CN111170930B - Simple preparation method of 5, 6-dihydropyridine-2 (1H) -ketone derivative - Google Patents
Simple preparation method of 5, 6-dihydropyridine-2 (1H) -ketone derivative Download PDFInfo
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Abstract
The invention provides a simple preparation method of a 5, 6-dihydropyridine-2 (1H) -ketone derivative. P-phenylenediamine is taken as a raw material, the p-phenylenediamine and delta-valerolactone are amidated, and the hydroxyl of the amidation product reacts with a halogenated reagent 1 or sulfonyl chloride to be condensed to obtain 1, 4-di (piperidine-2-ketone-1-yl) benzene; then halogenated and eliminated at the ortho position of carbonyl to obtain 1- (piperidine-2-ketone-1-yl) -4- (5, 6-dihydropyridine-2 (1H) -ketone-1-yl) benzene, and added with a halogenating reagent 3, eliminated or eliminated and substituted in the presence of morpholine to obtain the 5, 6-dihydropyridine-2 (1H) -ketone derivative (I). The preparation method has the advantages of cheap and easily-obtained raw materials, short steps and low cost; the process is simple and convenient to operate, reaction conditions are easy to realize, the generation amount of waste water is small, and the method is safe and green; high reaction selectivity in each step, high product yield and purity, and suitability for industrial production.
Description
Technical Field
The invention relates to a simple preparation method of a 5, 6-dihydropyridine-2 (1H) -ketone derivative, in particular to a preparation method of 1- (piperidine-2-ketone-1-yl) -4- (5, 6-dihydro-3-R substituent pyridine-2 (1H) -ketone-1-yl) benzene, belonging to the technical field of medical chemistry.
Background
Apixaban (Apixaban), chemically known as l- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide, is a novel direct factor Xa inhibitor developed by the company behcet and fevery, obtained in 3 months and 12 months of 2012 in 2011 from the european union and FDA approval in the united states, and commercially available under the trade name Eliquis, for the prevention of Venous Thromboembolism (VTE) and atrial fibrillation in adult hip or knee replacement patients. Wherein 1- (piperidin-2-one-1-yl) -4- (5, 6-dihydro-3-chloropyridin-2 (1H) -one-1-yl) benzene (I1) and 1- (piperidin-2-one-1-yl) -4- (5, 6-dihydro-3- (morpholin-4-yl) pyridin-2 (1H) -one-1-yl) benzene (I2) in the 5, 6-dihydropyridin-2 (1H) -one derivative (I) are key intermediates for preparing apixaban, and the chemical structural formula of the related compounds is shown as follows:
currently, the main preparation method of apixaban is as follows:
patent documents WO2003049681 and WO2004083177 propose two routes for preparing apixaban, see synthetic routes 1 and 2.
In the synthetic route 1, piperidine-2-ketone is taken as a raw material, phosphorus pentachloride is chlorinated to obtain 3, 3-dichloropiperidine-2-ketone, then one molecule of hydrogen chloride is eliminated under the action of potassium carbonate to obtain 3-chloro-5, 6-dihydropyridine-2 (1H) -ketone, then the 3- (morpholine-4-yl) -5, 6-dihydropyridine-2 (1H) -ketone is obtained by substitution reaction with morpholine, then the 3- (morpholine-4-yl) -5, 6-dihydropyridine-2 (1H) -ketone is cycloaddition-reacted with (Z) -2-chloro-2- [2- (4-methoxyphenyl) hydrazono ] ethyl acetate, 1- (4-methoxyphenyl) -7-oxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [3 ] is generated by the action of trifluoroacetic acid, 4-c ] pyridine-3-carboxylic acid ethyl ester, then condensed with 1- (4-iodophenyl) -2-piperidone to obtain 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidinyl) phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] -pyridine-3-carboxylic acid, and then the acid anhydride compound is generated by reacting with isobutyl chloroformate, and then the obtained product is ammonolyzed with ammonia to obtain apixaban, wherein the total yield is 5.2%, and the reaction equation of the synthetic route 1 is described as follows:
the synthetic route 2 uses 1- (4-iodophenyl) -3, 3-dichloropiperidine-2-ketone as raw material, and makes it and morpholine undergo the process of substitution reaction to obtain 1- (4-iodophenyl) -3- (morpholine-4-yl) -5, 6-dihydropyridine-2 (1H) -ketone, then uses piperidine-2-ketone and cuprous bromide-triphenylphosphine catalyst to prepare 1- [4- (2-oxopiperidinyl) phenyl ] -3- (morpholine-4-yl) -5, 6-dihydropyridine-2 (1H) -ketone, and makes it and (Z) -2-chloro-2- [2- (4-methoxyphenyl) hydrazono ] ethyl acetate undergo the process of cycloaddition, Reacting with hydrochloric acid to generate 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidinyl) phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] -pyridine-3-ethyl formate, and carrying out ammonolysis by using sodium methoxide to catalyze formamide to obtain the apixaban, wherein the total yield is 31.1-32.0%.
The iodo-substance raw materials 1- (4-iodophenyl) -2-piperidone and 1- (4-iodophenyl) -3, 3-dichloropiperidine-2-ketone used in the two preparation routes of apixaban are high in price, multiple in reaction steps, complex in operation and high in cost; the phosphorus pentachloride dichlorinated reaction in the synthetic route 1 has low selectivity, large amount of phosphorus-containing wastewater and no practical application value; in the synthetic route 2, 1- (piperidine-2-ketone-1-yl) -4- (5, 6-dihydro-3- (morpholine-4-yl) pyridine-2 (1H) -ketone-1-yl) benzene (I2) is used as a key intermediate, although the yield is higher than that of the synthetic route 1, the raw materials used in the preparation method are high in price, a cuprous bromide-triphenylphosphine catalyst is required for the reaction with piperidine-2-ketone, the reaction temperature is high, the total yield is low, the cost is high, and the wastewater amount is large.
The above synthetic route relates to the intermediate 5, 6-dihydropyridin-2 (1H) -one derivatives (I), of which especially 1- (piperidin-2-on-1-yl) -4- (5, 6-dihydro-3-chloropyridin-2 (1H) -on-1-yl) benzene (I1) and 1- (piperidin-2-on-1-yl) -4- (5, 6-dihydro-3- (morpholin-4-yl) pyridin-2 (1H) -on-1-yl) benzene (I2) are key intermediates for the preparation of apixaban, thus optimizing intermediate 5, the preparation method of the 6-dihydropyridine-2 (1H) -ketone derivative (I) has important significance for the synthesis of apixaban.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a simple preparation method of a 5, 6-dihydropyridine-2 (1H) -ketone derivative, in particular to a preparation method of 1- (piperidine-2-ketone-1-yl) -4- (5, 6-dihydro-3-R substituent pyridine-2 (1H) -ketone-1-yl) benzene. The preparation method has the advantages of cheap and easily-obtained raw materials, short steps and low cost; the process is simple and convenient to operate, reaction conditions are easy to realize, the generation amount of waste water is small, and the method is safe and green; high reaction selectivity in each step, high product yield and purity, and suitability for industrial production.
