CN115784961A - Synthesis method of oxacillin and intermediate thereof - Google Patents
Synthesis method of oxacillin and intermediate thereof Download PDFInfo
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- CN115784961A CN115784961A CN202111063792.3A CN202111063792A CN115784961A CN 115784961 A CN115784961 A CN 115784961A CN 202111063792 A CN202111063792 A CN 202111063792A CN 115784961 A CN115784961 A CN 115784961A
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Abstract
The invention provides a novel synthetic method of an oxacillin intermediate. The method comprises the following steps: (1) Reacting 2- (trifluoromethyl) phenylacetic acid serving as a raw material with ethyl chloroformate or isobutyl chloroformate in an inert solvent in the presence of alkali to generate mixed anhydride, and then reacting with ammonia to obtain a corresponding amide compound formula II; (2) Carrying out dehydration reaction on the amide compound formula II obtained in the step (1) in the presence of a dehydrating agent and an acid-binding agent to prepare an isonitrile compound formula III; (3) Cyclizing the isonitrile compound formula III obtained in the step (2) and ethyl 2-butynoate in the presence of alkali and a metal catalyst to form a pyrrole ring compound formula IV; the reaction formula is shown as follows:
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a synthetic method of an oxacillin intermediate, and further relates to a synthetic method of oxacillin.
Background
The title of the oxacillin ketone is (5P) -1- (2-hydroxyethyl) -N- [4- (methylsulfonyl) phenyl ] -4-methyl-5- [2- (trifluoromethyl) phenyl ] -1H-pyrrole-3-carboxamide, and the structural formula is as follows:
it is a selective Mineralocorticoid Receptor (MR) antagonist and is used for the treatment of hypertension.
At present, chinese patents CN105164105A and CN105473552A report the synthetic route of the oxacillin of the first three co-Ltd of the original research company. As can be seen from the above patent application, the construction of the key intermediate IV is one of the cores of the synthetic route of the oxacillin.
For example, patent documents CN102186817A and WO2021078135A1 disclose that the preparation method of the key intermediate iv is prepared by Suzuki coupling reaction, and the palladium catalyst used in the reaction is expensive and high in cost, and a ligand is also added, which is not beneficial to purification and industrial production.
Chinese patents CN105164105A and CN105473552A report synthetic routes for preparing a key intermediate IV through cyclization. The method takes 2-bromo-1- [2- (trifluoromethyl) phenyl ] propane-1-ketone as a starting material to react with ethyl cyanoacetate to obtain an intermediate 2. And then cyclizing and removing chlorine groups to obtain a key intermediate IV. The reaction formula is as follows:
the cyclization step of the route uses hydrogen chloride gas as a reaction material, which has strong corrosivity, and the palladium metal catalyst used in the chlorine group removing step is expensive and high in cost, so that the method is not beneficial to industrial scale-up production.
Furthermore, the development of a process for the preparation of pharmaceutically active compounds with high yield, high purity, simplicity, high efficiency, low cost and ease of industrial production remains challenging. Therefore, the invention provides a synthesis method of an oxacillin ketone intermediate, which has the advantages of high yield, simple post-treatment, low cost and easy industrialization, and simultaneously ensures that the product has purity meeting the requirement of registration of raw material medicines.
Disclosure of Invention
One of the purposes of the invention is to provide a novel synthetic method of an oxacillin intermediate, so as to solve the problems of low preparation yield, high cost, complex post-treatment and being not beneficial to industrial production of the existing synthetic method of the oxacillin intermediate.
