CN111116493B - Method for preparing Apabetalone, intermediate and preparation method of intermediate - Google Patents

Method for preparing Apabetalone, intermediate and preparation method of intermediate Download PDF

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CN111116493B
CN111116493B CN201911283144.1A CN201911283144A CN111116493B CN 111116493 B CN111116493 B CN 111116493B CN 201911283144 A CN201911283144 A CN 201911283144A CN 111116493 B CN111116493 B CN 111116493B
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apabetalone
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吴鹏飞
王晗
陈闻馨
万灵子
茆勇军
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Abstract

The invention provides a preparation method of Apabetalone, which comprises the following steps: reacting the first intermediate 2-bromo-4, 6-dimethoxybenzoic acid and the second intermediate 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride in an alkali-containing organic solvent under the action of a catalyst to obtain Apabetalone. The method has the advantages of total yield of over 33.4 percent, easily obtained raw materials, simple process, mild reaction conditions, simple post-treatment method, high yield of each step and total yield and capability of reducing the cost. Apabetalone is a medicament for treating cardiovascular diseases such as atherosclerosis and the like, and has good application prospect. The invention also provides an intermediate 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride for synthesizing Apabetalone, a preparation method thereof and a preparation method of a compound 2-bromo-4, 6-dimethoxybenzoic acid.

Description

Method for preparing Apabetalone, intermediate and preparation method of intermediate
Technical Field
The invention relates to the technical field of organic synthesis and preparation of raw material medicines, in particular to a method for preparing a blood fat reducing medicine Apabetalone (RVX-208), an intermediate and a preparation method of the intermediate.
Background
Apabetalone (RVX-208), chemical name: 2- [4- (2-hydroxyethoxy) -3, 5-dimethylphenyl ] -5, 7-dimethoxyquinazolin-4 (3H) -one, of the formula I, developed by Resverlogic corporation, is mainly used for treating cardiovascular diseases such as atherosclerosis, and is currently undergoing phase III clinical research.
Apabetalone (RVX-208) is a BETbrodomain inhibitor which acts selectively on the BD2 bromodomain, and intensive research on the drug helps to elucidate the physiological role played by the BD1 and BD2 bromodomains of BET brodomain. Apabetalone (RVX-208) also has the HIV latent activation effect and has great significance for the research on the HIV curative effect.
Figure BDA0002317309670000011
The preparation of Apabetalone (RVX-208) mainly comprises two methods:
the first method (US, 20080188467[ P ].2008-08-07) has a synthetic route shown in formula II. The method comprises the steps of using 3, 5-dimethoxyaniline as a starting material, synthesizing a first intermediate through cyclization, hydrolysis and amide formation, using 4-hydroxy-3, 5-dimethylbenzaldehyde as a raw material, etherifying, protecting group application, synthesizing a second intermediate, and finally synthesizing quinazolinone through cyclization to obtain Apabetalone (RVX-208), wherein the total yield is 4.8%.
Figure BDA0002317309670000021
The reaction conditions of the route are harsh, dangerous chemicals such as oxalyl chloride, hydrogen peroxide and the like are used, the reaction yield is low, and the industrial production of the route is restricted.
A second method (CN 108218798A, 2017.12.13), in which 3, 5-dimethoxybromobenzene is used as a raw material to prepare a first intermediate 2-bromo-4, 6-dimethoxybenzamide, 4-hydroxy-3, 5-dimethylbenzaldehyde is used as a raw material, etherification is performed, a protecting group is added to prepare a second intermediate, and the two intermediates are cyclized to generate Apabetalone (RVX-208) under the catalysis of ammonia water and cuprous bromide, with a total yield of 13.8%. The synthetic route is shown as formula III.
Figure BDA0002317309670000022
The route introduces a protecting group, increases reaction steps, uses a catalyst ligand in the cyclization process, and has lower overall yield.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of Apabetalone (RVX-208), which has the advantages of easily obtained raw materials, simple process, convenient operation, high yield and low cost, aiming at the defects in the prior art.
