CN117304043A - Esmolol hydrochloride and preparation of preparation thereof - Google Patents

Esmolol hydrochloride and preparation of preparation thereof Download PDF

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CN117304043A
CN117304043A CN202311239543.4A CN202311239543A CN117304043A CN 117304043 A CN117304043 A CN 117304043A CN 202311239543 A CN202311239543 A CN 202311239543A CN 117304043 A CN117304043 A CN 117304043A
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methyl
reaction
preparation
phenylpropionate
hydroxy
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蒋晨
诸葛明
汪建
钟齐昌
丁雅芳
庹皓
张巧云
余文杰
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Hangzhou Muyuan Biomedical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/04—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing carboxylic acids or their salts
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
    • C07D301/14—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic peracids, or salts, anhydrides or esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
    • C07D303/23—Oxiranylmethyl ethers of compounds having one hydroxy group bound to a six-membered aromatic ring, the oxiranylmethyl radical not being further substituted, i.e.
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
    • B01J2231/4261—Heck-type, i.e. RY + C=C, in which R is aryl

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  • Organic Chemistry (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention designs a novel esmololSynthetic route of the hydrochloride and preparation of methyl 3- [4- (allyloxy) phenyl with nanowire structure]Propionate intermediates ， The structure makes the intermediate more stable, and is favorable for improving the yield of target products. The invention selects p-bromophenol as raw material, firstly synthesizes methyl p-hydroxy cinnamate through Heck reaction with methyl acrylate under the catalysis of palladium acetate, and hydrogenates methyl p-hydroxy cinnamate under the catalysis of palladium carbon to obtain intermediate methyl p-hydroxy phenylpropionate, and simultaneously uses the synergistic effect of allyl bromide and hydroxyl to carry out etherification to obtain intermediate methyl 3- [4- (allyloxy) phenyl]The propionate is oxidized by m-chloroperoxybenzoic acid and isopropylamine epoxide and salified with hydrogen chloride to obtain the final product esmolol hydrochloride. The invention overcomes the defects of the traditional synthetic route, implements further optimization on the synthetic process, and has the advantages of easily available raw materials, simple operation and mild reaction conditions.

Description

Esmolol hydrochloride and preparation of preparation thereof
Technical Field
The invention belongs to the technical field of medicines, relates to an esmolol new preparation, and particularly relates to preparation of esmolol hydrochloride and a preparation thereof.
Background
Sepsis is a disorder or disturbance of the systemic response of a host caused by infection with bacteria, viruses, etc., and may occur as fatal multiple organ dysfunction syndrome, the most often involved system including: cardiovascular system, nervous system, renal system, liver system, etc. Severe wounds, burns, infections, shock, major surgery, etc. can cause sepsis, with approximately 3000 tens of thousands of diseases occurring annually worldwide. Epidemiological results show: in china, sepsis accounts for 12.6% of national disease mortality. In order to ensure the recovery of vital organ functions, current treatments of multiple organ dysfunction syndrome caused by sepsis are mainly anti-infective, maintenance of hemodynamic stability, nutritional support, vital organ function support and the like.
It is presently believed that causes of sepsis include, but are not limited to, intracellular Ca 2+ Concentration variation, inorganic phosphorus, alkaline pH, and highly reactive molecular oxygen species (ROS). The heart is one of the major target organs for early damage to sepsis, systemic organ failure and heart dysfunction are causally related, and subsequently induced septic shock and multiple organ dysfunction syndrome are dilemmas faced by clinicians. The central link in the process is myocardial apoptosis, which can cause the ejection fraction of the left chamber of the patient to drop by about 30%. The protective effects of beta blockers on the heart, whether used in heart failure or perioperative phase, have been accepted.
