CN116283886A - Preparation method of bicyclo-ethanol and application of bicyclo-ethanol in bicyclo-ethanol tablet - Google Patents

Preparation method of bicyclo-ethanol and application of bicyclo-ethanol in bicyclo-ethanol tablet Download PDF

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CN116283886A
CN116283886A CN202111558841.0A CN202111558841A CN116283886A CN 116283886 A CN116283886 A CN 116283886A CN 202111558841 A CN202111558841 A CN 202111558841A CN 116283886 A CN116283886 A CN 116283886A
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biphenyl
bicyclo
reaction
acid
ethanol
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刘军
周济
王丽莎
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Chongqing Changjie Pharmaceutical Co ltd
Chongqing Shenghuaxi Pharmaceutical Co Ltd
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Chongqing Changjie Pharmaceutical Co ltd
Chongqing Shenghuaxi Pharmaceutical Co Ltd
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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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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention provides a preparation method of bicyclo-ethanol, which takes biphenyl anhydride (II) as a starting material, obtains biphenyl aldehyde acid (III) through reduction reaction, and obtains biphenyl aldehyde ester (IV) through esterification reaction; and finally, carrying out reduction reaction on the biphenyl aldehyde ester (IV) to obtain the bicyclo alcohol (I). The synthesis method has the advantages of low cost, safety, environmental protection, simple and convenient operation and industrialization value. The bicyclo-ethanol prepared by the invention has good quality, and can be used for preparing the bicyclo-ethanol tablet for clinical use.

