CN113698392A - Preparation method of Prenster intermediate - Google Patents
Preparation method of Prenster intermediate Download PDFInfo
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- CN113698392A CN113698392A CN202111048500.9A CN202111048500A CN113698392A CN 113698392 A CN113698392 A CN 113698392A CN 202111048500 A CN202111048500 A CN 202111048500A CN 113698392 A CN113698392 A CN 113698392A
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Abstract
The invention provides a preparation method of a pransert intermediate, which adopts a compound C as a raw material to obtain the pransert intermediate after reaction; the high-yield Prenster intermediate prepared by the method has the advantages of mild reaction conditions, convenience in operation, high purity and high yield of the obtained Prenster intermediate and suitability for industrial production, so that a more valuable synthetic route is provided for preparing Prenster, good social benefits and economic benefits can be brought, and the economic value potential is higher.
Description
Technical Field
The invention relates to the technical field of organic matter synthesis pharmacy, in particular to a preparation method of a Prenster intermediate used for preparing a Prenster medicine.
Background
The brenst is a novel anti-asthma drug which is marketed in the middle of ninety years, is one of three leukotriene receptor antagonists which are widely concerned internationally at present, and is characterized by extremely low toxicity (more than 2000mg/kg of oral LD 50) and LTC resistance4、LTD4、LTE4All have significant inhibition, especially to LTD4The main component (causing the contraction of the smooth muscle of the trachea) has obvious inhibiting effect, and is clinically effective not only for the special asthma but also for the infectious type, mixed type, chronic type, paroxysmal type and non-seasonal bronchial asthma; no serious adverse reaction, no influence on p450 medicinal enzyme, and no medicine interaction.
The structural characteristics of the brewster determine that the synthesis of the pranlukast mainly comprises 2 segments of p-phenylbutoxybenzoic acid (A) and 8-amino-2- (1-hydro-tetrazole-5-oxy) -4-hydro-benzopyran-4-one (B), and the research focus is mainly focused on the compound B due to the stable and simpler structure of the compound A.
In the current reports on the synthesis process of brensted, the synthesis of the compound B mainly includes the following routes:
firstly, according to the report of Toda, 3-nitro-2-hydroxyacetophenone is taken as a raw material to be subjected to Claisen condensation with diethyl oxalate, and then heated to carry out reflux ring closing to construct a benzopyran ring; the cyano-group is synthesized by an amide dehydration method, the cyano-group compound reacts with sodium azide to synthesize tetrazole, and the nitro group on the compound is hydrogenated and reduced into amino under the catalysis of 5 percent Pd/C.
The Robert route and the Graham route are prepared by a method of adopting a palladium ligand compound as a catalyst for carbonyl formylation reaction, condensation under the action of potassium tert-butoxide, and closed-loop dehydration under an acidic condition to obtain a benzopyran ring.
And thirdly, carrying out addition reaction on the 2-cyanobenzopyran derivative and hydrogen sulfide gas under the catalysis of alkali to generate a 2-amino thiocarbonyl benzopyran derivative, then respectively reacting with anhydrous hydrazine to generate amino hydrazone, and carrying out nitrosation reaction with sodium nitrite under an acidic condition to obtain a tetrazole ring.
Giles, Hideki and Hayler add substituent groups on tetrazole, so that condensation reaction is easier, but the difficulty in synthesizing tetrazole with substituent groups on nitrogen is higher, and hazardous reagents such as lithium aluminum hydride and the like are used in final removal reaction, so that industrialization is not easy to realize.
The above routes have the disadvantages of severe reaction conditions, low yield, high toxicity and difficulty in removing impurities generated by the reaction.
Disclosure of Invention
Aiming at the defects and problems in the prior art, the invention provides a preparation method of a Prenster intermediate, which aims to solve the technical problems that: a synthesis method of the brensted intermediate compound B with mild reaction conditions and low impurities is developed, and conditions are provided for better preparation of brensted.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation method of a pransted intermediate adopts a compound C as a raw material, and adopts any scheme as follows to obtain the pransted intermediate;
the first scheme is as follows: the method comprises the following steps:
q1, compound D obtained by reaction starting from compound C, compound D being characterized in that: r1 is halogen, a group capable of polymerizing with hydroxyl to form ether; the R2 position is an ester group;
q2, condensing the compound D with o-acetaminophenol, performing cyclization reaction and hydrolysis reaction, and finally preparing a compound B with sodium azide;
scheme II: the method comprises the following steps:
q1, compound E obtained by reaction starting from compound C, compound E being characterized in that: r1 is halogen, group which can polymerize with hydroxyl to generate ether, and R3 is ester group;
q2, condensing the compound E and o-acetaminophenol, preparing hydroxyl in the original compound E into 4-triazole, and cyclizing to obtain a compound B;
the structure of compound C is as follows:
characterized in that R1 is halogen, a group capable of polymerizing with hydroxyl to generate ether; r2 and R3 are hydrogen radicals or radicals which can form esters with carboxylic acids.
