CN109867679B - Preparation method of piricaconide hydrochloride intermediate - Google Patents
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Abstract
The invention provides a preparation method of a piricarb hydrochloride intermediate, which is characterized by comprising the following steps: step one, carrying out polymerization reaction on butyrolactams (I) and gamma-butyrolactone (II) under strong alkali and preset conditions to generate N- (3-carboxypropyl) butyrolactams (III); step two, cyclizing N- (3-carboxypropyl) butyrolactam (III) in a monoisopropyl malonate solvent at high temperature and condensing with a monoester salt of malonic acid to generate 7 alpha-bipynolidine-acetate; the preferred option is to form 7 α -bispyridopyrrolidine-acetic acid isopropyl ester (v). And step three, hydrolyzing the 7 alpha-bipymetrozine-acetate in acid to generate corresponding pharmaceutically acceptable salts. The preparation method avoids expensive or difficultly obtained raw materials, avoids using liquid ammonia in the synthesis process, reduces reaction steps, and has the advantages of simple operation, less three wastes and high yield.
Description
Technical Field
The invention relates to a preparation method of a piricaritib hydrochloride intermediate, belonging to the field of medicines.
Background
The chemical name of the hydrochloride piricarb is N- (2, 6-dimethylphenyl) -2- (1,2,3,5,6, 7-hexahydro-pyrrolizidin-8-yl) acetamide hydrochloride (VII), which is an Ic antiarrhythmic drug and is used for treating supraventricular arrhythmia. Clinical tests show that the piricaritide hydrochloride has obvious improvement on supraventricular premature beat, ventricular premature beat, paroxysmal atrial fibrillation and atrial flutter.
According to the reports of the literatures (EP0089061, EP0153855, J.MED.CHEM 1985(28) 714) and the like), the compound (VII) is synthesized by using 7 alpha-dipyridyl-acetic acid hydrochloride (VI), 2, 6-dimethylaniline (VIII) and the like as raw materials.
Wherein, the intermediate VII is a large chemical product which is cheap and easy to obtain, and the intermediate VI is a key intermediate for synthesizing the piricaconide hydrochloride.
At present, there is little literature on the synthesis of 7 α -bispyridazine-acetic acid hydrochloride (vi). CN101914101 describes a preparation method of 7 α -bispyridyl-acetic acid hydrochloride (vi), which comprises the steps of firstly, in a strong ammonia water and ammonia gas atmosphere, generating bispyridyl hydrochloride from 1, 7-di-p-nitrobenzenesulfonate-4-heptanone, ammonia gas and ammonium chloride, then reacting with sodium cyanoacetate to generate 8-acetonitrile group bispyridyl, hydrolyzing under a strong acid condition, and purifying with acid and alkali to obtain 7 α -bispyridyl-acetic acid hydrochloride (vi):
the method has the advantages that the price of the raw material 1, 7-di-p-nitrobenzenesulfonate-4-heptanone is high, the synthesis is complicated, high-pressure ammonia gas is required for the reaction, and the method is not suitable for large-scale production.
EP0703233 describes a process for the synthesis of 7 α -bispyridyl-ethyl acetate starting from 1, 7-dichloro-4-heptanone by reaction with diethyl malonate monopotassium salt in an ammonia atmosphere, followed by hydrolysis under acidic conditions to give 7 α -bispyridyl-acetic acid hydrochloride (vi):
the method also has the defects that the price of the raw material 1, 7-dichloro-4-heptanone is high, high-pressure ammonia gas is required for the reaction, the total yield of the reaction is only 20 percent, and the method is not suitable for large-scale production.
The literature, "students on pyrrolizidines and related compounds, part IV.A. new route to 8-substitated pyrrolizidines" (Heterocycles,16(5), 755-8; 1981) describes the following synthesis of 7 α -bispyridazine-acetic acid hydrochloride (VI):
the raw material dicyclo-pyrrolidine is unstable and easy to polymerize into diploid, no factory is available at present, the yield of 8-acetonitrile dicyclo-pyrrolidine prepared from dicyclo-pyrrolidine and cyanoacetic acid is low, and the method is not suitable for quantitative production.
Disclosure of Invention
The invention aims to provide a preparation method of a piricarb hydrochloride intermediate, so as to solve the problems.