Description

Preparation method of bicyclo-ethanol and application of bicyclo-ethanol in bicyclo-ethanol tablet
Technical Field
The invention belongs to the field of pharmaceutical chemical synthesis, and particularly provides a preparation method of bicyclic alcohol.
Background
The bicyclo-ethanol (structural formula is shown as follows), chemical name is 4,4 '-dimethoxy-5, 6,5',6 '-bi-methylenedioxy-2-hydroxymethyl-2' -methoxycarbonyl biphenyl, is a new anti-hepatitis drug developed by the national academy of medical science pharmaceutical research, has obvious liver protection effect and a certain anti-hepatitis virus activity, and is marketed under the trade name of Baisaino (tablet) in 2001. The research of action mechanism shows that the dicyclo alcohol can remove free radicals to maintain the stability of liver cell membranes; protecting liver cell mitochondria from damage; inducing heat shock protein, inhibiting hepatic cell apoptosis caused by various signal transfer paths,
Figure 100002_DEST_PATH_IMAGE001
。
the preparation of bicyclic alcohols was originally reported in European patent EP 0353358. Biphenyl diester (V) is taken as a raw material, biphenyl dicarboxylic acid (VI) is obtained through hydrolysis reaction, and biphenyl anhydride (II) is obtained through dehydration of acetic anhydride; the biphenyl anhydride is reduced by sodium borohydride to obtain biphenyl alkyd (VII), and then the biphenyl lactone (VIII) is obtained by lactonization of p-toluenesulfonic acid; the bi-cyclic alcohol (I) is prepared by the bi-cyclic lactone through alcoholysis ring opening,
Figure 100002_DEST_PATH_IMAGE002
。
although the reaction condition of the preparation method is mild, the yield of the alcoholysis ring-opening step of the biphenyl lactone (VIII) is too low and only about 40 percent.
Patent CN1275961C reports a selective methylation method: the bicyclo alcohol is prepared by selectively methylating the diphenyl alkyd (VII) with diazomethane in high yield. The method has high yield, but the diazomethane is flammable and explosive, the safety risk is high,
Figure 100002_DEST_PATH_IMAGE003
。
patent CN103724317a reports a synthetic route for bicyclic alcohols: the biphenyl anhydride (II) is subjected to methanolysis and ring opening to obtain biphenyl ester acid (IX), and then is subjected to borane dimethyl sulfide selective reduction to obtain the bicyclo alcohol (I). The route, although the yield of each step is higher, also eliminates the high-risk reagent of diazomethane; but the borane dimethyl sulfide is expensive, has special odor of sulfide compounds, has high environmental protection pressure, also has certain potential safety hazard,
Figure 100002_DEST_PATH_IMAGE004
。
literature (bioorg. Med. Chem. Lett., 2012, 20 (8), 2540-2548) reports: the biphenyl ester acid (IX) and imidazole are subjected to condensation reaction under the EDCI effect to obtain imidazole amide (X), and the imidazole amide is reduced by sodium borohydride to obtain the bicyclic alcohol (I). The yield of each step of the route is higher, and the reducing agent borane dimethyl sulfide is eliminated; however, imidazole activating groups are newly introduced, and the condensing agent EDCI is high in price and has no advantage in cost; the dicyclo alcohol crude product prepared by the method has lower purity, needs column chromatography separation and refining, is complicated in operation,
Figure DEST_PATH_IMAGE005
。
CN201510304398 reports: the biphenyl ester acid (IX) is subjected to three steps of reaction of carboxyl functional group conversion acyl chloride, condensation reaction with mercaptothiazole and reduction reaction to obtain the bicyclic alcohol (I). This route, while eliminating the condensing agent used in the literature (bioorg. Med. Chem. Lett., 2012, 20 (8), 2540-2548), also introduces a mercaptothiazole activating group, adds a reaction step, has no cost advantage,
Figure DEST_PATH_IMAGE006
。
in summary, at present, the preparation method of the bicyclo-ethanol still has the defects of lower crude product purity, lower total yield, high safety risk, high environmental protection pressure, higher production cost and the like. Therefore, the invention aims to solve the defects, and researches and develops a bicyclo-ethanol synthesis route and a preparation method which are suitable for industrialization and have the advantages of technical indexes and economic indexes.
Disclosure of Invention
The preparation method of the bicyclo-ethanol (I) provided by the invention comprises the following steps:
(a) Reducing biphenyl anhydride (II) by using metal boron hydride to prepare biphenyl aldehyde acid (III);
(b) The biphenyl aldehyde acid (III) is subjected to esterification reaction to prepare biphenyl aldehyde ester (IV);
(c) The biphenyl aldehyde ester (IV) is reduced by metal boron hydride again to prepare bicyclic alcohol (I);
Figure DEST_PATH_IMAGE007
。
in step (a), the metal borohydride comprises lithium borohydride, sodium borohydride, potassium borohydride, and the like, preferably sodium borohydride and potassium borohydride; the dosage of the metal boron hydride is 0.25-0.5 equivalent of the biphenyl anhydride (II), namely the feeding mole ratio of the metal boron hydride to the biphenyl anhydride (II) is (0.25-0.5): 1; the temperature of the reduction reaction is-40 to-20 ℃; the solvent for the reduction reaction comprises dichloromethane, dichloroethane, ethyl acetate, chloroform, tetrahydrofuran, N-dimethylformamide, or a mixed solvent of two or more thereof. In general, metal borohydrides reduce internal anhydrides to lactones (see second edition of pharmaceutical Synthesis reactions, smelling the tough main braiding, P391); however, the biphenyl anhydride (II) contains a chiral shaft structure, has the phenomenon of anti-trans isomerism, and the two benzene rings are not positioned on the same plane, so that the ring tension of the internal anhydride in the biphenyl anhydride is enhanced, and biphenyl aldehyde acid (III) is generated by preferential ring opening in the reduction reaction; further, the amount of the reducing agent and the reaction temperature are controlled so that the reduction reaction stays at the stage of the biphenyl aldehyde acid.
In the step (b), the esterification reaction comprises the esterification reaction of biphenyl aldehyde acid (III) and a methylation reagent such as dimethyl sulfate, methyl iodide and the like under the action of an acid binding agent to generate biphenyl aldehyde ester (IV); also included are esterification reactions of biphenyl aldehyde acid (III) with methanol under the catalysis of sulfuric acid. The acid binding agent comprises organic base such as triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, and inorganic base such as sodium carbonate and potassium carbonate. The reaction solvent of the esterification reaction is acetone, acetonitrile and methanol.