In order to achieve the above objects, the first aspect of the present invention provides a novel process for synthesizing an intermediate compound of oxacillin, formula iv, comprising the following steps:
(1) Reacting 2- (trifluoromethyl) phenylacetic acid serving as a raw material with ethyl chloroformate or isobutyl chloroformate in an inert solvent in the presence of alkali to generate mixed anhydride, and then reacting with ammonia to obtain a corresponding amide compound formula II;
(2) Carrying out dehydration reaction on the amide compound formula II obtained in the step (1) in the presence of a dehydrating agent and an acid-binding agent to obtain an isonitrile compound formula III;
(3) Cyclizing the isonitrile compound formula III obtained in the step (2) and ethyl 2-butynoate in the presence of alkali and a metal catalyst to form a pyrrole ring compound formula IV;
the process route is as follows:
preferably, the inert solvent in step (1) includes but is not limited to one or more of the group consisting of halogenated hydrocarbon, benzene, toluene, diethyl ether, xylene, nitrobenzene, acetonitrile; the alkali is one or more of imidazole, pyridine, tetrabutylammonium fluoride, 2, 6-dimethylpyridine, potassium carbonate, N-diisopropylethylamine, sodium carbonate and triethylamine; the molar ratio of 2- (trifluoromethyl) phenylacetic acid to base is 1; the molar ratio of 2- (trifluoromethyl) phenylacetic acid to ethyl chloroformate or isobutyl chloroformate is 1 to 1.5; the reaction temperature is 0-room temperature; the reaction time is 12-36 hours.
Preferably, the dehydrating agent in step (2) is P 2 O 5 ，PCl 3 ，SOCl 2 ，COCl 2 ，ArSO 2 Cl，POCl 3 One or more of; the acid-binding agent is organic base or inorganic base, and the inorganic base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide and the like; the organic base is triethylamine or diisopropylamine; the solvent is selected from halogenated alkane, dichloromethane and dichloroethane.
Preferably, the base in step (3) is Pr 3 N, pyridine, DBU, TEEDA; the metal catalyst is Cu 2 O，CuCl，CuI，CuBr，Cu（OMe） 2 Copper powder.
The second aspect of the invention also provides an intermediate compound of the oxacillin, which is prepared by the synthesis process.
The third aspect of the present invention also provides a method for synthesizing a novel intermediate compound of oxacillin, formula V, which comprises the following steps: reacting the pyrrole ring compound of formula IV with a base in the presence of a solvent
Reacting to prepare a compound shown in formula V; the intermediate compound formula v has the following structural formula:
the X is halogen, and the A is hydroxyl or halogen.
Preferably, the solvent is an alcohol solvent, a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, an ether solvent or an amide solvent; the alcohol solvent includes but is not limited to ethanol; the halogenated hydrocarbon solvent includes but is not limited to dichloromethane or chloroform; the aromatic hydrocarbon solvent includes, but is not limited to, toluene, benzene, xylene or nitrobenzene; the ether solvent includes but is not limited to tetrahydrofuran, 1, 4-dioxane or the amide solvent includes but is not limited to N, N-dimethylacetamide, N-dimethylformamide; the alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, sodium hydride, potassium carbonate, sodium carbonate, 4-dimethylaminopyridine, N-diisopropylethylamine, triethylamine or pyridine; sodium hydroxide and lithium hydroxide are preferred; the reaction temperature in the step is room temperature to 80 ℃, preferably room temperature to 60 ℃, and the reaction time is 1 to 20 hours, preferably 2 to 3 hours.
The fourth aspect of the invention also provides an oxacillin intermediate compound of formula V, which is prepared by the synthesis process.
The fifth aspect of the invention also provides a novel method for synthesizing the epsipranten, which adopts the following technical scheme:
the compound of formula VI is obtained by the condensation reaction of the intermediate compound of formula V and 4-mesyl aniline under the action of a condensing agent, wherein the structural formula of the compound of formula VI is shown as follows:
preferably, the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1-Hydroxybenzotriazole (HOBT), the solvent is dry N, N-Dimethylformamide (DMF), and a certain amount of base is added, wherein the commonly used base is N, N-Diisopropylethylamine (DIPEA), triethylamine, pyridine, benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (PyBop), preferably N, N-Diisopropylethylamine (DIPEA).