An object of the present invention is to provide a piricarb hydrochloride intermediate, isopropyl 7 α -bispyridazine-acetate (v), which has an optimized yield in the reaction of the hydrolytic synthesis of 7 α -bispyridazine-acetic acid hydrochloride (vi), having the following structure:
the invention also aims to provide a synthesis process of the intermediate 7 alpha-bipyperrolidine-acetic acid hydrochloride (VI) of the piricamide hydrochloride, which takes butyrolactam and gamma-butyrolactone as raw materials to synthesize the 7 alpha-bipyperrolidine-acetic acid hydrochloride through dimerization, cyclization-condensation and hydrolysis. The process comprises the following steps:
the invention adopts the following technical scheme:
a preparation method of a piricaconide hydrochloride intermediate is characterized by comprising the following steps:
step one, carrying out polymerization reaction on butyrolactams (I) and gamma-butyrolactone (II) under the conditions of strong base and preset temperature to generate N- (3-carboxypropyl) butyrolactams (III);
step two, cyclizing N- (3-carboxypropyl) butyrolactam (III) in a monoisopropyl malonate solvent at a preset temperature and condensing with malonic acid monoester salt to generate 7 alpha-bipyperridine-acetate; the preferred option is to form 7 α -bispyridopyrrolidine-acetic acid isopropyl ester (v).
And step three, hydrolyzing the 7 alpha-bipymetrozine-acetate in acid to generate corresponding pharmaceutically acceptable salts.
Further, the preparation method of the intermediate of the piricarb hydrochloride also has the following characteristics: in the first step, the alkali is selected from one or a combination of at least two of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium metal, potassium metal, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide.
Preferably metallic sodium
Further, the preparation method of the intermediate of the piricarb hydrochloride also has the following characteristics: the amount of the base is 80-120%, preferably 100-110% of the amount of the compound (I) substance.
Further, the preparation method of the intermediate of the piricarb hydrochloride also has the following characteristics: in the first step, the reaction temperature is 50-250 ℃, preferably from 100 ℃ to 150 ℃.
Further, the preparation method of the intermediate of the piricarb hydrochloride also has the following characteristics: in the first step, alkali is added into gamma-butyrolactone (II), and the temperature is raised for reaction for 0-1 hour, preferably 0.5 hour. Butyl lactam is added dropwise, and the temperature is raised for reaction for 2 to 8 hours, preferably 4 to 5 hours.
Further, the preparation method of the intermediate of the piricarb hydrochloride also has the following characteristics: in the second step, the malonic acid monoester salt can be selected from, but not limited to, potassium malonate monoester salt, sodium malonate monoester salt, ammonium malonate monoester salt and the like, and potassium malonate monoester salt is preferred.
Further, the preparation method of the intermediate of the piricarb hydrochloride also has the following characteristics: in the second step, the potassium salt of malonic acid monoester can be selected from, but not limited to, potassium salt of malonic acid monomethyl ester, potassium salt of malonic acid monoethyl ester, potassium salt of malonic acid monoisopropyl ester, potassium salt of malonic acid mono-tert-butyl ester, potassium salt of malonic acid monobenzyl ester, potassium salt of malonic acid monoisopropyl ester, etc., preferably potassium salt of malonic acid monoisopropyl ester. The amount of the potassium monoisopropyl malonate is 100-150% of the amount of the compound (III), and preferably 120-130%.
Further, the preparation method of the intermediate of the piricarb hydrochloride also has the following characteristics: in the second step, the reaction is divided into a heating stage and a cooling stage, and the reaction temperature in the heating stage is as follows: 100-200 ℃, and the reaction temperature in the temperature reduction stage is as follows: 50-85 ℃; after the reaction is finished, the PH value is adjusted to 10-11, and the mixture is extracted by ethyl acetate, dried and concentrated to obtain the 7 alpha-bipypyrrole-acetic ester.
Further, the preparation method of the intermediate of the piricarb hydrochloride also has the following characteristics: in the third step, the compound (V) is dissolved in hydrochloric acid, the concentration of the hydrochloric acid is independently selected from 2-36%, preferably from 10-20%, the temperature is raised and the mixture is stirred, and the reaction temperature is independently selected from 0-150 ℃, preferably from 50-100 ℃.
