CN113999276B - Purification method and preparation method of desacetyl erigeron glycoside intermediate - Google Patents
Purification method and preparation method of desacetyl erigeron glycoside intermediate Download PDFInfo
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Abstract
The invention discloses a purification method and a preparation method of a desacetyl erigeron glycoside intermediate. Wherein, the purification method comprises the following steps: adding a poor solvent into a mixture of the crude compound shown in the formula A and the good solvent; wherein the good solvent is selected from halogenated hydrocarbon solvents and/or ether solvents with a cyclic structure, and the poor solvent is selected from one or more than two of alkane solvents, aromatic hydrocarbon solvents, alcohol solvents, nitrile solvents, ketone solvents, ester solvents and ether solvents without a cyclic structure. According to the invention, through the combination of two functionally supported solvents, not only can the purification effect of 12.1% -81.8% be realized and the impurities in the crude product be effectively removed, but also the solid of the intermediate of the desacetylmaohoridine can be separated out of the liquid without heating and cooling, so that the method has the advantages of low energy consumption, low cost, convenience in operation control, safety and environmental protection, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a purification method and a preparation method of a desacetyl erigeron glycoside intermediate.
Background
Deacetylbristled is a cardiotonic, 3- [ [ O-beta-D-glucopyranosyl- (1- & gt 4) -O-2, 6-dideoxy-beta-D-core-hexopyranosyl]Oxo-radicals]-12, 14-dihydroxy-cardioid-20 (22) -enelactone, formula C 47 H 74 O 19 CAS number: 17598-65-1, white crystalline powder, odorless, bitter in taste and hygroscopic in nature (see: chinese pharmacopoeia)2015, two parts), is mainly used for heart failure, acute and chronic contractile heart insufficiency, atrial fibrillation, paroxysmal tachycardia and other symptoms, has good effect and is marketed in a plurality of countries or regions such as China and Japan.
At present, the synthesis method of the desacetyl erigeron breviscapus mainly comprises the following two steps:
(1) Firstly, extracting the floxuridine C (CAS number: 17575-22-3) from digitalis, and then deacetylating the floxuridine C under the conditions of sodium methoxide and methanol to obtain deacetylated floxuridine;
(2) Digoxin reacts with 2,3,4, 6-tetraacetyloxy-alpha-D-glucopyranose bromide to generate a deacetyl erigeron glycoside intermediate (20), and the deacetyl erigeron glycoside intermediate is subjected to deacetyl reaction under the conditions of sodium methoxide and methanol to obtain the deacetyl erigeron glycoside (21), wherein the steps are as follows:
literature: regio-and Stereochemical Controlled Koenigs-Knorr-Type Monoglycosylation of Secondary Hydroxy Groups in Carbohydrates Utilizing the High Site Recognition Ability of Organotin catalysts, wataru Murammatsu a, and Hirofumi Yoshimatsu. Advanced Synthesis and Catalysis,2013,355:2518-2524.
Although the above method (2) discloses the main reaction conditions for synthesizing the desacetylmaohexaside intermediate, it is known that the steps such as separation and purification after the completion of the reaction have a great influence on the yield of the compound, but the document does not provide a method how to separate and purify the intermediate from the reaction liquid thereof, and further cannot obtain a solid product of the intermediate, particularly cannot obtain a solid product of high purity (. Gtoreq.90%) of the intermediate, and cannot ensure the yield of the solid product.
In addition, the method (2) also comprises the steps of preparing a deacetylated cetirizine glucosyl modified compound (see CN 109734768A), reacting the compound 5 and the compound 6 for 24 hours under the process condition, cooling, quenching the reaction with saturated ammonium chloride aqueous solution, diluting the solution with chloroform/acetone=1:1, filtering to remove insoluble matters, concentrating the solution, subjecting the residue to column chromatography to obtain an acetylated product of the compound 7, and deacetylating the acetylated product under the condition of sodium methoxide and methanol to obtain the compound 7, wherein the reaction formula is as follows:
although the method discloses a method for separating and purifying the deacetyl erigeron glycoside intermediate similar compound (acetylate of the compound 7) to obtain a solid product, column chromatography is adopted for separating and purifying, the operation is complicated, the industrial mass production is not favored, the description of the column chromatography is also ambiguous, specific information of a column and a solvent is not provided, and a person skilled in the art is difficult to know how to realize the method.
It follows that none of the aforementioned prior art techniques provides a complete solution to this problem for the solid product of desacetyl maohexaside intermediate, and further fails to guarantee the yield and purity of the product.
Disclosure of Invention
Aiming at the problems and/or the defects existing in the prior art, the invention aims to provide a purification method and a preparation method of a deacetyl erigeron glycoside intermediate. According to the invention, through the combination of two functionally supported solvents (good solvent/poor solvent), not only can the purification effect of 12.1% -81.8% be realized and the impurities in the crude product be effectively removed, but also the precipitation of the solid of the intermediate of the desacetylmaohoridine from the liquid can be realized without heating and cooling, so that the method has the advantages of low energy consumption, low cost, convenience in operation control, safety and environmental protection, and is suitable for industrial production.
The technical scheme provided by the invention is as follows:
a method for purifying a compound of formula a comprising the steps of: adding a poor solvent into a mixture of the crude compound shown in the formula A and the good solvent;
wherein the good solvent is halogenated hydrocarbon solvent and/or ether solvent with cyclic structure, and the poor solvent is one or more than two selected from alkane solvent, aromatic hydrocarbon solvent, alcohol solvent, nitrile solvent, ketone solvent, ester solvent and ether solvent without cyclic structure; preferably, the poor solvent is one or more selected from the group consisting of alcohol solvents, nitrile solvents, ketone solvents and ester solvents.
