CN110467612B - Simple preparation method of prostaglandin D2 receptor inhibitor compound - Google Patents
Simple preparation method of prostaglandin D2 receptor inhibitor compound Download PDFInfo
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The present invention provides a simple method for producing a prostaglandin D2 receptor inhibitor compound. The preparation method comprises the steps of taking 4-methylsulfonyl-2-trifluoromethylbenzylamine (II) and 3-acetyl glutaric diester (III) as raw materials, condensing and cyclizing, then carrying out addition reaction with 2-halogenated acrolein and pyridine cyclization reaction with ammonia, and finally hydrolyzing and acidifying with hydrochloric acid. The method has the advantages of simple operation, mild reaction conditions, less three wastes and environmental protection; the raw materials are cheap and easy to obtain, and the cost is low; high reaction selectivity, few byproducts, simple purification, high yield and purity, and contribution to the industrial production of the prostaglandin D2 receptor inhibitor compound Fevipiprant.
Description
Technical Field
The invention relates to a simple preparation method of a prostaglandin D2 receptor inhibitor compound Fevipiprant, belonging to the technical field of medicinal chemistry.
Background
Fevipiprant (I) having CAS number [872365-14-5] and chemical name [1- (4-methanesulfonyl-2-trifluoromethylphenyl) methyl-2-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl ] acetic acid, is a prostaglandin D2 receptor (DP2/CRTh2) inhibitor developed by Nowa, and is mainly used for treating asthma. According to the clinical I test, the candidate molecule has relatively excellent safety and tolerance, has great clinical development potential value, is clinically used in the third phase in the United states at present, and is a candidate medicine with great market prospect for treating mild-to-moderate persistent asthma, moderate-to-severe atopic dermatitis and allergic rhinitis.
The chemical structural formula of Fevipiprant is shown as follows:
currently, methods for synthesizing Fevipiprant are reported in the prior art.
For example, in WO2005123731, 4-methanesulfonyl-2-trifluoromethylbenzaldehyde is used as a raw material, and is subjected to reduction and bromination to obtain 4-methanesulfonyl-2-trifluoromethylbromobenzyl, which is then condensed, hydrolyzed and acidified with 2-methyl-1H-pyrrolo [2,3-b ] pyrid-3-yl-methyl acetate to obtain a target compound, and the corresponding synthetic route is shown in synthetic route 1.
However, in the above synthetic route 1, 2-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl-acetic acid methyl ester is expensive and not easily available; the reaction selectivity is low, and complicated purification is needed; meanwhile, conjugation of pyridine ring and pyrrole ring exists in the condensation step, which results in generation of pyridine ring alkylation by-products, the content of the by-products is higher than 40%, complicated separation is needed, the highest total yield is only about 50%, three wastes are large, and the method is not beneficial to industrial production of Fevipiprant.
For another example, chinese patent document CN106188040A discloses a method for preparing fevipirant from 2-amino-3-bromopyridine by using 2-amino-3-bromopyridine as a raw material, condensing with 4-methanesulfonyl-2-trifluoromethylbenzaldehyde to form a schiff base intermediate, reducing with sodium borohydride to prepare 3-bromo-N- (4- (methanesulfonyl) -2- (trifluoromethyl) phenyl) methyl-pyridin-2-amine, and then performing ullmann cyclization with 3-levulinic acid ester or 3-acetylmethylmalonate, followed by hydrolysis, acidification, or hydrolysis-decarboxylation, wherein the total yield is 57.0 to 73.7%.
However, the raw material 2-amino-3-bromopyridine used in the route is high in price and is not easy to obtain; the amount of the catalyst and the cocatalyst used in the Ullmann cyclization reaction is large, the reaction temperature is high, the reaction time is long (120 ℃, 12 hours), and the operation requirement is high; the obtained product has heavy color, large metal residue, large yield interval and large amount of three wastes, and is not beneficial to green industrial production.
Therefore, a green industrial production route with simple operation, low cost, high reaction selectivity and high yield is established, and the method has important significance for phase III clinical research and subsequent marketization of Fevipiprant.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a simple preparation method of a prostaglandin D2 receptor inhibitor compound Fevipiprant. The method is simple and convenient to operate, mild in reaction condition, less in three wastes and environment-friendly; the raw materials are cheap and easy to obtain, and the cost is low; high reaction selectivity, few byproducts, simple purification, high yield and purity, and contribution to the industrial production of Fevipiprant.
