CN114478465B - Preparation method of extrahepatic biliary tract toxin - Google Patents
Preparation method of extrahepatic biliary tract toxin Download PDFInfo
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- CN114478465B CN114478465B CN202111462982.2A CN202111462982A CN114478465B CN 114478465 B CN114478465 B CN 114478465B CN 202111462982 A CN202111462982 A CN 202111462982A CN 114478465 B CN114478465 B CN 114478465B
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- 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
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Abstract
The invention relates to a preparation method of extrahepatic biliary tract toxins; the preparation method of extrahepatic cholangiotoxin is adopted, and the deprotection reaction temperature, the reaction time, the material feeding ratio, the selection of a deprotection reagent and the like are optimized, so that the compound II with high purity and high yield can be unexpectedly obtained; especially, the invention selects hydrofluoric acid salt as a deprotection reagent, effectively solves the technical problem that TBAF is adopted to remove TBS to generate a ring-closing byproduct in the prior art, has good repeatability, milder reaction conditions, better yield, high purity of the obtained product and low post-treatment difficulty, provides guarantee for the subsequent preparation of high-quality medicines, and is suitable for small-scale preparation in laboratories and industrialized mass production.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of extrahepatic biliary tract toxins.
Background
The extrahepatic biliary tract comprises bile duct below the junction of left and right hepatic ducts, such as gallbladder, hepatic duct, cholecyst duct, common bile duct. Bile is produced by hepatocytes, collected by various levels of bile ducts in the liver, discharged from the hilum, and transported to the duodenum through the extrahepatic biliary tract. Bile ducts carry bile from the liver and gall bladder, and the gall bladder becomes the small intestine. Bile is a waste product required for proper digestion, fat absorption and removal of liver from green to yellowish-brown liquids. Biliary tract disorders are often referred to as cholangiopathy, are often non-staining disorders, particularly cholangitis, and may ultimately require liver transplantation. Cholangitis is characterized by inflammation (swelling and redness) in the bile duct. When bile ducts become inflamed or blocked, bile can back up into the liver, causing liver damage and other systemic problems. The primary forms of cholangiopathy include primary cholangitis (PBC), primary cholangitis (PSC), secondary cholangitis, and immune cholangitis.
Biliary closure (BA) is the most common cholestatic disease in children and is characterized by progressive inflammation of the intrahepatic bile duct and fibrous obstruction, and clinical practice shows that if not treated surgically, the infant dies usually before age 2. Recently, a novel extrahepatic biliary tract toxin biliatesone which is 1, 2-diaryl-2-acetone isoflavone is successfully separated and purified from chlorella Dysphania glomulifera and D.littoralis by foreign team, and after zebra fish is treated by using the naturally extracted biliatesone, the development defects of gall bladder and common bile duct of zebra fish larvae are aggravated along with the increase of the treatment concentration; studies have also shown that biliatesone destroys the apical polarity and single-layer cell integrity in the model of the three-dimensionally cultured bile duct epithelial cells, causing lumen blockage, similar to the pathological changes of the extrahepatic biliary tract in biliary tract occluded patients, this study result provides direct evidence for the hypothesis that biliary tract occlusion occurs in association with perinatal environmental toxin exposure, and also provides a new entry point for the study of biliary tract occlusion mechanisms.
Due to the fact that the production place of the extracted natural biliatesone raw material is single, the purification technology is complex, the yield is low and the like, the deep research of the biliatesone induced biliary tract locking animal model is greatly limited, and the exploration of biliary tract locking pathogenesis and prevention means in the industry is slow. The prior literature reports few methods for synthesizing biliatesone, which is extrahepatic biliary tract toxin, patent CN109593077A discloses a synthetic method of biliatesone, and the synthetic route is shown in the following chart:
the operation amount of the method is small, and the method is only in milligram level; when the inventor adopts tetrabutylammonium fluoride to remove the tertiary butyl dimethylsilyl protecting group in the technical scheme repeatedly, most of the obtained products are byproducts, and impurities are obviously increased during extraction and purification. Obviously, this method is not suitable for industrial scale-up.
Disclosure of Invention
The invention aims to provide a preparation method of extrahepatic biliary tract toxins, which aims to solve the problems mentioned in the background art.