In any of the above purification methods,
the halogenated hydrocarbon solvent is R a Cl x ，R a Is C 1 ～C 4 Alkyl, x is an integer from 1 to 6; preferably, said R a Methyl and/or ethyl, x is 2 or 3; more preferably, the halogenated hydrocarbon solvent is dichloromethane and/or dichloroethane.
In any of the above purification methods,
the ether solvent with the cyclic structure is selected from one or more than two of furan, methyl furan, tetrahydrofuran, methyl tetrahydrofuran, tetrahydropyran and 1, 4-dioxane; preferably, the ether solvent with a cyclic structure is tetrahydrofuran.
In any of the above purification methods,
the alkane solvent is C 2 ～C 8 An alkane; preferably, the alkane solvent is C 7 An alkane; more preferably, the alkane solvent is n-heptane.
In any of the above purification methods,
the aromatic hydrocarbon solvent is benzene and/or methyl substituted benzene; preferably, the aromatic hydrocarbon solvent is toluene.
In any of the above purification methods,
the alcohol solvent is C 1 ～C 4 An alcohol; preferably, the alcoholic solvent is selected from methanol, ethanol,One or more of n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol and tert-butanol; more preferably, the alcoholic solvent is methanol, isopropanol or tert-butanol.
In any of the above purification methods,
the nitrile solvent is R b -CN，R b Is C 1 ～C 4 An alkyl group; preferably, said R b Methyl and/or ethyl; more preferably, the nitrile solvent is acetonitrile.
In any of the above purification methods,
the ketone solvent isR c 、R d Independently selected from C 1 ～C 4 An alkyl group; preferably, said R c 、R d Independently selected from methyl and/or ethyl; more preferably, the ketone solvent is acetone.
In any of the above purification methods,
the ester solvent isR e 、R f Independently selected from C 1 ～C 4 An alkyl group; preferably, said R e 、R f Independently selected from methyl and/or ethyl; more preferably, the ester solvent is ethyl acetate.
In any of the above purification methods,
the ether solvent without the cyclic structure is R g -O-R h ，R g 、R h Independently selected from C 1 ～C 4 An alkyl group; preferably, said R g 、R h Independently selected from methyl and/or butyl; more preferably, the ether solvent without a cyclic structure is methyl tertiary butyl ether.
In any of the above purification methods,
the good solvent is selected from one or more than two of dichloromethane, dichloroethane, tetrahydrofuran and tetrahydropyran; preferably, the good solvent is dichloromethane and/or tetrahydrofuran.
In any of the above purification methods,
the poor solvent is selected from C 7 Alkanes, toluene, C 1 ～C 4 One or more of alcohol, acetonitrile, propionitrile, butyronitrile, acetone, butanone, ethyl formate, propyl formate, isopropyl formate, methyl acetate, ethyl acetate, vinyl acetate, propyl acetate, isopropyl acetate, diethyl ether, n-propyl ether, isopropyl ether, methyl n-butyl ether and methyl tert-butyl ether; preferably, the poor solvent is methanol, ethanol, isopropanol, t-butanol, acetonitrile, acetone or ethyl acetate.
In any of the above purification methods,
the polar parameter of the good solvent is 3.0 to 4.1, preferably 3.1 to 4.0.
In any of the above purification methods,
the polarity parameter of the poor solvent is 3.5 to 9.6, preferably 3.9 to 5.8.
In any of the above purification methods,
the volume ratio of the good solvent to the poor solvent is 1:1.5 to 20, preferably 1:2 to 10, for example, 1:2, 1:3, 3:10 or 1:4.
In any of the above purification methods,
the amount of the good solvent is 1.5 mL-20 mL, preferably 2.5 mL-12 mL, for example, 3mL, 5mL or 10mL, per gram of the crude compound represented by formula A.
In any of the above purification methods,
the amount of the poor solvent is 8 mL-50 mL, preferably 8 mL-40 mL, for example, 10mL, 15mL, 20mL, 30mL or 40mL, per gram of the crude compound represented by formula A.
In any of the above purification methods,
stirring a mixture of the crude compound shown in the formula A and the good solvent before adding the good solvent; the temperature of stirring is preferably 10℃to 40℃and more preferably 15℃to 30 ℃.
In any of the above purification methods,
after the poor solvent is added, the method can further comprise the following steps: stirring, filtering and drying.
The temperature of the stirring is preferably 10 to 40 ℃, more preferably 15 to 30 ℃.
The stirring time is preferably 2 to 20 hours, more preferably 4 to 15 hours.
In any of the above purification methods,
the purification method comprises the following steps: adding the crude product of the compound shown in the formula A into a good solvent, stirring and dissolving, adding a poor solvent, stirring, filtering and drying.
In any of the above purification methods,
the purity of the crude product of the compound shown in the formula A is less than or equal to 98wt%; preferably, the purity of the crude product of the compound shown in the formula A is 5-95 wt%; more preferably, the crude product of the compound represented by the formula A has a purity of 50wt% to 95wt% or 90wt% to 95wt%.
The invention also provides a preparation method of the compound shown in the formula A, which comprises the following steps:
wherein X is halogen, preferably Br;
(1) reacting digoxin shown in a formula E with a compound shown in a formula F and an auxiliary agent in an organic solvent to obtain a reaction solution of a deacetyl erigeron glycoside intermediate shown in a formula A;
(2) adding an ammonium chloride aqueous solution into the reaction solution obtained in the step (1), concentrating, adding a good solvent, separating the solution, concentrating an organic phase, and adding a poor solvent;
the types of the good solvent and the poor solvent are as described above.