Further, the preparation method of the intermediate of the piricarb hydrochloride also has the following characteristics: in the third step, after the reaction is finished, concentrating, recrystallizing and drying to obtain a compound (VI); the recrystallization solvent is independently selected from one or a mixture of at least two of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, butyl acetate, dichloromethane, trichloromethane, toluene, xylene, petroleum ether, n-hexane and n-heptane, preferably ethanol. Advantageous effects of the invention
Compared with the prior art, the invention has the advantages that the 7 alpha-bipypyrrolidine-acetic acid hydrochloride can be conveniently synthesized by using the cheap and easily obtained raw materials of butyrolactam and gamma-butyrolactone through three-step reaction, thereby avoiding expensive or difficultly obtained raw materials, avoiding using liquid ammonia in the synthesis process, reducing reaction steps, having simple and convenient operation, less three wastes and high yield. The total yield of the method for synthesizing the intermediate 7 alpha-bithick pyrrolidine-isopropyl acetate (V) by a one-pot method and then synthesizing the 7 alpha-bithick pyrrolidine-acetic acid hydrochloride (VI) by hydrolysis reaches 55-60 percent, which is far higher than the synthesis yield of the intermediate reported in the past literature;
the method provided by the invention has the advantages of mild reaction conditions, environmental friendliness and low cost, and is obviously superior to other synthetic technical routes reported in the prior art. The product obtained by the method has stable quality and is very suitable for industrial production of the piricarbone hydrochloride.
Drawings
FIG. 1 is the NMR spectrum of intermediate 7 alpha-bispyridyl-isopropyl acetate (V) in the invention.
FIG. 2 shows the NMR spectrum of intermediate 7 alpha-bispyridyl-methyl acetate (VIII).
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of intermediate 7 alpha-dipyridyl-ethyl acetate (IX) of the present invention.
FIG. 4 shows the NMR chart of intermediate 7 alpha-bispyridazine-acetic acid hydrochloride (VI) in accordance with the present invention.
Detailed Description
The present invention will be described in further detail with reference to examples. It is obvious to those skilled in the art that modifications or deletions made in accordance with the present invention are within the scope of the invention.
Example 1:
preparation of N- (3-carboxypropyl) butyrolactam (III)
Adding 18.4g (0.8mol) of metal sodium and 86.0g (1.0mol) of gamma-butyrolactone (II) into a 250mL four-mouth bottle with a mechanical stirring, condensing tube and thermometer in sequence, heating to 100 ℃, stirring, keeping the temperature, dropwise adding 85.0g (1.0mol) of butyrolactam (I), keeping the temperature for reaction for 2 hours, slowly pouring into ice water when the temperature is reduced to 70 ℃, adjusting the pH to 2-3 by using concentrated hydrochloric acid, filtering, washing with water, and drying to obtain 103.1g of white solid, wherein the melting point is 78-80 ℃, the target compound N- (3-carboxypropyl) butyrolactam (III), and the yield is: 60.3 percent.
Example 2:
preparation of N- (3-carboxypropyl) butyrolactam (III)
Adding 23.0g (1.0mol) of metal sodium and 86.0g (1.0mol) of gamma-butyrolactone (II) into a 250mL four-mouth bottle with a mechanical stirring, condensing tube and thermometer in sequence, heating to 130 ℃, stirring for 0.5 hour, keeping the temperature, dropwise adding 85.0g (1.0mol) of butyrolactam (I), keeping the temperature for reaction for 4 hours, slowly pouring into ice water when the temperature is reduced to 70 ℃, adjusting the pH to 2-3 with concentrated hydrochloric acid, filtering, washing with water, drying to obtain 145.7g of white solid, wherein the melting point is 78-80 ℃, and the yield is the target compound N- (3-carboxypropyl) butyrolactam (III): 85.2 percent.
Example 3:
preparation of N- (3-carboxypropyl) butyrolactam (III)
Adding 27.6g (1.2mol) of metal sodium and 86.0g (1.0mol) of gamma-butyrolactone (II) into a 250mL four-mouth bottle with a mechanical stirring, condensing tube and thermometer in sequence, heating to 250 ℃, stirring for 1 hour, preserving heat, dropwise adding 85.0g (1.0mol) of butyrolactam (I), preserving heat for reacting for 8 hours, slowly pouring into ice water when cooling to 70 ℃, adjusting pH to 2-3 with concentrated hydrochloric acid, filtering, washing with water, drying to obtain 150.0g of white solid, melting point of 78-80 ℃, obtaining the target compound N- (3-carboxypropyl) butyrolactam (III), yield: 87.7 percent.