The invention also provides an intermediate for preparing Apabetalone (RVX-208) and a preparation method of the intermediate.
The invention is realized by the following technical scheme:
the preparation route of the Apabetalone (RVX-208) is shown as a formula IV:
Figure BDA0002317309670000031
a process for preparing Apabetalone (RVX-208), comprising the steps of:
the first intermediate, namely the compound 2-bromo-4, 6-dimethoxybenzoic acid of the formula 3, and the second intermediate, namely the compound 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride of the formula 6, react in an alkali-containing organic solvent under the action of a catalyst to obtain Apabetalone.
The concentration of the 2-bromo-4, 6-dimethoxybenzoic acid is 0.4-0.8 mol/L, preferably 0.4-0.5 mol/L, and more preferably 0.45-0.2 mol/L; the molar ratio of the 2-bromo-4, 6-dimethoxybenzoic acid to the 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride is 1: 0.8 to 1.3, preferably 1: 1.1.
the base comprises: potassium carbonate, potassium phosphate or cesium carbonate, preferably cesium carbonate; the catalyst comprises: cuprous chloride, cuprous bromide, cuprous iodide and palladium acetate, preferably cuprous iodide, wherein the organic solvent is dimethyl sulfoxide.
The reaction conditions of the 2-bromo-4, 6-dimethoxybenzoic acid and the 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride are that the reaction is carried out for 6 to 18 hours at the temperature of 60 to 120 ℃, the temperature is preferably 75 to 85 ℃, and the time is preferably 10 to 12 hours.
After the reaction of the 2-bromo-4, 6-dimethoxybenzoic acid and 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride is finished, adding a saturated ammonium chloride solution, and extracting with an organic solvent, wherein the organic solvent is ethyl acetate or butyl acetate, and preferably ethyl acetate. And removing the organic solvent to obtain a solid, wherein the solvent removal method is vacuum concentration. Separating by using column chromatography, wherein the mobile phase is dichloromethane: the volume ratio of the methanol is 40:1, and the 2- [4- (2-hydroxyethoxy) -3, 5-dimethylphenyl ] -5, 7-dimethoxyquinazolin-4 (3H) -one is obtained.
The preparation method of the first intermediate, namely the compound 2-bromo-4, 6-dimethoxybenzoic acid of the formula 3, comprises the following steps:
in an organic solvent, acylating a compound 3, 5-dimethoxybromobenzene of a formula 1 and phosphorus oxychloride to obtain a compound 2-bromo-4, 6-dimethoxybenzaldehyde of a formula 2;
reacting the compound 2-bromo-4, 6-dimethoxybenzaldehyde of formula 2 with sodium chlorite and sulfamic acid in a solvent to obtain 2-bromo-4, 6-dimethoxybenzoic acid of formula 3.
In the step I, the organic solvent is N, N-dimethylformamide.
In the step I, the molar ratio of the 3, 5-dimethoxybromobenzene to the N, N-dimethylformamide to the phosphorus oxychloride is 1: 3-6: 1-1.5. Preferably 1:5 to 6:1.1 to 1.2.
In the step I, the 3, 5-dimethoxybromobenzene, N-dimethylformamide and phosphorus oxychloride react for 2-5 hours at 80-100 ℃, the temperature is preferably 90-100 ℃, and the time is preferably 3-4 hours.
And (3) after the 3, 5-dimethoxybromobenzene, N-dimethylformamide and phosphorus oxychloride react in the step I, quenching the mixture by using ice, standing the mixture for 6 to 12 hours at the temperature of between 0 and 25 ℃, preferably 10 to 12 hours, and filtering the mixture to obtain a solid, so as to obtain the 2-bromo-4, 6-dimethoxybenzaldehyde.