In any one of the above preparation methods,
in step (1), the auxiliary agent comprises a catalyst and/or a promoter;
preferably, the catalyst is selected from one or more of phenyl tin trichloride, diphenyl tin dichloride, triphenyl tin chloride, tetraphenyl tin, dimethyl tin dichloride, diphenyl tin oxide and diphenyl tin sulfide, and/or the promoter is selected from AgO, ag 2 O、Ag 2 CO 3 One or two or more of them;
more preferably, the catalyst is phenyl tin trichloride and/or diphenyl tin dichloride, and/or the accelerator is Ag 2 O。
In any one of the above preparation methods,
in the step (1), the auxiliary agent comprises pyridine compounds; preferably, the pyridine compound is selected from one or more of pyridine, picoline, bipyridine and picoline; more preferably, the pyridine compound is 5,5 '-dimethyl-2, 2' -bipyridine.
In any one of the above preparation methods,
in the step (1), the organic solvent is a nitrile solvent and/or an ether solvent with a cyclic structure; preferably, the nitrile solvent and the ether solvent having a cyclic structure are as defined above.
In any one of the above preparation methods,
in the step (2), the ammonium chloride aqueous solution is a saturated ammonium chloride aqueous solution.
In any one of the above preparation methods,
in the step (2), after the poor solvent is added, the following operations are further included: stirring, filtering and drying.
In any one of the above preparation methods,
step (2) comprises the following steps: adding an ammonium chloride aqueous solution into the reaction solution obtained in the step (1), concentrating, adding a good solvent, filtering, separating filtrate, taking an organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate until no fraction is obtained, adding a poor solvent, stirring, filtering, and drying.
In any one of the above preparation methods,
the preparation method also comprises the following step (3): purifying the product obtained in the step (2) according to the purification method.
In any one of the above preparation methods,
in the step (1), the compound represented by the formula F is used in an amount of 1.1 to 5mol, preferably 1.8 to 2.5mol, per mol of digoxin.
In any one of the above preparation methods,
in step (1), the catalyst is used in an amount of 0.01 to 0.5mol, preferably 0.08 to 0.2mol, per mol of digoxin.
In any one of the above preparation methods,
in the step (1), the accelerator is used in an amount of 1.1 to 5mol, preferably 1.2 to 1.8mol, per mol of digoxin.
In any one of the above preparation methods,
in the step (1), the pyridine compound is used in an amount of 0.2 to 2mol, preferably 0.5 to 1mol, per mol of digoxin.
In any one of the above preparation methods,
in the step (1), the amount of the organic solvent is 10 mL-100 mL, preferably 40 mL-60 mL, per gram of digoxin.
In any one of the above preparation methods,
in the step (1), the reaction temperature is 10-40 ℃, preferably 25-35 ℃; the reaction time is 30 to 72 hours, preferably 45 to 50 hours.
In any one of the above preparation methods,
in the step (2), the amount of the aqueous ammonium chloride solution is 1 mL-10 mL, preferably 4 mL-6 mL, for example, 5mL, per g of digoxin.
In any one of the above preparation methods,
in the step (2), the volume ratio of the good solvent to the poor solvent is 1:0.7-20, preferably 1:0.7-10, for example, 1:0.7, 1:0.8, 1:1 or 1:1.6.
In any one of the above preparation methods,
in the step (2), the amount of the good solvent used is 5 mL-20 mL, preferably 8 mL-12 mL, for example, 10mL, per gram of digoxin.
In any one of the above preparation methods,
in the step (2), the amount of the poor solvent is 5 mL-20 mL, preferably 7 mL-12 mL, for example, 7mL, 8mL or 10mL, per gram of digoxin.
In any one of the above preparation methods,
in the step (2), when the stirring operation is included, the temperature of the stirring is 10 ℃ to 40 ℃, preferably 15 ℃ to 30 ℃; the stirring time is 2 to 20 hours, preferably 4 to 15 hours.
The invention also provides a solvent combination for improving the purity of the compound shown in the formula A,
the solvent composition includes a good solvent and a poor solvent, the types of good solvents and poor solvents, the volume amounts of good solvents and poor solvents being as described in any of the previous schemes.
The invention also provides application of the solvent combination in improving the purity of the compound shown in the formula A;
the solvent composition comprises a good solvent and a poor solvent, wherein the types of the good solvent and the poor solvent, the volume and the dosage ratio of the good solvent and the poor solvent, and the dosage of the good solvent and the poor solvent are calculated according to each gram of the crude compound shown in the formula A.