Description of terms:
a compound of formula II: 4-methanesulfonyl-2-trifluoromethylbenzylamine (II);
a compound of formula III: 3-acetylglutaric diester (III);
a compound of formula IV: n- (4-methanesulfonyl-2-trifluoromethylphenyl) methyl-2-methyl-4, 5-dihydropyrrol-5-one-3-acetic acid ester (IV);
a compound of formula V: n- (4-methanesulfonyl-2-trifluoromethylphenyl) methyl-2-methyl-4- (2-halo-2-formyl) ethyl-4, 5-dihydropyrrol-5-one-3-acetate (v);
a compound of formula VI: [1- (4-methanesulfonyl-2-trifluoromethylphenyl) methyl-2-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl ] acetate (VI);
a compound of formula I: fevipiprant (I).
In the specification, the compound numbers are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula of the compound.
The technical scheme of the invention is as follows:
a process for the preparation of the prostaglandin D2 receptor inhibitor compound Fevipiprant of formula i, comprising the steps of:
(1) in a solvent, under the action of an acid catalyst, carrying out condensation and cyclization reaction on a compound shown in a formula II and a compound shown in a formula III to obtain a compound shown in a formula IV;
wherein in the structural formula of the compounds shown in the formulas III and IV, R is-CH3、-C2H5、-C3H7or-C4H9;
(2) Under the action of an alkali catalyst, carrying out addition reaction on a compound shown in the formula IV and 2-halogenated acrolein to prepare a compound shown in the formula V; in the presence of ammonia, pyridine cyclization of the compound of the formula V to obtain a compound of the formula VI; then obtaining Fevipiprant (I) through hydrolysis and hydrochloric acid acidification;
wherein, in the structural formula of the compound shown in the formula V, X is Cl or Br; in the structural formulas of the compounds shown in the formulas V and IV, the meaning of R is the same as that of R in the structural formula of the compound shown in the formula III.
According to the present invention, it is preferable that the solvent in the step (1) is azeotropic with water and has an azeotropic point of 50 to 100 ℃; preferably, the solvent is one or the combination of more than two of ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, 1, 2-dichloroethane, 1, 2-dichloropropane, toluene, cyclohexane, acetonitrile or tetrahydrofuran; the mass ratio of the solvent to the compound shown in the formula II is (5-30) to 1; preferably, the mass ratio of the solvent to the compound of the formula II is (7-14): 1.
According to the present invention, preferably, the acid catalyst in step (1) is protonic acid or Lewis acid, preferably one or a combination of two or more of p-toluenesulfonic acid, benzenesulfonic acid, 98 wt% concentrated sulfuric acid, zinc chloride, cuprous chloride or aluminum trichloride; the mass of the acid catalyst is 0.5-5.0% of that of the compound shown in the formula II; preferably, the mass of the acid catalyst is 1.0% to 3.0% of the mass of the compound of formula ii.
According to the invention, the molar ratio of the compound of formula III to the compound of formula II in step (1) is preferably (0.9-1.5): 1.
According to the present invention, it is preferable that the condensation reaction temperature in the step (1) is 30 to 50 ℃ and the cyclization reaction temperature is 60 to 100 ℃. The condensation reaction time is 2-4 hours, and the cyclization reaction time is 2-5 hours.
According to the present invention, it is preferable that the base catalyst in the step (2) is one or a combination of two or more of piperidine, tetrahydropyrrole, morpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), 4-dimethylaminopyridine, potassium tert-butoxide, sodium ethoxide or sodium methoxide; the mass of the alkali catalyst is 1.0-5.0% of that of the compound shown in the formula II; preferably, the mass of the base catalyst is 3.0-5.0% of the mass of the compound of formula II.
According to the present invention, it is preferred that the 2-halogenoacrolein in the step (2) is 2-chloroacrolein or 2-bromoacrolein; the molar ratio of the 2-halogenated acrolein to the compound of the formula II in the step (2) is (1.0-1.5): 1.
According to the present invention, it is preferable that the addition reaction temperature in the step (2) is 0 to 100 ℃; preferably, the temperature of the addition reaction in the step (2) is 30-50 ℃. The addition reaction time is 2-10 hours; preferably, the addition reaction time is 3 to 5 hours.