Example 4:
preparation of 7 alpha-bispyridyl-acetic acid isopropyl ester (V)
100g of monoisopropyl malonate and 94.05g (0.55mol) of N- (3-carboxypropyl) butyrolactam (III) are added into a 500mL four-necked flask with a mechanical stirrer and a thermometer, the mixture is heated to 100 ℃, stirred for 2 hours, cooled to 50 ℃, dropwise added with 93.5g (0.55mol) of monoisopropyl malonate potassium salt dissolved in 300mL of monoisopropyl malonate, stirred for 12 hours, cooled to room temperature, added into 500mL of water, adjusted to pH 10-11 with sodium hydroxide, extracted with dichloromethane (100mL x 3), the organic phases are combined, dried and concentrated to obtain 65.3g of 7 alpha-dipyridyl-acetic acid isopropyl ester (V) as colorless liquid with the yield of 56.3%. And (3) recovering the monoisopropyl malonate in the water phase, adjusting the pH value to 2-3 with hydrochloric acid, layering, drying the organic phase, concentrating to obtain a crude monoisopropyl malonate, and rectifying for repeated use.
Example 5:
preparation of 7 alpha-bispyridyl-acetic acid isopropyl ester (V)
100g of monoisopropyl malonate and 94.05g (0.55mol) of N- (3-carboxypropyl) butyrolactam (III) are added into a 500mL four-mouth bottle with a mechanical stirring thermometer, the temperature is raised to 140 ℃ and 145 ℃, the stirring is carried out for 2 hours, the temperature is reduced to 80-85 ℃, 112.2g (0.66mol) of monoisopropyl malonate potassium salt is dropwise added into 300mL of monoisopropyl malonate solution, the stirring is carried out for 12 hours, the temperature is reduced to room temperature, the solution is added into 500mL of water, the pH value is adjusted to 10-11 by sodium hydroxide, the solution is extracted by dichloromethane (100mL multiplied by 3), organic phases are combined, and the colorless liquid 7 alpha-bis-thick pyrrolidine-isopropyl acetate (V) is obtained after drying and concentration, wherein the yield is 77.0%. And (3) recovering the monoisopropyl malonate in the water phase, adjusting the pH value to 2-3 with hydrochloric acid, layering, drying the organic phase, concentrating to obtain a crude monoisopropyl malonate, and rectifying for repeated use.
As shown in FIG. 1, the NMR spectrum of the compound V1H (400MHz, CDCl3): delta 4.01(q,1H),3.01(m,2H),2.63(m,2H),2.23(s,2H),1.63-1.82(m,8H),1.11(d, 6H).
Example 6:
preparation of 7 alpha-bispyridyl-acetic acid isopropyl ester (V)
50g of monoisopropyl malonate and 37.02g (0.28mol) of N- (3-carboxypropyl) butyrolactam (III) are added into a 500mL four-mouth bottle with a mechanical stirring thermometer, the temperature is raised to 110 ℃, the stirring is carried out for 2 hours, the temperature is lowered to 80-85 ℃, 56.1g (0.33mol) of monoisopropyl malonate potassium salt is dropwise added into a solution of 300mL of monoisopropyl malonate, the stirring is carried out for 12 hours, the temperature is lowered to the room temperature, the solution is added into 500mL of water, the pH value is adjusted to 10-11 by sodium hydroxide, dichloromethane is used for extraction (100mL multiplied by 3), organic phases are combined, and the mixture is dried and concentrated to obtain 40.3g of colorless liquid 7 alpha-dipyridyl-acetic acid isopropyl ester (V), and the yield is 69.3%. And (3) recovering the monoisopropyl malonate in the water phase, adjusting the pH value to 2-3 with hydrochloric acid, layering, drying the organic phase, concentrating to obtain a crude monoisopropyl malonate, and rectifying for repeated use.
