CN113045510B - Preparation method of atralone - Google Patents
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- CN113045510B CN113045510B CN202110345947.6A CN202110345947A CN113045510B CN 113045510 B CN113045510 B CN 113045510B CN 202110345947 A CN202110345947 A CN 202110345947A CN 113045510 B CN113045510 B CN 113045510B
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- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
Abstract
The invention discloses a preparation method of atractylen, which comprises the following steps: an addition step, in which under an alkaline condition, 3-cyanobenzoate reacts with hydroxylamine hydrochloride by using a first mixed solvent to obtain an intermediate of a formula III; a condensation step, in which the intermediate of the formula III and o-fluorobenzoic acid are subjected to condensation reaction in a first organic solvent to obtain an intermediate of the formula IV; a cyclization step, namely catalyzing the intermediate in the formula IV by using Lewis acid in a second organic solvent, and performing intramolecular dehydration on the intermediate to obtain an intermediate in the formula V; and an ester hydrolysis step, in which the intermediate in the formula V is subjected to ester hydrolysis by using a second mixed solvent under an alkaline condition, so as to obtain the intermediate. The invention uses cheap raw materials to carry out four steps of addition, condensation, cyclization and ester hydrolysis, has mild reaction conditions, simple process and low cost, and is beneficial to industrial production. Meanwhile, the solvent in the reaction process can be basically recovered, the synthesis cost is low, and the reaction environment is good; in addition, the purification operation is simple, and the total yield and the product purity of the target compound, namely the atranone are high.
Description
Technical Field
The invention relates to the technical field of chemical medicines, in particular to a preparation method of a small molecular medicine, namely, atractylen.
Background
Duchenne Muscular Dystrophy (DMD) is an X-chromosome recessive genetic disease that occurs mainly in boys. Statistically, on average, one person suffers from this disease every 3500 newborn male infants worldwide. Before school age, patients are inconvenient to walk because skeletal muscles are continuously degenerated to cause muscle weakness or atrophy. Cystic Fibrosis (CF) is a fatal autosomal recessive disease with the major clinical symptoms of chronic obstructive pulmonary disease, one of the most common inherited diseases in caucasians. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The life span of patients with both diseases is very short, and the life quality is seriously influenced.
Although drugs for radically treating duchenne muscular dystrophy and cystic fibrosis have not been discovered, the development of drugs for controlling the condition and improving the quality of life of patients has never been stopped.
The Ataluren (English name: Ataluren, also named as PTC-124) and the chemical name of 3- [5- (2-fluorophenyl) -1,2, 4-oxadiazole-3-yl ] benzoic acid are oral experimental medicines developed by American PTC treatment companies and aim to correct Duchenne muscular dystrophy and cystic fibrosis caused by nonsense mutation by creating functional proteins. The design mechanism of the Atlanton is that the early stop code caused by gene mutation is ignored when the cell synthesizes the protein, and the whole process of protein synthesis is completed.
Patent documents WO2004091502a2 and WO2008030570a1 disclose astallurens and a method for its preparation, followed by patent US 2017/362192; CN 106279057A and Journal (Drug of the future,2008,33(9), 733; New Journal of Chemistry 2014,38, 3062-.
For example, patent CN106279057 adopts triphenylphosphine and equivalent halogenating agent to generate attarolone by ring closure under the condition of diethoxymethylsilane and bis (p-nitrophenyl) phosphate as reducing agents. The method requires the use of carbon tetrachloride, a class I solvent with carcinogenic toxicity, and the final product requires column chromatography purification.
In another example, CN111675672 discloses a method for preparing atranlan, which uses o-fluorobenzoyl chloride as a reaction raw material, but o-fluorobenzoyl chloride is unstable. The condensation step in the reaction process obtains an intermediate, the intermediate is subjected to ring closing under the action of tetrabutylammonium fluoride to obtain an aliskiren intermediate, and finally, aliskiren is obtained through hydrolysis, but actually, the yield of the aliskiren is far lower than 68% reported in the patent. More importantly, the reaction mechanism of the ring closure by tetrabutylammonium fluoride is still to be confirmed, and whether the ring closure of the intermediate can be successfully carried out is doubtful.
