CN111732531A - Method for preparing levamlodipine - Google Patents

Method for preparing levamlodipine Download PDF

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CN111732531A
CN111732531A CN202010644638.4A CN202010644638A CN111732531A CN 111732531 A CN111732531 A CN 111732531A CN 202010644638 A CN202010644638 A CN 202010644638A CN 111732531 A CN111732531 A CN 111732531A
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amlodipine
methyl
solvent
acid
mother liquor
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CN111732531B (en
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史卫明
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CHANGZHOU RUIMING PHARMACEUTICAL Co.,Ltd.
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史卫明
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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Abstract

The invention provides a method for preparing levamlodipine, belonging to the technical field of drug synthesis. The method provided by the invention comprises the following steps: concentrating the amlodipine split mother liquor to be dry, mixing the amlodipine split mother liquor with an oxidant and a first solvent, and carrying out oxidation reaction to obtain 2- ((2-aminoethoxy) methyl) -4- (2-chlorphenyl) -6-methyl-3, 5-pyridinedicarboxylic acid methyl ethyl ester; wherein the oxidant is an achiral reagent; mixing the 2- ((2-aminoethoxy) methyl) -4- (2-chlorphenyl) -6-methyl-3, 5-pyridinedicarboxylic acid methyl ethyl ester, a reducing agent and a second solvent, and carrying out reduction reaction to obtain an amlodipine racemate; and mixing the amlodipine racemate, a resolution reagent and a third solvent, and performing resolution treatment to obtain the levamlodipine. The method provided by the invention can effectively recycle the amlodipine in the amlodipine resolution mother liquor and convert the amlodipine into high-value levamlodipine.

Description

Method for preparing levamlodipine
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a method for preparing levamlodipine.
Background
Amlodipine is a dihydropyridine calcium channel receptor antagonist and is used for treating various types of hypertension and angina pectoris. Hypertension patients also show symptoms such as dizziness, headache, palpitation, fatigue and the like clinically, and can affect organs such as heart, brain, kidney and the like in severe cases to cause serious diseases such as myocardial infarction, renal failure, stroke paralysis and the like, so that high attention must be paid to the prevention and treatment of the diseases. Amlodipine (racemate) and levamlodipine are the first-line clinical hypotensor at present, and have clear mechanism and definite curative effect. The clinical comparison effect of amlodipine and levoamlodipine on hypertension treatment is reported in the literature (health of today 2016,15(10):165-166), and the results show that: the total effective rate of the levamlodipine group is 93.6 percent, which is higher than that of the amlodipine group (76.6 percent), the systolic pressure and the diastolic pressure after the administration are both lower than those of the amlodipine group, and the incidence rate of adverse reactions (4.3 percent) is lower than that of the amlodipine group (10.6 percent). The main adverse reactions of amlodipine are headache, edema and the like, the side effects are mainly caused by dextro-isomer, and levo-amlodipine is favored by more doctors and patients due to less adverse reactions.
At present, the industrial preparation method of the levamlodipine is only a resolution method, the method adopts cheap chiral acid such as D-tartaric acid, dibenzoyl D-tartaric acid and the like as a resolution reagent, forms salt with the amlodipine racemate, and utilizes the characteristic that the two formed salts are diastereoisomers to separate by adopting a recrystallization method. As is well known, the theoretical yield of the resolution method is only 50%, and the current yield is only about 45% at most due to factors such as recrystallization loss and the like in the actual operation process, so that about 55% of materials (mainly containing dextroamlodipine with an ee value of about 90% and a small amount of levoamlodipine) in the mother liquor (i.e. the amlodipine resolution mother liquor) obtained after resolution and recrystallization cannot be effectively utilized, and the materials are usually used as waste materials to enter a three-waste treatment system, so that the great resource waste is caused. In addition, the molecular structure of amlodipine contains chlorine atoms, so that the waste materials are easy to generate dioxin by adopting a common burning method to cause secondary pollution, and the waste materials can be treated more thoroughly by using higher burning temperature (such as above 800 ℃); in addition, the hydrogen chloride in the combustion tail gas needs to be absorbed and treated, so the treatment cost is much higher than that of the common organic waste. Therefore, how to effectively treat the amlodipine split mother liquor and realize resource utilization thereof is a problem which needs to be solved at present.
