CN113861167A - Preparation method of Voranolan fumarate - Google Patents
Preparation method of Voranolan fumarate Download PDFInfo
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- CN113861167A CN113861167A CN202111335839.7A CN202111335839A CN113861167A CN 113861167 A CN113861167 A CN 113861167A CN 202111335839 A CN202111335839 A CN 202111335839A CN 113861167 A CN113861167 A CN 113861167A
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Abstract
The invention provides a preparation method of Voranolan fumarate, which comprises the following steps: (1) carrying out an azide reaction on the compound of the formula I to obtain a compound of a formula II; (2) cyclizing the compound of the formula II and the compound of the formula III to obtain a compound of the formula IV; (3) carrying out condensation reaction on a compound shown in the formula IV and a compound shown in the formula VI to obtain a compound shown in the formula VII; (4) deprotecting the compound of formula VII with an acid to obtain Voronalane free base; (5) the Voranolan free alkali and fumaric acid form salt to obtain Voranolan fumarate. Compared with the prior art, the method for synthesizing the Voranolan fumarate has the advantages that the total yield of the Voranolan fumarate is improved to over 60 percent, and the yield is greatly improved. Furthermore, the compound of formula iv can be used as a new intermediate for the preparation of vorexant fumarate.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of vorexant fumarate and an intermediate thereof.
Background
Vorexazol fumarate (Vonoprazan fumarate) is a novel gastric acid secretion inhibitor developed by martial arts, japan.
The chemical name of Voranolan fumarate is 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine fumarate, and the structural formula is shown as follows:
CN102421753A discloses a synthetic route of vorexant, which takes 5- (2-fluorophenyl) -2-chloro-1H-pyrrole-3-nitrile as raw material, and the total yield is about 39%. One of the intermediates in the reaction route disclosed in this patent is susceptible to side reactions in preparation and difficult to work up, resulting in a reduction in product yield.
Therefore, it is important to provide a preparation method of vorexant fumarate with high purity and high yield to solve the problem of low yield of vorexant.
Disclosure of Invention
The invention provides a preparation method of vorexant fumarate and an intermediate thereof. The total yield of the Voranolan fumarate prepared by the reaction route disclosed by the invention is over 60 percent.
The technical scheme adopted by the invention is as follows:
the invention discloses a method for preparing a compound shown as a formula VII, which comprises the following steps:
carrying out condensation reaction on a compound shown as a formula IV and a compound shown as a formula VI to obtain a compound shown as a formula VII
The condensation reaction catalyst is an organorhodium reagent and an acid catalyst. Preferably, the organorhodium reagent is dimeric rhodium acetate. Wherein the acid catalyst can be trifluoroacetic acid, trimethylsilyl trifluoromethanesulfonate (TMSOTf) and the like.
Deprotecting the compound represented by formula VII prepared by the above method with an acid to obtain Voranol free base; and salifying the Voranol free alkali and fumaric acid to obtain Voranol fumarate.
In another aspect of the invention, the invention also discloses a compound shown as a formula IV, which is used as an intermediate for preparing the vorexant fumarate:
in another aspect of the present invention, the present invention also discloses a method for preparing the compound represented by the formula IV, which comprises the following steps: cyclizing the compound shown as the formula II and the compound shown as the formula III to obtain the compound shown as the formula IV
The above cyclization reaction catalyst is a copper catalyst and a ligand. The copper catalyst is cuprous acetate, cupric sulfate or cuprous iodide. Preferably, the copper catalyst is copper acetate. The ligand is selected from one of aminophenol, phenylenediamine, benzenediol and aniline, wherein the aminophenol can be selected from 2-aminophenol, 3-aminophenol or 4-aminophenol; the phenylenediamine can be selected from o-phenylenediamine, m-phenylenediamine or p-phenylenediamine; the diphenol may be catechol, resorcinol or hydroquinone. Further preferably, the ligand is 2-aminophenol, 3-aminophenol, 4-aminophenol, catechol or hydroquinone.