The high-yield Prenster intermediate prepared by the method has the advantages of mild reaction conditions, convenience in operation, high purity and high yield of the obtained Prenster intermediate and suitability for industrial production, so that a more valuable synthetic route is provided for preparing Prenster, good social benefits and economic benefits can be brought, and the economic value potential is higher.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
A preparation method of a pransted intermediate comprises the following steps:
q1, compound D obtained by reaction starting from compound C, compound D being characterized in that: r1 is halogen, a group capable of polymerizing with hydroxyl to form ether; the R2 position is an ester group;
q2, condensing the compound D with o-acetaminophenol, performing cyclization reaction and hydrolysis reaction, and finally preparing a compound B with sodium azide;
a preparation method of a pransted intermediate comprises the following steps:
q1, compound E obtained by reaction starting from compound C, compound E being characterized in that: r1 is halogen, group which can polymerize with hydroxyl to generate ether, and R3 is ester group;
q2, condensing the compound E and o-acetaminophenol, preparing hydroxyl in the original compound E into 4-triazole, and cyclizing to obtain a compound B;
in the above technical scheme, the structure of the compound C is as follows:
characterized in that R1 is halogen, a group capable of polymerizing with hydroxyl to generate ether; r2 and R3 are hydrogen radicals or radicals which can form esters with carboxylic acids.
Accordingly in the examples, the present invention provides 2 synthetic routes, the preferred structures of compound C in scheme 1 being compound 1 and compound 3, which structures are as follows:
the compound 1 or the compound 3 is taken as a starting material, and the specific synthetic route is as follows:
the greatest advantage of the synthetic route 1 is that the condensation cyclization reaction condition of the compound 5 is mild, the specific reaction is strong, and the generated impurities are easy to remove.
1. Synthetic scheme 1 example: synthetic route to pranlukast intermediate compound B starting from compound C, preferably compound 1 or compound 3:
synthesis of compound 2: adding 800ml of methanol into a reaction vessel, adding the compound 1, dropwise adding 300ml of thionyl chloride in an ice-water bath, heating and refluxing for reaction for 8 hours, concentrating to form viscous liquid, adding 400ml of methanol, heating to 40 ℃, uniformly stirring, concentrating to form a small volume, crystallizing, filtering and drying to obtain 214.6g of the compound 2, wherein the yield is 107.3%.
Synthesis of compound 3: adding 600ml of lithium hydroxide aqueous solution into a reaction container, dropwise adding a compound 2 methanol solution (adding the compound 2 obtained in the previous step into 300ml of methanol, heating and stirring until the mixture is dissolved), heating to 40 ℃, stirring and reacting for 8 hours, cooling to room temperature after the reaction is completed, adjusting the pH to be neutral by using dilute hydrochloric acid, adding ethyl acetate for extraction for 2 times, collecting an organic layer, drying by using anhydrous MgSO4, concentrating to a small volume, crystallizing, filtering and drying to obtain 190.4g of compound 3, wherein the yield is 88.7%.
Synthesis of compound 4: 500ml of a saturated aqueous NaCl solution was placed in a reaction vessel, NaOH was slowly added, 180g of o-acetaminophen was added, and 190.4g of Compound 3 was slowly added. The reaction was stirred at 60 ℃ for 15 hours, cooled to room temperature after completion of the reaction, and the pH was adjusted to 3 with hydrochloric acid. The organic phase was extracted 3 times with ethyl acetate, the organic phase layer was collected, then extracted 3 times with aqueous Na2CO3 solution, the aqueous Na2CO3 layer was collected, pH was adjusted to 2-3 with hydrochloric acid, and finally extracted 3 times with ethyl acetate, the ethyl acetate layer was collected, dried with anhydrous MgSO4, and dried in vacuo to give 241.4g of compound 4, yield 126.8%.