The sixth aspect of the invention also provides a second novel method for preparing the oxacillin, which adopts the following technical scheme: the formula V of the intermediate compound of the epsipranten ketone reacts with a proper acylating reagent to obtain an acyl chloride compound formula VII, and the acyl chloride compound formula VII reacts with 4-methylsulfonyl aniline to obtain a compound VI, wherein the structural formula of the acyl chloride compound formula VII is shown as follows:
preferably, the acylating agent is oxalyl chloride, the acylation reaction is preferably carried out in the presence of a base and a solvent, the base is an organic base or an inorganic base, including but not limited to triethylamine, N-diisopropylethylamine; the solvent is halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent or amide solvent; the halogenated hydrocarbon solvent includes but is not limited to dichloromethane or chloroform; the aromatic hydrocarbon solvent includes, but is not limited to, toluene, benzene, xylene or nitrobenzene; the ether solvent includes but is not limited to tetrahydrofuran, 1, 4-dioxane or the amide solvent includes but is not limited to N, N-dimethylacetamide and N, N-dimethylformamide.
The seventh aspect of the invention also provides the oxacillin ketone, which is prepared by any one of the synthesis processes.
By applying the technical scheme of the invention, the use of expensive palladium catalyst is avoided, and the cost is reduced; meanwhile, the use of ligand is avoided, the post-treatment is simple, and the purification is easy; the use of highly corrosive hydrogen chloride gas is avoided, and the industrial scale-up production is facilitated; compared with the prior document CN101006052A, the yield of the oxacillin intermediate compound formula IV prepared by applying the technical scheme of the invention is improved by 57.6 percent.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.
As described in the background art, the existing methods for synthesizing an intermediate of oxacillin have the problems of low preparation yield, high cost, complex post-treatment and being not suitable for industrial production. In order to solve the technical problems, the application provides a new synthetic method of an oxacillin intermediate compound, namely a formula IV, which comprises the following steps:
(1) Reacting 2- (trifluoromethyl) phenylacetic acid serving as a raw material with ethyl chloroformate or isobutyl chloroformate in an inert solvent in the presence of alkali to generate mixed anhydride, and then reacting with ammonia to obtain a corresponding amide compound formula II;
(2) Carrying out dehydration reaction on the amide compound formula II obtained in the step (1) in the presence of a dehydrating agent and an acid-binding agent to prepare an isonitrile compound formula III;
(3) Cyclizing the isonitrile compound shown in the formula III and ethyl 2-butynoate obtained in the step (2) in the presence of alkali and a metal catalyst to form a pyrrole ring compound IV;
the process route is as follows:
preferably, the inert solvent in step (1) includes but is not limited to one or more of the group consisting of halogenated hydrocarbon, benzene, toluene, diethyl ether, xylene, nitrobenzene, acetonitrile; the alkali is one or more of imidazole, pyridine, tetrabutylammonium fluoride, 2, 6-dimethylpyridine, potassium carbonate, N-diisopropylethylamine, sodium carbonate and triethylamine; the molar ratio of the 2- (trifluoromethyl) phenylacetic acid to the base is 1; the molar ratio of 2- (trifluoromethyl) phenylacetic acid to ethyl chloroformate or isobutyl chloroformate is 1 to 1.5; the reaction temperature is 0-room temperature; the reaction time is 12 to 36 hours.
Preferably, the dehydrating agent in step (2) is P 2 O 5 ，PCl 3 ，SOCl 2 ，COCl 2 ，ArSO 2 Cl，POCl 3 One or more of (a); the acid-binding agent is organic base or inorganic base, and the inorganic base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide and the like; the organic base is triethylamine or diisopropylamine; the solvent is selected from halogenated alkane, dichloromethane and dichloroethane.
Preferably, the base in step (3) is Pr 3 N, pyridine, DBU, TEEDA; the metal catalyst is Cu 2 O，CuCl，CuI，CuBr，Cu（OMe） 2 Copper powder.
The starting material, 2- (trifluoromethyl) phenylacetic acid (compound of formula I) can be obtained commercially.
The second aspect of the invention also provides an intermediate compound of the oxacillin, which is prepared by the synthesis process.
The third aspect of the invention also provides a synthesis method of the novel oxacillin intermediate compound of the formula V, which comprises the following steps:
the specific synthesis method comprises the following steps: reacting the pyrrole ring compound of formula IV obtained by the synthesis with a solvent in the presence of a base
The compound shown in the formula V is obtained through reaction preparation, wherein X is halogen, and A is hydroxyl or halogen.
