CN114195853B - Allochenodeoxycholic acid derivative, and synthesis method and application thereof - Google Patents
Allochenodeoxycholic acid derivative, and synthesis method and application thereof Download PDFInfo
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- CN114195853B CN114195853B CN202111628446.5A CN202111628446A CN114195853B CN 114195853 B CN114195853 B CN 114195853B CN 202111628446 A CN202111628446 A CN 202111628446A CN 114195853 B CN114195853 B CN 114195853B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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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
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- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses an allochenodeoxycholic acid derivative, a synthesis method and application thereof. The allochenodeoxycholic acid derivative is synthesized by taking allochenodeoxycholic acid as a starting material through multi-step reaction, and the reaction is simple and reliable. The diastereoisomer formed after the reaction of the derivative with the chiral compound can be used for detecting the optical purity of the chiral compound. Good separation can be obtained on a conventional achiral liquid chromatographic column, and the use of an expensive chiral chromatographic column is avoided.
Description
Technical Field
The invention belongs to the field of organic analytical chemistry, and particularly relates to an allochenodeoxycholic acid derivative, a synthesis method and application thereof.
Background
Chiral pharmacy is the leading field of the pharmaceutical industry, and the proportion of chiral drugs in newly synthesized drugs is up to more than 80% at present. Chiral compounds have two enantiomers which appear very similar, but not identical. When a chiral compound enters a living body, its two enantiomers often exhibit different biological activities. For chiral drugs, one isomer may be effective, while the other isomer may be ineffective or even harmful. The occurrence of a "reaction off" event in the 60's of the 20 th century is a typical example. At present, the detection and quality control of the content of the enantiomer in the synthesis of the chiral drugs become mandatory requirements.
Liquid chromatography is the first choice for detecting the content of enantiomers, and since enantiomers have completely consistent properties in an achiral environment, conventional chromatography cannot be used for analysis, and detection directly by using a chiral chromatographic column or detection by using the chiral chromatographic column after derivatization is the currently common method. However, chiral chromatographic columns are expensive and have a limited separation range, so that a plurality of chromatographic columns are usually purchased to screen out proper separation conditions, and only 90% of chiral compounds can be separated.
Taking choline glycerophosphate (GPC for short) as an example, the structure is as follows:
choline alfoscerate is an inner salt and has very large polarity, and even if a reverse phase condition which greatly damages a chiral chromatographic column or means such as derivatization reaction are used, the chiral chromatographic column cannot be used for effectively separating. Currently, the optical purity of the chiral material is determined by the industrial assumption that no isomerization occurs during the synthesis process. However, the relevant regulatory authorities have questioned this indirect method and need to provide more direct evidence of detection.
The chiral substance to be detected reacts with the chiral auxiliary agent to form diastereoisomers, the chemical and physical properties are no longer the same, and the detection can be carried out by using a conventional achiral chromatographic column, which is also a common method for detecting chiral purity (Eliel, ernest L. Stereospecificity of Organic Compounds,1994, P240). But the chiral auxiliary agents with high chiral purity, low price and strong chiral discrimination capability are not common. Generally, chiral carboxylic acids with chirality at the ortho-position of carboxyl group have better chiral discrimination ability, such as various amino acids, mandelic acid (Mandelic acid) and the like, but have the fatal disadvantage that racemization easily occurs under alkaline conditions. Manual modifications based on this can avoid undesirable racemization side reactions, such as the well-known Mosher reagent (Dale, j.a.; mosher, h.s.j.am.chem.soc.1973, 95, p 512), but the modifications result in high prices.
Cholic acid is a natural product with very high chiral purity, and is a potential chiral auxiliary. It has been reported to be used as a stationary phase for chiral chromatography columns (L.Vaton-Chanvrier, chromatographia 2001, 54, P31) or as a molecular clamp for chiral recognition of chiral molecules (Chenshuhua et al, proceedings of chemistry, 2002, 60, 355). However, there is no report of the use of the diastereoisomers formed by condensation for the purity determination of chiral compounds. The main reasons are that the common chiral centers of chenodeoxycholic acid and ursodeoxycholic acid are more than 3 carbons away from carboxylic acid, so that the chiral recognition capability is weak, the AB rings of molecules are cis-fused, the parent nucleus is spherical, and the intermolecular force between the parent nucleus and a straight-chain stationary phase on a C18 chromatographic column is insufficient.
Therefore, it is urgently needed to find a chiral auxiliary agent with excellent performance and low price, so that the diastereoisomer formed by condensation can be easily separated on a conventional C18 chromatographic column.