In summary, the synthetic route of artaglutian in the prior art mainly has the following disadvantages:
1. the reaction route is long, and the total yield is low;
2. expensive raw materials and noble metal catalysts are used in the synthesis process, or high-temperature, closed-tank and oxidation processes are adopted, so that the method is not suitable for industrial production;
3. gases such as sulfur dioxide, hydrogen chloride and the like can be generated in the synthesis process, so that the environment pollution is serious;
4. in the reaction process, organic solvents such as carbon tetrachloride and the like with strong carcinogenic toxicity are needed;
5. and the final purification adopts column chromatography operation, so that industrialization cannot be realized.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide the preparation method of the atranone, which has the advantages of short synthetic route, environmental friendliness, low production cost, avoidance of harsh reaction conditions and suitability for industrial production.
The purpose of the invention is realized by adopting the following technical scheme:
a preparation method of the atractylen comprises the following steps:
an addition step, in which a compound (3-cyanobenzoate) in a formula II reacts with hydroxylamine hydrochloride by using a first mixed solvent under an alkaline condition to obtain an intermediate in a formula III; wherein R in the compound of formula II1Is a hydrocarbyl group;
a condensation step, in which the intermediate of the formula III and o-fluorobenzoic acid are subjected to condensation reaction in a first organic solvent to obtain an intermediate of the formula IV;
a cyclization step, catalyzing the intermediate in the formula IV by using Lewis acid in a second organic solvent, and performing intramolecular dehydration on the intermediate to obtain an intermediate in the formula V;
ester hydrolysis, namely performing ester hydrolysis on the intermediate in the formula V by using a second mixed solvent under an alkaline condition to prepare a target compound, namely the atralen in the formula I;
the general synthetic route is shown below:
further, in the addition step, the reaction temperature is 15-80 ℃, preferably 15-60 ℃, and more preferably 15-45 ℃. In addition, methanol water or ethanol water is generally used as a solvent, and if the reaction temperature is higher than 80 ℃, the reflux occurs, and if the reaction temperature is lower than 15 ℃, the reaction is relatively slow, so the temperature is preferably 15-80 ℃.
Further, R in the compound of formula II1The alkyl group contains 1 to 4 carbon atoms, and includes methyl, ethyl, isopropyl, etc., preferably methyl or ethyl, more preferably methyl.
Further, in the addition step, the alkali condition is generally adjusted to be weak alkali, and the alkali substance for adjusting the alkali condition is sodium bicarbonate, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, lithium ethoxide, potassium hydroxide, sodium hydroxide or lithium hydroxide; the alkaline substance is preferably sodium bicarbonate or potassium bicarbonate; the amount of the strong base used is 1.0 to 5.0 times, more preferably 2.0 to 4.0 times, the molar amount of the compound of formula II.
Further, for the addition step, hydroxylamine hydrochloride is used in an amount of 1.0 to 3.0 equivalents, more preferably 1.5 to 2.5 equivalents, based on the molar amount of the compound of formula II.
Further, in the addition step, the first mixed solvent is a water and alcohol mixed solvent, the alcohol is one or any combination of methanol, ethanol, isopropanol and tert-butanol, and the volume ratio of water to alcohol is 1: 2.5-5; the usage amount of the first mixed solvent is 5-50 times of the volume of the compound of the formula II, and more preferably 20-30 times of the volume of the compound of the formula II. During the addition reaction, the hydroxylamine hydrochloride is dissolved in water, the 3-cyanobenzoate is dissolved in alcohol, and the mixed solvent of water and alcohol can be used for well dissolving the reaction raw materials and accelerating the reaction speed. The proportion of water and alcohol is preferably 1:2.5-5, the usage amount of the first mixed solvent is 5-50 times of the volume of the compound of the formula II, reaction raw materials can be fully dissolved within the parameter ranges, no solvent is wasted, the reaction efficiency is considered, and the method is economical and environment-friendly.
Further, for the addition step, the first mixed solvent is a mixed solvent of water and methanol, wherein the volume ratio of water to methanol is 1:2.5-5, and more preferably 1: 3.
Further, in the condensation step, the reaction temperature is 0 to 70 ℃, preferably 0 to 50 ℃, and more preferably 0 to 30 ℃. In the condensation reaction, a condensation agent CDI (N, N' -carbonyl diimidazole) is generally adopted for condensation, and the reaction temperature is controlled not to exceed 70 ℃ because the reaction temperature is too high, the CDI is decomposed and impurities are increased.
Further, in the condensation step, the condensation reaction is carried out by using a condensation agent CDI (N, N '-carbonyldiimidazole), wherein the amount of N, N' -carbonyldiimidazole used is 1.0 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents, and more preferably 1.0 to 1.2 equivalents based on the molar amount of the compound of formula II.