Disclosure of Invention
The invention aims to provide a method for preparing levamlodipine, which takes an amlodipine resolution mother liquor as a raw material, can change waste into valuable through oxidation, reduction and resolution treatment, effectively recycles amlodipine in the amlodipine resolution mother liquor, and converts the amlodipine into high-value levamlodipine.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a method for preparing levamlodipine, which comprises the following steps:
concentrating the amlodipine split mother liquor to be dry, mixing the amlodipine split mother liquor with an oxidant and a first solvent, and carrying out oxidation reaction to obtain 2- ((2-aminoethoxy) methyl) -4- (2-chlorphenyl) -6-methyl-3, 5-pyridinedicarboxylic acid methyl ethyl ester; wherein the oxidant is an achiral reagent;
mixing the 2- ((2-aminoethoxy) methyl) -4- (2-chlorphenyl) -6-methyl-3, 5-pyridinedicarboxylic acid methyl ethyl ester, a reducing agent and a second solvent, and carrying out reduction reaction to obtain an amlodipine racemate;
and mixing the amlodipine racemate, a resolution reagent and a third solvent, and performing resolution treatment to obtain the levamlodipine.
Preferably, the oxidant is at least one of hypochlorous acid, hypochlorite, hydrogen peroxide, peroxycarboxylic acid and m-chloroperoxybenzoic acid, and the ratio of the total amount of levoamlodipine and dextroamlodipine to the amount of the oxidant in the amlodipine resolution mother liquor is 1 (1-2).
Preferably, the first solvent is a mixed solvent of a first organic solvent and water, and the first organic solvent is at least one of ethyl acetate, dichloromethane, 1, 2-dichloroethane, toluene, and acetonitrile.
Preferably, the temperature of the oxidation reaction is 0-30 ℃.
Preferably, the reducing agent is borohydride and/or substituted borohydride, and the molar ratio of the 2- ((2-aminoethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-3, 5-pyridinedicarboxylic acid methyl ethyl ester to the reducing agent is 1 (1-1.5); the second solvent is carboxylic acid, and the dosage ratio of the 2- ((2-aminoethoxy) methyl) -4- (2-chlorphenyl) -6-methyl-3, 5-pyridine dicarboxylic acid methyl ethyl ester to the second solvent is 1mol (1.8-2.2) L.
Preferably, the reducing agent is KBH4、NaBH4、Ca(BH4)2、NaBH3Of CN, sodium methoxyborohydride, sodium acetoxyborohydride and sodium phenoxyborohydrideAt least one of; the second solvent is at least one of acetic acid, propionic acid, butyric acid and valeric acid.
Preferably, the temperature of the reduction reaction is 0-25 ℃.
Preferably, the resolving agent is D-tartaric acid or D-2, 3-di (benzoyloxy) tartaric acid, and the molar ratio of the resolving agent to the amlodipine racemate is (0.4-0.6): 1.
Preferably, the third solvent comprises at least one of dimethyl sulfoxide, methyl ethyl sulfoxide, and sulfolane.
Preferably, the splitting process further comprises: carrying out first solid-liquid separation on the system obtained after the splitting treatment to obtain a first liquid material and a first solid material; the first liquid material is used as amlodipine split mother liquor for cyclic application; and (3) dissolving the first solid material in water after washing, adjusting the pH value of the obtained water solution to be more than or equal to 9, separating out solids, carrying out second solid-liquid separation on the obtained system, and drying the obtained second solid material after washing to obtain the levamlodipine.
The invention provides a method for preparing levamlodipine, which comprises the following steps: concentrating the amlodipine split mother liquor to be dry, mixing the amlodipine split mother liquor with an oxidant and a first solvent, and carrying out oxidation reaction to obtain 2- ((2-aminoethoxy) methyl) -4- (2-chlorphenyl) -6-methyl-3, 5-pyridinedicarboxylic acid methyl ethyl ester; wherein the oxidant is an achiral reagent; mixing the 2- ((2-aminoethoxy) methyl) -4- (2-chlorphenyl) -6-methyl-3, 5-pyridinedicarboxylic acid methyl ethyl ester, a reducing agent and a second solvent, and carrying out reduction reaction to obtain an amlodipine racemate; and mixing the amlodipine racemate, a resolution reagent and a third solvent, and performing resolution treatment to obtain the levamlodipine. The method takes the amlodipine splitting mother liquor as a raw material, can change waste into valuable through oxidation, reduction and splitting treatment, effectively recycles the amlodipine in the amlodipine splitting mother liquor, converts the amlodipine into high-value levamlodipine, meets the requirement of the era theme for building a conservation-oriented society, and has great economic benefit and social benefit.
Detailed Description
The invention provides a method for preparing levamlodipine, which comprises the following steps:
concentrating the amlodipine split mother liquor to be dry, mixing the amlodipine split mother liquor with an oxidant and a first solvent, and carrying out oxidation reaction to obtain 2- ((2-aminoethoxy) methyl) -4- (2-chlorphenyl) -6-methyl-3, 5-pyridinedicarboxylic acid methyl ethyl ester; wherein the oxidant is an achiral reagent;
mixing the 2- ((2-aminoethoxy) methyl) -4- (2-chlorphenyl) -6-methyl-3, 5-pyridinedicarboxylic acid methyl ethyl ester, a reducing agent and a second solvent, and carrying out reduction reaction to obtain an amlodipine racemate;
and mixing the amlodipine racemate, a resolution reagent and a third solvent, and performing resolution treatment to obtain the levamlodipine.