Disclosure of Invention
The invention aims to: provides an allochenodeoxycholic acid derivative, a synthesis method and application thereof. The derivative takes AB ring trans-fused allochenodeoxycholic acid (with a structure of 5-alpha-H) with high optical purity and low price as a raw material, and a chiral auxiliary agent obtained by derivatizing 3,7 positions of the allochenodeoxycholic acid has very good chiral discrimination capability. The diastereoisomer obtained by condensing the derivative with chiral alcohol and chiral amine can be well separated on a conventional achiral liquid chromatographic column, and the chiral liquid chromatographic column can be used for detecting the optical purity of a chiral compound, thereby avoiding using an expensive chiral chromatographic column.
The invention provides an allochenodeoxycholic acid derivative which has the following structural formula:
in the formula, R is phenyl, substituted phenyl, condensed ring aryl and aromatic heterocyclic radical.
The substituted phenyl is p-methylphenyl, p-methoxyphenyl, p-chlorophenyl, p-bromophenyl or p-nitrophenyl.
The invention also provides a synthesis method of the allochenodeoxycholic acid derivative, which specifically comprises the following steps:
a. reacting a compound (allochenodeoxycholic acid) shown in the formula (I) with potassium carbonate and benzyl bromide in a solvent, adding water to separate out a compound (allochenodeoxycholic acid benzyl ester) shown in the formula (II) after the reaction is finished, washing solids with water, and drying;
b. dissolving a compound (allochenodeoxycholic acid benzyl ester) in a formula (II) in pyridine, reacting with acyl chloride, adding water to separate out a compound (3, 7 diacyl allochenodeoxycholic acid benzyl ester) in a formula (III), washing a solid with water, and drying;
the acyl chloride has a general formula shown in formula (V):
in the formula, R is phenyl, substituted phenyl, condensed ring aryl or aromatic heterocyclic radical;
c. dissolving a compound (3, 7 diacyl-acylchenodeoxycholic acid benzyl ester) in an organic solvent, adding a catalytic amount of palladium-carbon, continuously introducing hydrogen, filtering after the reaction is finished, draining, crystallizing and purifying to obtain a compound (IV).
In step a of the present invention, the solvent is N, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF); the proportion of the compound (allochenodeoxycholic acid), the solvent, the potassium carbonate and the benzyl bromide in the formula (I) is 1mol;
the reaction temperature of the step a is 10-50 ℃, and the reaction time is 0.5-10 h.
In step b, the proportion of the compound (allochenodeoxycholic acid benzyl ester) in the formula (II), pyridine and acyl chloride is 1mol;
the reaction temperature of the step b is 0-50 ℃, and the reaction time is 0.5-20 h.
In step c, the organic solvent is Tetrahydrofuran (THF), methanol, ethanol or isopropanol, the compound (3, 7 diacyl chenodeoxycholic acid benzyl ester) in the formula (III) and the organic solvent have a palladium-carbon ratio of 1-5L;
the reaction temperature of the step c is 0-50 ℃, and the reaction time is 2-20 h.
The invention also provides application of the allochenodeoxycholic acid derivative in optical purity detection of enantiomers.
The above allophenodeoxycholic acid derivatives can be used for detecting optical purity of enantiomer, and can be condensed with enantiomer having functional group capable of condensing with carboxylic acid, such as hydroxyl and amino to obtain diastereoisomer, and conventional liquid chromatography is used for detecting isomer ratio to obtain optical purity data of enantiomer;
the allochenodeoxycholic acid derivatives can be used for detecting the optical purity of choline alfoscerate, the choline alfoscerate and the allochenodeoxycholic acid derivatives are subjected to condensation reaction to obtain diastereoisomers, and the optical purity data of choline alfoscerate is obtained by detecting the isomer ratio through a conventional liquid chromatography.
Compared with the prior art, the invention has the advantages or beneficial effects that:
1) Allochenodeoxycholic acid derivatives have very good chiral discrimination ability (taking choline alfoscerate as an example), while more common chenodeoxycholic acid and ursodeoxycholic acid derivatives with similar structures have almost no chiral discrimination ability under the same conditions;
2) The allochenodeoxycholic acid is a steroid natural product, has very high optical purity, can be conveniently detected by using an ultraviolet detector by introducing a functional group with ultraviolet absorption, and is an indispensable condition as a detection-grade reagent;
3) The starting material for synthesizing the allochenodeoxycholic acid derivative is an byproduct in industrial production, and the price is low;
4) The derivatization reaction of allochenodeoxycholic acid is simple and reliable, and is easy to synthesize.