In another aspect of the present invention, the present invention also discloses a method for preparing a compound represented by formula ii, comprising the steps of:
carrying out azide reaction on the compound shown as the formula I to obtain the compound shown as the formula II
In the above-mentioned azide reaction, the azide reagent is selected from one of sodium azide, potassium azide, lithium azide, magnesium azide, cesium azide and barium azide. Preferably, the azidation reagent is sodium azide. Further preferably, the azidation reaction system in step (1) further comprises a chlorination reagent and triphenylphosphine. Wherein the chlorinating agent is selected from one of thionyl chloride, oxalyl chloride and trichloroisocyanuric acid.
In another aspect of the invention, the invention discloses a preparation method of vorexant fumarate, which comprises the following steps:
(1) carrying out azide reaction on the compound shown as the formula I to obtain the compound shown as the formula II
(2) Cyclizing the compound shown as the formula II and the compound shown as the formula III to obtain the compound shown as the formula IV
(3) Carrying out condensation reaction on a compound shown as a formula IV and a compound shown as a formula VI to obtain a compound shown as a formula VII
(4) Deprotecting the compound shown in the formula VII by using acid to obtain Voronalane free base;
(5) the Voranolan free alkali and fumaric acid form salt to obtain Voranolan fumarate.
In the azide reaction in the step (1), the azide reagent is selected from one of sodium azide, potassium azide, lithium azide, magnesium azide, cesium azide and barium azide. Preferably, the azidation reagent is sodium azide. Further preferably, the azidation reaction system in step (1) further comprises a chlorination reagent and triphenylphosphine. Wherein the chlorinating agent is selected from one of thionyl chloride, oxalyl chloride and trichloroisocyanuric acid.
The cyclization reaction catalyst in the step (2) is a copper catalyst and a ligand. The copper catalyst is cuprous acetate, cupric sulfate or cuprous iodide. Preferably, the copper catalyst is copper acetate. The ligand is selected from one of aminophenol, phenylenediamine, benzenediol and aniline, wherein the aminophenol can be selected from 2-aminophenol, 3-aminophenol or 4-aminophenol; the phenylenediamine can be selected from o-phenylenediamine, m-phenylenediamine or p-phenylenediamine; the diphenol may be catechol, resorcinol or hydroquinone. Further preferably, the ligand is 2-aminophenol, 3-aminophenol, 4-aminophenol, catechol or hydroquinone.
The condensation reaction catalyst in the step (3) is an organic rhodium reagent and an acid catalyst. Preferably, the organorhodium reagent is dimeric rhodium acetate. Wherein the acid catalyst can be trifluoroacetic acid, trimethylsilyl trifluoromethanesulfonate (TMSOTf) and the like.
In another aspect of the invention, there is also disclosed a process for preparing a compound of formula VI, comprising the steps of,
carrying out condensation reaction on the compound shown as the formula V and a trimethyl silanization reagent to obtain the compound shown as the formula VI
The trimethylsilylating agent is selected from one of iodotrimethylsilane, bromotrimethylsilane, hexamethyldisilazane and trimethylsilyldiethylamine. In some embodiments, the iodotrimethylsilane is prepared from chlorotrimethylsilane (Me)3SiCl) and NaI.
Compared with the prior art, the method for synthesizing the Voranolan fumarate has the advantages that the total yield of the Voranolan fumarate is improved to over 60 percent, and the yield is greatly improved. Furthermore, the compound of formula iv can be used as a new intermediate for the preparation of vorexant fumarate.
Although the compounds obtained in each step can be used in the next reaction in the form of a reaction mixture or a crude product, they can also be easily separated and purified from the corresponding reaction mixture by known separation and purification means such as recrystallization, distillation, chromatography and the like.
The detailed reaction route of the preparation method of Voranolan fumarate disclosed by the invention is as follows:
in the step (1), the azide reaction system comprises an azide reagent. In some specific embodiments, the azide reaction system further comprises triphenylphosphine and a chlorinating agent, wherein the chlorinating agent may be selected from thionyl chloride, oxalyl chloride, trichloroisocyanuric acid, and the like. The reaction solvent is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, DMF, ethyl acetate, xylene, trimethylbenzene, diethyl ether, isopropyl ether, methyl tert-butyl ether and methyl cyclopentyl ether.