The beneficial effects of the invention mainly comprise the following aspects:
(1) According to the invention, through researches, unexpected discovery that the addition of the poor solvent can change the solubility of the desacetylbristleside intermediate and/or impurities thereof in the good solvent, so that the solubility of the desacetylbristleside intermediate in the mixed solvent (good solvent/poor solvent) is reduced, thereby separating out solids thereof, and simultaneously, the solubility of the impurities in the mixed solvent is maintained or improved, thereby enabling the impurities to be remained in the liquid in the form of solution, and further realizing the purification of the crude desacetylbristleside intermediate;
in other words, the solvent combination of good solvent/poor solvent of the present invention, the two solvents are functionally supported by each other, cooperate cooperatively, and function together in two ways: firstly, the solubility of the intermediate of the desacetyl hairy glycoside is changed so that the intermediate of the desacetyl hairy glycoside can be separated out from the liquid, and secondly, impurities are left in the liquid in a solution form so as to improve the purity of the intermediate of the desacetyl hairy glycoside;
(2) According to the invention, through the solvent combination of good solvent/poor solvent, purification effects of different degrees of 12.1% -81.8% can be realized, and impurities in the crude product can be effectively removed, as shown in Table 1;
TABLE 1 calculation results of purification effect of each example
| Purity of crude product | Purity after purification | Purification effect | |
| Example 5 | 93.4％ | 98.8％ | 81.8％ |
| Example 6 | 93.4％ | 98.3％ | 74.2％ |
| Example 7 | 93.4％ | 98.1％ | 71.2％ |
| Example 8 | 93.4％ | 98.8％ | 81.8％ |
| Example 9 | 93.4％ | 97.8％ | 66.7％ |
| Example 10 | 93.4％ | 98.3％ | 74.2％ |
| Example 11 | 93.4％ | 98.0％ | 69.7％ |
| Example 12 | 93.4％ | 98.3％ | 74.2％ |
| Example 13 | 93.4％ | 98.1％ | 71.2％ |
| Example 14 | 93.4％ | 94.2％ | 12.1％ |
| Example 15 | 93.4％ | 97.5％ | 62.1％ |
| Example 16 | 93.4％ | 94.7％ | 19.7％ |
| Example 17 | 93.4％ | 96.5％ | 47.0％ |
| Example 18 | 93.4％ | 95.2％ | 27.3％ |
Wherein, the purification effect= (purity after purification-crude product purity)/(100% -crude product purity) ×100% can reflect the removal degree of impurities in the crude product;
(3) According to the invention, through the solvent combination of good solvent/poor solvent, the product purity is improved, impurities are effectively removed, the solid of the intermediate of the desacetylmaohoriside can be separated out from the liquid without heating and cooling, the energy consumption is low, the cost is low, the operation control is convenient, the safety and the environmental protection are realized, and the method is suitable for industrial production.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
The invention is illustrated in further detail by way of examples which follow, but are not intended to limit the scope of the invention to the examples.
In the present invention, the specific conditions are not specified, and the reagent or the apparatus used is carried out according to the conventional conditions or the conditions recommended by the manufacturer, and the reagent or the apparatus used is not specified by the manufacturer, and can be obtained by purchasing commercial products or prepared by a known method.
In connection with the definition of terms used in the present invention, unless otherwise indicated, the initial definition provided by the terms herein applies to the term throughout; to the extent that terms are not specifically defined herein, they should be given meanings that would be able to be given to those skilled in the art in light of the disclosure and/or the context.
The term "crude" has the same meaning as "crude product", "crude product" and the like.
The term "crude product of the deacetyl erigeron glycoside intermediate" can be a product with the purity less than or equal to 98wt percent prepared by a synthesis method of the deacetyl erigeron glycoside intermediate, or can be a product with the purity less than or equal to 98wt percent obtained by purchase.
The terms "good solvent" and "poor solvent" are relative concepts, and "good solvent" refers to a solvent that can dissolve (e.g., dissolve, etc., see: general examples of the two parts of the chinese pharmacopoeia, 2010 edition) the desacetyl makinoform intermediate and/or impurities thereof, and "poor solvent" refers to a solvent that cannot dissolve (e.g., hardly or insoluble, very slightly soluble, etc.) the desacetyl makinoform intermediate or that cannot dissolve the desacetyl makinoform intermediate after forming a mixed solvent with the good solvent.
The term "C a ～C b Alkyl "means any alkyl group containing a to b carbon atoms, and similarly, the term" C "is also intended 2 ～C 8 Alkane "," C 1 ～C 4 Alcohols "and the like; thus C 1 ～C 4 Alkyl refers to alkyl groups containing 1 to 4 carbon atoms, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.
The term "picoline" means that 1, 2 or more hydrogen atoms of pyridine are replaced with methyl groups, and similarly, the term "picoline".
The term "polarity parameter", which may also be referred to as polarity index, is capable of more fully reflecting the nature of the solvent, and reference may be made to the specification for definition and/or explanation: high performance liquid chromatography and application (second edition), incorporated by reference in Shilin, chemical industry Press, month 6 2005; the polarity parameter data of the solvent used in the present invention are derived from the above-mentioned specifications on pages 60 to 61, for example, the polarity parameter of methylene chloride is 3.1, the polarity parameter of tetrahydrofuran is 4.0, etc.
In the present invention, the solvent and/or catalyst may be one commonly used in this type of reaction in the art; the classification and/or explanation of solvents can be found in the handbook of solvents, edited by Cheng Nenglin (4 th edition, beijing: chemical industry Press).
Some of the schemes and examples below may omit details of common reactions, separation techniques, and analytical procedures, and some may omit secondary products from chemical reactions. In addition, in some cases, the reaction intermediates may be used in subsequent steps without isolation and/or purification.
In general, the chemical transformations described in the specification may be performed using substantially stoichiometric reactants, although some reactions may benefit from using an excess of one or more reactants. Any description of stoichiometry, temperature, etc., herein, whether or not the term "range" is used explicitly, is intended to include the endpoints as shown.
EXAMPLE 1 preparation of desacetyl Maohuaoside intermediate
The preparation method of the deacetyl erigeron glycoside intermediate comprises the following steps:
(1) In a reaction flask, digoxin 10g (12.81 mmol, formula C) 41 H 64 O 14 CAS number: 20830-75-5) to a solution of tetrahydrofuran (500 mL), followed by 0.44g (1.28 mmol) of diphenyltin dichloride, 4.45g (19.2 mmol) of silver oxide, 1.77g (9.6 mmol) of 5,5 '-dimethyl-2, 2' -bipyridine, 10.53g (25.6 mmol) of 2,3,4, 6-tetraacetoxy-alpha-D-glucopyranose bromide, formula C 14 H 19 BrO 9 CAS number: 572-09-8), heating to 30 ℃ to react for 48 hours to obtain a reaction solution;
(2) Adding 50mL saturated ammonium chloride aqueous solution into the reaction solution, concentrating to obtain a residual 50mL suspension, adding 100mL dichloromethane, filtering, separating filtrate, drying organic phase (dichloromethane phase) with anhydrous sodium sulfate, filtering, concentrating filtrate to obtain light yellow oily substance, adding 100mL methanol, stirring for 12 hr, filtering, and drying to obtain desacetylbristleside intermediate (formula C) 55 H 82 O 23 CAS number: 1469804-92-9, see the medicine intelligence data network: https:// db yaozh.com/biozhudebcompreonsearconnection = digoxin) crude 10.2g, white solid, 71.7% yield, 93.4% purity.