Preferably, the solvent is an alcohol solvent, a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, an ether solvent or an amide solvent; the alcohol solvent includes but is not limited to ethanol; the halogenated hydrocarbon solvent includes but is not limited to dichloromethane or chloroform; the aromatic hydrocarbon solvent includes, but is not limited to, toluene, benzene, xylene or nitrobenzene; the ether solvent includes but is not limited to tetrahydrofuran, 1, 4-dioxane or the amide solvent includes but is not limited to N, N-dimethylacetamide, N-dimethylformamide; the alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, sodium hydride, potassium carbonate, sodium carbonate, 4-dimethylaminopyridine, N-diisopropylethylamine, triethylamine or pyridine; sodium hydroxide and lithium hydroxide are preferred; the reaction temperature in the step is room temperature to 80 ℃, preferably room temperature to 60 ℃, and the reaction time is 1 to 20 hours, preferably 2 to 3 hours.
The fourth aspect of the invention also provides an oxacillin intermediate compound of formula V, which is prepared by the synthesis process.
The fifth aspect of the present invention further provides a novel method for synthesizing oxacillin, which comprises the following steps:
the specific synthesis method comprises the following steps: and (3) carrying out condensation reaction on the intermediate compound of the oxacillin ketone, namely the formula V, and 4-methylsulfonyl aniline under the action of a condensing agent to obtain the oxacillin ketone (a compound of a formula VI).
Preferably, the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1-Hydroxybenzotriazole (HOBT), the solvent is dry N, N-Dimethylformamide (DMF), and a certain amount of base is added, wherein the commonly used base is N, N-Diisopropylethylamine (DIPEA), triethylamine, pyridine, benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (PyBop), preferably N, N-Diisopropylethylamine (DIPEA).
The sixth aspect of the present invention further provides a second novel method for synthesizing epsipranten, which comprises the following steps:
the preparation method comprises the following steps: and (3) reacting the intermediate compound formula V of the epsipranten with a proper acylating reagent to obtain an acyl chloride compound formula VII, and then carrying out an acylation reaction on the acyl chloride compound formula VII and 4-methylsulfonylaniline to obtain a compound VI.
Preferably, the acylating agent is oxalyl chloride, and the acylation reaction is preferably carried out in the presence of a base, which is an organic or inorganic base, including but not limited to triethylamine, N-diisopropylethylamine; the solvent is halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent or amide solvent; the halogenated hydrocarbon solvent includes but is not limited to dichloromethane or chloroform; the aromatic hydrocarbon solvent includes, but is not limited to, toluene, benzene, xylene or nitrobenzene; the ether solvent includes but is not limited to tetrahydrofuran, 1, 4-dioxane or the amide solvent includes but is not limited to N, N-dimethylacetamide and N, N-dimethylformamide.
The seventh aspect of the invention also provides oxacillin, which is prepared by any one of the synthesis processes.
By applying the technical scheme of the invention, the use of expensive palladium catalyst is avoided, and the cost is reduced; meanwhile, the use of ligand is avoided, the post-treatment is simple, and the purification is easy; the use of highly corrosive hydrogen chloride gas is avoided, and the industrial scale-up production is facilitated; compared with the prior document CN101006052A, the yield of the oxacillin intermediate compound formula IV prepared by applying the technical scheme of the invention is improved by 57.6 percent.
Example 1 Synthesis of 2- (trifluoromethyl) phenylacetamide (amide Compound formula II)
To 500mL of 1, 4-dioxane solvent were added 20.4g (0.1mol, 1eq) of 2- (trifluoromethyl) phenylacetic acid and 13.0g (0.12mol, 1.2eq) of ethyl chloroformate, 4.7g (0.06mol, 0.6eq) of pyridine and 11.9g (0.15mol, 1.5eq) of ammonium hydrogencarbonate, and the mixture was stirred at room temperature for 12 hours to check completion of the reaction, followed by addition of ethyl acetate and brine for extraction, drying and concentration of the organic phase to obtain a crude product, followed by crystallization from ethyl acetate and petroleum ether to obtain 19.9g of the amide compound of formula II with a yield of 98.0%.