In the step (2), the cycloaddition reaction of alkyne and azide is carried out at room temperature, and the reaction solvent is one or more selected from methanol, ethanol, isopropanol, ethylene glycol monomethyl ether, ethylene glycol monobutyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and acetonitrile.
In the step (3), the molar ratio of the reaction of the formula VI to the reaction of the formula VI is 1:2-1: 4. 0.005-1mol of organic rhodium reagent is used per 1mol of compound VI; the acid catalyst is used in an amount of 0.025 to 5mol per 1mol of the compound VI. The reaction solvent is one or more selected from toluene, 2-methyltetrahydrofuran, dioxane, N-dimethylformamide, N-dimethylacetamide, 1, 2-dichloroethane, xylene, trimethylbenzene and methyl cyclopentyl ether.
In the step (4), the acid adopted for removing Boc from the compound VII is trifluoroacetic acid or hydrochloric acid to obtain Voranol free alkali, and then fumaric acid is added to obtain Voranol fumarate.
Detailed Description
Example 1
(1) Preparation of Compound II
Tetrahydrofuran is added into a reaction bottle, stirring is started, trichloroisocyanuric acid (13.9g, 0.06mol) is added, stirring is carried out until the solution is clear, triphenylphosphine (52.5g, 0.2mol) is added into the system at the temperature of 0-5 ℃ to form white suspension, compound I pyridine-3-sulfonic acid (15.9g, 0.1mol) is added into the reaction bottle, sodium azide (6.5g, 0.1mol) is added into the system, the temperature is raised to room temperature after the addition is finished, stirring is carried out at the room temperature until the reaction is finished, reduced pressure concentration is carried out until no fraction is produced, ethyl acetate and cold purified water are added into residues for washing, liquid separation is carried out, an organic phase is dried by anhydrous sodium sulfate, and compound II 17.3g is obtained after concentration, and the yield is 94%.
MS：m/z:185.0[M+1]
(2) Preparation of Compound IV
Acetonitrile is added into a reaction bottle at room temperature, stirring is started, a compound II (18.4g, 0.1mol), a compound III (18.6g, 0.11mol), 2-aminophenol (0.5g, 0.005mol) and copper acetate monohydrate (2g, 0.01mol) are added, stirring is carried out at room temperature until the reaction is finished, the reaction liquid is decompressed and concentrated to no fraction, and drying is carried out, so that 33.6g of a compound IV is obtained, and the yield is about 95%.
MS：m/z:354.1[M+1]
1H NMR(400MHz，CDCl3)：1.42(s,9H)，3.21(s,3H)，4.22(d,2H)，7.69(t,1H)，8.32(s,1H)， 8.43(d,1H)，8.89-8.91(d,2H)
(3) Preparation of Compound VII
Adding 1.2-dichloroethane into a reaction bottle at room temperature, starting stirring, adding a compound IV (35.3g, 0.1mol), dimeric rhodium acetate (0.44g, 0.001mol) and a compound VI (63.1g,0.3mol), heating to 80 ℃ after the addition, stirring to react until the reaction is finished, cooling to room temperature, dissolving trimethylsilyl trifluoromethanesulfonate (TMSOTf) (1.1g, 0.005mol) in 1.2-dichloroethane, adding the system, stirring at room temperature, adding purified water and dichloromethane into the system for extraction, washing a water phase twice by using dichloro, combining organic phases, washing once by using water, and concentrating under reduced pressure to obtain 36.5g of a compound VII with the yield of about 82%.