In the step II, the reaction is carried out for 1 to 4 hours at the temperature of 5 to 50 ℃, the temperature is preferably 20 to 30 ℃, and the time is preferably 2 to 4 hours; the solvent comprises tert-butanol or tetrahydrofuran, preferably tetrahydrofuran; the concentration of the 2-bromo-4, 6-dimethoxybenzaldehyde in the solvent is 0.2-1 mol/L, preferably 0.4-0.6 mol/L.
In step II, in one embodiment, 2-bromo-4, 6-dimethoxybenzaldehyde is reacted with chlorite and sulfamic acid in a molar ratio of 2-bromo-4, 6-dimethoxybenzaldehyde to chlorite and sulfamic acid of 1: 2-4: 2-4, preferably 1: 3.5: 3.5.
in step II, in another embodiment, 2-bromo-4, 6-dimethoxybenzaldehyde is reacted with chlorite in a molar ratio of 2-bromo-4, 6-dimethoxybenzaldehyde to chlorite of 1: 2-4, preferably 1: 3.5.
in step II, preferably, the chlorite is sodium chlorite.
And in the step II, after the reaction is finished, extracting, taking an organic phase, and concentrating under reduced pressure to obtain the 2-bromo-4, 6-dimethoxybenzoic acid.
A process for preparing the second intermediate, compound 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride of formula 6, comprising the steps of:
a. in an organic solvent containing alkali, reacting 4-cyano-3, 5-dimethylphenol as a compound of a formula 4 with 2-chloroethanol to prepare 4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile as a compound of a formula 5;
b. the compound 4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile of formula 5 is reacted with methanol and hydrogen chloride in an organic solvent, and then reacted with ammonia to prepare the compound 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride of formula 6.
The concentration of the 4-cyano-3, 5-dimethylphenol in the step a is 0.1-1 mol/L, and preferably 0.3-0.5 mol/L.
The molar ratio of the 4-cyano-3, 5-dimethylphenol, the 2-chloroethanol and the base in step a is 1: 4-8: 1 to 3.5, preferably 1: 5-6: 2-3, more preferably 1: 6: 3.
the organic solvent in the step a comprises acetonitrile, acetone and isopropanol, preferably acetonitrile; the base comprises potassium carbonate, diisopropylethylamine or sodium hydroxide, preferably potassium carbonate.
In the step a, the 4-cyano-3, 5-dimethylphenol and 2-chloroethanol react for 24 to 48 hours at 50 to 100 ℃, preferably 70 to 100 ℃ and 25 to 30 hours.
And (b) after the reaction of the 4-cyano-3, 5-dimethylphenol and the 2-chloroethanol is finished in the step a, filtering, extracting, taking an organic phase, washing with alkali, washing with a saturated sodium chloride solution, and performing thermal extraction with petroleum ether. The extraction solvent comprises ethyl acetate, butyl acetate, preferably ethyl acetate, and the base comprises sodium hydroxide, potassium hydroxide, preferably sodium hydroxide.
The concentration of the 4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile in the step b is 0.5-1.5 mol/L, and preferably 0.8-1 mol/L.
The 4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile described in step b: methanol: the molar ratio of hydrogen chloride is 1: 1-2: 1-10, preferably 1: 1.5-2: 5-10, more preferably 1: 2: 10.
the organic solvent in step b comprises diethyl ether or dioxane, preferably diethyl ether.
In the step b, the concentration of the ammonia in methanol is 5-10 mol/L, preferably 7 mol/L.
In the step b, the 4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile reacts with the methanol and the hydrogen chloride at the temperature of 0-30 ℃ for 24-72 hours, preferably at the temperature of 0-10 ℃ for 30-48 hours. Adding methanol solution of ammonia, and reacting at 0-30 deg.C for 24-48 hr, preferably at 20-25 deg.C, and preferably for 30-48 hr.