In order to achieve the above object, the present invention provides a process for preparing compound II, comprising the steps of:
deprotection reaction, namely reacting the compound I with a deprotection reagent to obtain a compound II;
the deprotection reagent is a hydrofluoric acid salt.
As a preferred embodiment of the present invention, the hydrofluoric acid salt is selected from triethylamine hydrofluoric acid salt and/or N, N-diisopropylethylamine tri-hydrofluoric acid salt.
As a preferable technical scheme of the invention, the hydrofluoric acid salt is triethylamine hydrofluoric acid salt.
As a preferable technical scheme of the invention, the molar ratio of triethylamine to hydrofluoric acid in the triethylamine hydrofluoric acid salt is 1:3.
As a preferable technical scheme of the invention, the preparation method comprises the following steps: mixing the compound I, hydrofluoric acid salt and an organic solvent, and stirring at room temperature under the protection of inert gas; and (5) after the reaction is finished, purifying to obtain the catalyst.
As a preferable technical scheme of the invention, the organic solvent is selected from one or more of tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide, ethyl acetate and dichloromethane.
As a preferable technical scheme of the invention, the molar ratio of the compound I to the hydrofluoric acid salt is 1 (2-3.4).
As a preferred embodiment of the present invention, the purified solvent is selected from the group consisting of water and acetonitrile.
As a preferable technical scheme of the invention, the purified solvent is a mixture of water and acetonitrile, wherein the volume ratio of water to acetonitrile is (1-3): 1.
as a preferable technical scheme of the invention, the stirring time is 3-5 h.
Advantageous effects
Compared with the prior art, the invention has the beneficial effects that:
1. the preparation method of extrahepatic cholangiotoxin is adopted, and the compound II with high purity can be unexpectedly obtained in high yield through the preferential deprotection reaction temperature, reaction time, material feeding ratio, deprotection reagent selection and the like; especially, the invention prefers hydrofluoric acid salt as a deprotection reagent, which effectively solves the technical problem that the removal of tert-butyl dimethyl silicon-based protecting group by tetrabutylammonium fluoride in the prior art can generate ring-closing byproducts.
2. The invention further reduces the purification difficulty of the compound II by optimizing the purification reagent and the reagent proportion, and solves the technical problem of deterioration in the conventional column chromatography purification process after finishing the post-treatment extraction.
3. The invention provides a method for synthesizing extrahepatic biliary tract toxins, which has higher yield and lower cost, and is beneficial to subsequent industrialized production.
4. The preparation method used in the invention has the advantages of mild reaction conditions, good yield, high purity of the obtained product and low post-treatment difficulty, and provides guarantee for the subsequent preparation of high-quality medicines, thus being suitable for small-scale preparation in laboratories and industrial mass production.
Detailed Description
The contents of the present invention can be more easily understood by referring to the following detailed description of preferred embodiments of the present invention and examples included. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, definitions, will control.
The term "prepared from …" as used herein is synonymous with "comprising". The terms "comprising," "including," "having," "containing," or any other variation thereof, as used herein, are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, step, method, article, or apparatus.
When an equivalent, concentration, or other value or parameter is expressed as a range, preferred range, or a range bounded by a list of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. When a numerical range is described herein, unless otherwise indicated, the range is intended to include its endpoints and all integers and fractions within the range.
The singular forms include plural referents unless the context clearly dictates otherwise. "optional" or "any" means that the subsequently described event or event may or may not occur, and that the description includes both cases where the event occurs and cases where the event does not.
Approximating language, in the specification and claims, may be applied to modify an amount that would not limit the invention to the specific amount, but would include an acceptable portion that would be close to the amount without resulting in a change in the basic function involved. Accordingly, the modification of a numerical value with "about", "about" or the like means that the present invention is not limited to the precise numerical value. In some examples, the approximating language may correspond to the precision of an instrument for measuring the value. In the present specification and claims, the range limitations may be combined and/or interchanged, such ranges including all the sub-ranges contained therein if not expressly stated.
Furthermore, the indefinite articles "a" and "an" preceding an element or component of the invention are not limited to the requirements of the number of elements or components (i.e. the number of occurrences). Thus, the use of "a" or "an" should be interpreted as including one or at least one, and the singular reference of an element or component also includes the plural reference unless the amount is obvious to the singular reference.