MS：m/z:446.1[M+1]
(4) Preparation of Vonola fumarate
Adding a compound VII (44.6g, 0.1mol) into a reaction bottle at room temperature, adding trifluoroacetic acid (100ml), controlling the temperature to be 0-5 ℃ and stirring, adding a 20% sodium carbonate solution to adjust the pH value to be 9-10, collecting an organic phase, adding dichloromethane into a water phase to extract once, combining the organic phase, washing twice, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to obtain Vonopalagen free alkali, adding methanol into the Vonopalagen free alkali to stir and dissolve, adding fumaric acid (11.6g, 0.1mol) into the reaction bottle at 25-30 ℃, heating to reflux, stirring, cooling, crystallizing and filtering, leaching a filter cake with methanol, drying by blowing at 40-50 ℃ to obtain 41.1g of Vonopalagen fumarate, wherein the yield is about 89%.
Example 2
(1) Preparation of Compound II
Adding methyl tert-butyl ether into a reaction bottle, starting stirring, adding thionyl chloride (7.14g, 0.06mol), stirring until the solution is clear, controlling the temperature to be 0-5 ℃, adding triphenylphosphine (52.5g, 0.2mol) into a system to form a white suspension, adding a compound I (15.9g, 0.1mol) into the reaction bottle, adding magnesium azide (10.8g, 0.1mol) into the system, heating to room temperature after the addition is finished, stirring at the room temperature until the reaction is finished, concentrating under reduced pressure until no fraction exists, adding ethyl acetate and cold purified water into residues, washing, separating, drying an organic phase by anhydrous sodium sulfate, and concentrating to obtain a compound II (16.9 g) with the yield of 92%.
MS：m/z:185.0[M+1]
(2) Preparation of Compound (IV)
Acetonitrile is added into a reaction bottle at room temperature, stirring is started, a compound II (18.4g, 0.1mol), a compound III (18.6g, 0.11mol), aniline (0.47g, 0.005mol) and cuprous iodide (1.9g, 0.01mol) are added, the reaction is stirred at room temperature until the reaction is finished, the reaction liquid is decompressed and concentrated to no fraction, and the reaction liquid is dried to obtain 32.5g of a compound IV, wherein the yield is about 92%.
MS：m/z:354.1[M+1]
1H NMR(400MHz，CDCl3)：1.42(s,9H)，3.21(s,3H)，4.22(d,2H)，7.69(t,1H)，8.32(s,1H)， 8.43(d,1H)，8.89-8.91(d,2H)
(3) Preparation of Compound VII
Adding 1.2-dichloroethane into a reaction bottle at room temperature, starting stirring, adding a compound IV (35.3g, 0.1mol), dimeric rhodium acetate (0.44g, 0.001mol) and a compound VI (63.1g,0.3mol), heating to 80 ℃ after the addition, stirring to react until the reaction is finished, cooling to room temperature, dissolving trifluoroacetic acid (0.57g, 0.005mol) in 1.2-dichloroethane, adding the system, stirring at room temperature, adding purified water and dichloromethane into the system, extracting, washing the water phase twice with dichloro, combining the organic phases, washing once with water, concentrating under reduced pressure to obtain 37.0g of a compound VII with a yield of about 83%.
MS：m/z:446.1[M+1]
(4) Preparation of Vonola fumarate
Adding a compound VII (44.6g, 0.1mol) into a reaction bottle at room temperature, adding a proper amount of hydrochloric acid, stirring at the temperature of 0-5 ℃, adding a 20% sodium carbonate solution to adjust the pH value to 9-10, collecting an organic phase, adding dichloromethane into a water phase to extract once, combining the organic phases, washing twice, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to obtain Vonopalagen free alkali, adding methanol into the Vonopalagen free alkali to stir and dissolve, adding fumaric acid (11.6g, 0.1mol) at the temperature of 25-30 ℃, heating to reflux, stirring, cooling, crystallizing, filtering, leaching a filter cake with methanol, and drying by air blowing at the temperature of 40-50 ℃ to obtain 41.5g of Vonopalagen fumarate, wherein the yield is about 90%.