The method takes the amlodipine splitting mother liquor as a raw material, can change waste into valuable through oxidation, reduction and splitting treatment, effectively recycles the amlodipine in the amlodipine splitting mother liquor, and converts the amlodipine into high-value levamlodipine. The source of the amlodipine resolution mother liquor is not particularly limited in the invention, and any amlodipine resolution mother liquor with a source well known to those skilled in the art can be used, and specifically, the amlodipine resolution mother liquor can be obtained by resolution (the resolution reagent preferably comprises D-tartaric acid or D-2, 3-di (benzoyloxy) tartaric acid) by a conventional method and recrystallization. In the invention, the amlodipine resolution mother liquor usually contains 10-20 wt% of amlodipine (the total amount of levorotatory isomer and dextrorotatory isomer), and the method for measuring the content of amlodipine in the amlodipine resolution mother liquor is not particularly limited, and can be a method well known by the technical personnel in the field. In the embodiment of the invention, the amlodipine resolution mother liquor is concentrated to be dry, sodium hydroxide solution and Dichloromethane (DCM) are added into the residue for first extraction, and liquid separation is carried out to obtain a first organic layer and a first water layer; adding DCM into the first water layer for second extraction, and separating liquid to obtain a second organic layer and a second water layer; and combining the first organic layer and the second organic layer, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, washing a filter cake, combining an obtained washing solution and a filtrate, evaporating to dryness, and drying the obtained residue in vacuum to constant weight to obtain a white solid, namely amlodipine (the total of levorotatory isomer and dextrorotatory isomer), wherein the content of amlodipine in the amlodipine resolution mother liquor can be obtained according to the quality of the obtained white solid and the quality of the amlodipine resolution mother liquor. The method for concentrating the amlodipine resolution mother liquor is not particularly limited, and the method well known by the technical personnel in the field can be adopted. In the invention, the concentration of the sodium hydroxide solution is preferably 8-12 wt%, and more preferably 10 wt%; the dosage ratio of the amlodipine resolution mother liquor to the sodium hydroxide solution and DCM during the first extraction is preferably 1g (0.8-1.2) mL, and more preferably 1g:1mL:1 mL; the amount of DCM used in the second extraction is preferably 1/2 of the amount of DCM used in the first extraction.
The method comprises the steps of concentrating an amlodipine resolution mother liquor to dryness, mixing the amlodipine resolution mother liquor with an oxidant and a first solvent, and carrying out oxidation reaction to obtain 2- ((2-aminoethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-3, 5-picolinic acid methyl ethyl ester; wherein the oxidant is an achiral reagent. In the present invention, the oxidizing agent is preferably at least one of hypochlorous acid (preferably, a 10% available chlorine aqueous solution is used), hypochlorite, hydrogen peroxide, peroxycarboxylic acid, and m-chloroperoxybenzoic acid, and more preferably hypochlorous acid, hypochlorite, hydrogen peroxide (preferably, 25% hydrogen peroxide by mass), peroxycarboxylic acid, or m-chloroperoxybenzoic acid, and the hypochlorite is preferably NaClO, KClO, or ca (clo)2The peroxycarboxylic acid is preferably peroxyacetic acid (preferably 15 mass percent of peroxyacetic acid aqueous solution is used); in the invention, the ratio of the total substance amount of the levamlodipine and the dextroamlodipine to the substance amount of the oxidant in the amlodipine resolution mother liquor is preferably 1 (1-2), and specifically can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.5, 1:1.7 or 1: 2. In the present invention, the first solvent is preferably a mixed solvent of a first organic solvent and water, the first organic solvent is preferably at least one of ethyl acetate, dichloromethane, 1, 2-dichloroethane, toluene, and acetonitrile, and more preferably ethyl acetate, dichloromethane, 1, 2-dichloroethane, toluene, or acetonitrile; the volume ratio of the first organic solvent to the water in the first solvent is preferably (1.8-2.2): 1, and more preferablyThe selection is 2: 1.
In the present invention, it is preferable that after the amlodipine resolution mother liquor is concentrated to dryness, the obtained residue is mixed with the first solvent, and the oxidizing agent is slowly added in portions under the stirring condition, followed by the oxidation reaction. In the invention, the stirring speed is preferably 800-1200 rpm, and more preferably 900-1100 rpm; the oxidation reaction is exothermic reaction, and the oxidant is slowly added in batches under the condition of violent stirring, so that the flushing is avoided; the specific operation mode of the present invention for the slow batch-wise addition of the oxidizing agent is not particularly limited, and may be any mode known to those skilled in the art.