According to the present invention, it is preferable that the ammonia in step (2) is ammonia gas, ammonia water, an ammonia methanol solution or an ammonia ethanol solution; the molar ratio of ammonia to the compound of formula II is (3.0-5.0): 1.
according to the present invention, it is preferable that the pyridine cyclization reaction temperature in the step (2) is 30 to 100 ℃; preferably, the pyridine cyclization reaction temperature is 50-70 ℃. The cyclization reaction time of pyridine is 2-8 hours; preferably, the pyridine cyclization reaction time is 3 to 5 hours.
According to the present invention, it is preferable that the hydrolysis in step (2) is carried out in the presence of a base using an aqueous solution of sodium hydroxide, potassium hydroxide or lithium hydroxide having a mass concentration of 10% to 50%; the molar ratio of the base to the compound of formula II is (1.0-2.0): 1.
according to the present invention, it is preferable that the hydrolysis reaction temperature in step (2) is 0 to 100 ℃; preferably, the hydrolysis reaction temperature is 20-40 ℃. The hydrolysis reaction time is 1-5 hours; preferably, the hydrolysis reaction time is 2 to 3 hours.
According to the present invention, preferably, in the step (2), the reaction solution obtained after the hydrolysis reaction is separated into layers, activated carbon is added to the separated water layer, and the mixture is stirred and decolored at 20 to 30 ℃ for 0.5 to 2 hours, filtered, and then acidified with hydrochloric acid.
According to the invention, preferably, the hydrochloric acid acidification in the step (2) is performed by using hydrochloric acid with the mass concentration of 20-35% to adjust the pH value of the system to 2.0-2.5.
According to the present invention, it is preferred that the reaction in step (1) and the reaction in step (2) are carried out in a "one-pot" manner, and the product obtained in step (1) is directly subjected to the reaction in step (2) without isolation.
The preparation steps of the present invention are depicted in scheme 3 below:
wherein in the structural formula of the compounds of the formulas III, IV, V and VI, R is-CH3、-C2H5、-C3H7or-C4H9(ii) a In the structural formula of the compound of the formula V, X is Cl or Br.
The invention has the technical characteristics and beneficial effects that:
1. the invention provides a novel Fevipiprant preparation method, which comprises the steps of using 4-methylsulfonyl-2-trifluoromethylbenzylamine (II) and 3-acetyl glutaric diester (III) as raw materials, obtaining N- (4-methylsulfonyl-2-trifluoromethylphenyl) methyl-2-methyl-4, 5-dihydropyrrole-5-ketone-3-acetic ester (IV) through condensation-cyclization reaction, then preparing N- (4-methylsulfonyl-2-trifluoromethylphenyl) methyl-2-methyl-4- (2-halo-2-formyl) ethyl-4, 5-dihydropyrrole-5-ketone-3-acetic ester (V) through addition reaction with 2-halogenated acrolein, then the intermediate is cyclized with ammonia by pyridine to obtain [1- (4-methylsulfonyl-2-trifluoromethylphenyl) methyl-2-methyl-1H-pyrrolo [2,3-b ] pyridine-3-yl ] acetate (VI), and the acetate is hydrolyzed and acidified by hydrochloric acid under alkaline condition to obtain Fevipiprant (I).
2. The method has the advantages of cheap and easily-obtained raw materials, short process flow, mild reaction conditions, simple and convenient operation, easy realization and low cost, and Fevipiprant (I) can be prepared by a one-pot method; the production of three wastes in the preparation process is less, and the process is green and environment-friendly; the method has the advantages of high reaction selectivity, few byproducts, simple purification, high yield and purity (the total yield can reach 88.6 percent), no metal residue problem and contribution to the industrial production of Fevipiprant.
3. The reaction selectivity involved in the route of the invention is high, the probability of the side reaction of diamidation of two molecules of 4-methylsulfonyl-2-trifluoromethylbenzylamine (II) and one molecule of 3-acetyl glutaric diester (III) is reduced by temperature programmed condensation-cyclization reaction, the high activity of amide ortho methylene of the compound shown in the formula IV and the addition of 2-halogenated acrolein are utilized, the high selectivity of the reaction in the whole route is established, and the obtained product has good color and luster, high yield and high purity.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The raw materials and reagents used in the examples are all commercially available products. In the examples, "%" is a mass percentage unless otherwise specified.
The yields in the examples are all molar yields.