Reacting 4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile with methanol and hydrogen chloride in the step b, filtering, and dissolving the solid in an organic solvent, wherein the organic solvent comprises methanol and dioxane, and methanol is preferred. Further addition of ammonia in methanol, 4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile: the molar ratio of the methanol solution of ammonia (calculated by ammonia) is 1: 1.2-1.5. After the reaction is finished, the solvent is decompressed and concentrated to obtain 4- (2-hydroxyethoxy) -3, 5-dimethyl benzamidine hydrochloride.
The invention provides an intermediate for synthesizing Apabetalone (RVX-208), namely 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride of a compound shown in a formula 6, wherein the structural formula is as follows:
Figure BDA0002317309670000051
the invention also provides a preparation method of an intermediate for synthesizing Apabetalone (RVX-208), namely 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride of a compound shown in a formula 6, which comprises the following steps:
a. in an organic solvent containing alkali, reacting 4-cyano-3, 5-dimethylphenol as a compound of a formula 4 with 2-chloroethanol to prepare 4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile as a compound of a formula 5;
b. the compound 4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile of formula 5 is reacted with methanol and hydrogen chloride in an organic solvent, and then reacted with ammonia to prepare the compound 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride of formula 6.
The method takes 3, 5-dimethoxy bromobenzene and 4-cyano-3, 5-dimethylphenol as raw materials, and prepares a target compound (Apabetalone (RVX-208), formula 7) through 5 steps of reactions such as acylation, oxidation, etherification, ammonolysis, cyclization and the like, wherein the total yield is more than 33.4%; the total yield of Apabetalone (RVX-208) prepared by the method can reach 47.6 percent based on 4-cyano-3, 5-dimethylphenol. Compared with the prior art, the method has the advantages that:
(1) common 4-cyano-3, 5-dimethylphenol and 3, 5-dimethoxybromobenzene are used as starting materials, and common chemicals such as N, N-dimethylformamide, hydrogen chloride, methanol and the like and common solvents are used in the intermediate step, so that the method has the advantage of easily obtaining the raw materials.
(2) The method has the advantages of simple process, few reaction steps, mild reaction conditions and more convenient operation; the treatment method after the reaction is simple and convenient, and the discharge of experimental waste is reduced; is suitable for scale-up preparation.
(3) The method adopts a convergent synthesis strategy, is favorable for improving the total yield and reducing the risk of chemical synthesis, and is more suitable for amplified preparation.
(4) The method has the advantages of high yield and total yield of each step, simple reaction condition and raw materials and capability of reducing the cost. The target compound is Apabetalone (RVX-208) which is a medicament for treating cardiovascular diseases such as atherosclerosis and the like, and phase III clinical research is currently carried out, so that the target compound is beneficial to industrial production of the bulk drug after the bulk drug is on the market, promotes the development of economic technology and has good application prospect.
(5) The invention provides a new intermediate 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride (formula 6) for synthesizing Apabetalone (RVX-208), a preparation method thereof and a new preparation method of a compound 2-bromo-4, 6-dimethoxybenzoic acid (formula 3).
Detailed Description
The technical solution of the present invention will be described below with reference to specific examples.
EXAMPLE 12 preparation of bromo-4, 6-dimethoxybenzaldehyde (1)
3, 5-dimethoxybromobenzene (20g,90mmol) is added into a 250mL three-necked bottle, N-dimethylformamide (33.6g, 459.7mmol) is added, stirring is carried out at 0 ℃, then phosphorus oxychloride (16.88g, 108mmol) is added dropwise, the reaction is stirred for 30min at room temperature after the dropwise addition is finished, and then the reaction is heated to 100 ℃ for 4 h. After the reaction was completed, the reaction solution was poured into 100mL of crushed ice, allowed to stand at 25 ℃ for 12 hours, filtered, and the filter cake was washed with petroleum ether to obtain 19.7g of 2-bromo-4, 6-dimethoxybenzaldehyde in a yield of 87.2%.
1H NMR(400MHz,CDCl3)δ10.33(s,1H),6.80(d,J＝2.2Hz,1H),6.45(d,J＝2.2Hz, 1H),3.91(s,3H),3.89(s,3H).