Beta blockers have many functions, particularly in terms of their action on the heart, and their mechanism is very complex, including that beta blockers have a certain antagonism against damage to the heart from an adrenergic transmitter point of view. Esmolol hydrochloride, a beta blocker with quick action, short duration and small side effects, has been continuously demonstrated to exert its myocardial protecting function by slowing down heart rate and reducing myocardial oxygen consumption. Its chemical name is 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } benzene methyl propionate hydrochloride, the active ingredient is S-configuration, but the current patent drug is administered in the form of racemate. It is metabolized in vivo and can be hydrolyzed to almost inactive carboxylic acids. It can resist the action of adrenaline to excite heart, reduce heart automation, prolong effective refractory period, reduce conductivity and excitability, so that it can slow down heart rate, reduce myocardial contractility and reduce myocardial oxygen consumption, and can be used for curing arrhythmia, relieving angina pectoris and reducing blood pressure. However, the traditional esmolol hydrochloride synthetic route is excessively complex in esterification reaction, bromination reaction and process operation, so that the product yield is lower due to more byproducts, and meanwhile, the raw material price is high, the purity of the target product is poor, and impurities are not easy to remove. Therefore, the route for synthesizing esmolol hydrochloride is improved and optimized, and the product yield is improved, so that the method is a main research target of us.
In order to improve the therapeutic effect of esmolol hydrochloride on myocarditis, the invention designs a novel esmolol hydrochloride synthesis route from the aspects of raw material price and product yield, and prepares a methyl 3- [4- (allyloxy) phenyl ] propionate intermediate with a nanowire structure. The invention selects p-bromophenol as raw material, firstly synthesizes p-hydroxy methyl cinnamate with methyl acrylate through Heck reaction under the catalysis of palladium acetate, and screens alkali and solvent used in the step to determine the reaction condition under the optimal yield. The method comprises the steps of preparing methyl p-hydroxy phenylpropionate serving as an intermediate by catalytic hydrogenation of methyl p-hydroxy cinnamate through palladium-carbon, etherifying by utilizing the synergistic effect of allyl bromide and hydroxyl to obtain methyl 3- [4- (allyloxy) phenyl ] propionate serving as an intermediate, oxidizing by opening epoxide through m-chloroperoxybenzoic acid and isopropylamine, and salifying with hydrogen chloride to obtain the final product esmolol hydrochloride. The invention further optimizes the synthetic route and the process operation, so that the route has the advantages of easily available raw materials, simple and convenient operation, mild reaction conditions and certain potential industrialization prospect.
Disclosure of Invention
Aiming at the problems, the invention provides a preparation method of esmolol hydrochloride and a preparation thereof, which comprises the following specific preparation steps:
S1, sequentially adding 3-6g of p-bromophenol, 96-100mL of acetonitrile, 0.8-1.0g of tri (o-methylphenyl) phosphine, 0.3-0.6g of palladium acetate and 25-30mL of triethylamine into a 250mL single-port bottle, replacing air in the reaction bottle with nitrogen, injecting 6-12g of methyl acrylate into the reaction bottle by using a syringe, and carrying out nitrogen protection heating reflux reaction for 4-6h. Adding 80-100mL of ethyl acetate to dissolve, adding 240-270mL of water, stirring for 10-15min, regulating the pH to 3.00-4.00 with 6-8mol/L of hydrochloric acid, separating an organic phase, extracting an aqueous phase with 100-120mL of ethyl acetate for 2 times, combining the organic phases, extracting with saturated sodium chloride for 1 time, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and carrying out flash column chromatography on the residue by using ethyl acetate/petroleum ether to obtain white solid methyl p-hydroxycinnamate. In the step, two cheap and easily available reagents, namely 4-bromophenol and methyl acrylate, are selected as initial raw materials, and are coupled with the methyl acrylate through Heck reaction under the catalysis of palladium acetate, so that a methyl propionate fragment in a target product can be constructed with high selectivity and economy. The reaction solution was concentrated under reduced pressure on a rotary evaporator to promote separation of the organic phase from the aqueous phase. The dosage of methyl acrylate is 2 times of the mole number of p-bromophenol, and the reaction is carried out for 4.0 to 6.0 hours in the presence of alkali, which is favorable for C-C bond coupling to generate the p-hydroxy methyl cinnamate.