In step (c), the metal borohydride comprises lithium borohydride, sodium borohydride, potassium borohydride, and the like, preferably sodium borohydride and potassium borohydride; the dosage of the metal boron hydride is 0.5-1 equivalent of the biphenyl aldehyde ester (IV), namely the feeding mole ratio of the metal boron hydride to the biphenyl aldehyde ester (IV) is (0.5-1): 1; the temperature of the reduction reaction is 0-25 ℃; the solvent for the reduction reaction comprises dichloromethane, dichloroethane, ethyl acetate, chloroform, tetrahydrofuran, N-dimethylformamide, or a mixed solvent of two or more thereof.
The raw material biphenyl anhydride (II) used in the preparation method provided by the invention can be conveniently prepared from biphenyl diester according to the literature method in the prior art.
Compared with the prior art, the preparation method of the bicyclo-ethanol provided by the invention uses the metal boron hydride compound to reduce twice to prepare the bicyclo-ethanol (I), thereby skillfully eliminating reagents (diazomethane and borane dimethyl sulfide) with high safety risks and environmental protection pressure; meanwhile, no activating group is newly introduced; the reaction steps are shorter; the yield is higher (the single-step molar yield is more than 85 percent); the operation is simple. Overall, the method has the advantages of technical indexes and economic indexes. In addition, the bicyclo-ethanol crude product prepared by the method has high purity and good quality, and can be directly used as a co-preparation.
The following description of the invention is intended to be illustrative, and is to be taken as being within the scope of the invention, as various alternatives or combinations may be devised by those of ordinary skill in the art as well as conventional approaches.
EXAMPLE 1 preparation of biphenylic acid (III)
50g (134 mmol) of biphenyl anhydride (II) is added into 500mL of tetrahydrofuran, the temperature is reduced to-40 ℃, 1.5g (40 mmol,0.3 equivalent) of sodium borohydride is added, the reaction is carried out for 2 hours under heat preservation, the solvent is distilled off under reduced pressure, 500mL of water is added, 6mol/L hydrochloric acid is used for adjusting the pH to 1-2, 45g of biphenyl aldehyde acid (III) is obtained after filtration, the molar yield is 90%, the HPLC content is 98.5%, and HRMS: [ M+H ]375.0701, [ M+Na ]397.0507, [ M+K ]413.0805.
EXAMPLE 2 preparation of biphenylic acid (III)
50g (134 mmol) of biphenyl anhydride (II) is added into 600mL of dichloromethane, the temperature is reduced to minus 20 ℃, 3.6g (67 mmol,0.5 equivalent) of potassium borohydride is added, the reaction is carried out for 3 hours under the condition of heat preservation, the solvent is distilled off under reduced pressure, 600mL of water is added, 6mol/L hydrochloric acid is used for adjusting the pH to 1-2, 44g of biphenyl aldehyde acid (III) is obtained after filtration, the molar yield is 88%, and the HPLC content is 98.2%.
EXAMPLE 3 preparation of biphenylic acid (III)
50g (134 mmol) of biphenyl anhydride (II) is added into 200mL of dry N, N-dimethylformamide, the temperature is reduced to minus 30 ℃, 1.3g (33.5 mmol,0.25 equivalent) of sodium borohydride is added, the reaction is carried out for 1.5 hours under heat preservation, 800mL of water is added, the pH is regulated to 1-2 by 6mol/L hydrochloric acid, 45g of biphenyl aldehyde acid (III) is obtained after filtration, the molar yield is 90%, and the HPLC content is 98.6%.
EXAMPLE 4 preparation of Biphenyl aldehyde ester (IV)
40g (107 mmol) of biphenyl aldehyde acid (III), 22g (161 mmol) of anhydrous potassium carbonate and 13.9g (110 mmol) of dimethyl sulfate are added into 300mL of acetonitrile, stirred at normal temperature for reaction for 4H, filtered, and the reaction solvent is distilled off, 38.2g of biphenyl aldehyde ester (IV) is obtained by purification, the molar yield is 92%, the HPLC content is 99.1%, and the molar yield is HRMS: [ M+H ]389.0816, [ M+Na ]411.0641, [ M+K ]427.0334.
EXAMPLE 5 preparation of Biphenyl aldehyde ester (IV)
40g (107 mmol) of biphenyl aldehyde acid (III), 16.3g (161 mmol) of triethylamine and 15.6g (110 mmol) of methyl iodide are added into 400mL of acetone, stirred at normal temperature for reaction for 3 hours, filtered, the reaction solvent is distilled off, and 38.6g of biphenyl aldehyde ester (IV) is obtained by purification, the molar yield is 93%, and the HPLC content is 99.2%.
EXAMPLE 6 preparation of Biphenyl aldehyde ester (IV)
40g (107 mmol) of biphenyl aldehyde acid (III) and 5g of concentrated sulfuric acid are added into 120mL of methanol, reflux stirring reaction is carried out for 3h, the reaction solvent is distilled off, 200mL of ice water is added, stirring crystallization is carried out, filtration and purification are carried out, 36.5g of biphenyl aldehyde ester (IV) is obtained, the molar yield is 88%, and the HPLC content is 98.2%.
EXAMPLE 7 preparation of bicyclic alcohol (I)
35g (90 mmol) of biphenyl aldol ester (IV) and 1.7g (45 mmol) of sodium borohydride are added into 350mL of tetrahydrofuran for reaction for 4 hours at 25 ℃, the reaction solvent is distilled off under reduced pressure, 400mL of water is added, the pH is regulated to 1-2 by 6mol/L of hydrochloric acid, 32g of bicyclo alcohol (I) is obtained through filtration, the molar yield is 90%, the HPLC content is 99.4%, and HRMS: [ M+H-H ] 2 O]373.0869。
EXAMPLE 8 preparation of Bicyclol (I)
35g (90 mmol) of biphenyl aldol ester (IV) and 4.9g (90 mmol) of potassium borohydride are added into 300mL of ethyl acetate for reaction for 8 hours at 0 ℃, the reaction solvent is distilled off under reduced pressure, 350mL of water is added, the pH is regulated to 1-2 by 6mol/L of hydrochloric acid, 31g of bicyclo alcohol (I) is obtained through filtration, the molar yield is 88%, and the HPLC content is 99.5%.
EXAMPLE 9 preparation of Bicyclol tablet
500g of bicyclo-ethanol (prepared in a general clean area), 2.5kg of lactose, 500g of starch and 60g of low-substituted hydroxypropyl cellulose which are prepared according to the method of the embodiment are uniformly mixed, a proper amount of 1% hydroxymethyl cellulose sodium solution is added to prepare a soft material, and the soft material is granulated, dried, sieved and granulated, 30g of magnesium stearate and 130g of talcum powder are added, uniformly mixed and tabletted according to the specification of 25mg to obtain the bicyclo-ethanol tablet.