In the invention, the temperature of the oxidation reaction is preferably 0-30 ℃, and specifically, the temperature of the oxidation reaction can be controlled within the range of 0-10 ℃, 10-20 ℃ or 20-30 ℃; the oxidation reaction end point is preferably monitored by thin-layer chromatography until the amlodipine in the amlodipine splitting mother liquor is completely consumed, namely the oxidation reaction is finished; in the present invention, the oxidation reaction is preferably carried out under a stirring condition, and the stirring speed is preferably 100 to 1200rpm, and more preferably 300 to 500 rpm.
After the oxidation reaction, in the invention, preferably, the system obtained after the oxidation reaction is subjected to liquid separation, the organic layer is washed by water, saturated saline solution and anhydrous Na2SO4And (2) filtering after drying, washing a filter cake twice, combining the obtained washing liquid with the filtrate, evaporating to dryness, recrystallizing the residue by using an ethanol water solution with the volume fraction of 88-92% (preferably 90%) to obtain a light yellow solid, and drying in vacuum to constant weight to obtain the 2- ((2-aminoethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-3, 5-pyridinedicarboxylic acid methyl ethyl ester.
After obtaining methyl ethyl 2- ((2-aminoethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-3, 5-pyridinedicarboxylate, the invention mixes the methyl ethyl 2- ((2-aminoethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-3, 5-pyridinedicarboxylate, a reducing agent and a second solvent, and performs a reduction reaction to obtain amlodipine racemate. In the present invention, the reducing agent is preferably a borohydride and/or a substituted borohydride, more preferably KBH4、NaBH4、Ca(BH4)2、NaBH3At least one of CN, sodium methoxyborohydride, sodium acetoxyborohydride and sodium phenoxyborohydride, wherein the molar ratio of the 2- ((2-aminoethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-3, 5-pyridinedicarboxylic acid methyl ethyl ester to the reducing agent is preferably 1 (1-1.5), and specifically can be 1:1.1, 1:1.2, 1:1.3 or 1: 1.5; the second solvent is preferably carboxylic acid, more preferably at least one of acetic acid, propionic acid, butyric acid and valeric acid, the butyric acid is preferably n-butyric acid or isobutyric acid, the valeric acid is preferably n-valeric acid, and the using ratio of the 2- ((2-aminoethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-3, 5-pyridinedicarboxylic acid methyl ethyl ester to the second solvent is preferably 1mol (1.8-2.2) L, more preferably 1mol: 2L.
In the invention, preferably, the 2- ((2-aminoethoxy) methyl) -4- (2-chlorphenyl) -6-methyl-3, 5-pyridine dicarboxylic acid methyl ethyl ester is dissolved in a second solvent, and a reducing agent is slowly added for reduction reaction. In the invention, the temperature of the reduction reaction is preferably 0-25 ℃, and particularly, the temperature of the reduction reaction can be controlled within the range of 0-5 ℃, 5-15 ℃ or 15-25 ℃; the invention preferably monitors the end point of the reduction reaction by thin-layer chromatography until the methyl ethyl 2- ((2-aminoethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-3, 5-pyridinedicarboxylate in the system is completely consumed, namely the reduction reaction is finished. In the invention, the reduction reaction is preferably carried out under a stirring condition, and the stirring speed is preferably 100-1200 rpm, and more preferably 800-1100 rpm.
After the reduction reaction, the system obtained by the reduction reaction is preferably subjected to reduced pressure distillation to recover the second solvent, then water is added into the residue, stirring is carried out, a white precipitate is separated out, filtering and washing are carried out on a filter cake, and recrystallization is carried out by using a mixed solvent of acetone and petroleum ether (the volume ratio of acetone to petroleum is preferably 1 (0.8-1.2), more preferably 1:1), so as to obtain a light yellow powdery solid, namely the amlodipine racemate.
After the amlodipine racemate is obtained, the method mixes the amlodipine racemate, the resolution reagent and the third solvent, and performs resolution treatment to obtain the levamlodipine. In the present invention, the resolving agent is preferably D-tartaric acid or D-2, 3-bis (benzoyloxy) tartaric acid, and the molar ratio of the resolving agent to the amlodipine racemate is preferably (0.4 to 0.6) to 1, and specifically may be 0.45:1, 0.5:1, 0.55:1 or 0.6: 1. In the present invention, the third solvent preferably includes at least one of dimethyl sulfoxide, methyl ethyl sulfoxide, and sulfolane, specifically dimethyl sulfoxide, methyl ethyl sulfoxide, and sulfolane, and may also be used in combination with acetone or ethanol, specifically, the third solvent is more preferably a sulfolane/ethanol mixed solvent (the volume ratio of sulfolane to ethanol is preferably 1:1), a dimethyl sulfoxide/acetone mixed solvent (the volume ratio of dimethyl sulfoxide to acetone is preferably 4:1), dimethyl sulfoxide, methyl ethyl sulfoxide, or sulfolane.