Example 1: preparation of Fevipiprant (I)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer, a water separator and a reflux condenser were charged 200 g of toluene, 25.3 g (0.1 mol) of 4-methanesulfonyl-2-trifluoromethylbenzylamine (II), 21.0 g (0.1 mol) of dimethyl 3-acetylglutarate (III)1) 0.5 g of p-toluenesulfonic acid, stirred at 45 to 50 ℃ for 2 hours and at 82 to 85 ℃ for 4 hours, and water azeotropically removed is removed. Cooled to 20 to 25 ℃, 1.0 g of DBU, 10.0 g (0.11 mol) of 2-chloroacrolein was added, and the reaction was stirred at 40 to 45 ℃ for 4 hours. 40.0 g (0.4 mol) of a 17 wt% methanolic ammonia solution was added and the reaction was stirred at 50 to 55 ℃ for 4 hours. Cooling to 20-25 ℃, adding 250 g of water and 30 g of 20 wt% sodium hydroxide aqueous solution, stirring and reacting for 2 hours at 25-30 ℃, layering, adding 0.5 g of activated carbon into a separated water layer, stirring and decoloring for 1 hour at 25-30 ℃, filtering, acidifying the filtrate by using 35 wt% hydrochloric acid until the pH value of the system is 2.0-2.5, filtering and drying to obtain 37.5 g of white solid Fevipiprant (I), wherein the yield is 87.9%, and the liquid phase purity is 99.9%.
The nuclear magnetic data of the product obtained are as follows:
1H NMR(400MHz,DMSO-d6):
2.26(3H,s),3.26(3H,s),3.66(2H,s),5.71(2H,s),6.46(1H,d J=8.3),7.07(1H,dd J=7.7,4.8),7.96(1H,d,J=7.8),8.01(1H,d,J=8.3),8.11(1H,d,J=4.7),8.22(1H,s),12.28(1H,brs).
example 2: preparation of Fevipiprant (I)
Is connected with a stirring device, a thermometer and a water separatorAnd a reflux condenser were placed in a 500-ml four-necked flask, to which were added 200 g of 1, 2-dichloroethane, 25.3 g (0.1 mol) of 4-methanesulfonyl-2-trifluoromethylbenzylamine (II), 23.0 g (0.1 mol) of diethyl 3-acetylglutarate (III)2) 0.5 g of 98 wt% concentrated sulfuric acid, stirring at 45 to 50 ℃ for 2 hours, and stirring at 70 to 75 ℃ for 5 hours, and simultaneously separating off the water azeotropically separated off. Cooled to 20 to 25 ℃ and 1.2 g DBU, 13.5 g (0.1 mol) 2-bromoacrolein and stirred for reaction at 35 to 40 ℃ for 4 hours. 40.0 g (0.4 mol) of a 17 wt% methanolic ammonia solution was added and the reaction was stirred at 50 to 55 ℃ for 4 hours. Cooling to 20-25 ℃, adding 250 g of water and 30 g of 20 wt% sodium hydroxide aqueous solution, stirring and reacting for 2 hours at 20-25 ℃, layering, adding 0.5 g of activated carbon into a separated water layer, stirring and decoloring for 1 hour at 25-30 ℃, filtering, acidifying the filtrate by using 35 wt% hydrochloric acid until the pH value of the system is 2.0-2.5, filtering and drying to obtain 37.3 g of white solid Fevipiprant (I), wherein the yield is 87.5%, and the liquid phase purity is 99.8%.
Example 3: preparation of Fevipiprant (I)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer, a water separator and a reflux condenser were charged 200 g of toluene, 25.3 g (0.1 mol) of 4-methanesulfonyl-2-trifluoromethylbenzylamine (II), 21.0 g (0.1 mol) of dimethyl 3-acetylglutarate (III)1) 0.5 g of p-toluenesulfonic acid, stirred at 40 to 45 ℃ for 3 hours and at 82 to 85 ℃ for 4 hours, and water azeotropically removed is removed. Cooled to 20 to 25 ℃ and 1.2 g DBU, 13.5 g (0.1 mol) 2-bromoacrolein and reacted with stirring at 40 to 45 ℃ for 4 hours. 40.0 g (0.4 mol) of a 17 wt% methanolic ammonia solution was added and the reaction was stirred at 50 to 55 ℃ for 4 hours. Cooling to 20-25 ℃, adding 250 g of water and 35 g of 20 wt% potassium hydroxide aqueous solution, stirring at 20-25 ℃ for 2 hours for reaction, layering, adding 0.5 g of activated carbon into the separated water layer, stirring at 25-30 ℃ for decoloration for 1 hour, filtering, acidifying the filtrate by using 35 wt% hydrochloric acid until the pH value of the system is 2.0-2.5, filtering and drying to obtain 37.8 g of white solid Fevipiprant (I), wherein the yield is 88.6% and the liquid phase purity is 99.9%.