Example 7:
preparation of 7 alpha-bispyridyl-acetic acid isopropyl ester (V)
50g of monoisopropyl malonate and 37.02g (0.28mol) of N- (3-carboxypropyl) butyrolactam (III) are added into a 500mL four-mouth bottle with a mechanical stirring thermometer, the temperature is raised to 140 ℃ and 145 ℃, the stirring is carried out for 2 hours, the temperature is reduced to 60 ℃, 51.2g (0.33mol) of monoisopropyl malonate sodium salt is dropped into 300mL of monoisopropyl malonate solution, the stirring is carried out for 12 hours, the temperature is reduced to room temperature, the solution is added into 500mL of water, the pH value is adjusted to 10-11 by sodium hydroxide, the solution is extracted by dichloromethane (100mL multiplied by 3), organic phases are combined, and the mixture is dried and concentrated to obtain colorless liquid 7 alpha-dipyridyl-isopropyl acetate (V) 35.7g with the yield of 61.4%. And (3) recovering the monoisopropyl malonate in the water phase, adjusting the pH value to 2-3 with hydrochloric acid, layering, drying the organic phase, concentrating to obtain a crude monoisopropyl malonate, and rectifying for repeated use.
Example 8:
preparation of 7 alpha-bispyridyl-acetic acid isopropyl ester (V)
100g of monoisopropyl malonate and 94.05g (0.55mol) of N- (3-carboxypropyl) butyrolactam (III) are added into a 500mL four-mouth bottle with a mechanical stirring thermometer, the temperature is raised to 200 ℃, the stirring is carried out for 2 hours, the temperature is reduced to 80-85 ℃, 139.0g (0.825mol) of potassium monoisopropyl malonate is dropped into 300mL of monoisopropyl malonate, the stirring is carried out for 12 hours, the temperature is reduced to room temperature, the mixture is added into 500mL of water, the pH value is adjusted to 10-11 by sodium hydroxide, the mixture is extracted by dichloromethane (100mL multiplied by 3), organic phases are combined, and the mixture is dried and concentrated to obtain 89.3g of 7 alpha-dipyridyl-isopropyl acetate (V) which is colorless liquid, and the yield is 77.0%. And (3) recovering the monoisopropyl malonate in the water phase, adjusting the pH value to 2-3 with hydrochloric acid, layering, drying the organic phase, concentrating to obtain a crude monoisopropyl malonate, and rectifying for repeated use.
Example 9:
preparation of 7 alpha-bis-pynolidine-methyl acetate (VIII)
50g of monomethyl malonate, 37.02g of N- (3-carboxypropyl) butyrolactam (III) (0.28mol) are added into a 500mL four-mouth bottle with a mechanical stirring thermometer, the temperature is raised to 145 ℃, the stirring is carried out for 2 hours, the temperature is reduced to 80-85 ℃, 43.7g (0.28mol) of potassium monomethyl malonate is dropped into 300mL of monomethyl malonate solution, the stirring is carried out for 12 hours, the temperature is reduced to the room temperature, the solution is added into 500mL of water, the pH value is adjusted to 10-11 by sodium hydroxide, dichloromethane is used for extraction (100mL multiplied by 3), organic phases are combined, and after drying and concentration, 14.9g of 7 alpha-dipyridyl-methyl acetate (VIII) which is colorless liquid is obtained, and the yield is 37.6%.
Example 10:
preparation of 7 alpha-bis-pynolidine-methyl acetate (VIII)
50g of monomethyl malonate, 37.02g of N- (3-carboxypropyl) butyrolactam (III) (0.28mol) are added into a 500mL four-mouth bottle with a mechanical stirring thermometer, the temperature is raised to 145 ℃, the stirring is carried out for 2 hours, the temperature is reduced to 80-85 ℃, 51.5g (0.33mol) of potassium monomethyl malonate is dropped into 300mL of monomethyl malonate solution, the stirring is carried out for 12 hours, the temperature is reduced to the room temperature, the solution is added into 500mL of water, the pH value is adjusted to 10-11 by sodium hydroxide, dichloromethane is used for extraction (100mL multiplied by 3), organic phases are combined, and 16.2g of 7 alpha-dipyrrolidine-methyl acetate (VIII) which is colorless liquid is obtained after drying and concentration, and the yield is 40.8%.
As shown in FIG. 2, Compound VIII 1H NMR (400MHz, CDCl3): Δ 3.63(s,3H),3.01(m,2H),2.54(m,2H),2.42(s,2H),1.59-1.96(m, 8H).