EXAMPLE 22 preparation of bromo-4, 6-dimethoxybenzaldehyde (2)
3, 5-dimethoxybromobenzene (20g,90mmol) is added into a 250mL three-necked bottle, N-dimethylformamide (33.6g, 459.7mmol) is added, stirring is carried out at 0 ℃, then phosphorus oxychloride (16.88g, 108mmol) is added dropwise, the reaction is stirred for 30min at room temperature after the dropwise addition is finished, and then the reaction is heated to 80 ℃ for 6 h. After the reaction was completed, the reaction solution was poured into 100mL of crushed ice, allowed to stand at 25 ℃ for 12 hours, filtered, and the filter cake was washed with petroleum ether to obtain 16.8g of 2-bromo-4, 6-dimethoxybenzaldehyde in a yield of 74.4%.
The results of the spectrum measurements were the same as in example 1.
EXAMPLE 32 preparation of bromo-4, 6-dimethoxybenzoic acid (1)
2-bromo-4, 6-dimethoxybenzaldehyde (5g, 20.4mmol) was charged into a 250mL reaction flask, and then tetrahydrofuran (50mL) was added and dissolved with stirring, and then sulfamic acid (6.93g,71.4mmol,3.5eq) was added and dissolved with stirring. Sodium chlorite (6.46g,71.4mmol) was weighed and dissolved in water (25mL), and the solution was dropped into a reaction flask and reacted at 25 ℃ for 1 hour. Ethyl acetate was added for extraction (75 mL. times.2) and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (75mL), dried over anhydrous sodium sulfate, and spin-dried to give 4.3g of 2-bromo-4, 6-dimethoxybenzoic acid in 80.4% yield.
1H NMR(400MHz,DMSO)δ13.08(s,1H),6.79(d,J＝2.1Hz,1H),6.65(d,J＝2.1Hz, 1H),3.81(s,3H),3.79(s,3H).
EXAMPLE 42 preparation of bromo-4, 6-dimethoxybenzoic acid (2)
2-bromo-4, 6-dimethoxybenzaldehyde (5g, 20.4mmol) was charged into a 250mL reaction flask, and tetrahydrofuran (50mL) was added. Sodium chlorite (6.46g,71.4mmol) was weighed and dissolved in water (25mL), and the solution was dropped into a reaction flask and reacted at 25 ℃ for 1 hour. Ethyl acetate was added for extraction (75 mL. times.2) and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (75mL), dried over anhydrous sodium sulfate, and spin-dried to give 3.6g of 2-bromo-4, 6-dimethoxybenzoic acid in 67.3% yield.
The results of the spectrum measurements were the same as in example 3.
EXAMPLE 54 preparation (1) of (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile
4-cyano-3, 5-dimethylphenol (5g,34mmol) was charged into a 250mL three-necked flask, acetonitrile (80mL) was added, and the mixture was dissolved with stirring. Potassium carbonate (14.2g,102mmol) was added, the mixture was stirred at room temperature for 30min, then the temperature was raised to 80 ℃, 2-chloroethanol (16.4g,204mmol,6eq) was added dropwise, and the reaction was carried out for 30h after completion of the dropwise addition within 1 h. Filtering and removing inorganic salts. Extraction was performed twice with ethyl acetate (50mL × 2), the organic phases were combined, washed once with 2M sodium hydroxide solution, twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was spin dried to give a brown solid. Adding petroleum ether into a reaction bottle filled with brown solid, heating to 60 ℃, layering the liquid, separating the upper layer liquid while the liquid is hot, cooling and crystallizing to obtain needle-shaped white crystals, recovering mother liquor, repeatedly heating, layering, and crystallizing until no solid is separated out. 5.4g of 4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile was obtained in 83.1% yield.