In order to solve the technical problems, the invention provides a preparation method of a compound II, which comprises the following steps:
deprotection reaction, namely reacting the compound I with a deprotection reagent to obtain a compound II;
the deprotection reagent is a hydrofluoric acid salt.
Preferably, the hydrofluoric acid salt is selected from triethylamine hydrofluoric acid salt and/or N, N-diisopropylethylamine tri-hydrofluoric acid salt.
In some preferred embodiments, the hydrofluoric acid salt is triethylamine hydrofluoric acid salt.
In some preferred embodiments, the molar ratio of triethylamine to hydrofluoric acid in the triethylamine hydrofluoride salt is 1:3.
Preferably, the triethylamine hydrofluoric acid salt is triethylamine tri-hydrofluoric acid salt (CAS number 73602-61-6).
In some preferred embodiments, the preparation method comprises the steps of: mixing the compound I, hydrofluoric acid salt and an organic solvent, and stirring at room temperature under the protection of inert gas; and (5) after the reaction is finished, purifying to obtain the catalyst.
In some preferred embodiments, the organic solvent is selected from one or more of tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide, ethyl acetate, dichloromethane.
Preferably, the volume ratio of the organic solvent to the deprotecting reagent is (8-13): 1.
Preferably, the volume ratio of the organic solvent to the deprotecting reagent is 10:1.
Preferably, the organic solvent is tetrahydrofuran.
In some preferred embodiments, the molar ratio of compound I to hydrofluoride is 1 (2-3.4).
Preferably, the molar ratio of the compound I to the hydrofluoric acid salt is 1:2.6.
In some preferred embodiments, the purified solvent is selected from the group consisting of water and acetonitrile.
In some preferred embodiments, the volume ratio of water to acetonitrile is (1-3): 1.
in some preferred embodiments, the deprotection reaction is stirred for 3 to 5 hours.
Preferably, the stirring time of the deprotection reaction is 4h.
Examples
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedure, in which no specific conditions are noted in the examples below, is generally carried out according to conventional conditions.
The raw materials or reagents used in the examples were commercially available unless otherwise specified.
The room temperature described in the examples is 10 to 20 ℃. Unless otherwise indicated, the reagents described were used without purification. All solvents were purchased from commercial suppliers such as Aldrich (Aldrich) and used without treatment.
The reaction was judged to be terminated by TLC analysis and/or by LCMS analysis by consumption of starting material. Thin Layer Chromatography (TLC) for analysis was performed on glass plates (EMD Chemicals) pre-coated with silica gel 60f 254.25 mm plates, iodination on UV light (254 nm) and/or silica gel, and/or heating with TLC staining such as alcohol phosphomolybdic acid, ninhydrin solution, potassium permanganate solution or ceric sulfate solution.
Abbreviations used in the present invention have the usual meaning in the art, such as: THF represents tetrahydrofuran, EA represents ethyl acetate, TBAF represents tetrabutylammonium fluoride, TBS represents a tert-butyldimethylsilyl protecting group.
In the case of example 1,preparation of Compound II
Compound I (1.0 g,2.26 mmol), THF (10 mL), triethylamine trihydrofluoride (1.0 mL,0.989 g/mL) were added to the reaction flask, nitrogen-protected, and stirred at room temperature for 4h; after the reaction, column chromatography (water/acetonitrile=1:1-3:1) is used for purification to obtain a compound II (0.58 g,79%, LCMS purity 96%), and further, the obtained compound II can be further subjected to high performance liquid chromatography to prepare a high-purity product with purity of > 99%.
1H NMR(400MHz,CDCl 3 )δ7.43(s,1H),7.30–7.24(m,1H),7.15(dd,J＝7.5,1.5Hz,1H),6.97(d,J＝8.1Hz,1H),6.92(t,J＝7.4Hz,1H),6.30(s,1H),6.06(s,1H),6.03(s,2H),3.99(s,3H),3.75(s,3H).
In the case of example 2,preparation of Compound II
Compound I (1.0 g,2.26 mmol), THF (5.6 mL), triethylamine trihydrofluoride (0.7 mL,0.989 g/mL) were added to the reaction flask, nitrogen protected, stirred at room temperature for 4h; after the completion of the reaction, column chromatography (water/acetonitrile=1:1 to 3:1) was performed to obtain compound II (0.56 g, 76%).