Further, for the condensation step, the first organic solvent is N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or dimethylsulfoxide, preferably N, N-dimethylformamide or N, N-dimethylacetamide; more preferably N, N-dimethylformamide, which tends to promote the condensation reaction of CDI. The dosage of the first organic solvent is 5-50 times of the volume of the intermediate of the formula III, preferably 10-30 times of the volume, and more preferably 10-15 times of the volume.
Further, for the cyclization step, the second organic solvent is one or any combination of tetrahydrofuran, 1, 2-dichloroethane, dichloromethane, cyclopentyl methyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1, 4-dioxane, toluene, xylene, chlorobenzene, benzotrifluoride, 2-methyltetrahydrofuran, acetonitrile and chloroform in an aprotic organic solvent; preferably one or any combination of toluene, xylene and chlorobenzene. The dosage of the second organic solvent is 5-50 times of the volume of the intermediate of the formula IV, preferably 10-30 times of the volume, and more preferably 10-15 times of the volume.
Further, for the ring closure step, the lewis acid is one or any combination of p-toluenesulfonic acid, p-toluenesulfonic acid hydrate, p-toluenesulfonic acid pyridinium salt, benzenesulfonic acid, camphorsulfonic acid, acetic acid, sulfamic acid and taurine; more preferably p-toluenesulfonic acid or pyridinium p-toluenesulfonate.
Further, in the ester hydrolysis step, the reaction temperature is 15-80 ℃, preferably 15-60 ℃, and more preferably 15-45 ℃. The hydrolysis reaction is carried out in an organic solvent-water system, and the reflux can be caused when the temperature is high, the side reaction is increased, impurities are generated, and the purity of the final product is influenced, so the reaction temperature is controlled to be 15-80 ℃, and the reaction efficiency, the product yield and the purity are high at the temperature.
Further, for the ester hydrolysis step, the basic substance adjusting the basic condition is lithium hydroxide, sodium hydroxide or potassium hydroxide; the using amount of the alkaline substance is 1.0-5.0 times, preferably 1.0-3.0 times, and more preferably 1.5-2.5 times of the molar amount of the intermediate of the formula V.
Further, for the ester hydrolysis step, the second mixed solvent is a mixed solvent of water and a water-miscible organic solvent, wherein the water-miscible organic solvent is one or any combination of methanol, ethanol, isopropanol, tetrahydrofuran and 1, 4-dioxane, preferably one or a combination of methanol and 1, 4-dioxane; the volume ratio of water to the water-miscible organic solvent is 1:2-1: 5; the using amount of the second mixed solvent is 5-50 times of the volume of the intermediate of the formula V, preferably 10-20 times of the volume, and more preferably 10-15 times of the volume.
Compared with the prior art, the invention has the beneficial effects that:
(1) the preparation method of the atralone takes cheap raw materials of 3-cyanobenzoic acid and hydroxylamine hydrochloride as raw materials and comprises four reaction steps of addition, condensation, cyclization and ester hydrolysis, and is mild in reaction conditions, simple in synthesis process, low in synthesis cost and beneficial to industrial production.
(2) The preparation method of the atraumatic adopts cheap mixed solvent in the reaction process, and the solvent can be basically recycled, so the synthesis cost is low and the reaction environment is good.
(3) According to the preparation method of the atralone, the mixed solvent is used in the last step of ester hydrolysis reaction, and the product with the grade of the bulk drug can be obtained through recrystallization operation, so that the approval of the national process of the bulk drug can be easily realized.
(4) The preparation method of the atractylen provided by the invention has the advantages that the total yield of the atractylen is high and can reach more than 90%, and the purity of the atractylen is high and is more than 99.5%.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of a target compound I provided by an embodiment of the invention;
FIG. 2 shows LCMS spectrum A of object compound I provided by the present invention;
FIG. 3 shows LCMS spectrum B of object compound I provided by the present invention.
Detailed Description
The present invention will be further described with reference to the accompanying drawings and the detailed description, and it should be noted that any combination of the embodiments or technical features described below can be used to form a new embodiment without conflict. The raw materials, equipments and the like used in the following examples are commercially available unless otherwise specified.
Examples 1 to 4
Preparation of a compound of formula III, the reaction is as follows:
example 1: hydroxylamine hydrochloride (139.0g,2mol) and water (2L) were added to a reaction flask at 25 ℃, followed by adjusting the solution pH to 8 using sodium bicarbonate, dissolving the compound of formula ii (161.2g, 1mol) in 6L of methanol, dropping into the above reaction solution, maintaining the internal temperature at 20-25 ℃, after the dropping was completed, stirring and reacting for 6 hours, TLC showed complete reaction of the raw materials, concentrating the reaction solution under reduced pressure, followed by adding water for dilution, and extracting with ethyl acetate. The organic phase was dried over an appropriate amount of anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum to give 186.4g of a white solid compound (compound of formula III) in 96% yield.