Claims (10)

1. A process for the preparation of bicyclic alcohols (I),
Figure DEST_PATH_IMAGE001
the method comprises the following steps:
reducing biphenyl anhydride (II) by using metal boron hydride to prepare biphenyl aldehyde acid (III);
Figure DEST_PATH_IMAGE002
the biphenyl aldehyde acid (III) is subjected to esterification reaction to prepare biphenyl aldehyde ester (IV);
Figure DEST_PATH_IMAGE003
the diphenyl aldehyde ester (IV) is reduced by metal boron hydride to prepare bicyclic alcohol (I);
Figure DEST_PATH_IMAGE004
。
2. the method of claim 1, wherein the metal borohydride in step (a) and step (c) is lithium, sodium or potassium borohydride.
3. The process according to claim 1, wherein the molar ratio of feed of the metal borohydride compound for reduction reaction to the biphenyl anhydride (II) in step (a) is from (0.25 to 0.5): 1.
4. The method of claim 1, wherein the temperature of the reduction reaction in step (a) is from-40 ℃ to-20 ℃.
5. The method according to claim 1, wherein the solvent for the reduction reaction in step (a) and step (c) is methylene chloride, ethylene dichloride, ethyl acetate, chloroform, tetrahydrofuran, N-dimethylformamide, or a mixed solvent of two or more thereof.
6. The process according to claim 1, wherein the esterification reaction in step (b) is an esterification reaction of the biphenylic acid (III) with the methylating agent dimethyl sulfate or methyl iodide under the action of the acid binding agent triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, sodium carbonate or potassium carbonate.
7. The process according to claim 1, wherein the esterification in step (b) is carried out by esterification of biphenyl aldehyde acid (III) with methanol under the catalysis of sulfuric acid.
8. The process according to claim 1, wherein the reaction solvent for the esterification reaction in step (b) is acetone, acetonitrile or methanol.
9. The process according to claim 1, wherein the molar ratio of feed of the metal borohydride compound to the biphenyl aldol ester (IV) in step (c) is from (0.5 to 1): 1.
10. The method of claim 1, wherein the temperature of the reduction reaction in step (c) is from 0 to 25 ℃.
CN202111558841.0A 2021-12-20 2021-12-20 Preparation method of bicyclo-ethanol and application of bicyclo-ethanol in bicyclo-ethanol tablet Pending CN116283886A (en)

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