EXAMPLE 2 Synthesis of an Isonitrile Compound formula III
Dissolving 10.2g of 2- (trifluoromethyl) phenylacetamide (0.05 mol) in 100mL of dichloroethane, adding 12.6g of triethylamine (0.125 mol), reducing the temperature of a reaction system to below-10 ℃, dropwise adding 0.05mol of phosphorus oxychloride, after dropwise adding for about 20 minutes, controlling the reaction temperature to be below 0 ℃, continuously stirring for 1 hour, then heating to 25 to 30 ℃, dropwise adding 20% of sodium carbonate solution into the reaction solution, continuously stirring for 5 to 10 minutes after dropwise adding, standing for layering, washing an organic phase for 2 times by using 5% of sodium carbonate solution, drying by using anhydrous magnesium sulfate, filtering, and concentrating under reduced pressure at below 20 ℃ to obtain 9.0g of an isonitrile compound formula III, wherein the yield is 97.3%.
EXAMPLE 3 preparation of ethyl 4-methyl-5- [2- (trifluoromethyl) phenyl ] -1H-pyrrole-3-carboxylate (Exsacinone intermediate compound IV)
To 500mL of 1, 4-dioxane solvent were added 0.36g (2.5 mmol, 0.05 eq) of cuprous oxide and 7.65g (0.05 mol,1 eq) of DBU, 6.73g (0.06 mol,1.2 eq) of ethyl 2-butynoate and 9.25g (0.05 mol,1 eq) of isonitrile compound formula III under an argon atmosphere, and the mixture was stirred at 100 ℃ for 2 hours to check completion of the reaction, the reaction mixture was cooled to room temperature, and then filtered, ethyl acetate and a saturated aqueous solution of sodium chloride were added to the filtrate to extract the mixture, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified to obtain 12.3g of ethyl 4-methyl-5- [2- (trifluoromethyl) phenyl ] -1H-pyrrole-3-carboxylate in 83% yield.
1 H-NMR(400MHz，DMSO-d 6 ) δ 8.43(s, 1H), 7.79(m, 1H),7.63-7.39(m, 4H), 4.33-4.29(m, 2H),2.19(s, 3H)，1.37-1.34（m, 3H）。
EXAMPLE 4 preparation of 1- (2-hydroxyethyl) 4-methyl-5- [2- (trifluoromethyl) phenyl ] -1H-pyrrole-3-carboxylic acid
Dissolving 15g (0.05 mol,1 eq) of 4-methyl-5- [2- (trifluoromethyl) phenyl ] -1H-pyrrole-3-carboxylic acid ethyl ester in 300ml of dichloroethane at room temperature, adding 10.1g (0.05 mol,1 eq) of tetraethylammonium bromide, dropwise adding 20% NaOH aqueous solution (100 ml) into the reaction solution under stirring, continuing to react for 1H at room temperature after about 30min, heating the reaction solution to 60 ℃ for 2H, detecting complete reaction by using a dot plate, cooling the reaction solution to room temperature, adjusting the pH to 5 to 6 by using 2N hydrochloric acid, standing for layering, extracting the aqueous phase for 2 times by using dichloromethane, combining the organic phases, drying and concentrating to obtain 14.7g of 1- (2-hydroxyethyl) 4-methyl-5- [2- (trifluoromethyl) phenyl ] -1H-pyrrole-3-carboxylic acid with the yield of 94%.
EXAMPLE 6 preparation of 1- (2-hydroxyethyl) -N- [4- (methylsulfonyl) phenyl ] -4-methyl-5- [2- (trifluoromethyl) phenyl ] -1H-pyrrole-3-carboxamide
3.77g (0.022 mol, 1.1 eq) of 4-methanesulfonylaniline, 6.26g (0.02 mol, 1.0 eq) of the intermediate compound formula V of the epothilone intermediate compound, 6.26g (0.03 mol, 1.0 eq) of HOBT 4.05g (0.03 mol,1.5 eq), EDCI 5.75g (0.03 mol,1.5 eq), DIPEA 5.16g (0.04 mol, 2.0 eq) were added to a reaction flask, 300mL of DCM was added, the reaction was followed by TLC, after completion of the reaction, 100mL of saturated aqueous sodium chloride solution was added and extracted, the organic phase was washed 3 times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, evaporated off the solvent, and washed with ethyl acetate: the mixed solvent of petroleum ether with the volume ratio of 1.