The mixing sequence of the amlodipine racemate, the resolution reagent and the third solvent is not specially limited, and the components are uniformly mixed. In the invention, the temperature of the splitting treatment is preferably 15-60 ℃, and more preferably 30-60 ℃. In the invention, the time for the resolution treatment is preferably 2-10 h, and more preferably 3-6 h. In the invention, the resolution treatment is preferably carried out under a stirring condition, and the stirring speed is preferably 100-1200 rpm, and more preferably 500-800 rpm.
After the resolution treatment, the system obtained after the resolution treatment is preferably subjected to first solid-liquid separation to obtain a first liquid material and a first solid material; the first liquid material is used as amlodipine split mother liquor for cyclic application; and (3) dissolving the first solid material in water after washing, adjusting the pH value of the obtained water solution to be more than or equal to 9, separating out solids, carrying out second solid-liquid separation on the obtained system, and drying the obtained second solid material after washing to obtain the levamlodipine. The first solid-liquid separation and the second solid-liquid separation are not particularly limited, and the solid-liquid separation can be realized by adopting filtration; the reagent used for washing the first solid material is preferably a third solvent so as to be convenient for recycling and reusing the solvent; the concentration of the NaOH solution is not particularly limited, the pH value of the aqueous solution can be adjusted to be more than or equal to 9 (the pH value of the aqueous solution is preferably 9-10), and under the condition of the pH value, a white and slightly yellowish green solid is precipitated from the system, namely the levamlodipine; the reagent used to wash the second solid material is preferably water.
In the invention, the first liquid material is circularly used as the amlodipine splitting mother liquor, and specifically, the first liquid material can be directly and independently treated, or a plurality of batches of the first liquid materials can be combined for post-treatment, which is not specially limited in the invention; the treatment method is preferably performed by referring to the oxidation, reduction and resolution treatment method in the above technical solution, and details are not repeated here.
The amlodipine splitting mother liquor generally belongs to waste materials needing incineration treatment, and the method provided by the invention prepares the levamlodipine from the amlodipine splitting mother liquor serving as a raw material, so that waste is changed into valuable, and great economic benefit and social benefit are realized; the reaction route of the method is shown as the formula a:
Figure BDA0002572572770000071
the process of the present invention will now be described in detail with reference to formula a. Firstly, amlodipine (mainly containing dextroamlodipine and a small amount of levoamlodipine, wherein dextroamlodipine is shown as a structure shown in a formula 1 in a formula a) contained in an amlodipine resolution mother liquor is oxidized by an oxidant, and both the dextroamlodipine and the levoamlodipine contained in the amlodipine resolution mother liquor can be oxidized to generate 2- ((2-aminoethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-3, 5-pyridinedicarboxylic acid methyl ethyl ester (namely, a compound with the structure shown in the formula 2 in the formula a is marked as a compound 2) because the oxidant is an achiral reagent; the 2- ((2-aminoethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-3, 5-pyridinedicarboxylic acid methyl ethyl ester is reduced by a reducing agent to obtain amlodipine racemate (the structure shown in the formula 3 in the formula a is schematic), and the amlodipine racemate is subjected to resolution treatment to obtain levoamlodipine (namely the compound shown in the formula 4 in the formula a).
In the method provided by the invention, the total yield of two steps of reaction of oxidation and reduction treatment can reach more than 80%, and the yield of resolution treatment can reach about 45%; meanwhile, mother liquor (namely the first liquid material) generated after the splitting treatment can be independently or combined in batches for recycling by adopting the method, so that great economic benefit and social benefit are realized.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Measuring the content of amlodipine (the total amount of levorotatory isomer and dextrorotatory isomer) in the amlodipine resolution mother liquor:
taking 100g (the mass is recorded as m) of amlodipine resolution mother liquor (D-tartaric acid is taken as a resolving agent)1) Concentrating to dryness, adding 100mL of 10 wt% sodium hydroxide solution and 100mL of Dichloromethane (DCM) to the residue, and separating to obtain a first organic layer and a first aqueous layer; adding 50mL of DCM into the first water layer for extraction once to obtain a second organic layer and a second water layer; combining the first organic layer and the second organic layer, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, evaporating the filtrate to dryness, and vacuum drying the obtained residue to constant weight to obtain white solid, namely amlodipine (total levorotatory body and dextrorotatory body), wherein the mass of the white solid is m1The content of amlodipine (total amount of levorotatory isomer and dextrorotatory isomer) in the amlodipine resolution mother liquor is that R is 100 percent × m2/m1(ii) a R is usually between 10 and 20%.