Description of terms:
a compound of formula II: p-phenylenediamine;
a compound of formula III: n, N' -bis (5-hydroxy-N-pentanoyl) p-phenylenediamine;
a compound of formula IV: n, N' -di (5-L substituent N-pentanoyl) p-phenylenediamine;
a compound of formula V: 1, 4-bis (piperidin-2-one-1-yl) benzene;
a compound of formula VI: 1- (piperidin-2-one-1-yl) -4- (5, 6-dihydropyridin-2 (1H) -one-1-yl) benzene;
5, 6-dihydropyridin-2 (1H) -one derivatives, i.e. compounds of formula I: 1- (piperidin-2-one-1-yl) -4- (5, 6-dihydro-3-R substituent pyridin-2 (1H) -one-1-yl) benzene;
the compound numbers in the specification are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula.
The technical scheme of the invention is as follows:
a process for the preparation of a 5, 6-dihydropyridin-2 (1H) -one derivative comprising the steps of:
(1) obtaining a compound shown in a formula III by performing amidation reaction on a compound shown in a formula II and delta-valerolactone;
(2) preparing a compound of formula IV by subjecting a compound of formula III and a halogenating agent 1 to halogenation, or subjecting a compound of formula III and sulfonyl chloride to sulfonylation; then carrying out condensation reaction on the compound shown in the formula IV to obtain a compound shown in the formula V;
in the structural formula of the compound shown in the formula IV, a substituent L is Cl, Br, methylsulfonyloxy, p-toluenesulfonyloxy or phenylsulfonyloxy;
(3) obtaining a compound of formula VI by halogenating the compound of formula V with a halogenating agent 2 at an ortho position with respect to the carbonyl group, followed by elimination of a molecule of hydrogen halide;
(4) 5, 6-dihydropyridin-2 (1H) -one derivatives (I) are obtained by the addition reaction of the carbon-carbon double bond of the compound of formula VI with a halogenating agent 3, followed by elimination of one molecule of hydrogen halide or elimination of substitution reaction in the presence of morpholine.
Preferably, according to the invention, in step (1), the amidation reaction of the compound of formula II with delta-valerolactone is carried out in solvent A.
Preferably, the solvent A is one or a combination of N, N-dimethylformamide, N-dimethylacetamide, toluene, xylene, chlorobenzene or delta-valerolactone; the mass ratio of the solvent A to the compound of the formula II is (2-15) to 1; further preferably, the mass ratio of the solvent A to the compound of the formula II is (3-8): 1.
Preferably, the molar ratio of delta valerolactone to the compound of formula II is (2.0-5.0): 1; further preferably, the molar ratio of delta valerolactone to the compound of formula II is (2.1-2.5): 1.
preferably, the amidation reaction temperature is 50 to 150 ℃; further preferably, the amidation reaction temperature is 90-120 ℃; the amidation reaction time is 1 to 8 hours; further preferably, the amidation reaction time is 3 to 5 hours.
Preferably, according to the present invention, in step (2), the preparation of the compound of formula V from the compound of formula III comprises the steps of: in a solvent B, carrying out halogenation reaction on a compound shown in a formula III and a halogenating reagent 1, or, in a solvent C and in the presence of an acid-binding agent 1, carrying out sulfonylation reaction on the compound shown in the formula III and sulfonyl chloride to prepare a compound shown in a formula IV; then in a solvent D and under the action of alkali, the compound of the formula IV undergoes a condensation reaction to obtain the compound of the formula V.
Preferably, the preparation of the compound of formula V from the compound of formula IV comprises the steps of; uniformly mixing a solvent D1 and alkali to obtain a reaction solution; dissolving a compound shown in the formula IV in a solvent D2 to obtain a mixed solution; dropwise adding the mixed solution into the reaction solution for 1-3 hours, and then carrying out condensation reaction at 60-150 ℃; the solvent D1 and the solvent D2 are the same as the solvent D, and the total mass of the solvent D1 and the solvent D2 is the same as the mass of the solvent D.
Preferably, the solvent B is one or a combination of dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, benzene or toluene; the mass ratio of the solvent B to the compound shown in the formula III is (3-15) to 1; further preferably, the mass ratio of the solvent B to the compound of the formula III is (5-10): 1.
Preferably, the halogenating agent 1 is thionyl chloride, phosgene, diphosgene, triphosgene or phosphorus tribromide, and the molar ratio of the halogenating agent 1 to the compound of formula iii is (0.5-4.0): 1.
preferably, the halogenation reaction temperature is 20-100 ℃; further preferably, the halogenation reaction temperature is 50-70 ℃. The halogenation reaction time is 1-10 hours; further preferably, the halogenation reaction time is 2 to 6 hours.
Preferably, the solvent C is one or a combination of dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, benzene or toluene; the mass ratio of the solvent C to the compound shown in the formula III is (3-15) to 1; further preferably, the mass ratio of the solvent C to the compound of the formula III is (5-10): 1.
Preferably, the acid-binding agent 1 is an inorganic base or an organic base, and the inorganic base is selected from potassium carbonate, potassium hydroxide, sodium carbonate, sodium hydroxide, lithium carbonate or lithium hydroxide; the organic base is selected from triethylamine, tri-n-propylamine, diisopropylethylamine or pyridine.
Preferably, the sulfonyl chloride is methylsulfonyl chloride, benzenesulfonyl chloride or p-methylbenzenesulfonyl chloride.
Preferably, the mole ratio of the sulfonyl chloride, the acid-binding agent 1 and the compound of the formula III is (2.0-3.0): (2.0-3.0): 1.
preferably, the sulfonylation reaction temperature is-20-60 ℃; further preferably, the sulfonylation reaction temperature is 0 to 20 ℃. The sulfonylation reaction time is 1-10 hours; further preferably, the sulfonylation reaction time is 2 to 4 hours.
Preferably, the solvent D is N, N-dimethylformamide or N, N-dimethylacetamide; the mass ratio of the solvent D to the compound of the formula III is 3:1-15: 1; further preferably, the mass ratio of the solvent D to the compound of the formula III is 5:1-8: 1.
Preferably, the alkali is potassium carbonate, sodium carbonate, lithium carbonate or lithium hydroxide; the molar ratio of the base to the compound of formula III is (2.0-3.0): 1.
preferably, the condensation reaction temperature is 60-150 ℃; further preferably, the condensation reaction temperature is 90 to 120 ℃. The condensation reaction time is 2-10 hours; further preferably, the condensation reaction time is 3 to 6 hours.
Preferably, according to the invention, in step (3), the preparation of the compound of formula VI from the compound of formula V comprises the steps of: in a solvent E and under the action of a catalyst, performing halogenation reaction on the compound shown in the formula V and a halogenating reagent 2 at one ortho position of a carbonyl group; then in a solvent F and under the action of an acid-binding agent 2, a molecule of hydrogen halide is eliminated to obtain the compound shown in the formula VI.