1 H-NMR（400MHz，DMSO-d 6 ）δ: 7.94-7.90（m, 2H），7.86-7.78（m, 3H），7.69-7.65（m, 2H），7.64-7.62（m, 1H），7.36-7.33（m, 1H），7.29（s, 1H）4.39-4.35（m, 2H），3.29-3.10（m, 5H），2.18（s, 3H）。
Comparative example 1
Referring to the preparation method of example 16 in the prior document CN101006052A, 4-methyl-5- [2- (trifluoromethyl) phenyl ] -1H-pyrrole-3-carboxylic acid ethyl ester is prepared in 21.5% yield by replacing the starting material methyl cyanoacetate with ethyl cyanoacetate.
Comparative example 2
Referring to the preparation method of reference example 3 in prior document WO2010098286A1, 1- (2-hydroxyethyl) -N- [4- (methylsulfonyl) phenyl ] -4-methyl-5- [2- (trifluoromethyl) phenyl ] -1H-pyrrole-3-carboxamide was obtained in a total yield of 7.6%.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A novel synthetic method of an oxacillin intermediate compound formula IV comprises the following steps:
(1) Reacting 2- (trifluoromethyl) phenylacetic acid serving as a raw material with ethyl chloroformate or isobutyl chloroformate in an inert solvent in the presence of alkali to generate mixed anhydride, and then reacting with ammonia to obtain a corresponding amide compound shown in a formula II;
(2) Carrying out dehydration reaction on the amide compound formula II obtained in the step (1) in the presence of a dehydrating agent and an acid-binding agent to obtain an isonitrile compound formula III;
(3) Cyclizing the isonitrile compound shown in the formula III and ethyl 2-butynoate obtained in the step (2) in the presence of alkali and a metal catalyst to form a pyrrole ring compound shown in the formula IV;
the process route is as follows:
2. the method of claim 1, wherein the inert solvent in step (1) includes but is not limited to one or more of the group consisting of halogenated hydrocarbons, benzene, toluene, diethyl ether, xylene, nitrobenzene, acetonitrile; the alkali is one or more of imidazole, pyridine, tetrabutylammonium fluoride, 2, 6-dimethylpyridine, potassium carbonate, N-diisopropylethylamine, sodium carbonate and triethylamine; the molar ratio of the 2- (trifluoromethyl) phenylacetic acid to the base is 1; the molar ratio of 2- (trifluoromethyl) phenylacetic acid to ethyl chloroformate or isobutyl chloroformate is 1 to 1.5; the reaction temperature is 0-room temperature; the reaction time is 12-36 hours.
3. The synthesis method according to claim 1, wherein the dehydrating agent in step (2) is P 2 O 5 ，PCl 3 ，SOCl 2 ，COCl 2 ，ArSO 2 Cl，POCl 3 One or more of; the acid-binding agent is organic base or inorganic base, and the inorganic base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide and the like; the organic base is triethylamine or diisopropylamine; the solvent is selected from halogenated alkane, dichloromethane and dichloroethane.
4. The method according to claim 1, wherein the base in step (3) is Pr 3 N, pyridine, DBU, TEEDA; the metal catalyst is Cu 2 O，CuCl，CuI，CuBr，Cu（OMe） 2 Copper powder.
5. A new synthetic method of an oxacillin intermediate compound shown as a formula V comprises the following steps: a pyrrole ring compound of formula IV obtained by the synthesis method of claims 1-4, in a solvent in the presence of a base, and
reacting to prepare a compound shown in a formula V; the intermediate compound formula v has the following structural formula:
the X is halogen, and the A is hydroxyl or halogen.