EXAMPLE 2 preparation of desacetyl Maohuaoside intermediate
(1) In a reaction flask, 10g (12.81 mmol) of digoxin was added to a tetrahydrofuran (500 mL) solution, 0.44g (1.28 mmol) of diphenyl tin dichloride, 4.45g (19.2 mmol) of silver oxide, 1.77g (9.6 mmol) of 5,5 '-dimethyl-2, 2' -bipyridine and 10.53g (25.6 mmol) of 2,3,4, 6-tetraacetyloxy-alpha-D-glucopyranose bromide were further added, and the mixture was heated to 30℃to react for 48 hours to obtain a reaction solution;
(2) After 50mL of saturated ammonium chloride aqueous solution was added to the reaction solution, the mixture was concentrated to a remaining 50mL of a suspension, 100mL of methylene chloride was added, the mixture was filtered, the filtrate was separated, the organic phase (methylene chloride phase) was dried over anhydrous sodium sulfate, the filtrate was filtered, the filtrate was concentrated to a non-distillate, a pale yellow oily substance was obtained, 100mL of isopropyl alcohol was added, stirring was carried out for 12 hours, suction filtration and drying were carried out, 9.5g of a crude product of a desacetylmaohorin intermediate was obtained, and a white solid was obtained in a yield of 66.8% and a purity of 91.5%.
EXAMPLE 3 preparation of desacetyl Maohuaoside intermediate
(1) In a reaction flask, 10g (12.81 mmol) of digoxin was added to a tetrahydrofuran (500 mL) solution, 0.44g (1.28 mmol) of diphenyl tin dichloride, 4.45g (19.2 mmol) of silver oxide, 1.77g (9.6 mmol) of 5,5 '-dimethyl-2, 2' -bipyridine and 10.53g (25.6 mmol) of 2,3,4, 6-tetraacetyloxy-alpha-D-glucopyranose bromide were further added, and the mixture was heated to 30℃to react for 48 hours to obtain a reaction solution;
(2) After 50mL of saturated ammonium chloride aqueous solution was added to the reaction solution, the mixture was concentrated to a remaining 50mL of a suspension, 100mL of methylene chloride was added, the mixture was filtered, the filtrate was separated, the organic phase (methylene chloride phase) was dried over anhydrous sodium sulfate, the filtrate was filtered, the filtrate was concentrated to a non-distillate, a pale yellow oily substance was obtained, 80mL of acetonitrile was added, stirring was carried out for 12 hours, the mixture was suction-filtered and dried, 9.1g of a crude product of desacetylmaohoriside intermediate was obtained, and a white solid was obtained in a yield of 64.0% and a purity of 90.8%.
EXAMPLE 4 preparation of desacetylbristleside intermediate
(1) In a reaction flask, 10g (12.81 mmol) of digoxin was added to a tetrahydrofuran (500 mL) solution, 0.44g (1.28 mmol) of diphenyl tin dichloride, 4.45g (19.2 mmol) of silver oxide, 1.77g (9.6 mmol) of 5,5 '-dimethyl-2, 2' -bipyridine and 10.53g (25.6 mmol) of 2,3,4, 6-tetraacetyloxy-alpha-D-glucopyranose bromide were further added, and the mixture was heated to 30℃to react for 48 hours to obtain a reaction solution;
(2) After 50mL of saturated ammonium chloride aqueous solution was added to the reaction solution, the mixture was concentrated to a remaining 50mL of a suspension, 100mL of methylene chloride was added, the mixture was filtered, the filtrate was separated, the organic phase (methylene chloride phase) was dried over anhydrous sodium sulfate, the filtrate was filtered, the filtrate was concentrated to a non-distillate, a pale yellow oily substance was obtained, 70mL of ethanol was added, stirring was carried out for 12 hours, the mixture was suction-filtered and dried, 9.4g of a crude product of desacetylmaohoriside intermediate was obtained, and a white solid was obtained in a yield of 66.1% and a purity of 92.3%.
EXAMPLE 5 purification of crude desacetyl Maohuaoside intermediate
1g of crude product of the intermediate of desacetyl hairy glycoside (purity 93.4%) is added into 3 times volume (3 mL) of dichloromethane at room temperature, stirred and dissolved, 10 times volume (10 mL) of isopropanol is added, stirred for 5 hours, filtered by suction and dried to obtain the intermediate of desacetyl hairy glycoside, white solid, yield 64% and purity 98.8%.