Preferably, the solvent E is one or a combination of more than two of dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane or chlorobenzene; the mass ratio of the solvent E to the compound of the formula V is 2-15: 1; further preferably, the mass ratio of the solvent E to the compound of the formula V is (5-10): 1.
Preferably, the catalyst is organic phosphorus phosphite or organic amine, and the organic phosphorus phosphite is selected from one or a combination of more than two of trimethyl phosphite, triethyl phosphite, tripropyl phosphite, tributyl phosphite or triphenyl phosphite; the organic amine is one or the combination of more than two of tri-N-butylamine, 4-dimethylaminopyridine, N-methylpiperidine or pyridine; the catalyst is 0.1-5.0% of the compound of formula V; further preferably, the catalyst is present in an amount of 0.5 to 3.0% by mass of the compound of formula V.
Preferably, the halogenating reagent 2 is chlorine, bromine, N-chlorosuccinimide, N-bromosuccinimide, hydrochloric acid-sodium hypochlorite, hydrochloric acid-hydrogen peroxide, hydrobromic acid-hydrogen peroxide, hydrochloric acid-sodium chlorate, phosphorus trichloride, phosphorus pentachloride or trichloroisocyanuric acid; further preferably, the halogenating reagent 2 is chlorine, bromine, hydrochloric acid-hydrogen peroxide or hydrobromic acid-hydrogen peroxide; the molar ratio of the compound participating in the halogenation reaction in the halogenating reagent 2 to the compound of the formula V is (0.9-1.5): 1; further preferably, the molar ratio of the compound participating in the halogenation reaction in the halogenating reagent 2 to the compound of the formula V is (1.0-1.2): 1.
Preferably, the halogenation reaction temperature is 20-100 ℃; further preferably, the halogenation reaction temperature is 30-60 ℃. The halogenation reaction time is 2-8 hours; further preferably, the halogenation reaction time is 3 to 6 hours.
The halogenation reaction of the compound shown in the formula V and the halogenating reagent 2 at one ortho position of the carbonyl group needs to control the dosage of the halogenating reagent 2 and enhance the reaction monitoring, the conversion rate of raw materials is controlled to be 95-98%, and unconverted raw materials are easy to remove so as to reduce side reactions.
Preferably, the solvent F is N, N-dimethylformamide or N, N-dimethylacetamide; the mass ratio of the solvent F to the compound of the formula V is 3:1-15: 1; further preferably, the mass ratio of the solvent F to the compound of formula V is 3:1-8: 1.
Preferably, the acid-binding agent 2 is an inorganic base or an organic base, the inorganic base is selected from one or a combination of potassium carbonate, sodium carbonate, calcium carbonate, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, potassium acetate, sodium acetate or calcium acetate, and the organic base is selected from one or a combination of triethylamine or tri-n-butylamine; the molar ratio of the acid-binding agent 2 to the compound of the formula V is (1.0-1.5): 1.
Preferably, the elimination reaction temperature is 50-150 ℃; further preferably, the elimination reaction temperature is 90-130 ℃. The elimination reaction time is 1-4 hours; further preferably, the elimination reaction time is 2 to 3 hours.
Preferably, according to the invention, the preparation of the 5, 6-dihydropyridin-2 (1H) -one derivative (I) from the compound of formula vi in step (4) comprises the steps of: in a solvent G, carrying out addition reaction on the carbon-carbon double bond of the compound shown in the formula VI and a halogenated reagent 3; then eliminating one molecule of hydrogen halide in a solvent H in the presence of an acid-binding agent 3 to obtain a 5, 6-dihydropyridine-2 (1H) -ketone derivative (I), or eliminating substitution reaction in a solvent J in the presence of an acid-binding agent 3 and morpholine to obtain the 5, 6-dihydropyridine-2 (1H) -ketone derivative (I).
Preferably, the solvent G, the solvent H and the solvent J are one or a combination of more than two of dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, acetonitrile, N-dimethylformamide or chlorobenzene; the mass ratio of the solvent G to the solvent H or the solvent J to the compound shown in the formula VI is (2-15) to 1; further preferably, the mass ratio of the solvent G, the solvent H or the solvent J to the compound of the formula VI is (5-10): 1.
Preferably, the halogenating reagent 3 is chlorine, bromine, hydrochloric acid-hydrogen peroxide, hydrochloric acid-sodium hypochlorite, hydrobromic acid-hydrogen peroxide or hydrochloric acid-sodium chlorate; further preferably, the halogenating reagent 3 is chlorine, bromine, hydrochloric acid-hydrogen peroxide or hydrobromic acid-hydrogen peroxide; the molar ratio of the compound participating in the halogenation reaction in the halogenating reagent 3 to the compound shown in the formula VI is (1.0-3.0): 1; further preferably, the molar ratio of the compound participating in the halogenation reaction in the halogenating reagent 3 to the compound of the formula VI is (1.1-2.5): 1.
Preferably, the temperature of the addition reaction is 20-100 ℃; further preferably, the temperature of the addition reaction is 30-50 ℃. The addition reaction time is 1-6 hours; further preferably, the addition reaction time is 2 to 4 hours.
Preferably, the acid-binding agent 3 is an inorganic base or an organic base, the inorganic base is selected from one or a combination of potassium carbonate, sodium carbonate, calcium carbonate, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate or lithium carbonate, and the organic base is selected from one or a combination of triethylamine, tri-n-butylamine, piperidine or morpholine; the molar ratio of the acid-binding agent 3 to the compound shown in the formula VI is (1.0-1.5): 1.
Preferably, the molar ratio of morpholine to compound of formula VI is from 1.0 to 1.5: 1.
Preferably, the temperature of the elimination reaction and the temperature of the elimination substitution reaction are both 30-120 ℃; further preferably, the temperature of the elimination reaction and the temperature of the elimination substitution reaction are both 30-100 ℃. The elimination reaction and the elimination substitution reaction are both carried out for 1-6 hours; further preferably, the elimination reaction and the elimination substitution reaction are carried out for 2 to 4 hours.
According to the invention, the 5, 6-dihydropyridin-2 (1H) -one derivative (I) is preferably shown in the structural formula, wherein a substituent R is chlorine, morpholine-4-yl or bromine.
The work-up of the products obtained in the various steps of the process according to the invention can be carried out with reference to the state of the art. The post-treatment method of the product obtained in the preferred steps of the invention is as follows:
after the reaction in the step (1) is finished, cooling the reaction liquid to 20-25 ℃, filtering, washing a filter cake with a solvent A, and drying to obtain the compound I; or cooling the reaction liquid to 50-70 ℃, distilling under reduced pressure to recover the solvent A, recrystallizing the remainder with methanol, filtering, washing the filter cake with water, and drying to obtain the compound.