Synthesis of compound 5: 490g of concentrated sulfuric acid is added into a reaction container A, after the concentrated sulfuric acid is cooled to 5 ℃, 241.4g of compound 4 dissolved by adding water is slowly dropped into the reaction container A, the mixture is stirred and reacted for 16 hours, after the reaction is finished, the reaction mixture is cooled to room temperature, 1.5L of purified water is poured into the reaction container B, the temperature is controlled to be 0-5 ℃, the reaction product in the reaction container A is slowly dropped into the reaction container B, 1.2L of dichloromethane is added for stirring, an organic layer is separated, 1L of purified water is added, the pH value is adjusted to about 7 by using a 5% sodium carbonate aqueous solution, the organic layer is separated again, the concentrated filtration is carried out, and the vacuum reduced pressure drying is carried out at the temperature of 40 ℃, so that 5172.8 g of the compound is obtained, and the yield is 71.6%.
Synthesis of compound 6: dissolving the compound 5 obtained in the previous step in 900ml of DMF, introducing dry ammonia gas while stirring, gradually changing the color of the reaction solution from yellow to red, pouring the reaction solution into cold water, adjusting the reaction solution to acidity by using dilute hydrochloric acid, crystallizing, filtering and drying to obtain a compound 6, 145.7g and a yield of 84.3 percent
Synthesis of compound 7: adding DMF 800ml, SOCl 220 ml and the compound 6 in the previous step into a single-mouth bottle, stirring at 7.5 ℃ for 6h, pouring into cold water, and filtering to obtain the compound 7 with the yield of 127.6g and the yield of 87.6 percent.
Synthesis of compound 8: adding the compound 7 obtained in the previous step, 27g of ammonium chloride, 28g of sodium azide and 1000ml of DMF into a reaction vessel, heating for 4.5h, cooling, pouring into ice water, adjusting the acidity with dilute hydrochloric acid, and filtering to obtain 117.0g of a finished product with the yield of 91.7%.
Synthesis of compound B: adding 600ml of dichloromethane into a reaction container, adding 60g of pyridine and 80g of acetic anhydride, stirring uniformly, adding the compound 8 obtained in the previous step, heating to 35 ℃, heating for 5 hours, cooling, pouring into ice water, adjusting the pH value to be neutral, filtering and drying to obtain 94g of a compound B, wherein the yield is 80.3%.
2. Scheme 2 example: the compound 1 or the compound 9 is used as a starting material, and the specific synthetic route is as follows:
preferred structures for compound C in scheme 2 are compound 1 and compound 9, which have the following structures:
the specific synthetic route is as follows:
the synthetic route 2 has mild reaction conditions, the yield is greatly improved compared with the synthetic route 1, and the synthetic route is suitable for industrial production.
2. Scheme 2 example:
synthesis of compound 2: adding 800ml of methanol into a reaction vessel, adding the compound 1, dropwise adding 300ml of thionyl chloride in an ice-water bath, heating and refluxing for reaction for 8 hours, concentrating to form viscous liquid, adding 400ml of methanol, heating to 40 ℃, uniformly stirring, concentrating to form a small volume, crystallizing, filtering and drying to obtain 214.2g of the compound 2, wherein the yield is 107.1%.
Synthesis of compound 9: adding 500ml water into a reaction container, adding the compound 2 obtained in the previous step while stirring, dropwise adding 300ml sodium hydroxide methanol solution, heating to 60 ℃, stirring and reacting for 2 hours, cooling to room temperature after complete reaction, adjusting pH to be neutral with dilute hydrochloric acid, adding ethyl acetate for extraction for 2 times, collecting an organic layer, and using anhydrous MgSO4Drying, concentrating to a small volume, crystallizing, filtering, and drying to obtain 185.1g of compound 9 with a yield of 86.4%.
Synthesis of compound 10: 500ml of a saturated aqueous NaCl solution was placed in a reaction vessel, NaOH was slowly added, 190g of o-acetaminophen was added, and 185.1g of Compound 9 was slowly added. The reaction was stirred at 60 ℃ for 15 hours, cooled to room temperature after completion of the reaction, and the pH was adjusted to 3 with hydrochloric acid. Extracting with ethyl acetate for 3 times, collecting organic phase layer, and adding Na2CO3Extracting with water solution for 3 times, collecting Na2CO3The aqueous layer was adjusted to pH 2-3 with hydrochloric acid, and finally extracted 3 times with ethyl acetate, and the ethyl acetate layer was collected and over anhydrous MgSO4Drying and further vacuum drying gave 219.7g of Compound 10, 118.7% yield.
