid chromatography detection, fig. 3 shows a high performance liquid chromatography spectrogram (the detection wavelength of a detector is 228 nm) of the bicyclol prepared in the embodiment, a table in fig. 3 shows peak results of the high performance liquid chromatography spectrogram, including retention time, peak area percentage and the like, according to fig. 3, the bicyclol prepared in the embodiment has the purity of 99.958% and each single impurity is less than 0.1%.
Example 4
Step S1, adding 10.0g (26.6 mmol) of bicycloalkyl acid and 0.96g (39.9 mmol, 1.5 eq) of sodium hydride into 20ml of acetone at 10-20 ℃, and stirring for about 20 min.
Step S2, dropwise adding 10ml of acetone solution dissolved with 14.9g (79.8 mmol, 3.0 eq) of methyl p-toluenesulfonate, wherein the dropwise adding time is about 30min, and stirring and reacting at 10-20 ℃ for about 3 h.
And step S3, after TLC monitoring reaction is finished, filtering, collecting filtrate, dropwise adding 90ml of water under stirring at 10-20 ℃, keeping room temperature for stirring for 2 hours after dropwise adding, filtering, and drying a filter cake to obtain 7.5g of crude bicyclol, wherein the yield of the crude bicyclol is 72.2%.
Step S4, refluxing and dissolving the crude bicyclol product with 80ml of toluene, adding 0.5g of activated carbon for decoloring for 30min, carrying out hot filtration, stirring the filtrate at room temperature for 1h, separating out a solid, filtering, recrystallizing the filter cake with toluene/acetonitrile (4: 1), filtering, and drying to obtain 6.0g of bicyclol, wherein the yield of bicyclol is 80.0 percent
The obtained bicyclol is subjected to high performance liquid chromatography detection, fig. 4 shows a high performance liquid chromatography spectrogram of the bicyclol prepared in the embodiment, (the detection wavelength of a detector is 228 nm), a table in fig. 4 shows peak results of the high performance liquid chromatography spectrogram, including the contents of retention time, peak area percentage and the like, and according to fig. 4, the detection result prepared in the embodiment shows that the bicyclol has the purity of 99.920% and each single impurity is less than 0.1%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. A preparation method of bicyclol is characterized by comprising the following steps:
adding bicycloalkylic alcohol acid and a base into a reaction solvent;
adding a methyl p-toluenesulfonate solution for reaction to obtain bicyclol;
the equivalent ratio of the dicyclic alcohol acid to the methyl p-toluenesulfonate is 1.0-3.0;
adding a methyl p-toluenesulfonate solution for reaction to obtain bicyclol, wherein the reaction comprises the following steps:
dropwise adding a methyl p-toluenesulfonate solution dissolved by a reaction solvent for reaction;
after the reaction is finished, filtering, adding water into the filtrate to perform crystal approaching, and filtering again to obtain a crude product of the bicyclol;
and purifying the crude product of the bicyclol to obtain the bicyclol.
2. The preparation method of bicyclol according to claim 1, wherein in the step of adding methyl p-toluenesulfonate solution to react to obtain bicyclol, the reaction temperature is controlled to be 0-50 ℃.
3. The preparation method of bicyclol according to claim 1, wherein in the step of adding methyl p-toluenesulfonate solution to react to obtain bicyclol, the reaction temperature is controlled to be 0-5 ℃.
4. The method for preparing bicycloalkanol of claim 1, wherein in the step of adding bicycloalkylic acid and base to the reaction solvent, the ratio of the mass of bicycloalkylic acid to the volume of reaction solvent comprises 1 g: 2ml to 20 ml.
5. The method for preparing bicycloalkanol of claim 1, wherein in the step of adding bicycloalkylic acid and base to the reaction solvent, the ratio of the mass of bicycloalkylic acid to the volume of reaction solvent comprises 1 g: 3ml to 10 ml.
6. The method for preparing bicycloalkanol of claim 1, wherein in the step of adding bicycloalkylic acid and base to the reaction solvent, when the base is sodium hydride, the ratio of equivalents of bicycloalkylic acid to sodium hydride is in the range of 1.0 to 4.0.
7. A process for the preparation of a bicyclic alcohol according to claim 1 wherein said reaction solvent comprises one or more of acetonitrile, acetone, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, propyl acetate, butyl acetate, dichloromethane, chloroform.
8. The preparation method of bicyclol according to claim 1, wherein after the reaction is finished, filtering is carried out, water is added into the filtrate to drive crystallization, and filtering is carried out again to obtain a crude bicyclol product, wherein the volume ratio of the reaction solvent to the added water is 1: 1-1: 5.
9. A method for preparing bicyclol as claimed in claim 1, wherein in said step of purifying the crude bicyclol to obtain bicyclol, the recrystallization solvent used in the recrystallization step comprises one or more of ethyl acetate, n-heptane, toluene, dichloromethane, absolute ethanol, absolute methanol, isopropanol, acetonitrile, acetone, 1, 4-dioxane, petroleum ether, methyl tert-butyl ether and anisole.
10. Use of a bicyclic alcohol according to any one of claims 1 to 9 for the preparation of a medicament,
the bicyclol is used as a standard reference substance when checking related substances of the bicyclol.
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| CN112250658A (en) * | 2020-12-21 | 2021-01-22 | 北京鑫开元医药科技有限公司 | Formylated bicyclol and preparation method thereof |
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