Example 3
(1) Preparation of Compound II
Tetrahydrofuran is added into a reaction bottle, stirring is started, oxalyl chloride (7.6g, 0.06mol) is added, stirring is carried out until the mixture is dissolved, triphenylphosphine (52.5g, 0.2mol) is added into the system at the temperature of 0-5 ℃ to form white suspension, compound I (15.9g, 0.1mol) is added into the reaction bottle, potassium azide (8.1g, 0.1mol) is added into the system, the temperature is raised to room temperature after the addition, the mixture is stirred at the room temperature until the reaction is finished, the mixture is concentrated under reduced pressure until no fraction is formed, ethyl acetate and cold purified water are added into the residue to wash the mixture, the mixture is separated, the organic phase is dried by anhydrous sodium sulfate, and 17.5g of compound II is obtained after the concentration, and the yield is 95%.
MS：m/z:185.0[M+1]
(2) Preparation of Compound IV
Acetonitrile is added into a reaction bottle at room temperature, stirring is started, a compound II (18.4g, 0.1mol), a compound III (18.6g, 0.11mol), 4-aminophenol (0.5g, 0.005mol) and copper sulfate (2.5g, 0.01mol) are added, stirring is carried out at room temperature until the reaction is finished, the reaction liquid is decompressed and concentrated to no fraction, and drying is carried out, so that 33.2g of a compound IV is obtained, and the yield is about 94%.
MS：m/z:354.1[M+1]
1H NMR(400MHz，CDCl3)：1.42(s,9H)，3.21(s,3H)，4.22(d,2H)，7.69(t,1H)，8.32(s,1H)， 8.43(d,1H)，8.89-8.91(d,2H)
(3) Preparation of Compound VII
Adding 1.2-dichloroethane into a reaction bottle at room temperature, starting stirring, adding a compound IV (35.3g, 0.1mol), dimeric rhodium acetate (0.44g, 0.001mol) and a compound VI (63.1g,0.3mol), heating to 80 ℃ after the addition, stirring to react until the reaction is finished, cooling to room temperature, dissolving trimethylsilyl trifluoromethanesulfonate (TMSOTf) (1.1g, 0.005mol) in 1.2-dichloroethane, adding the system, stirring at room temperature, adding purified water and dichloromethane into the system for extraction, washing a water phase twice by using dichloro, combining organic phases, washing once by using water, and concentrating under reduced pressure to obtain 37.4g of a compound VII with the yield of about 84%.
MS：m/z:446.1[M+1]
(4) Preparation of Vonola fumarate
Adding a compound VII (44.6g, 0.1mol) into a reaction bottle at room temperature, adding trifluoroacetic acid (100ml), controlling the temperature to be 0-5 ℃ and stirring, adding a 20% sodium carbonate solution to adjust the pH value to be 9-10, collecting an organic phase, adding dichloromethane into a water phase to extract once, combining the organic phase, washing twice, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to obtain Vonopalagen free alkali, adding methanol into the Vonopalagen free alkali to stir and dissolve, adding fumaric acid (11.6g, 0.1mol) into the reaction bottle at 25-30 ℃, heating to reflux, stirring, cooling, crystallizing and filtering, leaching a filter cake with methanol, drying by blowing at 40-50 ℃ to obtain 41.1g of Vonopalagen fumarate, wherein the yield is about 89%.
Example 4
(1) Preparation of Compound II
Tetrahydrofuran is added into a reaction bottle, stirring is started, oxalyl chloride (7.6g, 0.06mol) is added, stirring is carried out until the mixture is dissolved, triphenylphosphine (52.5g, 0.2mol) is added into the system at the temperature of 0-5 ℃ to form white suspension, compound I (15.9g, 0.1mol) is added into the reaction bottle, barium azide (22.1g, 0.1mol) is added into the system, the temperature is raised to room temperature after the addition, the mixture is stirred at the room temperature until the reaction is finished, the mixture is concentrated under reduced pressure until no fraction is formed, ethyl acetate and cold purified water are added into the residue to wash the mixture, the mixture is separated, the organic phase is dried by anhydrous sodium sulfate, and 17.3g of compound II is obtained after the concentration, and the yield is 94%.