Drawings
FIG. 1 is a chromatogram of the diastereomer formed by the condensation of a sample to be tested (mixture of R-GPC and S-GPC) with 3,7 dibenzoyl-allochenodeoxycholate.
Detailed Description
The present invention will be further described with reference to the following examples, but is not limited thereto.
Example 1
Synthesis of 3, 7-dibenzoyl allochenodeoxycholic acid
a. 392g (1 mol) of allochenodeoxycholic acid were dissolved in 1L of dry anhydrous DMF and 207g (1.5 mol) of K were rapidly weighed 2 CO 3 Added into the reaction system. After stirring for 15min, 130mL (1.1 mol) of BnBr was added dropwise at room temperature, the reaction was stirred at room temperature for 20h, and completion was confirmed by Thin Layer Chromatography (TLC). Pouring the solution into 5L of 1mol/L dilute hydrochloric acid, collecting the precipitated solid, washing with water for 3 times, and drying to obtain 485g of crude allochenodeoxycholic acid benzyl ester.
b. The obtained crude product of allochenodeoxycholic acid benzyl ester is dissolved in 1L of dry pyridine, 257ml (2.2 mol) of benzoyl chloride is dripped in the ice bath, the mixture is transferred to room temperature after dripping is finished and stirred for reaction for 20h, and TLC confirms that the reaction is complete. Pouring the solution into 5L of dilute hydrochloric acid with the concentration of 4mol/L, collecting precipitated solid, washing with water for 3 times, and drying to obtain 700g of crude 3, 7-dibenzoyl-allochenodeoxycholic acid benzyl ester.
c. Dissolving the crude product of 3,7 dibenzoyl-p-chenodeoxycholic acid benzyl ester in 2L Tetrahydrofuran (THF), filtering through a silica gel short column of 20g to remove residual trace pyridine salt to avoid catalyst poisoning, transferring the solution into a three-port bottle with a bubbler, purging with nitrogen to remove air in the system, adding 10g palladium-carbon with the concentration of 10%, and slowly introducing hydrogen. After 5h at rt, TLC showed the reaction was complete. Filtering the solution to remove palladium carbon, concentrating until partial solid is separated out, and adding a proper amount of petroleum ether until a large amount of solid is separated out. Freezing overnight, filtering, recrystallizing the solid with ethyl acetate petroleum ether to obtain 520g of 3, 7-dibenzoyl-allochenodeoxycholic acid solid, concentrating the filtrate, and performing column chromatography to obtain 45g of a white solid product with a total yield of 92% in three steps. mp:212 to 214 ℃. 1 H NMR(400MHz，Chloroform-d)δ8.07(d，J＝7.7Hz，2H)，7.92(d，J＝7.7Hz，2H)，7.59(t，J＝7.4Hz，1H)，7.50(t，J＝7.4Hz，1H)，7.44(t，J＝7.6Hz，2H)，7.29(t，J＝7.7Hz，2H)，5.29(s，1H)，5.22(s，1H)，0.92(s，3H)，0.91(d，J＝5.9Hz，3H)，0.69(s，3H)。
Application example 1
Choline Glycerophosphate (GPC) optical purity detection
(1) Esterification reaction conditions: 120mg (0.2 mmol) of purified 3,7 dibenzoyl-chenodeoxycholic acid were added 36mg (0.22 mmol) of N' N-Carbonyldiimidazole (CDI), 1ml of anhydrous Dichloromethane (DCM), and stirred at room temperature for 1 hour. 13mg (0.05 mmol) choline alfoscerate (GPC), 75ul (0.5 mmol) 1, 8-diazabicycloundec-7-ene (DBU) were added and stirred until the starting material disappeared.
(2) R and S isomer standard synthesis: esters of S-GPC and R-GPC were synthesized by the method described in (1), respectively, and pure products were obtained as standards by column chromatography.
(3) Liquid chromatography conditions: using Shimadzu 20A series liquid chromatograph, 4.6mm X250mm ODS-3 chromatographic column; 95% methanol 5% mobile phase of water containing 0.1% formic acid, 1mL/min flow rate, 35 ℃, PDA detector, 230nm, under which condition the baseline of two isomer control is completely separated, R configuration retention time is 26.4min, S configuration retention time is 29.4min.
(4) And (3) detecting the optical purity: the ester of the GPC sample to be tested was synthesized under the esterification reaction conditions in the step (1) of the application example, and the resulting solution was diluted to 2ml with methanol after 10. Mu.L of the solution was stirred for 15min to quench the excess esterified active intermediate, as shown in FIG. 1, and the product was determined to have an optical purity by HPLC analysis, as shown in FIG. 1, and to have R and S isomers at 25.7min and 28.7min, respectively, and an ee value of 84.3%.