Example 2: hydroxylamine hydrochloride (139.0g,2mol) and water (2L) were added to a reaction flask at 25 ℃, followed by adjusting the solution pH to 8 using potassium bicarbonate, dissolving the compound of formula ii (161.2g, 1mol) in 6L of methanol, dropwise adding to the above reaction solution, maintaining the internal temperature at 40-45 ℃, after completion of the dropwise addition, continuing the reaction for 4 hours with stirring, TLC showed complete reaction of the starting materials, concentrating the reaction solution under reduced pressure, followed by dilution with water, and extraction with ethyl acetate. The organic phase was dried over an appropriate amount of anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum to obtain 174.6g of a white solid compound (compound of formula III) in a yield of 90%.
Example 3: hydroxylamine hydrochloride (139.0g,2mol) and water (2L) were added to a reaction flask at 25 ℃, followed by adjustment of the solution pH to 8 using potassium carbonate, the compound of formula ii (161.2g, 1mol) was dissolved in 6L of methanol, dropwise added to the above reaction solution, the internal temperature was maintained at 15-20 ℃, after completion of the dropwise addition, the reaction was continued with stirring for 6 hours, TLC showed complete reaction of the starting material, the reaction solution was concentrated under reduced pressure, followed by dilution with water, and extraction with ethyl acetate. The organic phase was dried over an appropriate amount of anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum to obtain 182.5g of a white solid compound (compound of formula III) with a yield of 94%.
Example 4: hydroxylamine hydrochloride (139.0g,2mol) and water (2L) were added to a reaction flask at 25 ℃, followed by adjusting the solution pH to 8 using sodium carbonate, dissolving the compound of formula ii (161.2g, 1mol) in 6L of ethanol, dropwise adding to the above reaction solution, maintaining the internal temperature at 20-25 ℃, after completion of the dropwise addition, continuing the reaction with stirring for 6 hours, TLC showed complete reaction of the starting material, concentrating the reaction solution under reduced pressure, followed by dilution with water, and extraction with ethyl acetate. The organic phase was dried over an appropriate amount of anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum to obtain 184.8g of a white solid compound (a compound of formula III) with a yield of 95%.
Examples 5 to 6
Preparation of a compound of formula IV, the reaction scheme is shown below:
example 5: DMF (2L), o-fluorobenzoic acid (140.1g, 1mol) and CDI (194.6g, 1.2mol) were added to the reaction flask at 25 deg.C, followed by stirring for 1 hour until no gas escaped, cooling to 5-10 deg.C, then adding compound of formula III (194.2g, 1mol), and stirring was continued for 3 hours. After TLC monitoring of complete disappearance of the starting material, the reaction solution was poured into 10L of ice water to precipitate a large amount of white solid, which was filtered through a Buchner funnel and dried in vacuo to obtain 291.0g of the compound (formula IV) as a white solid in 92% yield.
Example 6: DMF (2L), o-fluorobenzoic acid (140.1g, 1mol) and CDI (194.6g, 1.2mol) were added to the reaction flask at 25 deg.C, followed by stirring for 1 hour until no gas escaped, maintaining the temperature at 25-30 deg.C, then compound of formula III (194.2g, 1mol) was added and stirring was continued for 3 hours. After TLC monitoring of complete disappearance of the starting material, the reaction solution was poured into 10L of ice water to precipitate a large amount of white solid, which was filtered through a Buchner funnel and dried in vacuo to obtain 283.0g of the compound (formula IV) as a white solid in 89% yield.
In examples 5 to 6, o-fluorobenzoic acid is used for the condensation reaction, so that the stability is good, and o-fluorobenzoyl chloride with poor stability is avoided, so that the reaction is more controllable.
Examples 7 to 8
Preparation of a compound of formula V, the reaction is shown below:
example 7: to a reaction flask were added compound of formula IV (316.3g, 1mol), toluene (10L) and p-toluenesulfonic acid (19g, 0.1 mol). After the subsequent heating for azeotropic water separation for 20 hr, TLC monitoring the complete disappearance of the material, the solvent was concentrated under reduced pressure and vacuum dried to obtain 283.4g of the white solid compound (the compound of formula V) in 95% yield.