Example 2
Preparation of methyl ethyl 2- ((2-aminoethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-3, 5-pyridinedicarboxylate (noted as compound 2):
300g of amlodipine resolution mother liquor (D-tartaric acid is used as a resolving agent; the content of amlodipine is measured to be 15 wt% by the method of example 1 by taking levorotatory isomer and dextrorotatory isomer together) is concentrated to be dry, 600mL of ethyl acetate and 300mL of water are added into residue, 0.12mol of calcium hypochlorite is slowly added in batches under the condition of strong stirring at 1100rpm, and the system temperature is kept during the adding processControlling the temperature to be 20-30 ℃, stirring at 300rpm after adding for oxidation reaction, monitoring the reaction end point by using a thin-layer chromatography, and ending the reaction until amlodipine in the amlodipine resolution mother liquor is completely consumed; separating the obtained system after the reaction is finished, washing the organic layer with water, washing with saturated saline water and then with anhydrous Na2SO4Drying, filtering, washing a filter cake twice, combining the obtained washing liquid with the filtrate, evaporating to dryness, recrystallizing the residue by using an ethanol water solution with the volume fraction of 90% to obtain a light yellow solid, and drying in vacuum to constant weight to obtain the product, wherein the yield is 93.4% (specifically shown as a reaction number 1 in Table 1).
Product characterization data were as follows:
IR (liquid film method, cm)-1):3376,2951,1730,1595,1436,1232,1109,1045。
1H-NMR(400MHz,CDCl3):0.92(3H,t,J＝7.1Hz),2.65(3H,s),2.75(2H,brs,D2Disappearance after O exchange), 2.83(2H, t, J ═ 4.9Hz),3.49 to 3.54(5H, m),4.00(2H, q, J ═ 14.22Hz),4.78(1H, d, J ═ 12.7Hz),4.84(1H, d, J ═ 12.6Hz),7.18(1H, d × d, J ═ 12.6Hz), and so on1＝7.3Hz,J2＝1.7Hz),7.27-7.35(2H,m),7.42(1H,d,J＝7.3Hz)。
13C-NMR(100MHz,CDCl3):13.37,23.16,41.69,52.10,61.24,73.09,73.31,126.03,128.10,129.03,129.75,130.19,132.81,134.90,156.02,156.26,166.54,167.28.ESI-MS(m/z):,407,409[M+H+]The abundance ratio of signals 407 to 409 was 3: 1.
The results obtained by carrying out the oxidation reaction under other conditions in a similar manner as described above are shown in Table 1 (specifically, as shown in reaction Nos. 2 to 35, the conditions not shown are the same as those described above).
Table 1 reaction results for preparing compound 2 from amlodipine resolution mother liquor under different conditions
Figure BDA0002572572770000091
Figure BDA0002572572770000101
Note:"MCPBA" in Table 1 is m-chloroperoxybenzoic acid; "HClO" used is an aqueous hypochlorous acid solution having an available chlorine of 10%; ' CH3COOOH is 15% of peroxyacetic acid aqueous solution; ' H2O2Hydrogen peroxide with the mass fraction of 25 percent is used; the molar ratio refers to the molar ratio of amlodipine (sum of levorotatory isomer and dextrorotatory isomer) to oxidant in the amlodipine resolution mother liquor.
As is clear from table 1, the oxidation reaction was carried out under the above conditions, and the oxidation effect was excellent and the yield was satisfactory.
Example 3
Preparation of amlodipine racemate:
compound 2(406.9g, 1mol) was mixed with glacial acetic acid (2L) with stirring and KBH was added slowly4(81g, 1.5mol), stirring at 1100rpm for 2h after the addition is finished, and monitoring the reaction end point by thin-layer chromatography; after the reaction is finished, acetic acid is recovered by reduced pressure distillation, then 2L of water is added into the residue, stirring is carried out, a white precipitate is separated out, filtering is carried out, a filter cake is washed by water, and recrystallization is carried out by using a mixed solvent of acetone and petroleum ether (the volume ratio of acetone to petroleum is 1:1) to obtain a light yellow powdery solid, namely amlodipine racemate, wherein the yield is 377.4g and 92.3 percent (specifically shown as reaction number 1 in Table 2).
The nuclear magnetism, mass spectrum signal and HPLC retention time of the product are consistent with those of the standard product.