And (3) after the reaction in the step (2) is finished, filtering the hot reaction solution, washing a filter cake by using a solvent D, combining the filtrates, distilling the filtrate under reduced pressure to recover the solvent D, recrystallizing the residue by using isopropanol, filtering and drying to obtain the compound I.
And (4) after the reaction in the step (3) is finished, filtering the hot reaction solution, washing a filter cake by using a solvent F, combining the filtrates, distilling the filtrate under reduced pressure to recover the solvent F, recrystallizing the remainder by using isopropanol, filtering, and drying the filter cake to obtain the compound.
After the reaction in the step (4) is finished, cooling the reaction liquid to 20-25 ℃, layering, extracting a water layer for 3 times by using a solvent H or J, combining organic phases, distilling and recovering the solvent H or J, recrystallizing residues by using isopropanol, filtering, and drying a filter cake to obtain the compound I; or cooling the reaction solution to 20-25 deg.C, adding water, layering, extracting water layer with solvent H or J for 3 times, mixing organic phases, distilling to recover solvent H or J, recrystallizing the residue with isopropanol, filtering, and drying the filter cake; or filtering the hot reaction solution, washing the filter cake with a solvent H or J, combining the filtrates, distilling the filtrate under reduced pressure to recover the solvent H or J, cooling the filter cake to 20-25 ℃, adding water and the solvent H or J, layering, extracting the water layer with the solvent H or J for 3 times, combining the organic phases, distilling to recover the solvent H or J, recrystallizing the remainder with isopropanol, filtering, and drying the filter cake to obtain the compound.
The process of the present invention is depicted as scheme 3 below:
wherein, the substituent L is chlorine, bromine, methylsulfonyloxy, phenylsulfonyloxy or p-toluenesulfonyloxy; r is chlorine, morpholine-4-yl or bromine.
The 5, 6-dihydropyridine-2 (1H) -ketone derivative (I) prepared by the invention can be used for preparing apixaban according to the prior art, and the preparation route can be shown as follows:
the invention has the technical characteristics and beneficial effects that:
1. the invention takes p-phenylenediamine as a raw material, the p-phenylenediamine and delta-valerolactone are utilized to prepare N, N' -di (5-hydroxy-N-valeryl) p-phenylenediamine through amidation, and the hydroxyl of the amidation product reacts with a halogenated reagent 1 or sulfonyl chloride to be condensed to obtain 1, 4-di (piperidine-2-ketone-1-yl) benzene; then halogenated and eliminated at the ortho position of the carbonyl group to obtain 1- (piperidine-2-ketone-1-yl) -4- (5, 6-dihydropyridine-2 (1H) -ketone-1-yl) benzene, and then added with a halogenating reagent 3, eliminated or eliminated and substituted in the presence of morpholine to obtain 1- (piperidine-2-ketone-1-yl) -4- (5, 6-dihydro-3-R substituent pyridine-2 (1H) -ketone-1-yl) benzene (I).
2. The invention does not use the iodo material with high price and poor stability, and the raw material is cheap and easy to obtain and has low cost; the method has the advantages of short steps, simple and convenient process operation, mild reaction conditions, easy realization, less three wastes, environmental protection; the method does not use high-temperature coupling reaction with high temperature and more side reactions, has good stability of raw materials and intermediate products, has single reaction site of reaction functional groups in each step, high reaction selectivity, high product purity and yield (the total yield can reach 78.3 percent), and is beneficial to industrial production.
3. In the prior art for preparing the compound shown in the formula I, a piperidone segment is introduced firstly, and then the piperidone segment is further converted into a chloro-alkene or enamine structure (namely the compound shown in the formula I) through the same-carbon double-chloro reaction at the ortho position of amide, so that the compound has the defects of high requirement on the activity of a chloro-reagent, high temperature and more side reactions when the iodo-substance is used for introducing a second piperidone segment. The method simultaneously introduces two piperidone segments, performs monohalogenation on the ortho-position of the carbonyl of the amide by using easy-to-perform and controlled monohalogenation reaction, then eliminates one molecule of hydrogen halide to obtain a carbon-carbon double bond, and the obtained carbon-carbon double bond is easy to be added with a halogenating reagent to obtain an o-carbon disubstituted compound.
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 N, N' -bis (5-hydroxy-N-pentanoyl) p-phenylenediamine (III)
Into a 1000 ml four-neck flask equipped with a stirrer, a thermometer and a condenser, 350 g of toluene, 30 g of N, N-dimethylformamide, 54.0 g (0.5 mol) of p-phenylenediamine (II) and 120 g (1.2 mol) of delta-valerolactone were added, heated, stirred at 105 ℃ and 110 ℃ for reaction for 4 hours, cooled to 20-25 ℃, filtered, washed with 30 g of toluene and dried to obtain 141.7 g of N, N' -bis (5-hydroxy-N-valeryl) p-phenylenediamine (III), the yield was 92.0% and the liquid phase purity was 99.6%.
Example 2: preparation of N, N' -bis (5-hydroxy-N-pentanoyl) p-phenylenediamine (III)
250 g of N, N-dimethylformamide, 54.0 g (0.5 mol) of p-phenylenediamine (II) and 120 g (1.2 mol) of delta-valerolactone are added into a 500 ml four-neck flask which is connected with a stirrer, a thermometer and a condenser, heated, stirred and reacted at 120 ℃ for 4 hours, cooled to 50-70 ℃, decompressed and distilled to recover the N, N-dimethylformamide, and the remainder is recrystallized by 400 g of 75% methanol, filtered, washed by 30 g of water and dried to obtain 143.6 g of N, N' -bis (5-hydroxy-N-valeryl) p-phenylenediamine (III), wherein the yield is 93.2% and the liquid phase purity is 99.8%.
Example 3: preparation of 1, 4-di (piperidin-2-on-1-yl) benzene (V)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a 30 wt% aqueous sodium hydroxide absorption apparatus were charged 150 g of 1, 2-dichloroethane and 30.8 g (0.1 mol) of N, N' -bis (5-hydroxy-N-pentanoyl) p-phenylenediamine (III) obtained by the method of example 2, heated while maintaining the internal temperature at 30 to 40 ℃, and a solution of 35.7 g (0.3 mol) of thionyl chloride and 60 g of 1, 2-dichloroethane was added dropwise over 2 hours, after which the reaction was stirred at 55 to 60 ℃ for 3 hours. Cooling to 30 ℃, changing into a reduced pressure distillation device, carrying out reduced pressure distillation to recover 1, 2-dichloroethane and excessive thionyl chloride (used for next batch of reaction after content analysis), cooling to 20-25 ℃ after distillation is finished, dissolving the obtained residue N, N' -di (5-chloro-N-pentanoyl) p-phenylenediamine with 100 g of N, N-Dimethylformamide (DMF), and transferring to a constant pressure dropping funnel for later use. 100 g of DMF and 30.0 g of potassium carbonate are added into a 500 ml four-neck flask which is connected with a stirrer, a thermometer and a distillation device, the mixture is heated, the obtained N, N' -bis (5-chloro-N-valeryl) p-phenylenediamine solution is dropwise added at the internal temperature of 105-plus-110 ℃ for 2 hours, then the dropwise addition is completed, the stirring reaction is carried out for 3 hours at the temperature of 115-plus-120 ℃, a small amount of low fraction (aqueous DMF) is evaporated, the mixture is filtered while the mixture is hot, the filter cake is washed by 20 g of DMF, the filtrate is combined, the DMF is recovered by reduced pressure distillation, the residue is recrystallized by isopropanol, filtered and dried to obtain 25.5 g of 1, 4-bis (piperidin-2-on-1-yl) benzene (V), the yield is 93.8 percent, and the liquid phase purity is 99.7 percent.