Example 8: to a reaction flask were added compound of formula IV (316.3g, 1mol), xylene (10L) and pyridinium p-toluenesulfonate (25.1g, 0.1 mol). Then heating for azeotropic water separation for 20 hours, after TLC monitoring that the raw material completely disappears, concentrating the solvent under reduced pressure, and drying in vacuum to obtain 280.5g of white solid compound (compound of formula V) with 94% yield.
Examples 7 to 8 break through the tradition, change the tradition method of ring closure using quaternary ammonium salt catalyst (tradition method has low yield), but carry out the cyclization reaction under the catalysis condition of lewis acid, the reaction efficiency is high, and the product yield is high.
Examples 9 to 10
Preparation of a compound of formula VI, the reaction is shown below:
example 9: adding 1, 4-dioxane (3L) and a compound (298.3g and 1mol) of the formula V into a reaction bottle at 25 ℃, then dripping an aqueous solution (2L) dissolved with lithium hydroxide (83.9g and 2mol) into the reaction solution within half an hour, continuing stirring at 20-15 ℃ for 8 hours after finishing dripping, monitoring the reaction of raw materials by TLC, adding water to adjust the pH to be 2, separating out a large amount of white solid, filtering by a Buchner funnel, and washing a filter cake by a small amount of water. Vacuum drying gave 279.2g of the title compound I in 98% yield and 99.78% purity.
Example 10: adding 1, 4-dioxane (3L) and a compound (298.3g and 1mol) of the formula V into a reaction bottle at 25 ℃, then dripping an aqueous solution (2L) dissolved with lithium hydroxide (83.9g and 2mol) into the reaction solution within half an hour, continuing stirring at 40-45 ℃ for 8 hours after finishing dripping, monitoring the reaction of raw materials by TLC, adding water to adjust the pH to be 2, separating out a large amount of white solid, filtering by a Buchner funnel, and washing a filter cake by a small amount of water. Vacuum drying gave the compound of formula I as a white solid powder weighing 260.8g, 92% yield and 99.6% purity.
As shown in fig. 1-3, the nuclear magnetic hydrogen spectrum and LCMS spectrum of the compound of formula I obtained in example 10 are shown.1H NMR(400MHz,CDCl3)δ13.38(brs,1H),8.64(s,1H),8.34-8.17(m,3H),7.84-7.74(m,2H),7.59-7.49(m,2H)；LCMS[M+1]+285.1, it can be seen that the compound of formula I obtained in example 10 is artoluron.
The preparation method of the atraumatic substance provided by the embodiment of the invention is prepared by taking cheap raw materials of 3-cyanobenzoic acid and hydroxylamine hydrochloride as raw materials and performing four reaction steps of addition, condensation, cyclization and ester hydrolysis, and has the advantages of mild reaction conditions, simple synthesis process and low synthesis cost, thereby being beneficial to industrial production. Meanwhile, a cheap mixed solvent is adopted in the reaction process, and the solvent can be basically recycled, so that the synthesis cost is low and the reaction environment is good. In addition, the mixed solvent is used in the last step of ester hydrolysis reaction, and the product with the grade of the bulk drug can be obtained through recrystallization operation, so that the approval of the national process of the bulk drug can be easily realized. In addition, the total yield of the target compound, namely the atractylenium tataricum is high and can reach more than 90%, and the product purity is high and is more than 99.5%.
The compound medicine I obtained in the embodiments 9-10 of the invention can be used for treating Duchenne muscular dystrophy and cystic fibrosis.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.
Claims (8)
1. The preparation method of the atractylen is characterized by comprising the following steps:
an addition step, under the alkaline condition that the reaction temperature is 15-80 ℃; reacting a compound (3-cyanobenzoate) in a formula II with hydroxylamine hydrochloride by using a first mixed solvent to obtain an intermediate in a formula III; wherein R in the compound of formula II1Is a hydrocarbyl group;
a condensation step, namely performing condensation reaction on the intermediate in the formula III and o-fluorobenzoic acid in a first organic solvent at the reaction temperature of 0-70 ℃ to obtain an intermediate in the formula IV; condensing by using a condensing agent N, N' -carbonyldiimidazole in the condensation reaction;
a cyclization step, catalyzing the intermediate in the formula IV by using Lewis acid in a second organic solvent, and performing intramolecular dehydration on the intermediate to obtain an intermediate in the formula V; the Lewis acid is one or any combination of p-toluenesulfonic acid, p-toluenesulfonic acid hydrate, p-toluenesulfonic acid pyridinium, benzenesulfonic acid, camphorsulfonic acid, acetic acid, sulfamic acid and taurine;
ester hydrolysis, namely performing ester hydrolysis on the intermediate in the formula V by using a second mixed solvent at the reaction temperature of 15-80 ℃ under an alkaline condition to prepare a target compound aliskiren in the formula I;
the general synthetic route is shown below:
2. the process for preparing artolurons according to claim 1, characterized in that R in the compound of formula II1Is a hydrocarbon group having 1 to 4 carbon atoms.