MS：m/z:185.0[M+1]
(2) Preparation of Compound IV
Acetonitrile is added into a reaction bottle at room temperature, stirring is started, a compound II (18.4g, 0.1mol), a compound III (18.6g, 0.11mol), catechol (0.55g, 0.005mol) and cuprous acetate (1.23g, 0.01mol) are added, stirring is carried out at room temperature until the reaction is finished, the reaction liquid is decompressed and concentrated to no fraction, and drying is carried out, so that 32.8g of a compound IV is obtained, and the yield is about 93%.
MS：m/z:354.1[M+1]
1H NMR(400MHz，CDCl3)：1.42(s,9H)，3.21(s,3H)，4.22(d,2H)，7.69(t,1H)，8.32(s,1H)， 8.43(d,1H)，8.89-8.91(d,2H)
(3) Preparation of Compound VII
Adding 1.2-dichloroethane into a reaction bottle at room temperature, starting stirring, adding a compound IV (35.3g, 0.1mol), dimeric rhodium acetate (0.44g, 0.001mol) and a compound VI (63.1g,0.3mol), heating to 80 ℃ after the addition, stirring to react until the reaction is finished, cooling to room temperature, dissolving trimethylsilyl trifluoromethanesulfonate (TMSOTf) (1.1g, 0.005mol) in 1.2-dichloroethane, adding the system, stirring at room temperature, adding purified water and dichloromethane into the system for extraction, washing a water phase twice by using dichloro, combining organic phases, washing once by using water, and concentrating under reduced pressure to obtain 37.4g of a compound VII with the yield of about 84%.
MS：m/z:446.1[M+1]
(4) Preparation of Vonola fumarate
Adding a compound VII (44.6g, 0.1mol) into a reaction bottle at room temperature, adding trifluoroacetic acid (100ml), controlling the temperature to be 0-5 ℃ and stirring, adding a 20% sodium carbonate solution to adjust the pH value to be 9-10, collecting an organic phase, adding dichloromethane into a water phase to extract once, combining the organic phase, washing twice, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to obtain Vonopalagen free alkali, adding methanol into the Vonopalagen free alkali to stir and dissolve, adding fumaric acid (11.6g, 0.1mol) into the reaction bottle at 25-30 ℃, heating to reflux, stirring, cooling, crystallizing and filtering, leaching a filter cake with methanol, drying by blowing at 40-50 ℃ to obtain 41.1g of Vonopalagen fumarate, wherein the yield is about 89%.
Example 5
(1) Preparation of Compound II
Tetrahydrofuran is added into a reaction bottle, stirring is started, oxalyl chloride (7.6g, 0.06mol) is added, stirring is carried out until the mixture is dissolved, triphenylphosphine (52.5g, 0.2mol) is added into the system at the temperature of 0-5 ℃ to form a white suspension, a compound I (15.9g, 0.1mol) is added into the reaction bottle, lithium azide (4.9g, 0.1mol) is added into the system, the temperature is increased to the room temperature after the addition, the stirring is carried out at the room temperature until the reaction is finished, the mixture is concentrated under reduced pressure until no fraction is formed, ethyl acetate and cold purified water are added into the residue to wash the mixture, the mixture is separated, the organic phase is dried by anhydrous sodium sulfate, and the compound II is obtained after the concentration, wherein the compound II is 17.1g, and the yield is 93%.
MS：m/z:185.0[M+1]
(2) Preparation of Compound IV
Acetonitrile is added into a reaction bottle at room temperature, stirring is started, a compound II (18.4g, 0.1mol), a compound III (18.6g, 0.11mol), hydroquinone (0.55g, 0.005mol) and cuprous acetate (1.23g, 0.01mol) are added, stirring is carried out at room temperature until the reaction is finished, the reaction liquid is decompressed and concentrated to no fraction, and drying is carried out, so that 32.8g of a compound IV is obtained, and the yield is about 93%.