6. The synthesis method according to claim 5, wherein the solvent is an alcohol solvent, a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, an ether solvent or an amide solvent; the alcohol solvent includes but is not limited to ethanol; the halogenated hydrocarbon solvent includes but is not limited to dichloromethane or chloroform; the aromatic hydrocarbon solvent includes, but is not limited to, toluene, benzene, xylene or nitrobenzene; the ether solvent includes but is not limited to tetrahydrofuran, 1, 4-dioxane or the amide solvent includes but is not limited to N, N-dimethylacetamide, N-dimethylformamide; the alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, sodium hydride, potassium carbonate, sodium carbonate, 4-dimethylaminopyridine, N-diisopropylethylamine, triethylamine or pyridine; sodium hydroxide and lithium hydroxide are preferred; the reaction temperature in the step is room temperature to 80 ℃, preferably room temperature to 60 ℃, and the reaction time is 1 to 20 hours, preferably 2 to 3 hours.
7. A novel method for synthesizing the oxacillin is characterized in that the oxacillin intermediate compound obtained by the synthesis method of claims 5 to 6, a formula V and 4-mesyl aniline are subjected to condensation reaction under the action of a condensing agent to obtain a compound VI, wherein the structural formula of the compound VI is as follows:
8. the process according to claim 7, wherein the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1-Hydroxybenzotriazole (HOBT), the solvent is dry N, N-Dimethylformamide (DMF), and a certain amount of a base is added, the commonly used bases being N, N-Diisopropylethylamine (DIPEA), triethylamine, pyridine, benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (PyBop), preferably N, N-Diisopropylethylamine (DIPEA).
9. A novel method for preparing the axacinone is characterized in that an axacinone intermediate compound formula V obtained by the synthetic method of claims 5 to 6 reacts with a proper acylating reagent to obtain an acyl chloride compound VII, and the acyl chloride compound formula VII is further acylated with 4-methanesulfonyl aniline to obtain a compound VI, wherein the structural formula of the acyl chloride compound formula VII is as follows:
10. the synthesis method according to claim 9, wherein the acylating agent is oxalyl chloride, and the acylation reaction is preferably carried out in the presence of a base and a solvent, wherein the base is an organic base or an inorganic base, including but not limited to triethylamine, N-diisopropylethylamine; the solvent is halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent or amide solvent; the halogenated hydrocarbon solvent includes but is not limited to dichloromethane or chloroform; the aromatic hydrocarbon solvent includes, but is not limited to, toluene, benzene, xylene or nitrobenzene; the ether solvent includes but is not limited to tetrahydrofuran, 1, 4-dioxane or the amide solvent includes but is not limited to N, N-dimethylacetamide and N, N-dimethylformamide.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111063792.3A CN115784961A (en) | 2021-09-10 | 2021-09-10 | Synthesis method of oxacillin and intermediate thereof |
| PCT/CN2022/080532 WO2023035571A1 (en) | 2021-09-10 | 2022-03-13 | Synthesis method for esaxerenone and intermediate thereof |
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| CA2593156C (en) * | 2005-01-10 | 2015-05-05 | Exelixis, Inc. | Heterocyclic carboxamide compounds as steroid nuclear receptors ligands |
| ES2448498T3 (en) * | 2007-04-09 | 2014-03-14 | Daiichi Sankyo Company, Limited | Atropisomer of pyrrole derivative |
| JP5767586B2 (en) * | 2008-10-08 | 2015-08-19 | エグゼリクシス， インコーポレイテッド | Atropisomers of (hydroxyalkyl) pyrrole derivatives |
| WO2010098286A1 (en) * | 2009-02-25 | 2010-09-02 | 第一三共株式会社 | Pharmaceutical preparation containing mineralcorticoid receptor antagonist |
| HUE041725T2 (en) * | 2013-04-10 | 2019-05-28 | Daiichi Sankyo Co Ltd | CRYSTAL OF (S)-1-(2-HYDROXYETHYL)-4-METHYL-N- [4-(METHYLSULFONYL)PHENYL]-5-[2-(TRIFLUOROMETHYL)& xA;PHENYL]- 1H-PYRROLE-3-CARBOXAMIDE |
| CN105473552B (en) * | 2013-08-27 | 2017-11-10 | 第一三共株式会社 | Method for producing azole derivatives and its intermediate |
| CA3136989A1 (en) * | 2019-10-25 | 2021-04-29 | Sunshine Lake Pharma Co., Ltd. | Pyrrole amide compound and use thereof |
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