By means of nuclear magnetic resonance (Nuclear Magnetic Resonance) detection,
acetopilin intermediate 1 H-NMR(CDCl 3 )：δ5.95(d,1H),5.23(t,1H),5.04(m,2H),4.88(m,5H),4.60(d,1H),4.24(d,1H),4.20(d,3H),4.03(d,1H),3.82(m,4H),3.36(m,2H),3.23(m,3H),2.10(s,3H),2.05(s,6H),2.03(s,3H),1.91(m,6H),1.72(m,10H),1.52(m,8H),1.26(m,16H),0.98(d,1H),0.94(d,2H),0.82(d,3H)；
Acetopilin intermediate 13 C-NMR(CDCl 3 )：δ174.64,174.52,170.54,170.15,169.34,169.11,117.66,101.20,98.20(2C),95.44,85.88,83.71,82.57,82.20,75.10，75.06，73.65，72.36，72.11，71.10，68.34，68.23，68.08，67.67，66.63，66.34，66.45,61.75,55.49,45.63,41.43,37.15,36.85,35.96,35.00,33.27,33.22,32.59,32.32,30.31,27.39,26.35,25.36,23.64,23.52,21.67,21.62,20.65,20.55,20.53,18.16(2C),17.81,8.92。
EXAMPLE 6 purification of crude desacetyl Maohuaoside intermediate
1g of crude product of the intermediate of desacetyl hairy glycoside (purity 93.4%) was added to 3 times (3 mL) of methylene chloride at room temperature, stirred and dissolved, then 10 times volume (10 mL) of acetonitrile was added, stirred for 5 hours, and then suction filtered and dried to obtain the intermediate of desacetyl hairy glycoside, white solid, yield 66% and purity 98.3%.
EXAMPLE 7 purification of crude desacetyl Maohuaoside intermediate
1g of crude product of the intermediate of desacetyl hairy glycoside (purity 93.4%) was added to 3 times (3 mL) of methylene chloride at room temperature, stirred and dissolved, then 30 times volume (30 mL) of methanol was added, stirred for 5 hours, and then suction filtered and dried to obtain the intermediate of desacetyl hairy glycoside, white solid, yield 62%, purity 98.1%.
EXAMPLE 8 purification of crude desacetyl Maohuaoside intermediate
1g of crude product of the intermediate of desacetyl hairy glycoside (purity 93.4%) was added to 3 times (3 mL) of methylene chloride at room temperature, stirred and dissolved, then 10 times volume (10 mL) of acetone was added, stirred for 5 hours, and then suction filtered and dried to obtain the intermediate of desacetyl hairy glycoside, white solid, yield 63% and purity 98.8%.
EXAMPLE 9 purification of crude desacetyl Maohuaoside intermediate
1g of crude desacetyl erigeron intermediate (purity 93.4%) was added to 3 times (3 mL) of dichloromethane at room temperature, stirred for dissolution, then 10 times volume (10 mL) of ethyl acetate was added, stirred for 5h, then suction filtered and dried to obtain the desacetyl erigeron intermediate as a white solid with a yield of 61% and a purity of 97.8%.
EXAMPLE 10 purification of crude desacetyl Maohuaoside intermediate
1g of crude product of the intermediate of desacetyl hairy glycoside (purity 93.4%) is added into 10 times (10 mL) tetrahydrofuran at room temperature, stirred and dissolved, then 20 times volume (20 mL) of isopropanol is added, stirred for 5 hours, filtered by suction and dried to obtain the intermediate of desacetyl hairy glycoside, white solid, yield 62.5% and purity 98.3%.
EXAMPLE 11 purification of crude desacetyl Maohuaoside intermediate
1g of crude product of the intermediate of desacetyl hairy glycoside (purity 93.4%) is added into 10 times (10 mL) tetrahydrofuran at room temperature, stirred and dissolved, then 20 times volume (20 mL) of acetone is added, stirred for 5h, and then suction filtration and drying are carried out, thus obtaining the intermediate of desacetyl hairy glycoside, white solid with the yield of 63% and the purity of 98.0%.
EXAMPLE 12 purification of crude desacetyl Maohuaoside intermediate
1g of crude product of the intermediate of desacetyl hairy glycoside (purity 93.4%) is added into 10 times (10 mL) tetrahydrofuran at room temperature, stirred and dissolved, then 20 times volume (20 mL) of ethyl acetate is added, stirred for 5h, filtered by suction and dried to obtain the intermediate of desacetyl hairy glycoside, white solid, yield 64% and purity 98.3%.
EXAMPLE 13 purification of crude desacetyl Maohuaoside intermediate
1g of crude product of the intermediate of desacetyl hairy glycoside (purity 93.4%) is added into 10 times (10 mL) tetrahydrofuran at room temperature, stirred and dissolved, then 30 times volume (30 mL) of methanol is added, stirred for 5h, and then suction filtered and dried, thus obtaining the intermediate of desacetyl hairy glycoside, white solid with the yield of 64% and the purity of 98.1%.
EXAMPLE 14 purification of crude desacetyl Maohuaoside intermediate
1g of crude product of the intermediate of desacetyl hairy glycoside (purity 93.4%) was added to 10 times (10 mL) of methylene chloride at room temperature, stirred and dissolved, then 40 times volume (40 mL) of toluene was added, stirred for 5 hours, and then suction filtered and dried to obtain the intermediate of desacetyl hairy glycoside, white solid, yield 52%, purity 94.2%.
EXAMPLE 15 purification of crude desacetyl Maohuaoside intermediate
1g of crude product of the intermediate of desacetyl hairy glycoside (purity 93.4%) is added into 5 times (5 mL) of dichloromethane at room temperature, stirred and dissolved, then 20 times volume (20 mL) of tertiary butanol is added, stirred for 5 hours, filtered by suction and dried to obtain the intermediate of desacetyl hairy glycoside, white solid, yield 64% and purity 97.5%.