MS：m/z:354.1[M+1]
1H NMR(400MHz，CDCl3)：1.42(s,9H)，3.21(s,3H)，4.22(d,2H)，7.69(t,1H)，8.32(s,1H)， 8.43(d,1H)，8.89-8.91(d,2H)
(3) Preparation of Compound VII
Adding 1.2-dichloroethane into a reaction bottle at room temperature, starting stirring, adding a compound IV (35.3g, 0.1mol), dimeric rhodium acetate (0.44g, 0.001mol) and a compound VI (63.1g,0.3mol), heating to 80 ℃ after the addition, stirring to react until the reaction is finished, cooling to room temperature, dissolving trimethylsilyl trifluoromethanesulfonate (TMSOTf) (1.1g, 0.005mol) in 1.2-dichloroethane, adding the system, stirring at room temperature, adding purified water and dichloromethane into the system for extraction, washing a water phase twice by using dichloro, combining organic phases, washing once by using water, and concentrating under reduced pressure to obtain 37.4g of a compound VII with the yield of about 84%.
MS：m/z:446.1[M+1]
(4) Preparation of Vonola fumarate
Adding a compound VII (44.6g, 0.1mol) into a reaction bottle at room temperature, adding trifluoroacetic acid (100ml), controlling the temperature to be 0-5 ℃ and stirring, adding a 20% sodium carbonate solution to adjust the pH value to be 9-10, collecting an organic phase, adding dichloromethane into a water phase to extract once, combining the organic phase, washing twice, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to obtain Vonopalagen free alkali, adding methanol into the Vonopalagen free alkali to stir and dissolve, adding fumaric acid (11.6g, 0.1mol) into the reaction bottle at 25-30 ℃, heating to reflux, stirring, cooling, crystallizing and filtering, leaching a filter cake with methanol, drying by blowing at 40-50 ℃ to obtain 41.1g of Vonopalagen fumarate, wherein the yield is about 89%.
Example 6
Process for preparing compounds of formula VI
Adding acetonitrile into a reaction bottle, starting stirring, adding a compound V (13.8g, 0.1mol) and sodium iodide (18.0g, 0.12mol), replacing nitrogen for three times, stirring at room temperature, adding triethylamine and trimethylchlorosilane (13.0g, 0.12mol) into the system, stirring at room temperature, cooling to below 0 ℃, controlling the temperature to be not more than 0 ℃, adding a saturated ammonium chloride solution and petroleum ether into the system, separating liquid, washing a water phase twice with the petroleum ether, combining organic phases, washing with ice water and saturated ammonium chloride, drying with anhydrous sodium sulfate, concentrating under reduced pressure until no fraction is formed, distilling and purifying residues under reduced pressure to obtain a compound VI 20.4g, wherein the yield is 97%.
Example 7
Process for preparing compounds of formula VI
Adding acetonitrile into a reaction bottle, starting stirring, adding a compound V (13.8g, 0.1mol), replacing nitrogen for three times, stirring at room temperature, adding triethylamine and hexamethyldisilazane (19.3g, 0.12mol) into the system, stirring at room temperature, cooling to below 0 ℃, controlling the temperature to be not more than 0 ℃, adding a saturated ammonium chloride solution and petroleum ether into the system, separating, washing a water phase twice with petroleum ether, combining organic phases, washing with ice water and saturated ammonium chloride, drying with anhydrous sodium sulfate, concentrating under reduced pressure until no fraction is formed, distilling and purifying residues under reduced pressure to obtain 19.4g of a compound VI with the yield of 92%.
Example 8
Process for preparing compounds of formula VI
Adding acetonitrile into a reaction bottle, starting stirring, adding a compound V (13.8g, 0.1mol), replacing nitrogen for three times, stirring at room temperature, adding triethylamine and trimethylsilyldiethylamine (17.4g, 0.12mol) into the system, stirring at room temperature, cooling to below 0 ℃, controlling the temperature to be not more than 0 ℃, adding a saturated ammonium chloride solution and petroleum ether into the system, separating liquid, washing a water phase twice with petroleum ether, combining organic phases, washing with ice water and saturated ammonium chloride, drying with anhydrous sodium sulfate, concentrating under reduced pressure until no fraction is produced, distilling and purifying residues under reduced pressure to obtain 19.4g of a compound VI with the yield of 92%.