Example 11:
preparation of 7 alpha-bis-pynolidine-methyl acetate (VIII)
50g of monomethyl malonate and 37.02g (0.28mol) of N- (3-carboxypropyl) butyrolactam (III) are added into a 500mL four-necked flask with a mechanical stirring thermometer, the temperature is raised to 200 ℃, the stirring is carried out for 2 hours, the temperature is lowered to 80-85 ℃, 65.5g (0.42mol) of potassium monomethyl malonate is dropwise added into a solution of 300mL of monomethyl malonate, the stirring is carried out for 12 hours, the temperature is lowered to room temperature, the solution is added into 500mL of water, the pH value is adjusted to 10-11 by sodium hydroxide, dichloromethane extraction (100mL multiplied by 3) is carried out, organic phases are combined, and after drying and concentration, 13.1g of 7 alpha-bispyridyl-methyl acetate (VIII) as colorless liquid is obtained, and the yield is 33.0%.
Example 12:
preparation of 7 alpha-dipyridyl-ethyl acetate (IX)
50g of monoethyl malonate and 0.28mol of N- (3-carboxypropyl) butyrolactam (III) are added into a 500mL four-mouth bottle with a mechanical stirring thermometer, the temperature is raised to 200 ℃, the stirring is carried out for 2 hours, the temperature is reduced to 50 ℃, 0.28mol of potassium monoethyl malonate is dropwise added into a solution of 300mL monomethyl malonate, the stirring is carried out for 12 hours, the temperature is reduced to room temperature, the solution is added into 500mL of water, the pH value is adjusted to 10-11 by sodium hydroxide, dichloromethane (100mL multiplied by 3) is used for extraction, organic phases are combined, and colorless liquid 7 alpha-dipyridyl-ethyl acetate (IX) 12.7g is obtained after drying and concentration, and the yield is 38.7%.
Compound IX 1H NMR (400MHz, CDCl 3). delta.4.09 (q,2H),3.00(m,2H),2.53(m,2H),2.39(s,2H),1.57-1.97(m,8H),1.22(t, 3H).
Example 13:
preparation of 7 alpha-dipyridyl-ethyl acetate (IX)
50g of monoethyl malonate and 37.02g (0.28mol) of N- (3-carboxypropyl) butyrolactam (III) are added into a 500mL four-mouth bottle with a mechanical stirring thermometer, the temperature is raised to 145 ℃, the stirring is carried out for 2 hours, the temperature is reduced to 80-85 ℃, 51.5g (0.33mol) of potassium monoethyl malonate is dropped into 300mL of monomethyl malonate solution, the stirring is carried out for 12 hours, the temperature is reduced to room temperature, the solution is added into 500mL of water, the pH is adjusted to 10-11 by sodium hydroxide, dichloromethane is used for extraction (100mL multiplied by 3), organic phases are combined, and after drying and concentration, 16.2g of 7 alpha-dipyridyl-ethyl acetate (IX) which is colorless liquid is obtained, and the yield is 49.6%.
Example 14:
preparation of 7 alpha-dipyridyl-ethyl acetate (IX)
50g of monoethyl malonate and 0.28mol of N- (3-carboxypropyl) butyrolactam (III) are added into a 500mL four-mouth bottle with a mechanical stirring thermometer, the temperature is raised to 140 ℃ and 145 ℃, the stirring is carried out for 2 hours, the temperature is lowered to 80-85 ℃, 0.42mol of potassium monoethyl malonate is dropwise added into a 300mL solution of monomethyl malonate, the stirring is carried out for 12 hours, the temperature is lowered to the room temperature, the mixture is added into 500mL of water, the pH value is adjusted to 10-11 by sodium hydroxide, dichloromethane extraction (100mL multiplied by 3) is carried out, organic phases are combined, and after drying and concentration, 10.35g of 7 alpha-bithick pyrrolidine-ethyl acetate (IX) which is colorless liquid is obtained, and the yield is 31.7%.