The results obtained by carrying out the reduction reaction under other conditions in a similar manner as described above are shown in Table 2 (specifically, as shown in reaction Nos. 2 to 19, the conditions not shown are the same as those described above).
Table 2 reaction results for preparing amlodipine racemate from compound 2 under different conditions
Figure BDA0002572572770000111
Figure BDA0002572572770000121
Note: in table 2, "reducing system" means "reducing agent/reaction solvent"; "molar ratio" refers to the molar ratio of compound 2 to reducing agent.
As is clear from table 2, the reduction reaction was carried out under the above conditions, and the reduction effect was excellent and the yield was satisfactory.
Example 4
Preparation of levamlodipine
Mixing 2L dimethyl sulfoxide (DMSO), amlodipine racemate (498.83g, 1.22mol), D-tartaric acid (109.57g, 0.73mol) and 0.5L acetone at room temperature, heating to 60 ℃ within 1h under the stirring condition of 500rpm, keeping the temperature for 0.5h, completely clarifying the system at this time, naturally cooling to room temperature within 2h to separate out white solid, filtering, collecting filtrate for circulation treatment (namely carrying out the treatment processes of examples 1 to 4), washing a filter cake by using a mixed solvent of DMSO and acetone (the volume ratio of DMSO to acetone is 4:1), dissolving the washed filter cake into water, dropwise adding an NaOH solution until the pH value of the system is 10, separating out white slightly yellowish green solid, filtering, washing the filter cake by using water, carrying out vacuum drying to constant weight to obtain 225.4g of levoamlodipine, keeping the retention time of mass spectrometry signals and HPLC consistent with that of a standard product, wherein the yield is 45.2%, the chemical purity is more than 99.9 percent, and the ee value is more than 99.9 percent (specifically shown as reaction number 1 in Table 3); wherein, the chemical purity is measured by a high performance liquid chromatography normalization method, and the optical purity is measured by a high performance liquid chromatography (chiral chromatographic column) according to the quality standard of the medicine related to the version 2010 of Chinese pharmacopoeia.
The results obtained by performing the resolution treatment under other conditions by the similar method are shown in table 3 (specifically, as shown in reaction numbers 2 to 12, the conditions not shown are the same as the above method).
TABLE 3 results of the resolution treatment under different conditions
Figure BDA0002572572770000131
Note: in table 3, "amount of resolving agent" means the molar ratio of resolving agent to amlodipine racemate.
As can be seen from table 3, the resolution treatment under the above conditions can achieve a good resolution effect, and the yield, chemical and optical purity of levamlodipine are satisfactory.
Example 5
The amlodipine splitting mother liquor is circularly applied for a plurality of times to prepare the levoamlodipine:
collecting three batches of filtrate obtained by filtering after the splitting treatment in the embodiment 4, combining the three batches of filtrate together to be used as an amlodipine splitting mother liquor, treating the mother liquor according to the methods of the embodiments 1 to 4 to prepare the levoamlodipine, and recording the levoamlodipine as the 1 st cycle treatment process; the yield, chemical purity and optical purity of the prepared levamlodipine are not statistically different from those obtained in example 4 after a total of 5 cycles of treatment according to the above method.
By the above example treatment method, each time the amlodipine splitting mother liquor is subjected to one cycle treatment process, taking the conditions shown as reaction number 1 in tables 1 to 3 as examples, the obtained levamlodipine yield is 93.4% × 92.3.3% × 45.2.2% ═ 39.0%, which is equivalent to converting 39.0% of chlorine-containing "waste materials" (mainly dextroamlodipine and a small amount of levorotatory bodies) in the amlodipine splitting mother liquor into valuable levoamlodipine (the market price of the current levamlodipine exceeds one million/ton), the residual amount of amlodipine (mainly dextroamlodipine and a small amount of levorotatory bodies) in the amlodipine splitting mother liquor is 1-39.0%: 61.0%, and the cyclic treatment process can generate the "splitting mother liquor", which can be further treated by the cycle operation of examples 1 to 4, and when the cycle treatment is performed 5 times, chlorine-containing organic "waste materials" can only remain (1-39.0%)5The utilization rate of waste material is up to 1-8.4% ~ 91.6%. The data show that after the amlodipine splitting mother liquor is treated for many times, the chlorine-containing organic waste generated in the preparation process of the levamlodipine can be reduced to a very low level, and the amlodipine in the amlodipine splitting mother liquor can be recycled to the maximum extent, so that the waste is changed into valuable, the requirement of the era on building a conservation-oriented society is met, and great economic benefit and social benefit are achieved.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (10)

1. A method for preparing levamlodipine, comprising the steps of:
concentrating the amlodipine split mother liquor to be dry, mixing the amlodipine split mother liquor with an oxidant and a first solvent, and carrying out oxidation reaction to obtain 2- ((2-aminoethoxy) methyl) -4- (2-chlorphenyl) -6-methyl-3, 5-pyridinedicarboxylic acid methyl ethyl ester; wherein the oxidant is an achiral reagent;
mixing the 2- ((2-aminoethoxy) methyl) -4- (2-chlorphenyl) -6-methyl-3, 5-pyridinedicarboxylic acid methyl ethyl ester, a reducing agent and a second solvent, and carrying out reduction reaction to obtain an amlodipine racemate;
and mixing the amlodipine racemate, a resolution reagent and a third solvent, and performing resolution treatment to obtain the levamlodipine.