Synthesis of compound 11: dissolving the compound 10 obtained in the previous step in 900ml of DMF, introducing dry ammonia gas while stirring, gradually changing the color of the reaction liquid from yellow to red, pouring the reaction liquid into cold water, adjusting the reaction liquid to acidity by using dilute hydrochloric acid, crystallizing, filtering and drying to obtain a compound 11, 211.8g and the yield of 96.4%.
Synthesis of compound 12: adding DMF 900ml and SOCl into a single-mouth bottle225ml of the compound 11 obtained in the previous step are stirred at 6 ℃ for 6 hours, poured into cold water and filtered to obtain 189.3g of the compound 12 with the yield of 89.4%.
Synthesis of compound 13: adding the compound 12 obtained in the previous step, 30g of ammonium chloride, 32g of sodium azide and 1000ml of DMF into a reaction vessel, heating for 4.5h, cooling, pouring into ice water, adjusting the acidity with dilute hydrochloric acid, and filtering to obtain 205.2g of a finished product with the yield of 108.4%.
Synthesis of compound 14: adding 500ml of water into a reaction container, adding the compound 13 obtained in the previous step while stirring, dropwise adding 200ml of sodium hydroxide methanol solution, heating to 60 ℃, stirring and reacting for 2 hours, cooling to room temperature after complete reaction, adjusting the pH to be neutral by using dilute hydrochloric acid, adding ethyl acetate for extraction for 1 time, collecting an organic layer, concentrating to a small volume, crystallizing, filtering and drying to obtain 187.2g of the compound 14 with the yield of 91.2%.
Synthesis of compound 8: adding 510g of concentrated sulfuric acid into a reaction container A, cooling to 5 ℃, slowly dropping 187.2g of a compound 14 dissolved by adding water, stirring and reacting for 20 hours, after the reaction is finished, cooling the reaction mixture to room temperature, pouring 1.5L of purified water into a reaction container B, controlling the temperature to be 0-5 ℃, slowly dropping the reaction product in the reaction container A into the reaction container B, adding 1.2L of dichloromethane, stirring, separating an organic layer, adding 1L of purified water, adjusting the pH to about 7 by using a 5% sodium carbonate aqueous solution, separating the organic layer again, concentrating, filtering, and drying under vacuum and reduced pressure at 40 ℃ to obtain 14158.3 g of the compound, wherein the yield is 84.6%.
Ninthly, synthesizing the compound B: 600ml of dichloromethane is added into a reaction vessel, 60g of pyridine and 80g of acetic anhydride are added, after uniform stirring, the compound 8 obtained in the previous step is added, the temperature is raised to 35 ℃, the mixture is heated for 5 hours, the mixture is cooled and poured into ice water, the pH value is adjusted to be neutral, and the mixture is filtered and dried to obtain 112.9g of compound B, the yield is 71.3%.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (1)
1. A preparation method of a Prenster intermediate is characterized by comprising the following steps: a compound C is used as a raw material, and a pransted intermediate is obtained by adopting any scheme as follows;
the first scheme is as follows: the method comprises the following steps:
q1, compound D obtained by reaction starting from compound C, compound D being characterized in that: r1 is halogen, a group capable of polymerizing with hydroxyl to form ether; the R2 position is an ester group;
q2, condensing the compound D with o-acetaminophenol, performing cyclization reaction and hydrolysis reaction, and finally preparing a compound B with sodium azide;
scheme II: the method comprises the following steps:
q1, compound E obtained by reaction starting from compound C, compound E being characterized in that: r1 is halogen, group which can polymerize with hydroxyl to generate ether, and R3 is ester group;
q2, condensing the compound E and o-acetaminophenol, preparing hydroxyl in the original compound E into 4-triazole, and cyclizing to obtain a compound B;
the structure of compound C is as follows:
characterized in that R1 is halogen, a group capable of polymerizing with hydroxyl to generate ether; r2 and R3 are hydrogen radicals or radicals which can form esters with carboxylic acids.
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