Example 15
Preparation of 7 alpha-bispyridyl-acetic acid hydrochloride (VI)
59.1g (0.28moL) of 7 alpha-dipyridyl-isopropyl acetate (V) and 100mL of 2% hydrochloric acid are added into a 500mL four-mouth bottle with a mechanical stirring thermometer, the mechanical stirring is started, the temperature is increased to 150 ℃ for reaction for 12 hours, the temperature is reduced, the reaction liquid is concentrated to be dry, 100mL of absolute ethyl alcohol is added, the temperature is increased to reflux, the solution is cooled to 0-5 ℃ after being dissolved and is stirred for 0.5 hour, the solution is filtered and dried at 50-55 ℃, and 40.56g of white solid 7 alpha-dipyridyl-acetic acid hydrochloride (VI) is obtained, the yield is 70.5% as shown in figure 4, and the compound VI 1H NMR (400MHz, DMSO-d6): delta 13.72(s,1H),10.70(s,1H),3.48(m,2H),3.06(m,2H),2.90(s,2H),1.88-2.07(m, 8H).
Example 16
Preparation of 7 alpha-bispyridyl-acetic acid hydrochloride (VI)
Adding 59.1g (0.28moL) of 7 alpha-dipyridyl-isopropyl acetate (V) and 100mL of 20% hydrochloric acid into a 500mL four-mouth bottle with a mechanical stirrer and a thermometer, starting mechanical stirring, heating to 80 ℃, reacting for 12 hours, cooling, concentrating the reaction solution to dryness, adding 100mL of absolute ethyl alcohol, heating to reflux, cooling to 0-5 ℃ after the solution is dissolved, stirring for 0.5 hours, filtering, drying at 50-55 ℃, and obtaining 52.36g of white solid 7 alpha-dipyridyl-acetic acid hydrochloride (VI), wherein the yield is 91.0%
Example 17
Preparation of 7 alpha-bispyridyl-acetic acid hydrochloride (VI)
Adding 59.1g (0.28moL) of 7 alpha-dipyridyl-isopropyl acetate (V) and 100mL of 36% hydrochloric acid into a 500mL four-mouth bottle with a mechanical stirrer and a thermometer, starting mechanical stirring, heating to 50 ℃, reacting for 12 hours, cooling, concentrating the reaction solution to dryness, adding 100mL of absolute ethyl alcohol, heating to reflux, cooling to 0-5 ℃ after the solution is dissolved, stirring for 0.5 hours, filtering, drying at 50-55 ℃, obtaining 47.76g of white solid 7 alpha-dipyridyl-acetic acid hydrochloride (VI), wherein the yield is 83.0%
Example 18:
preparation of 7 alpha-bispyridyl-acetic acid hydrochloride (VI)
27.6g (0.14moL) of 7 alpha-dipyridyl-methyl acetate (VIII) and 100mL of concentrated hydrochloric acid are added into a 500mL four-mouth bottle with a mechanical stirrer and a thermometer, the mechanical stirrer is started, the temperature is increased to 80 ℃ for reaction for 12 hours, the temperature is reduced, the reaction liquid is concentrated to be dry, 100mL of methanol is added, the temperature is increased to reflux, the solution is cooled to 0-5 ℃ after being dissolved and cleared, the stirring is carried out for 0.5 hour, the solution is filtered, the drying is carried out at 50-55 ℃, 19.4g of white solid 7 alpha-dipyridyl-acetic acid hydrochloride (VI) is obtained, and the yield is 75.8%.
Example 19:
preparation of 7 alpha-bispyridyl-acetic acid hydrochloride (VI)
Adding 25.6g (0.14moL) of 7 alpha-dipyrrolidine-ethyl acetate (IX) and 100mL of concentrated hydrochloric acid into a 500mL four-mouth bottle with a mechanical stirrer and a thermometer, mechanically stirring, heating to 80 ℃, reacting for 12 hours, cooling, concentrating the reaction solution to dryness, adding 100mL of methanol, heating to reflux, cooling to 0-5 ℃, stirring for 0.5 hour after the solution is dissolved, filtering, drying at 50-55 ℃, obtaining 21.5g of white solid 7 alpha-dipyrrolidine-acetic acid hydrochloride (VI), wherein the yield is 78.1 percent
In the above embodiments, the hydrochloride salt is prepared, and in other embodiments, the pharmaceutically acceptable sulfate, phosphate, p-toluenesulfonate, oxalate, etc. may be prepared. The preparation of pharmaceutically acceptable salts is a well-known procedure for those skilled in the art and will not be described further herein.