In the case of example 3,preparation of Compound II
Compound I (1.0 g,2.26 mmol), THF (15.6 mL), triethylamine trihydrofluoride (1.2 mL,0.989 g/mL) were added to the reaction flask, nitrogen-protected, stirred at room temperature for 4h; after the reaction, purification by column chromatography (water/acetonitrile=1:1 to 3:1) gave compound II (0.57 g, 77%).
In the case of example 4,preparation of Compound II
Compound I (90 mg,0.203 mmol), THF (5 mL), tetrabutylammonium fluoride (1 mol/L,0.6 mL) (CAS No. 429-41-4) were added to the reaction flask, and stirred at room temperature under nitrogen for 16h; ending the reaction; the reaction system is very heterogeneous, and LCMS detects that the crude product contains about 15% of the target product compound II, H is added 2 O (10 mL), extract with EA (10 mL. Times.3), combine the organic phases, wash with brine (10 mL. Times.5), separate the liquid, detect the organic phase, LCMS detect the decrease in the crude product to 8% of the target product compound II, column chromatography (Petroleum ether/ethyl acetate=2:1-4:1) to give the product.
In example 5 the process was carried out,preparation of Compound II
Compound I (100 mg,0.226 mmol), THF (10 mL), hydrogen fluoride-pyridine (67.2 mg,0.678 mmol) were added to the reaction flask, nitrogen protected, stirred at room temperature for 16h; after the completion of the reaction, purification by column chromatography (water/acetonitrile=1:1 to 3:1) gave compound II (7 mg, 10%).
In example 6 the process was carried out,preparation of Compound II
Compound I (1.0 g,2.26 mmol), THF (4 mL), triethylamine trihydrofluoride (0.4 mL,0.989 g/mL) were added to the reaction flask, nitrogen protected, stirred at room temperature for 4h; after the reaction was completed, purification by column chromatography (water/acetonitrile=1:1 to 3:1) gave compound II (0.44 g, 60%).
In example 7,preparation of Compound II
Compound I (1.0 g,2.26 mmol), THF (14 mL), triethylamine trihydrofluoride (1.4 mL,0.989 g/mL) were added to the reaction flask, nitrogen-protected, and stirred at room temperature for 4h; after the completion of the reaction, column chromatography (water/acetonitrile=1:1 to 3:1) was performed to obtain compound II (0.41 g, 56%).
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.
Claims (6)
1. A process for the preparation of compound II comprising the steps of:
deprotection reaction, namely reacting the compound I with a deprotection reagent to obtain a compound II;
the deprotection reagent is hydrofluoric acid salt;
the hydrofluoric acid salt is triethylamine hydrofluoric acid salt;
the triethylamine hydrofluoric acid salt is triethylamine hydrofluoric acid salt;
the molar ratio of the compound I to the hydrofluoric acid salt is 1: (2-3.4).
2. The preparation method according to claim 1, characterized in that the preparation method comprises the steps of: mixing the compound I, hydrofluoric acid salt and an organic solvent, and stirring at room temperature under the protection of inert gas; and (5) after the reaction is finished, purifying to obtain the catalyst.
3. The preparation method according to claim 2, wherein the organic solvent is one or more selected from tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide, ethyl acetate and dichloromethane.
4. The method of claim 2, wherein the purified solvent is selected from the group consisting of water and acetonitrile.
5. The method of claim 4, wherein the purified solvent is a mixture of water and acetonitrile, wherein the volume ratio of water to acetonitrile is (1-3): 1.
6. the method of claim 2, wherein the stirring time is 3 to 5 hours.
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| CN202111462982.2A CN114478465B (en) | 2021-12-03 | 2021-12-03 | Preparation method of extrahepatic biliary tract toxin |
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| CN109593077A (en) * | 2017-09-30 | 2019-04-09 | 复旦大学附属儿科医院 | Extrahepatic biliary passages toxin Biliatresone and preparation method thereof, pharmaceutical composition and purposes |
| CN111440142B (en) * | 2019-01-16 | 2021-06-18 | 上海璎黎药业有限公司 | Morpholinyl quinazoline compounds, processes for their preparation and intermediates therefor |
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