Claims (9)
1. An allochenodeoxycholic acid derivative is characterized by having the following structural formula:
in the formula, R is phenyl or substituted phenyl;
the substituted phenyl is p-methylphenyl, p-methoxyphenyl, p-chlorophenyl, p-bromophenyl or p-nitrophenyl.
2. A method for synthesizing allochenodeoxycholic acid derivatives as claimed in claim 1, which comprises the steps of:
a. reacting the compound of the formula (I) with potassium carbonate and benzyl bromide in a solvent, adding water to precipitate a compound of the formula (II) after the reaction is finished, washing the solid with water, and drying;
the solvent is N, N-dimethylformamide, dimethyl sulfoxide and tetrahydrofuran;
b. dissolving the compound of formula (II) in pyridine, reacting with acyl chloride, adding water to separate out the compound of formula (III), washing the solid with water, and drying;
the general formula of the acyl chloride is shown as the formula (V):
in the formula, R is phenyl or substituted phenyl;
c. dissolving the compound of the formula (III) in an organic solvent, adding a catalytic amount of palladium-carbon, continuously introducing hydrogen, filtering after the reaction is finished, pumping out, crystallizing and purifying to obtain a compound of the formula (IV);
the organic solvent is tetrahydrofuran, methanol, ethanol or isopropanol.
3. The method for synthesizing allochenodeoxycholic acid derivatives of claim 2, wherein: in the step a, the proportion of the compound of the formula (I), the solvent, the potassium carbonate and the benzyl bromide is 1-5L.
4. The method for synthesizing allochenodeoxycholic acid derivatives of claim 2, wherein: the proportion of the compound of formula (II), pyridine and acyl chloride in step b is 1mol.
5. The method for synthesizing allochenodeoxycholic acid derivatives according to claim 2, wherein: the proportion of the compound in the formula (III) in the step c to the organic solvent to palladium-carbon is 1mol.
6. Use of an allochenodeoxycholic acid derivative of any one of claims 1-5 for the detection of the optical purity of enantiomers.
7. Use of allochenodeoxycholic acid derivatives according to claim 6, characterized in that: the enantiomer has a functional group capable of condensing with carboxylic acid, and is subjected to condensation reaction with allochenodeoxycholic acid derivatives to obtain a diastereomer, and the enantiomer optical purity data is obtained by detecting the isomer ratio through a conventional liquid chromatography.
8. Use of allochenodeoxycholic acid derivatives according to claim 7, characterized in that: the functional group condensable with carboxylic acid is a hydroxyl group or an amine group.
9. The use of allochenodeoxycholic acid derivatives according to claim 6, characterized in that: the enantiomer is choline alfoscerate, the choline alfoscerate and the allochenodeoxycholic acid derivatives are subjected to condensation reaction to obtain diastereoisomers, and the optical purity data of the choline alfoscerate can be obtained by detecting the isomer ratio through conventional liquid chromatography.
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| CN105837652A (en) * | 2016-04-12 | 2016-08-10 | 哈尔滨理工大学 | Betulinic acid-phosphatide composites, and preparing method and uses thereof |
| WO2017101789A1 (en) * | 2015-12-14 | 2017-06-22 | 四川思路迪药业有限公司 | Compound having anti-cancer effect, and method for preparation thereof and application thereof |
| CN113134094A (en) * | 2021-04-25 | 2021-07-20 | 哈尔滨市纳溶特剂新材料有限责任公司 | Preparation method and application of liposome-like body |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017101789A1 (en) * | 2015-12-14 | 2017-06-22 | 四川思路迪药业有限公司 | Compound having anti-cancer effect, and method for preparation thereof and application thereof |
| CN105837652A (en) * | 2016-04-12 | 2016-08-10 | 哈尔滨理工大学 | Betulinic acid-phosphatide composites, and preparing method and uses thereof |
| CN113134094A (en) * | 2021-04-25 | 2021-07-20 | 哈尔滨市纳溶特剂新材料有限责任公司 | Preparation method and application of liposome-like body |
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| 新型鹅去氧胆酸分子裂缝的设计合成;刘兴利等;《化学研究与应用》;20070330;第19卷(第3期);330-333 * |
| 鹅去氧胆酸分子裂缝对手性分子的识别性能研究;周彩娥等;《西南民族大学学报·自然科学版》;20070215;第33卷(第1期);64-67 * |
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