Example 4: preparation of 1, 4-di (piperidin-2-on-1-yl) benzene (V)
200 g of dichloromethane, 30.8 g (0.1 mol) of N, N' -bis (5-hydroxy-N-pentanoyl) p-phenylenediamine (III) obtained by the method of example 1 and 23.0 g of triethylamine are added into a 500 ml four-neck flask which is connected with a stirrer, a thermometer, a reflux condenser and a device connected with a 30 wt% sodium hydroxide aqueous solution absorption device, the mixture is cooled, a solution of 39.0 g (0.22 mol) of benzene sulfonyl chloride and 100 g of dichloromethane is dropwise added at a temperature of between 5 and 10 ℃, the dropwise addition is finished within about 2 hours, and then the stirring reaction is carried out for 4 hours at a temperature of between 15 and 20 ℃. Filtration, washing of the filter cake with 50 g of dichloromethane, combining the filtrates, recovery of dichloromethane by distillation, cooling to 20-25 ℃ and dissolution of the obtained residue N, N' -bis (5-benzenesulfonyloxy-N-pentanoyl) p-phenylenediamine with 100 g of N, N-Dimethylformamide (DMF) and transfer to a constant pressure dropping funnel for further use. 100 g of DMF and 30.0 g of potassium carbonate are added into a 500 ml four-neck flask which is connected with a stirrer, a thermometer and a distillation device, the mixture is heated, the internal temperature is kept between 90 ℃ and 95 ℃, the obtained N, N' -bis (5-benzenesulfonyloxy-N-pentanoyl) p-phenylenediamine solution is dropwise added for 2 hours, then the dropwise addition is completed, the stirring reaction is carried out for 5 hours at the temperature between 95 ℃ and 100 ℃, a small amount of low fraction (aqueous DMF) is evaporated, the mixture is filtered while the mixture is hot, the filter cake is washed by 20 g of DMF, the filtrate is combined, the DMF is recovered by reduced pressure distillation, the residue is recrystallized by isopropanol, filtered and dried, and 25.2 g of 1, 4-bis (piperidin-2-one-1-yl) benzene (V) is obtained, the yield is 92.6 percent, and the liquid phase purity is 99.6 percent.
Example 5: preparation of 1- (piperidin-2-one-1-yl) -4- (5, 6-dihydropyridin-2 (1H) -one-1-yl) benzene (VI)
Into a 1000 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser, a gas-guide tube and a 30 wt% aqueous sodium hydroxide solution absorber, 350 g of 1, 2-dichloroethane, 54.4 g (0.2 mol) of 1, 4-bis (piperidin-2-on-1-yl) benzene (V) obtained by the method of example 4 and 1.0 g of triethyl phosphite were charged, heated, maintained at 45 to 50 ℃ and 14.2 g (0.2 mol) of chlorine gas was slowly introduced, after completion of the introduction for about 3 to 4 hours, the reaction was stirred at 50 to 55 ℃ for 4 hours, cooled to 20 to 25 ℃, the solvent was recovered by distillation under reduced pressure, and the residue was dissolved in 100 g of DMF and transferred to a constant pressure dropping funnel for further use. 100 g of DMF and 30.5 g of potassium carbonate are added into a 500 ml four-neck flask which is connected with a stirrer, a thermometer and a distillation device, the mixture is heated, the internal temperature is kept between 95 ℃ and 100 ℃, the obtained intermediate product solution is dropwise added after 2 hours, then the mixture is stirred and reacted for 3 hours at 100 ℃ and 105 ℃, a small amount of low fraction (aqueous DMF) is evaporated, the mixture is filtered while the mixture is hot, 20 g of DMF is used for washing a filter cake, the filtrate is combined, the filtrate is subjected to reduced pressure distillation for recovering the DMF, and the residue is recrystallized by isopropanol, filtered and dried to obtain 49.6 g of 1- (piperidine-2-ketone-1-yl) -4- (5, 6-dihydropyridine-2 (1H) -ketone-1-yl) benzene (VI), the yield is 91.9 percent, and the liquid phase purity is 99.7 percent.
Example 6: preparation of 1- (piperidin-2-one-1-yl) -4- (5, 6-dihydropyridin-2 (1H) -one-1-yl) benzene (VI)
Into a 1000 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a 30 wt% aqueous sodium hydroxide solution absorber, 300 g of methylene chloride, 54.4 g (0.2 mol) of 1, 4-bis (piperidin-2-on-1-yl) benzene (V) obtained by the method of example 3 and 1.0 g of triethyl phosphite were charged, heated while maintaining the temperature between 30 and 40 ℃, 35.6 g (0.2 mol) of N-bromosuccinimide were introduced in portions, the addition was completed within 1 to 2 hours, and thereafter, the reaction was stirred at 40 to 45 ℃ for 3 hours, cooled to 20 to 25 ℃, the solvent was recovered by distillation under reduced pressure, and the residue was dissolved in 100 g of DMF and transferred to a constant pressure dropping funnel for further use. 100 g of DMF and 30.5 g of potassium carbonate are added into a 500 ml four-neck flask which is connected with a stirrer, a thermometer and a distillation device, the mixture is heated, the internal temperature is kept between 95 ℃ and 100 ℃, the obtained intermediate product solution is dropwise added after 2 hours, then the mixture is stirred and reacted for 3 hours at 100 ℃ and 105 ℃, a small amount of low fraction (aqueous DMF) is evaporated, the mixture is filtered while the mixture is hot, 20 g of DMF is used for washing a filter cake, the filtrate is combined, the filtrate is subjected to reduced pressure distillation for recovering the DMF, and the residue is recrystallized by isopropanol, filtered and dried to obtain 50.8 g of 1- (piperidine-2-ketone-1-yl) -4- (5, 6-dihydropyridine-2 (1H) -ketone-1-yl) benzene (VI), the yield is 94.1 percent and the liquid phase purity is 99.8 percent.