1H NMR(400MHz,DMSO)δ13.08(s,1H),6.79(d,J＝2.1Hz,1H),6.65(d,J＝2.1Hz, 1H),3.81(s,3H),3.79(s,3H).
EXAMPLE 64- (2-Hydroxyethoxy) -3, 5-dimethylbenzonitrile preparation (2)
4-cyano-3, 5-dimethylphenol (5g,34mmol) was charged into a 250mL three-necked flask, acetone (80mL) was added, and dissolved with stirring. Potassium carbonate (14.2g,102mmol) was added, the mixture was stirred at room temperature for 30min, then the temperature was raised to 60 ℃, 2-chloroethanol (16.4g,204mmol,6eq) was added dropwise, and the reaction was carried out for 30h after completion of the dropwise addition within 1 h. Filtering and removing inorganic salts. Extraction was performed twice with ethyl acetate (50mL × 2), the organic phases were combined, washed once with 2M sodium hydroxide solution, twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was spin dried to give a brown solid. Adding petroleum ether into a reaction bottle filled with brown solid, heating to 60 ℃, layering the liquid, separating the upper layer liquid while the liquid is hot, cooling and crystallizing to obtain needle-shaped white crystals, recovering mother liquor, repeatedly heating, layering, and crystallizing until no solid is separated out. 4.9g of 4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile was obtained in a yield of 75.4%.
The results of the spectrum measurements were the same as in example 5.
EXAMPLE 74- (2-Hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride preparation (1)
4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile (4g,21mmol) was charged into a 100mL reaction flask, ether (20mL) was added, the mixture was dissolved with stirring, methanol (1.35g,42mmol) was added, and hydrogen chloride gas was introduced into the flask in an amount of 0.21mol for 2 hours. After 2 days at 0 ℃ a white solid precipitated. The solid was collected by filtration and hydrogen chloride was removed to give 4.4g of a solid. The collected white solid, methanol (20mL), 7M ammonia in methanol (4.5 mL) was added to a 100mL reaction flask and reacted at 25 ℃ for 2 days. The reaction mixture was spin-dried, and 4.06 g of 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride was obtained in 79.1% yield.
1H NMR(400MHz,DMSO)δ9.24(d,J＝40.0Hz,4H),7.60(s,2H),4.98(t,J＝5.3Hz,1H), 3.87(t,J＝4.9Hz,2H),3.72(dd,J＝9.6,4.8Hz,2H),2.31(s,6H).
EXAMPLE 84 preparation of (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride
4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile (4g,21mmol) was charged into a 100mL reaction flask, ether (20mL) was added, the mixture was dissolved with stirring, methanol (1.35g,42mmol) was added, and hydrogen chloride gas was introduced into the flask in an amount of 0.21mol for 2 hours. After 2 days at 0 ℃ a white solid precipitated. The solid was collected by filtration and hydrogen chloride was removed to give 4.4g of a solid. The collected white solid, methanol (20mL), 7M ammonia in methanol (4mL) was added to a 100mL reaction flask and reacted at 25 ℃ for 2 days. The reaction mixture was spin-dried, and 3.94g of 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride was obtained in a yield of 76.8%.
The results of the spectrum measurements were the same as in example 7.
EXAMPLE 9 preparation (1) of Apabetalone (RVX-208)
2-bromo-4, 6-dimethoxybenzoic acid (1.95g, 7.4mmol),4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride (2g,8.2mmol), cuprous iodide (0.14g,0.75mmol), and cesium carbonate (4.89g,14.8mmol) were weighed into a 100mL three-necked flask, dimethylsulfoxide (15mL) was added, and the mixture was reacted at 80 ℃ for 12 hours under an inert gas atmosphere. The reaction was quenched by addition of saturated ammonium chloride solution (50mL), the aqueous phase was extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solvent was removed by rotary evaporation, and column chromatography was performed (mobile phase: dichloromethane: methanol ═ 40: 1).
Apabetalone (RVX-208) was obtained in an amount of 2.01 g. The yield thereof was found to be 72.5%.