Example 4: preparation of Fevipiprant (I)
Is connected with a stirring device, a thermometer and a water diversion deviceInto a 500 ml four-necked flask equipped with a reflux condenser, 250 g of 2-butanol, 25.3 g (0.1 mol) of 4-methanesulfonyl-2-trifluoromethylbenzylamine (II), 21.0 g (0.1 mol) of dimethyl 3-acetylglutarate (III)1) 0.5 g of zinc chloride, stirring and reacting at 45-50 ℃ for 2 hours, stirring and reacting at 85-100 ℃ for 4 hours, and simultaneously separating out water separated out azeotropically. Cooled to 20 to 25 ℃ and 1.2 g DBU, 13.5 g (0.1 mol) 2-bromoacrolein and reacted with stirring at 40 to 45 ℃ for 4 hours. 40.0 g (0.4 mol) of a 17 wt% aqueous ammonia solution was added, and the reaction was stirred at 50 to 55 ℃ for 4 hours. Cooling to 20-25 ℃, adding 250 g of water and 30 g of 20 wt% sodium hydroxide aqueous solution, stirring and reacting for 2 hours at 25-30 ℃, layering, adding 0.5 g of activated carbon into a separated water layer, stirring and decoloring for 1 hour at 25-30 ℃, filtering, acidifying a filtrate by using 35 wt% hydrochloric acid until the pH value of the system is 2.0-2.5, filtering and drying to obtain 36.3 g of white solid Fevipiprant (I), wherein the yield is 85.1%, and the liquid phase purity is 99.6%.
Comparative example: preparation of Fevipiprant (I)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer, a water separator and a reflux condenser were charged 200 g of toluene, 25.3 g (0.1 mol) of 4-methanesulfonyl-2-trifluoromethylbenzylamine (II), 21.0 g (0.1 mol) of dimethyl 3-acetylglutarate (III)1) 0.5 g of p-toluenesulphonic acid, the reaction is stirred at 82 to 85 ℃ for 4 hours, and water which is azeotropically removed is simultaneously removed. Cooled to 20 to 25 ℃, 1.0 g of DBU, 10.0 g (0.11 mol) of 2-chloroacrolein was added, and the reaction was stirred at 40 to 45 ℃ for 4 hours. 40.0 g (0.4 mol) of a 17 wt% methanolic ammonia solution was added and the reaction was stirred at 50 to 55 ℃ for 4 hours. Cooling to 20-25 ℃, adding 250 g of water and 30 g of 20 wt% sodium hydroxide aqueous solution, stirring and reacting for 2 hours at 25-30 ℃, layering, adding 0.5 g of activated carbon into a separated water layer, stirring and decoloring for 1 hour at 25-30 ℃, filtering, acidifying the filtrate by using 35 wt% hydrochloric acid until the pH value of the system is 2.0-2.5, filtering and drying to obtain 29.3 g of white solid Fevipiprant (I), wherein the yield is 68.7%, and the liquid phase purity is 99.5%.
From the comparison of the above examples with this comparative example, it can be seen that: the temperature programming and stepwise progress of the condensation and cyclization reactions have a large influence on the reaction yield. The analysis reason is that the temperature programming and the sectional proceeding are beneficial to the reaction of the carbonyl of the 4-methylsulfonyl-2-trifluoromethylbenzylamine and the 3-acetyl dimethyl glutarate, so that the side reaction of the diamidation of two molecules of the 4-methylsulfonyl-2-trifluoromethylbenzylamine and one molecule of the 3-acetyl dimethyl glutarate is reduced, although the generated side product can be removed by the hydrolysis reaction (the diamidation side product and the alkali do not react at the use temperature, the diamidation side product is dissolved in the organic solvent, is not dissolved in the water and can be removed in the layering process), the purity of the target product is not influenced basically, but the yield of the target product is not improved favorably.