Claims (20)
1. A process for preparing a compound of formula vii, comprising the steps of:
carrying out condensation reaction on a compound shown as a formula IV and a compound shown as a formula VI to obtain a compound shown as a formula VII
2. The process for producing a compound represented by the formula VII according to claim 1, wherein the condensation reaction catalyst comprises an organorhodium reagent and an acid catalyst.
3. A process for the preparation of a compound of formula vii as claimed in claim 2 wherein the organorhodium reagent is dimeric rhodium acetate.
4. A compound of formula IV:
5. a process for preparing a compound of formula iv according to claim 4, comprising the steps of: carrying out cyclization reaction on a compound shown as a formula II and a compound shown as a formula III to obtain a compound shown as a formula IV
6. The process for preparing a compound of formula iv according to claim 5, wherein the cyclization catalyst is a copper catalyst and a ligand.
7. The method of claim 6, wherein the copper catalyst is cuprous acetate, cupric sulfate, or cuprous iodide.
8. The method of claim 6, wherein the ligand is selected from the group consisting of aminophenols, phenylenediamines, benzenediols, and anilines.
9. A process for preparing a compound of formula ii, said process comprising the steps of:
carrying out azide reaction on the formula I to obtain a compound shown as a formula II
10. The method for preparing the compound represented by the formula ii according to claim 9, wherein the azide reaction is performed using an azide reagent selected from the group consisting of sodium azide, potassium azide, lithium azide, magnesium azide, cesium azide and barium azide.
11. A preparation method of Voranolan fumarate is characterized by comprising the following steps:
deprotecting a compound of formula VII prepared according to the process of claim 1 with an acid to obtain Voranol free base; and salifying the Voranol free alkali and fumaric acid to obtain Voranol fumarate.
12. A preparation method of Voranolan fumarate is characterized by comprising the following steps:
(1) carrying out azide reaction on the compound shown as the formula I to obtain the compound shown as the formula II
(2) Cyclizing the compound shown as the formula II and the compound shown as the formula III to obtain the compound shown as the formula IV
(3) Carrying out condensation reaction on a compound shown as a formula IV and a compound shown as a formula VI to obtain a compound shown as a formula VII
(4) Deprotecting the compound shown in the formula VII by using acid to obtain Voronalane free base;
(5) the Voranolan free alkali and fumaric acid form salt to obtain Voranolan fumarate.
13. The process for preparing Vonola fumarate of claim 12, wherein in the azidation reaction of step (1), the azidation reagent used is one selected from the group consisting of sodium azide, potassium azide, lithium azide, magnesium azide, cesium azide and barium azide.
14. The process for the preparation of vorexant fumarate according to claim 12, wherein the cyclization catalyst in step (2) is a copper catalyst and a ligand.
15. The process for the preparation of vorexan fumarate according to claim 14, wherein the copper catalyst is cuprous acetate, cupric sulfate or cuprous iodide.
16. The process for the preparation of vorexant fumarate of claim 14, wherein the ligand is selected from one of aminophenol, phenylenediamine, benzenediol and aniline.
17. The process for the preparation of vorexant fumarate according to claim 12, wherein the condensation reaction catalyst in step (3) is an organorhodium reagent and an acid catalyst.
18. The process for the preparation of vorexant fumarate of claim 17, wherein the organorhodium reagent is dimeric rhodium acetate.
19. A process for preparing a compound of formula VI, comprising the steps of,
carrying out condensation reaction on the compound shown as the formula V and a trimethyl silanization reagent to obtain the compound shown as the formula VI
20. The method of claim 19, wherein the trimethylsilylating agent is selected from the group consisting of iodotrimethylsilane, bromotrimethylsilane, hexamethyldisilazane, and trimethylsilyldiethylamine.
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