EXAMPLE 16 purification of crude desacetyl Maohuaoside intermediate
1g of crude product of the intermediate of desacetyl hairy glycoside (purity 93.4%) was added to 5 times (5 mL) of methylene chloride at room temperature, stirred and dissolved, then 15 times volume (15 mL) of methyl tertiary butyl ether was added, stirred for 5 hours, then suction filtered and dried to obtain the intermediate of desacetyl hairy glycoside, white solid, yield 71%, purity 94.7%.
EXAMPLE 17 purification of crude desacetyl Maohuaoside intermediate
1g of crude product of the intermediate of desacetyl hairy glycoside (purity 93.4%) is added into 10 times (10 mL) tetrahydrofuran at room temperature, stirred and dissolved, then 20 times volume (20 mL) toluene is added, stirred for 5h, and then suction filtration and drying are carried out, thus obtaining the intermediate of desacetyl hairy glycoside, white solid with the yield of 43% and the purity of 96.5%.
EXAMPLE 18 purification of crude desacetyl Maohuaoside intermediate
1g of crude product of the intermediate of desacetyl hairy glycoside (purity 93.4%) is added into 10 times (10 mL) tetrahydrofuran at room temperature, stirred and dissolved, then 20 times volume (20 mL) of n-heptane is added, stirred for 5h, filtered by suction and dried to obtain the intermediate of desacetyl hairy glycoside, white solid, yield 42% and purity 95.2%.
Claims (19)
1. A method for purifying a compound of formula a comprising the steps of: adding a poor solvent into a mixture of the crude compound shown in the formula A and the good solvent;
wherein, the liquid crystal display device comprises a liquid crystal display device,
the poor solvent is a halogenated hydrocarbon solvent, and the poor solvent is one or more than two of an alcohol solvent, a nitrile solvent, a ketone solvent and an ester solvent;
or the good solvent is an ether solvent with a cyclic structure, and the poor solvent is one or more than two of alkane solvents, aromatic hydrocarbon solvents, alcohol solvents, ketone solvents and ester solvents;
the halogenated hydrocarbon solvent is dichloromethane;
the ether solvent with the cyclic structure is tetrahydrofuran;
the alkane solvent is n-heptane;
the aromatic hydrocarbon solvent is benzene or methyl substituted benzene;
the alcohol solvent is methanol, isopropanol or tertiary butanol;
the nitrile solvent is acetonitrile;
the ketone solvent is acetone;
the ester solvent is ethyl acetate;
the volume and dosage ratio of the good solvent to the poor solvent is 1:2-10.
2. The purification method according to claim 1, wherein,
the polarity parameter of the good solvent is 3.0-4.1;
or alternatively, the first and second heat exchangers may be,
the polarity parameter of the poor solvent is 3.5-9.6.
3. A purification method according to claim 2, wherein,
the polarity parameter of the good solvent is 3.1-4.0;
or alternatively, the first and second heat exchangers may be,
the polarity parameter of the poor solvent is 3.9-5.8.
4. The purification method according to claim 1, wherein,
the dosage of the good solvent is 1.5 mL-20 mL based on each gram of the crude compound shown in the formula A;
or alternatively, the first and second heat exchangers may be,
the consumption of the poor solvent is 8 mL-50 mL per gram of crude compound shown in the formula A;
or alternatively, the first and second heat exchangers may be,
stirring a mixture of the crude compound shown in the formula A and the good solvent before adding the good solvent;
or alternatively, the first and second heat exchangers may be,
after the poor solvent is added, the method can further comprise the following steps: stirring, filtering and drying;
or alternatively, the first and second heat exchangers may be,
the purification method comprises the following steps: adding the crude product of the compound shown in the formula A into a good solvent, stirring and dissolving, then adding a poor solvent, stirring, filtering and drying;
or alternatively, the first and second heat exchangers may be,
the purity of the crude product of the compound shown in the formula A is less than or equal to 98wt%.
5. The purification method according to claim 4, wherein,
the dosage of the good solvent is 2.5 mL-12 mL based on each gram of the crude compound shown in the formula A;
or alternatively, the first and second heat exchangers may be,
the consumption of the poor solvent is 8 mL-40 mL based on each gram of the crude compound shown in the formula A;
or alternatively, the first and second heat exchangers may be,
the temperature of stirring the mixture of the crude product of the compound shown in the formula A and the good solvent is 10-40 ℃;
or alternatively, the first and second heat exchangers may be,
the temperature of stirring after the poor solvent is added is 10-40 ℃; stirring time after the poor solvent is added is 2-20 h;
or alternatively, the first and second heat exchangers may be,
the purity of the crude product of the compound shown in the formula A is 5-95 wt%.
6. The purification method according to claim 4, wherein,
the temperature of stirring the mixture of the crude product of the compound shown in the formula A and the good solvent is 15-30 ℃;
or alternatively, the first and second heat exchangers may be,
the temperature of stirring after the poor solvent is added is 15-30 ℃; the stirring time after the poor solvent is added is 4-15 h;
or alternatively, the first and second heat exchangers may be,
the purity of the crude product of the compound shown in the formula A is 50-95 wt%.
7. The purification method according to claim 4, wherein,
the purity of the crude product of the compound shown in the formula A is 90-95 wt%.
8. A process for the preparation of a compound of formula a comprising the steps of:
wherein X is halogen;
(1) reacting digoxin shown in a formula E with a compound shown in a formula F and an auxiliary agent in an organic solvent to obtain a reaction solution of a deacetyl erigeron glycoside intermediate shown in a formula A;
(2) adding an ammonium chloride aqueous solution into the reaction solution obtained in the step (1), concentrating, adding a good solvent, separating the solution, concentrating an organic phase, and adding a poor solvent;
the good solvent and the poor solvent are as defined in claim 1.