Claims (9)
1. A process for preparing a prostaglandin D2 receptor inhibitor compound of formula i, comprising the steps of:
(1) in a solvent, under the action of an acid catalyst, carrying out condensation and cyclization reaction on a compound shown in a formula II and a compound shown in a formula III to obtain a compound shown in a formula IV;
the solvent is one or the combination of more than two of ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, 1, 2-dichloroethane, 1, 2-dichloropropane, toluene, cyclohexane, acetonitrile or tetrahydrofuran; the acid catalyst is one or the combination of more than two of p-toluenesulfonic acid, benzenesulfonic acid, 98 wt% concentrated sulfuric acid, zinc chloride, cuprous chloride or aluminum trichloride; the condensation reaction temperature is 30-50 ℃, and the cyclization reaction temperature is 60-100 ℃;
wherein in the structural formula of the compounds shown in the formulas III and IV, R is-CH3、-C2H5、-C3H7or-C4H9;
(2) Under the action of an alkali catalyst, carrying out addition reaction on a compound shown in the formula IV and 2-halogenated acrolein to prepare a compound shown in the formula V; in the presence of ammonia, pyridine cyclization of the compound of the formula V to obtain a compound of the formula VI; then obtaining Fevipiprant (I) through hydrolysis and hydrochloric acid acidification;
the alkali catalyst is one or the combination of more than two of piperidine, tetrahydropyrrole, morpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), 4-dimethylaminopyridine, potassium tert-butoxide, sodium ethoxide or sodium methoxide; the temperature of the addition reaction is 0-100 ℃; the pyridine cyclization reaction temperature is 30-100 ℃; the hydrolysis is carried out in the presence of alkali, wherein the alkali is a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution or a lithium hydroxide aqueous solution with the mass concentration of 10-50%; the hydrolysis reaction temperature is 0-100 ℃;
wherein, in the structural formula of the compound shown in the formula V, X is Cl or Br; in the structural formulas of the compounds shown in the formulas V and IV, the meaning of R is the same as that of R in the structural formula of the compound shown in the formula III.
2. The method of preparing a prostaglandin D2 receptor inhibitor compound according to claim 1, wherein step (1) includes one or more of the following conditions:
(a) the mass ratio of the solvent to the compound shown in the formula II is (5-30) to 1;
(b) the mass of the acid catalyst is 0.5-5.0% of that of the compound shown in the formula II;
(c) the molar ratio of the compound shown in the formula III to the compound shown in the formula II is (0.9-1.5): 1.
3. The method of preparing a prostaglandin D2 receptor inhibitor compound according to claim 1, wherein step (2) includes one or more of the following conditions:
(a) the mass of the alkali catalyst is 1.0-5.0% of that of the compound shown in the formula II;
(b) the 2-halogenated acrolein is 2-chloroacrolein or 2-bromoacrolein; the molar ratio of the 2-halogenated acrolein to the compound of the formula II in the step (2) is (1.0-1.5): 1.
4. The method of preparing a prostaglandin D2 receptor inhibitor compound according to claim 1, wherein the addition reaction temperature in step (2) is 30-50 ℃.
5. The method of preparing a prostaglandin D2 receptor inhibitor compound according to claim 1, wherein the ammonia in step (2) is ammonia gas, ammonia water, ammonia methanol solution or ammonia ethanol solution; the molar ratio of ammonia to the compound of formula II is (3.0-5.0): 1.
6. the method of preparing a prostaglandin D2 receptor inhibitor compound according to claim 1, wherein the pyridine ring-closure reaction temperature in step (2) is 50-70 ℃.
7. The method of preparing a prostaglandin D2 receptor inhibitor compound according to claim 1, wherein step (2) includes one or more of the following conditions:
(a) the molar ratio of the base to the compound of formula II is (1.0-2.0): 1;
(b) the hydrolysis reaction temperature is 20-40 ℃;
(c) separating reaction liquid obtained after hydrolysis reaction, adding active carbon into separated water layer, stirring and decolorizing at 20-30 deg.C for 0.5-2 hr, filtering, and acidifying with hydrochloric acid.
8. The method of preparing a prostaglandin D2 receptor inhibitor compound according to claim 1, wherein the hydrochloric acid acidification in step (2) is performed using hydrochloric acid at a mass concentration of 20-35% until the pH of the system is 2.0-2.5.
9. The method for producing a prostaglandin D2 receptor inhibitor compound according to claim 1, wherein the reaction in step (1) and the reaction in step (2) are carried out in a "one-pot method", and the product obtained in step (1) is directly subjected to the reaction in step (2) without isolation.
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CN106188040B (en) * | 2016-06-28 | 2018-03-23 | 浙江宏鑫染化材料有限公司 | A kind of Fevipiprant and its intermediate preparation method |
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