S2, sequentially adding 4-6g of methyl p-hydroxy cinnamate prepared in the step S1, 80-100mL of methanol, 0.5-0.8g of 5% palladium/carbon and hydrogen into a 250mL single-port bottle, replacing air in the reaction bottle with the hydrogen, stirring at normal temperature and normal pressure for 3-5h under the hydrogen atmosphere, performing TLC monitoring reaction, after the reaction of the methyl p-hydroxy cinnamate is finished, performing suction filtration, eluting the palladium/carbon with 3-5mL of methanol, and concentrating the filtrate on a rotary evaporator under reduced pressure to obtain white solid methyl p-hydroxyphenylpropionate. In the step, hydrogen is selected as a reducing gas, palladium/carbon is used as a catalyst to reduce C=C in the methyl hydroxycinnamate, so that the reaction efficiency is greatly improved, meanwhile, the relative molecular mass of the hydrogen is very small, and the hydrogen can freely pass through various cell membranes and has no influence on the hemodynamics of an organism, and the conventional indexes such as body temperature, blood pressure, pH value, oxygen partial pressure and the like.
S3, taking 3-6g of methyl p-hydroxyphenylpropionate obtained in the step S2, sequentially adding 100-110mL of acetone, 5-7g of potassium carbonate and 0.3-0.6g of potassium iodide into a reaction bottle, replacing air in the reaction bottle by nitrogen, sucking 5-7g of allyl bromide by a syringe, injecting the allyl bromide into the reaction bottle, reacting for 8-10h at room temperature, monitoring the reaction by TLC, completely reacting the methyl p-hydroxyphenylpropionate, filtering, leaching a filter cake by a small amount of acetone, concentrating the filtrate under reduced pressure on a rotary evaporator, and carrying out flash column chromatography on the residue by ethyl acetate/petroleum ether to obtain light yellow oily substance which is methyl 3- [4- (allyloxy) phenyl ] propionate. The methyl p-hydroxyphenylpropionate is etherified with allyl bromide under the action of potassium carbonate, and an intermediate is obtained.
S4, taking 3-6g of methyl 3- [4- (allyloxy) phenyl ] propionate prepared in the step S3, sequentially adding 150-170mL of methylene dichloride and 4-7g of m-chloroperoxybenzoic acid into a reaction bottle, carrying out reflux reaction for 3-5h at 40 ℃, monitoring by TLC, cooling the reaction liquid to room temperature, adding 150-200mL of 1mol/L sodium thiosulfate solution to quench the reaction, stirring for 15-20min, standing for layering, separating an organic phase, continuously extracting the aqueous phase with 140-160mL of methylene dichloride for 2 times, combining the organic phases, extracting with saturated sodium bicarbonate for 1 time, drying with anhydrous sodium sulfate, carrying out suction filtration and concentration, and carrying out flash column chromatography on the residue by ethyl acetate/petroleum ether silica gel to obtain an off-white solid which is 4- (oxirane methoxy) -phenylpropionate. The m-chloroperoxybenzoic acid selected in the step is favorable for efficiently converting the electron-rich olefin into the ethylene oxide, and is characterized by mild reaction conditions, and the olefin can be oxidized into the epoxy in a low-boiling point solvent such as methylene dichloride.
S5, 2-3g of the 4- (oxiranemethoxy) -phenylpropionate prepared in the step S4 is taken and dissolved in 42-50mL of methanol, 4-7g of isopropylamine is added, heating reflux is carried out for 5-8h, TLC monitoring is carried out, the reaction liquid is concentrated under reduced pressure on a rotary evaporator to obtain yellowish solid, namely 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate. The isopropylamine added in the step is favorable for substitution reaction with ethylene oxide methoxy to generate methyl ethylamino, so that important intermediate of methyl 4- { [3- (1-methyl ethylamino) -2-hydroxy ] propoxy } phenylpropionate is further obtained, and meanwhile, no byproducts are generated in the step, so that the yield of the product is improved.