9. The method for preparing a compound of formula a according to claim 8, wherein X is Br.
10. The process for producing a compound of formula A according to claim 8, wherein,
in step (1), the auxiliary agent comprises a catalyst or a promoter;
or alternatively, the first and second heat exchangers may be,
in the step (1), the organic solvent is a nitrile solvent and/or an ether solvent with a cyclic structure;
or alternatively, the first and second heat exchangers may be,
in the step (2), the ammonium chloride aqueous solution is a saturated ammonium chloride aqueous solution;
or alternatively, the first and second heat exchangers may be,
in the step (2), after the poor solvent is added, the following operations are further included: stirring, filtering and drying;
or alternatively, the first and second heat exchangers may be,
step (2) comprises the following steps: adding an ammonium chloride aqueous solution into the reaction solution obtained in the step (1), concentrating, adding a good solvent, filtering, separating filtrate, taking an organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate until no fraction is obtained, adding a poor solvent, stirring, filtering, and drying;
or alternatively, the first and second heat exchangers may be,
the preparation method also comprises the following step (3): purifying the product obtained in the step (2) according to the purification method of any one of claims 1 to 6.
11. The process for producing a compound of formula A according to claim 10, wherein,
in the step (1), the catalyst is selected from one or more of phenyl tin trichloride, diphenyl tin dichloride, triphenyl tin chloride, tetraphenyl tin, dimethyl tin dichloride, diphenyl tin oxide and diphenyl tin sulfide, or the accelerator is selected from AgO and Ag 2 O、Ag 2 CO 3 One or two or more of them;
or alternatively, the first and second heat exchangers may be,
in the step (1), the nitrile solvent and the ether solvent having a cyclic structure are defined in claim 1.
12. The process for producing a compound of formula A according to claim 10, wherein,
in the step (1), the catalyst is phenyl tin trichloride and/or diphenyl tin dichloride, or the accelerator is Ag 2 O。
13. The process for producing a compound of formula A according to claim 10, wherein,
in the step (1), the dosage of the compound shown in the formula F is 1.1 to 5mol per mol of digoxin;
or alternatively, the first and second heat exchangers may be,
in the step (1), the catalyst is used in an amount of 0.01 to 0.5mol per mol of digoxin;
or alternatively, the first and second heat exchangers may be,
in the step (1), the using amount of the accelerator is 1.1 to 5mol per mol of digoxin;
or alternatively, the first and second heat exchangers may be,
in the step (1), the dosage of the organic solvent is 10 mL-100 mL according to each gram of digoxin;
or alternatively, the first and second heat exchangers may be,
in the step (1), the reaction temperature is 10-40 ℃; the reaction time is 30-72 hours;
or alternatively, the first and second heat exchangers may be,
in the step (2), the dosage of the ammonium chloride aqueous solution is 1-10 mL according to each gram of digoxin;
or alternatively, the first and second heat exchangers may be,
in the step (2), the volume and the dosage ratio of the good solvent to the poor solvent is 1:0.7-20;
or alternatively, the first and second heat exchangers may be,
in the step (2), the dosage of the good solvent is 5-20 mL per gram of digoxin;
or alternatively, the first and second heat exchangers may be,
in the step (2), the dosage of the poor solvent is 5-20 mL per gram of digoxin;
or alternatively, the first and second heat exchangers may be,
in the step (2), when stirring operation is included, the temperature of stirring is 10-40 ℃; the stirring time is 2-20 h.
14. The process for producing a compound of formula A according to claim 13, wherein,
in the step (1), the compound shown in the formula F is used in an amount of 1.8 to 2.5mol per mol of digoxin;
or alternatively, the first and second heat exchangers may be,
in the step (1), the catalyst is used in an amount of 0.08mol to 0.2mol per mol of digoxin;
or alternatively, the first and second heat exchangers may be,
in the step (1), the using amount of the accelerator is 1.2 to 1.8mol per mol of digoxin;
or alternatively, the first and second heat exchangers may be,
in the step (1), the dosage of the organic solvent is 40-60 mL according to each gram of digoxin;
or alternatively, the first and second heat exchangers may be,
in the step (1), the reaction temperature is 25-35 ℃; the reaction time is 45-50 h;
or alternatively, the first and second heat exchangers may be,
in the step (2), the dosage of the ammonium chloride aqueous solution is 4-6 mL according to each gram of digoxin;
or alternatively, the first and second heat exchangers may be,
in the step (2), the volume and the dosage ratio of the good solvent to the poor solvent is 1:0.7-10;
or alternatively, the first and second heat exchangers may be,
in the step (2), the dosage of the good solvent is 8-12 mL per gram of digoxin;
or alternatively, the first and second heat exchangers may be,
in the step (2), the dosage of the poor solvent is 7-12 mL per gram of digoxin;
or alternatively, the first and second heat exchangers may be,
in the step (2), when stirring operation is included, the temperature of stirring is 15-30 ℃; the stirring time is 4-15 h.
15. The process for producing a compound of formula A according to claim 10, wherein,
in the step (1), the auxiliary agent comprises a pyridine compound.
16. The process for producing a compound of formula A according to claim 15, wherein,
in the step (1), the pyridine compound is one or more selected from pyridine, picoline, bipyridine and picoline.
17. The process for producing a compound of formula A according to claim 16, wherein,
in the step (1), the pyridine compound is 5,5 '-dimethyl-2, 2' -bipyridine.
18. The process for producing a compound of formula A according to claim 17, wherein,
in the step (1), the pyridine compound is used in an amount of 0.2 to 2mol per mol of digoxin.
19. The process for producing a compound of formula A according to claim 18, wherein,
in the step (1), the pyridine compound is used in an amount of 0.5 to 1mol per mol of digoxin.
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