3. The process for preparing atraumatic according to claim 1, characterized in that for the condensation step the condensation is carried out by means of a condensation agent N, N '-carbonyldiimidazole, wherein the amount of N, N' -carbonyldiimidazole used is 1.0 to 2.0 equivalents relative to the molar amount of the compound of formula II.
4. The process for preparing aliskiren according to claim 1, wherein, for the condensation step, the first organic solvent is N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or dimethylsulfoxide; the dosage of the first organic solvent is 5-50 times of the volume of the intermediate of the formula III.
5. The method of preparing atranline according to claim 1, characterized in that for the cyclization step, the second organic solvent is one or any combination of tetrahydrofuran, 1, 2-dichloroethane, dichloromethane, cyclopentyl methyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1, 4-dioxane, toluene, xylene, chlorobenzene, trifluorotoluene, 2-methyltetrahydrofuran, acetonitrile and chloroform in an aprotic organic solvent;
the dosage of the second organic solvent is 5-50 times of the volume of the intermediate of the formula IV.
6. The method of preparing attarolun according to claim 1, wherein for the addition step, the basic substance that adjusts basic conditions is sodium bicarbonate, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, lithium ethoxide, potassium hydroxide, sodium hydroxide, or lithium hydroxide; the using amount of the alkaline substance is 1.0-5.0 times of the molar amount of the compound shown in the formula II;
the using amount of the hydroxylamine hydrochloride is 1.0-3.0 equivalent of the molar amount of the compound shown in the formula II;
the first mixed solvent is a mixed solvent of water and alcohols, and the alcohols are one or any combination of methanol, ethanol, isopropanol and tert-butanol; the usage amount of the first mixed solvent is 5-50 times of the volume of the compound of the formula II.
7. The method for preparing attulellan according to claim 6, wherein the first mixed solvent is a mixed solvent of water and methanol, and the volume ratio of the water to the methanol is 1: 2.5-5.
8. The method for preparing atra according to claim 1, characterized in that for the step of ester hydrolysis, the alkaline substance adjusting the alkaline conditions is lithium hydroxide, sodium hydroxide or potassium hydroxide; the using amount of the alkaline substance is 1.0-5.0 times of the molar weight of the intermediate of the formula V;
the second mixed solvent is a mixed solvent of water and an organic solvent which is mutually soluble with water, wherein the organic solvent which is mutually soluble with water is one or any combination of methanol, ethanol, isopropanol, tetrahydrofuran and 1, 4-dioxane; the volume ratio of water to the water-miscible organic solvent is 1:2-1: 5; the second mixed solvent is used in an amount of 5-50 times by volume of the intermediate of formula V.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1802360A (en) * | 2003-04-11 | 2006-07-12 | Ptc治疗公司 | 1,2,4-oxadiazole benzoic acid compounds |
| CN101535284A (en) * | 2006-09-08 | 2009-09-16 | Ptc医疗公司 | Processes for the preparation of 1,2,4-oxadiazole benzoic acids |
| CN105461650A (en) * | 2014-09-12 | 2016-04-06 | 杭州普晒医药科技有限公司 | Oxdiazole compound solvate and preparation method thereof |
| CN111675672A (en) * | 2020-05-12 | 2020-09-18 | 石家庄市度智医药科技有限公司 | Method for preparing astallurens |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1802360A (en) * | 2003-04-11 | 2006-07-12 | Ptc治疗公司 | 1,2,4-oxadiazole benzoic acid compounds |
| CN101535284A (en) * | 2006-09-08 | 2009-09-16 | Ptc医疗公司 | Processes for the preparation of 1,2,4-oxadiazole benzoic acids |
| CN105461650A (en) * | 2014-09-12 | 2016-04-06 | 杭州普晒医药科技有限公司 | Oxdiazole compound solvate and preparation method thereof |
| CN111675672A (en) * | 2020-05-12 | 2020-09-18 | 石家庄市度智医药科技有限公司 | Method for preparing astallurens |
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