2. The method according to claim 1, wherein the oxidant is at least one of hypochlorous acid, hypochlorite, hydrogen peroxide, peroxycarboxylic acid and m-chloroperoxybenzoic acid, and the ratio of the total amount of the levoamlodipine and the dextroamlodipine to the amount of the oxidant in the amlodipine resolution mother liquor is 1 (1-2).
3. The method according to claim 2, wherein the first solvent is a mixed solvent of a first organic solvent and water, and the first organic solvent is at least one of ethyl acetate, dichloromethane, 1, 2-dichloroethane, toluene, and acetonitrile.
4. A process according to any one of claims 1 to 3, wherein the temperature of the oxidation reaction is from 0 to 30 ℃.
5. The method according to claim 1, wherein the reducing agent is borohydride and/or substituted borohydride, and the molar ratio of the 2- ((2-aminoethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-3, 5-pyridinedicarboxylic acid methyl ethyl ester to the reducing agent is 1 (1-1.5); the second solvent is carboxylic acid, and the dosage ratio of the 2- ((2-aminoethoxy) methyl) -4- (2-chlorphenyl) -6-methyl-3, 5-pyridine dicarboxylic acid methyl ethyl ester to the second solvent is 1mol (1.8-2.2) L.
6. The method of claim 5, wherein the reducing agent is KBH4、NaBH4、Ca(BH4)2、NaBH3At least one of CN, sodium methoxyborohydride, sodium acetoxyborohydride and sodium phenoxyborohydride; the second solvent is at least one of acetic acid, propionic acid, butyric acid and valeric acid.
7. The method of claim 1, 5 or 6, wherein the temperature of the reduction reaction is 0 to 25 ℃.
8. The method according to claim 1, wherein the resolving agent is D-tartaric acid or D-2, 3-di (benzoyloxy) tartaric acid, and the molar ratio of the resolving agent to the amlodipine racemate is (0.4-0.6): 1.
9. The method of claim 1 or 8, wherein the third solvent comprises at least one of dimethyl sulfoxide, methyl ethyl sulfoxide, and sulfolane.
10. The method according to claim 1 or 8, wherein the splitting process further comprises: carrying out first solid-liquid separation on the system obtained after the splitting treatment to obtain a first liquid material and a first solid material; the first liquid material is used as amlodipine split mother liquor for cyclic application; and (3) dissolving the first solid material in water after washing, adjusting the pH value of the obtained water solution to be more than or equal to 9, separating out solids, carrying out second solid-liquid separation on the obtained system, and drying the obtained second solid material after washing to obtain the levamlodipine.
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US5708177A (en) * 1995-09-01 1998-01-13 Bayer Aktiengesellschaft Process for the preparation of optically active ortho-substituted 4-aryl-dihydropyridines
CN101798280A (en) * 2010-03-22 2010-08-11 河北师范大学 Method for preparing S-(-)-amlodipine and R-(+)-amlodipine by chirally resolving racemic amlodipine
CN103896783A (en) * 2012-12-27 2014-07-02 重庆华邦制药有限公司 Recycling method of dextral impurities of levosalbutamol derivatives
CN106083717A (en) * 2016-06-07 2016-11-09 浙江永太药业有限公司 The racemization recovery method of by-product in the fractionation mother solution of a kind of dextromethorphan hydrobromide intermediate

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5708177A (en) * 1995-09-01 1998-01-13 Bayer Aktiengesellschaft Process for the preparation of optically active ortho-substituted 4-aryl-dihydropyridines
CN101798280A (en) * 2010-03-22 2010-08-11 河北师范大学 Method for preparing S-(-)-amlodipine and R-(+)-amlodipine by chirally resolving racemic amlodipine
CN103896783A (en) * 2012-12-27 2014-07-02 重庆华邦制药有限公司 Recycling method of dextral impurities of levosalbutamol derivatives
CN106083717A (en) * 2016-06-07 2016-11-09 浙江永太药业有限公司 The racemization recovery method of by-product in the fractionation mother solution of a kind of dextromethorphan hydrobromide intermediate

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