Claims (9)
1. A preparation method of a piricaconide hydrochloride intermediate is characterized by comprising the following steps:
firstly, performing nucleophilic substitution reaction on butyrolactams and gamma-butyrolactone at a preset temperature in one or a composition of at least two of sodium hydroxide, potassium hydroxide, sodium metal, potassium metal, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide to generate N- (3-carboxypropyl) butyrolactams;
step two, cyclizing N- (3-carboxypropyl) butyrolactam in a monoisopropyl malonate solvent at a preset temperature and condensing with a monoester salt of malonic acid to generate 7 alpha-bipyperridine-acetate, wherein the reaction is divided into a heating stage and a cooling stage, and the reaction temperature of the heating stage is as follows: 100-200 ℃, and the reaction temperature in the temperature reduction stage is as follows: 50-85 ℃; after the reaction is finished, adjusting the pH value to 10-11, extracting with ethyl acetate, drying and concentrating to obtain 7 alpha-bipynolidine-acetate;
and step three, hydrolyzing the 7 alpha-bipymetrozine-acetate in acid to generate corresponding pharmaceutically acceptable salts.
2. The process for preparing a piricaconide hydrochloride intermediate according to claim 1, wherein:
one or the combination of at least two of sodium hydroxide, potassium hydroxide, sodium metal, potassium metal, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide is used in 80-120% of the compound butyrolactam.
3. The process for preparing a piricaconide hydrochloride intermediate according to claim 1, wherein:
in the first step, the reaction temperature is 50-250 ℃.
4. The process for preparing a piricaconide hydrochloride intermediate according to claim 1, wherein:
in the first step, one or a composition of at least two of sodium hydroxide, potassium hydroxide, metal sodium, metal potassium, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide is added into gamma-butyrolactone, the temperature is raised for reaction for 0 to 1 hour, butyrolactam is dropwise added, and the temperature is raised for reaction for 2 to 8 hours.
5. The process for preparing a piricaconide hydrochloride intermediate according to claim 1, wherein:
in the second step, the malonic acid monoester salt is selected from malonic acid monoester potassium salt, malonic acid monoester sodium salt or malonic acid monoester ammonium salt.
6. The process for preparing a piricaconide hydrochloride intermediate according to claim 5, wherein:
in the second step, the potassium malonate monoester salt is selected from potassium malonate monomethyl ester salt, potassium malonate monoethyl ester salt, potassium malonate monoisopropyl ester salt, potassium malonate mono-tert-butyl ester salt or potassium malonate mono-benzyl ester salt, and the dosage of the potassium malonate mono-isopropyl ester salt is 100% -150% of the dosage of the N- (3-carboxypropyl) butyrolactam substance.
7. The process for preparing a piricaconide hydrochloride intermediate according to claim 1, wherein:
in the third step, 7 alpha-bipyrolidine-acetate is dissolved in hydrochloric acid, the concentration of the hydrochloric acid is 2-36 percent, the temperature is raised and the stirring is carried out, and the reaction temperature is 50-100 ℃.
8. The process for preparing a piricaconide hydrochloride intermediate according to claim 1, wherein:
in the third step, after the reaction is finished, concentrating, recrystallizing and drying to obtain hydrochloride of the compound 7 alpha-bipyperridine-acetate; the recrystallization solvent is one or a mixture of at least two of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, butyl acetate, dichloromethane, trichloromethane, toluene, xylene, petroleum ether, n-hexane and n-heptane.
9. The process for preparing a piricaconide hydrochloride intermediate according to claim 1, wherein:
the dosage of the metal sodium is 110 percent of 100 percent of the amount of the butyrolactam substances,
in the first step, the reaction temperature is 100-150 ℃,
in the first step, alkali is added into gamma-butyrolactone, the temperature rise reaction is carried out for 0.5 hour, butyrolactam is dripped, the temperature rise reaction is carried out for 4 to 5 hours,
in the second step, the malonic acid monoester salt is potassium monoisopropyl malonate,
the dosage of the potassium monoisopropyl malonate is 120-130% of the N- (3-carboxypropyl) butyrolactam substance,
in the third step, 7 alpha-bipynolidine-acetate is dissolved in hydrochloric acid, the concentration of the hydrochloric acid is 10 to 20 percent,
and in the third step, after the reaction is finished, concentrating, recrystallizing and drying to obtain hydrochloride of the 7 alpha-bipyperrolidine-acetate, wherein the recrystallization solvent is ethanol.
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