1H NMR(400MHz,DMSO)δ11.82(s,1H),7.90(s,2H),6.74(d,J＝2.3Hz,1H),6.52 (d,J＝2.2Hz,1H),4.90(s,1H),3.90(s,3H),3.88–3.83(m,5H),3.74(d,J＝4.4Hz,2H), 2.32(s,6H).
EXAMPLE 10 preparation (2) of Apabetalone (RVX-208)
2-bromo-4, 6-dimethoxybenzoic acid (1.95g, 7.4mmol),4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride (2g,8.2mmol), cuprous iodide (0.14g,0.75mmol) and potassium carbonate (2.08g,14.8mmol) were weighed into a 100mL three-necked flask, dimethylsulfoxide (15mL) was added, and the mixture was reacted at 80 ℃ for 12 hours under inert gas. The reaction was quenched by addition of saturated ammonium chloride solution (50mL), the aqueous phase was extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solvent was removed by rotary evaporation, and column chromatography was performed (mobile phase: dichloromethane: methanol ═ 40: 1).
Apabetalone (RVX-208)1.42g was obtained. The yield thereof is 51.5%
The results of the spectrum measurements were the same as in example 9.
As can be seen from examples 1 to 4, the yield of the intermediate 2-bromo-4, 6-dimethoxybenzoic acid prepared from the raw material 2-bromo-4, 6-dimethoxybenzaldehyde reaches 70.1%;
as can be seen from examples 5 to 8, the total yield of the intermediate 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride prepared from the raw material 4-cyano-3, 5-dimethylphenol was 65.7%;
the yield of Apabetalone (RVX-208) synthesized from intermediate 2-bromo-4, 6-dimethoxybenzoic acid and intermediate 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride was 72.5%.
The total yield of the whole line reaches 33.4 percent.
It should be noted that the above-mentioned embodiments are only for illustrating the technical concept and features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered in the protection scope of the present invention.

Claims (6)

1. A method for preparing Apabetalone, comprising the steps of:
reacting a first intermediate 2-bromo-4, 6-dimethoxybenzoic acid and a second intermediate 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride in an alkali-containing organic solvent under the action of a catalyst to obtain Apabetalone;
the concentration of the 2-bromo-4, 6-dimethoxybenzoic acid is 0.4-0.8 mol/L, and the molar ratio of the 2-bromo-4, 6-dimethoxybenzoic acid to the 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride is 1: 0.8-1.3, wherein the alkali is cesium carbonate, the catalyst is selected from cuprous chloride, cuprous bromide or cuprous iodide, and the organic solvent is dimethyl sulfoxide;
the reaction conditions are that the reaction is carried out for 6 to 18 hours at the temperature of between 60 and 120 ℃, after the reaction is finished, saturated ammonium chloride solution is added, organic solvent is used for extraction, the organic solvent is removed to obtain solid, and column chromatography separation is used.
2. The process for preparing Apabetalone of claim 1, wherein said first intermediate, 2-bromo-4, 6-dimethoxybenzoic acid, comprises the steps of:
in an organic solvent, acylating 3, 5-dimethoxy bromobenzene and phosphorus oxychloride to obtain 2-bromo-4, 6-dimethoxy benzaldehyde;
reacting 2-bromo-4, 6-dimethoxybenzaldehyde with sodium chlorite in a solvent to obtain 2-bromo-4, 6-dimethoxybenzoic acid;
in the step I, the organic solvent is N, N-dimethylformamide, the molar ratio of the 3, 5-dimethoxybromobenzene to the N, N-dimethylformamide to the phosphorus oxychloride is 1: 3-6: 1-1.5, the reaction condition is that the reaction is carried out for 2-5 hours at the temperature of 80-100 ℃, after the reaction is finished, ice is used for quenching, the reaction is carried out for standing, and the solid is obtained by filtering;
and in the step II, reacting for 1-4 hours at 5-50 ℃, wherein the solvent is tert-butyl alcohol or tetrahydrofuran, the concentration of the 2-bromo-4, 6-dimethoxybenzaldehyde in the solvent is 0.2-1 mol/L, extracting after the reaction is finished, and concentrating under reduced pressure organic phase to obtain the 2-bromo-4, 6-dimethoxybenzoic acid.