Example 7: preparation of 1- (piperidin-2-one-1-yl) -4- (5, 6-dihydro-3-chloropyridin-2 (1H) -one-1-yl) benzene (I1)
Adding 180 g of 1, 2-dichloroethane and 27.0 g (0.1 mol) of 1- (piperidin-2-one-1-yl) -4- (5, 6-dihydropyridin-2 (1H) -one-1-yl) benzene (VI) obtained by the method of example 5 into a 500 ml four-neck flask connected with a stirring device, a thermometer, a reflux condenser, a gas-guide tube and a 30 wt% sodium hydroxide aqueous solution absorption device, heating, keeping the temperature between 25 and 30 ℃, slowly introducing 7.8 g (0.11 mol) of chlorine gas, finishing the introduction for about 1 to 2 hours, stirring and reacting for 4 hours at the temperature between 30 and 35 ℃, adding 100 g of water (the water is added to dissolve the generated triethylamine hydrochloride so as to be convenient for separating a target product), 12.5 g (0.12 mol) of triethylamine, stirring and reacting for 3 hours at the temperature between 80 and 85 ℃, cooling to 20-25 deg.c, separating layers, extracting the water layer with 1, 2-dichloroethane for 3 times, 30 g each time, combining the organic phases, recovering the solvent by distillation, recrystallizing with isopropanol, drying to obtain 28.2 g of 1- (piperidin-2-on-1-yl) -4- (5, 6-dihydro-3-chloropyridin-2 (1H) -on-1-yl) benzene (I1), yield 92.6%, purity of the liquid phase 99.8%.
The nuclear magnetic data of the product obtained are as follows:
1HNMR(DMSO-d6,400MHz)
7.33(d,2H),7.28(d,2H),7.06(t,1H),3.85(t,2H),3.60(t,2H),2.61(m,2H),2.39(t,2H),1.90-1.78(m,4H)
example 8: preparation of 1- (piperidin-2-one-1-yl) -4- (5, 6-dihydro-3-chloropyridin-2 (1H) -one-1-yl) benzene (I1)
200 g of dichloromethane, 27.0 g (0.1 mol) of 1- (piperidin-2-one-1-yl) -4- (5, 6-dihydropyridin-2-one-1-yl) benzene (VI) obtained by the method of example 6 and 25.0 g of 35% hydrochloric acid were added to a 500 ml four-neck flask equipped with a stirrer, a thermometer, a reflux condenser, a constant pressure dropping funnel and a 30 wt% aqueous sodium hydroxide solution absorber, 12.5 g (0.11 mol) of 30% hydrogen peroxide was slowly dropped in the flask at a temperature of 25 to 30 ℃ until the dropping was completed within about 1 to 2 hours, and after that, the mixture was stirred at a temperature of 30 to 35 ℃ for 4 hours, 15.0 g of potassium carbonate was stirred at a temperature of 30 to 35 ℃ for 3 hours, cooled to 20 to 25 ℃, layered, the aqueous layer was extracted 3 times with 1, 2-dichloroethane, each 30 g of the aqueous layer, the organic layers were combined, the solvent was recovered by distillation, recrystallized from isopropanol and dried to give 27.2 g of 1- (piperidin-2-on-1-yl) -4- (5, 6-dihydro-3-chloropyridin-2-on-1-yl) benzene (I1) in 89.3% yield and 99.2% liquid phase purity.
Example 9: preparation of 1- (piperidin-2-one-1-yl) -4- [5, 6-dihydro-3- (morpholin-4-yl) pyridin-2 (1H) -one-1-yl ] benzene (I2)
Adding 180 g of 1, 2-dichloroethane and 27.0 g (0.1 mol) of 1- (piperidin-2-one-1-yl) -4- (5, 6-dihydropyridin-2 (1H) -one-1-yl) benzene (VI) obtained by the method of example 5 into a 500 ml four-neck flask which is connected with a stirring device, a thermometer, a reflux condenser, a gas-guide tube and a 30 wt% sodium hydroxide aqueous solution absorption device, heating, keeping the temperature between 25 and 30 ℃, slowly introducing 7.8 g (0.1 mol) of chlorine gas, finishing the introduction within about 1 to 2 hours, stirring and reacting at the temperature of 30 to 35 ℃ for 4 hours, adding 15.0 g of triethylamine, 10.5 g of morpholine, stirring and reacting at the temperature of 80 to 85 ℃ for 4 hours, cooling to 20 to 25 ℃, adding 150 g of water, layering, extracting the water layer by using 1, 2-dichloroethane for 3 times, the organic phases were combined each time for 30 g, the solvent was recovered by distillation, recrystallized from isopropanol and dried to give 33.2 g of 1- (piperidin-2-one-1-yl) -4- [5, 6-dihydro-3- (morpholin-4-yl) pyridin-2 (1H) -one-1-yl ] benzene (I2) in 93.5% yield and 99.9% purity in the liquid phase.
The nuclear magnetic data of the product obtained are as follows:
1HNMR(CDCl3,400MHz)
7.35(d,2H),7.25(d,2H),5.66(t,1H),3.86-3.75(m,6H),3.65-3.59(m,2H),2.91-2.82(m,4H),2.60-2.58(m,2H),2.42-2.22(m,2H),2.05-2.00(m,4H)
example 10: preparation of 1- (piperidin-2-one-1-yl) -4- [5, 6-dihydro-3- (morpholin-4-yl) pyridin-2 (1H) -one-1-yl ] benzene (I2)
200 g of dichloromethane and 27.0 g (0.1 mol) of 1- (piperidin-2-one-1-yl) -4- (5, 6-dihydropyridin-2 (1H) -one-1-yl) benzene (VI) obtained by the method of example 6 are added into a 500 ml four-neck flask connected with a stirring device, a thermometer, a reflux condenser, a constant pressure dropping funnel and a 30 wt% sodium hydroxide aqueous solution absorption device, heated, kept at 25 to 30 ℃, and then a solution of 16.5 g (0.1 mol) of bromine and 50 g of dichloromethane is slowly dropped into the flask for about 1 to 2 hours, and then stirred and reacted at 30 to 35 ℃ for 4 hours, the solvent is recovered by reduced pressure distillation, and the residue is dissolved in 100 g of DMF and transferred to the constant pressure dropping funnel for standby. Adding 100 g of DMF, 15.0 g of triethylamine and 10.5 g of morpholine into a 500 ml four-neck flask which is connected with a stirrer, a thermometer and a distillation device, heating, keeping the internal temperature between 95 and 100 ℃, dropwise adding the obtained intermediate product solution for 2 hours, stirring and reacting for 3 hours at the temperature between 95 and 100 ℃, filtering while hot, washing a filter cake with 20 g of DMF, combining filtrates, carrying out reduced pressure distillation to recover DMF, cooling to 20 to 25 ℃, adding 100 g of water and 100 g of dichloromethane, layering, extracting a water layer with dichloromethane for 3 times, 30 g each time, combining organic phases, distilling to recover a solvent, recrystallizing isopropanol, and drying to obtain 33.8 g of 1- (piperidin-2-keto-1-yl) -4- [5, 6-dihydro-3- (morpholin-4-yl) pyridine-2 (1H) -keto-1-yl ] benzene (I2), the yield is 95.2 percent, and the purity of the liquid phase is 99.8 percent.
Comparative example: preparation of 1, 4-di (piperidin-2-on-1-yl) benzene (V)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a 30 wt% aqueous sodium hydroxide absorption apparatus were charged 150 g of 1, 2-dichloroethane and 30.8 g (0.1 mol) of N, N' -bis (5-hydroxy-N-pentanoyl) p-phenylenediamine (III) obtained by the method of example 2, heated while maintaining the internal temperature at 30 to 40 ℃, and a solution of 35.7 g (0.3 mol) of thionyl chloride and 60 g of 1, 2-dichloroethane was added dropwise over 2 hours, after which the reaction was stirred at 55 to 60 ℃ for 3 hours. Cooling to 30 ℃, changing into a reduced pressure distillation device, recovering 1, 2-dichloroethane and excessive thionyl chloride (used for the next batch reaction after content analysis) by reduced pressure distillation, cooling to 20-25 ℃ after the distillation is finished, dissolving the obtained residue N, N' -di (5-chloro-N-pentanoyl) p-phenylenediamine with 200 g of N, N-Dimethylformamide (DMF), transferring to a 500 ml four-neck flask connected with a stirrer, a thermometer and a distillation device, adding 30.0 g of potassium carbonate, heating, stirring and reacting at the temperature of 115 ℃ and 120 ℃ for 3 hours, simultaneously distilling a small amount of low fraction (aqueous DMF), filtering while hot, washing a filter cake with 20 g of DMF, combining filtrates, distilling the filtrate under reduced pressure to recover DMF, adding 350 g of isopropanol into the residue, heating and refluxing, filtering while hot, recrystallizing the filtrate, drying to obtain 12.7 g of 1, 4-bis (piperidin-2-on-1-yl) benzene (V) in 46.6% yield and 97.7% purity in the liquid phase.
The comparative example shows that the dropwise addition of the intermediate N, N '-bis (5-chloro-N-pentanoyl) p-phenylenediamine is beneficial to reducing the concentration of the intermediate N, N' -bis (5-chloro-N-pentanoyl) p-phenylenediamine in the system and reducing the side reaction among molecules. The concentration of the intermediate is not controlled, a large amount of side products insoluble in hot isopropanol is generated, and the reaction yield is low.
Claims (12)
1. A process for the preparation of a 5, 6-dihydropyridin-2 (1H) -one derivative comprising the steps of:
(1) obtaining a compound shown in a formula III by performing amidation reaction on a compound shown in a formula II and delta-valerolactone; the amidation reaction of the compound of formula II and delta-valerolactone is carried out in solvent A;
(2) preparing a compound of formula IV by subjecting a compound of formula III and a halogenating agent 1 to halogenation, or subjecting a compound of formula III and sulfonyl chloride to sulfonylation; then carrying out condensation reaction on the compound shown in the formula IV to obtain a compound shown in the formula V; the halogenating reagent 1 is thionyl chloride, phosgene, diphosgene, triphosgene or phosphorus tribromide;
in the structural formula of the compound shown in the formula IV, a substituent L is Cl, Br, methylsulfonyloxy, p-toluenesulfonyloxy or phenylsulfonyloxy;
(3) obtaining a compound of formula VI by halogenating the compound of formula V with a halogenating agent 2 at an ortho position with respect to the carbonyl group, followed by elimination of a molecule of hydrogen halide; the halogenated reagent 2 is chlorine, bromine, N-chlorosuccinimide, N-bromosuccinimide, hydrochloric acid-sodium hypochlorite, hydrochloric acid-hydrogen peroxide, hydrobromic acid-hydrogen peroxide, hydrochloric acid-sodium chlorate or trichloroisocyanuric acid;
(4) the 5, 6-dihydropyridine-2 (1H) -ketone derivative I is obtained by carrying out addition reaction on a carbon-carbon double bond of a compound shown in a formula VI and a halogenating agent 3, and then eliminating one molecule of hydrogen halide or carrying out elimination substitution reaction in the presence of morpholine; the halogenating reagent 3 is chlorine, bromine, hydrochloric acid-hydrogen peroxide, hydrochloric acid-sodium hypochlorite, hydrobromic acid-hydrogen peroxide or hydrochloric acid-sodium chlorate;
wherein, in the 5, 6-dihydropyridine-2 (1H) -ketone derivative I, a substituent R is chlorine, morpholine-4-yl or bromine.
2. The process for the preparation of 5, 6-dihydropyridin-2 (1H) -one derivatives according to claim 1, characterized in that in step (1) one or more of the following conditions are included:
a. the solvent A is one or a combination of N, N-dimethylformamide, N-dimethylacetamide, toluene, xylene, chlorobenzene or delta-valerolactone; the mass ratio of the solvent A to the compound of the formula II is (2-15) to 1;
b. the molar ratio of the delta-valerolactone to the compound of the formula II is (2.0-5.0): 1;
c. the amidation reaction temperature is 50-150 ℃.
3. The process for preparing 5, 6-dihydropyridin-2 (1H) -one derivatives according to claim 2, characterized in that the amidation reaction temperature is 90-120 ℃.
4. The process for preparing 5, 6-dihydropyridin-2 (1H) -one derivatives according to claim 1, characterized in that the preparation of the compound of formula v from the compound of formula iii in step (2) comprises the steps of: in a solvent B, carrying out halogenation reaction on a compound shown in a formula III and a halogenating reagent 1, or, in a solvent C and in the presence of an acid-binding agent 1, carrying out sulfonylation reaction on the compound shown in the formula III and sulfonyl chloride to prepare a compound shown in a formula IV; and carrying out condensation reaction on the compound shown in the formula IV in a solvent D under the action of alkali to obtain the compound shown in the formula V.
5. The process for the preparation of 5, 6-dihydropyridin-2 (1H) -one derivatives according to claim 4 characterized by comprising one or more of the following conditions:
a. the preparation of the compound of formula V from the compound of formula IV comprises the steps of; uniformly mixing a solvent D1 and alkali to obtain a reaction solution; dissolving a compound shown in the formula IV in a solvent D2 to obtain a mixed solution; dropwise adding the mixed solution into the reaction solution, and after dropwise adding is completed for 1-3 hours, carrying out condensation reaction at 60-150 ℃; the solvent D1 and the solvent D2 are the same as the solvent D, and the total mass of the solvent D1 and the solvent D2 is the same as the mass of the solvent D;
b. the solvent B and the solvent C are one or a combination of dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, benzene or toluene; the mass ratio of the solvent B or the solvent C to the compound shown in the formula III is (3-15): 1;
c. the molar ratio of the halogenating agent 1 to the compound of formula III is (0.5-4.0): 1;
d. the temperature of the halogenation reaction is 20-100 ℃;
e. the acid-binding agent 1 is inorganic base or organic base, and the inorganic base is selected from potassium carbonate, potassium hydroxide, sodium carbonate, sodium hydroxide, lithium carbonate or lithium hydroxide; the organic base is selected from triethylamine, tri-n-propylamine, diisopropylethylamine or pyridine;
f. the sulfonyl chloride is methylsulfonyl chloride, benzene sulfonyl chloride or p-methylbenzene sulfonyl chloride;
g. the mole ratio of the sulfonyl chloride, the acid-binding agent 1 and the compound shown in the formula III is (2.0-3.0): (2.0-3.0): 1;
h. the sulfonylation reaction temperature is-20-60 ℃;
i. the solvent D is N, N-dimethylformamide or N, N-dimethylacetamide; the mass ratio of the solvent D to the compound of the formula III is 3:1-15: 1;
j. the alkali is potassium carbonate, sodium carbonate, lithium carbonate or lithium hydroxide; the molar ratio of the base to the compound of formula III is (2.0-3.0): 1;
k. the condensation reaction temperature is 60-150 ℃.