3. The process of claim 2, wherein in step ii, 2-bromo-4, 6-dimethoxybenzaldehyde is reacted with chlorite and sulfamic acid, and the molar ratio of 2-bromo-4, 6-dimethoxybenzaldehyde to chlorite and sulfamic acid is 1: 2-4: 2 to 4, or,
in the step II, 2-bromo-4, 6-dimethoxybenzaldehyde reacts with chlorite, and the molar ratio of the 2-bromo-4, 6-dimethoxybenzaldehyde to the chlorite is 1: 2 to 4.
4. The process of claim 1, wherein said second intermediate, 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride, is prepared by a process comprising the steps of:
a. in an organic solvent containing alkali, 4-cyano-2, 6-dimethylphenol reacts with 2-chloroethanol to prepare 4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile;
b. 4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile reacts with methanol and hydrogen chloride in an organic solvent, the mixture is filtered, and the obtained solid reacts with ammonia to prepare 4- (2-hydroxyethoxy) -3, 5-dimethylbenzamidine hydrochloride.
5. The method for preparing Apabetalone according to claim 4, wherein the concentration of the 4-cyano-2, 6-dimethylphenol in step a is 0.1 to 1mol/L, and the molar ratio of the 4-cyano-2, 6-dimethylphenol to the 2-chloroethanol to the base is 1: 4-8: 1-3.5, reacting the organic solvent with potassium carbonate, diisopropylethylamine or sodium hydroxide for 24-48 hours at 50-100 ℃, filtering, extracting, taking an organic phase, washing with alkali, washing with a saturated sodium chloride solution, and performing petroleum ether thermal extraction.
6. The method of claim 4, wherein the concentration of said 4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile in step b is 0.5 to 1.5mol/L, and the ratio of said 4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile: methanol: the molar ratio of hydrogen chloride is 1: 1-2: 1-10, the organic solvent is diethyl ether or dioxane, the ammonia is a methanol solution of ammonia, the 4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile reacts with methanol and hydrogen chloride at the temperature of 0-30 ℃ for 24-72 hours, the reaction condition is 24-48 hours at the temperature of 0-30 ℃ after the methanol solution of ammonia is added, and after the reaction is finished, the mixture is concentrated under reduced pressure, and the molar ratio of the 4- (2-hydroxyethoxy) -3, 5-dimethylbenzonitrile to the ammonia is 1: 1.2-1.5.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106892872A (en) * 2015-12-19 2017-06-27 西安瑞联新材料股份有限公司 A kind of synthetic method of 2- (4- bromophenyls) -4- xenyl -6- phenyl pyrimidines
CN108218798A (en) * 2017-12-13 2018-06-29 南方医科大学 The preparation method of Apabetalone
CN108997226A (en) * 2018-07-23 2018-12-14 合肥学院 A kind of synthesis technology of cardiovascular drug Apabetalone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106892872A (en) * 2015-12-19 2017-06-27 西安瑞联新材料股份有限公司 A kind of synthetic method of 2- (4- bromophenyls) -4- xenyl -6- phenyl pyrimidines
CN108218798A (en) * 2017-12-13 2018-06-29 南方医科大学 The preparation method of Apabetalone
CN108997226A (en) * 2018-07-23 2018-12-14 合肥学院 A kind of synthesis technology of cardiovascular drug Apabetalone

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
A Simple and Efficient Approach to Quinazolinones under Mild Copper-Catalyzed Conditions;Xiaowei Liu et al.;《Angew. Chem. Int. Ed.》;20091231;第48卷;第348-351页 *

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