6. The process for the preparation of 5, 6-dihydropyridin-2 (1H) -one derivatives according to claim 5 characterized by comprising one or more of the following conditions:
i. the temperature of the halogenation reaction is 50-70 ℃;
ii. The sulfonylation reaction temperature is 0-20 ℃;
iii, the condensation reaction temperature is 90-120 ℃.
7. The process for preparing 5, 6-dihydropyridin-2 (1H) -one derivatives according to claim 1, characterized in that the preparation of the compound of formula vi from the compound of formula v in step (3) comprises the steps of: in a solvent E and under the action of a catalyst, performing halogenation reaction on the compound shown in the formula V and a halogenating reagent 2 at one ortho position of a carbonyl group; then in a solvent F and under the action of an acid-binding agent 2, a molecule of hydrogen halide is eliminated to obtain the compound shown in the formula VI.
8. The process for the preparation of 5, 6-dihydropyridin-2 (1H) -one derivatives according to claim 7 characterized by comprising one or more of the following conditions:
a. the solvent E is one or the combination of more than two of dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane or chlorobenzene; the mass ratio of the solvent E to the compound of the formula V is 2-15: 1;
b. the catalyst is organic phosphorus phosphite or organic amine, and the organic phosphorus phosphite is selected from one or the combination of more than two of trimethyl phosphite, triethyl phosphite, tripropyl phosphite, tributyl phosphite or triphenyl phosphite; the organic amine is one or the combination of more than two of tri-N-butylamine, 4-dimethylaminopyridine, N-methylpiperidine or pyridine; the catalyst is 0.1-5.0% of the compound of formula V;
c. the molar ratio of the compound participating in the halogenation reaction in the halogenating reagent 2 to the compound of the formula V is (0.9-1.5): 1;
d. the temperature of the halogenation reaction is 20-100 ℃;
e. the solvent F is N, N-dimethylformamide or N, N-dimethylacetamide; the mass ratio of the solvent F to the compound of the formula V is 3:1-15: 1;
f. the acid-binding agent 2 is inorganic base or organic base, the inorganic base is selected from one or a combination of potassium carbonate, sodium carbonate, calcium carbonate, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, potassium acetate, sodium acetate or calcium acetate, and the organic base is selected from one or a combination of triethylamine or tri-n-butylamine; the molar ratio of the acid-binding agent 2 to the compound of the formula V is (1.0-1.5): 1;
g. the elimination reaction temperature is 50-150 ℃.
9. The process for the preparation of 5, 6-dihydropyridin-2 (1H) -one derivatives according to claim 8 characterized by comprising one or more of the following conditions:
i. the halogenating reagent 2 is chlorine, bromine, hydrochloric acid-hydrogen peroxide or hydrobromic acid-hydrogen peroxide;
ii. The temperature of the halogenation reaction is 30-60 ℃;
and iii, the elimination reaction temperature is 90-130 ℃.
10. The process for preparing 5, 6-dihydropyridin-2 (1H) -one derivatives according to claim 1, characterized in that the preparation of 5, 6-dihydropyridin-2 (1H) -one derivatives (i) from the compounds of formula vi in step (4) comprises the steps of: in a solvent G, carrying out addition reaction on the carbon-carbon double bond of the compound shown in the formula VI and a halogenated reagent 3; then eliminating one molecule of hydrogen halide in a solvent H in the presence of an acid-binding agent 3 to obtain a 5, 6-dihydropyridine-2 (1H) -ketone derivative (I), or eliminating substitution reaction in a solvent J in the presence of an acid-binding agent 3 and morpholine to obtain the 5, 6-dihydropyridine-2 (1H) -ketone derivative (I).
11. The process for the preparation of 5, 6-dihydropyridin-2 (1H) -one derivatives according to claim 10 characterized by comprising one or more of the following conditions:
a. the solvent G, the solvent H and the solvent J are one or the combination of more than two of dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, acetonitrile, N-dimethylformamide or chlorobenzene; the mass ratio of the solvent G to the solvent H or the solvent J to the compound shown in the formula VI is (2-15) to 1;
b. the molar ratio of the compound participating in the halogenation reaction in the halogenating reagent 3 to the compound shown in the formula VI is (1.0-3.0): 1;
c. the temperature of the addition reaction is 20-100 ℃;
d. the acid-binding agent 3 is inorganic base or organic base, the inorganic base is selected from one or the combination of potassium carbonate, sodium carbonate, calcium carbonate, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate or lithium carbonate, and the organic base is selected from one or the combination of triethylamine, tri-n-butylamine, piperidine or morpholine; the molar ratio of the acid-binding agent 3 to the compound shown in the formula VI is (1.0-1.5) to 1;
e. the mol ratio of the morpholine to the compound shown in the formula VI is 1.0-1.5: 1;
f. the temperature of the elimination reaction and the temperature of the elimination substitution reaction are both 30-120 ℃.
12. The process for the preparation of 5, 6-dihydropyridin-2 (1H) -one derivatives according to claim 11 characterized by comprising one or more of the following conditions:
i. the halogenating reagent 3 is chlorine, bromine, hydrochloric acid-hydrogen peroxide or hydrobromic acid-hydrogen peroxide;
ii. The temperature of the addition reaction is 30-50 ℃;
and iii, the temperature of the elimination reaction and the temperature of the elimination substitution reaction are both 30-100 ℃.
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| CN104030972A (en) * | 2014-06-17 | 2014-09-10 | 河北序能生物技术有限公司 | Synthesis method for pyridone |
| CN105732622A (en) * | 2016-04-18 | 2016-07-06 | 山东罗欣药业集团股份有限公司 | Preparation method of apixaban |
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| CN104030972A (en) * | 2014-06-17 | 2014-09-10 | 河北序能生物技术有限公司 | Synthesis method for pyridone |
| CN105732622A (en) * | 2016-04-18 | 2016-07-06 | 山东罗欣药业集团股份有限公司 | Preparation method of apixaban |
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