S6, 2-5g of methyl 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate prepared in the step S5 is dissolved in 40-50mL of methyl tertiary butyl ether, air in a reaction bottle is replaced by nitrogen, the temperature of the reaction liquid is reduced to-5 ℃, 3-5mol/L of hydrogen chloride methanol solution is slowly added dropwise, then the reaction is carried out for 1-3h at-5 ℃, a large amount of off-white solid is generated in the system, suction filtration is carried out, a filter cake is leached by cold tertiary butyl methyl ether, and phosphorus pentoxide is dried in vacuum to obtain white solid which is esmolol hydrochloride. In the new synthetic route of the step, the traditional methanol is not used as a solvent, but methyl tertiary butyl ether is used as a solvent to dissolve methyl 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate, and 3-6mol/L of hydrogen chloride methanol solution is dropwise added at the temperature of minus 5 ℃ until no solid is separated out, so that the yield of the final product esmolol hydrochloride can be effectively improved.
Preferably: in the step S1, 3g of p-bromophenol, 96mL of acetonitrile, 0.8g of tris (o-methylphenyl) phosphine, 0.3g of palladium acetate, 25mL of triethylamine and nitrogen were sequentially added to a 250mL single-port flask to replace air in the reaction flask, and 6g of methyl acrylate was injected into the reaction flask by a syringe.
Preferably: in the step S1, reflux reaction is performed for 4 hours under the protection of nitrogen, 80mL of ethyl acetate is added to the solution for dissolution, 240mL of water is added, stirring is performed for 10min, and 6mol/L hydrochloric acid is used for regulating the pH to 3.
Preferably: 4g of the methyl p-hydroxy cinnamate prepared in the step S1 is added into the step S2.
Preferably: in the step S2, 80mL of methanol and 0.5g of 5% palladium/carbon are added, air in the reaction flask is replaced by hydrogen, and the mixture is stirred for 3 hours at normal temperature and normal pressure under the hydrogen atmosphere.
Preferably: in the step S3, 3g of methyl p-hydroxyphenylpropionate obtained in the step S2, 100mL of acetone, 5g of potassium carbonate and 0.3g of potassium iodide are sequentially added into a reaction bottle, and nitrogen replaces air in the reaction bottle.
Preferably: in the step S3, 5g of allyl bromide is sucked by a syringe and injected into a reaction bottle, the reaction is carried out for 8 hours at room temperature, TLC monitors the reaction, and the reaction of methyl p-hydroxyphenylpropionate is complete and suction filtration is carried out.
Preferably: in the step S4, 3g of methyl 3- [4- (allyloxy) phenyl ] propionate prepared in the step S3, 150mL of methylene dichloride and 4g of m-chloroperoxybenzoic acid are sequentially added into a reaction bottle, and reflux reaction is carried out for 3h at 40 ℃.
Preferably: and (3) cooling the reaction liquid in the step (S4) to room temperature, adding 150mL of 1mol/L sodium thiosulfate solution to quench the reaction, stirring for 15min, and standing for layering.
Preferably: in the step S5, 2g of the methyl 4- (oxiranylmethoxy) -phenylpropionate obtained in the step S4 is dissolved in 42mL of methanol, 4g of isopropylamine is added, and the mixture is heated and refluxed for 5 hours.
Preferably: in step S6, 2g of methyl 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate prepared in step S5 was taken and dissolved in 40mL of methyl tert-butyl ether.
Preferably: in the step S6, the nitrogen replaces air in the reaction bottle, the temperature of the reaction solution is reduced to-5 ℃, 3mol/L of hydrogen chloride methanol solution is slowly added dropwise, and then the reaction is carried out for 1h at the temperature of-5 ℃.
The invention has the advantages that:
1. the synthetic route provided by the invention is further optimized in the reaction process and the process operation, so that the raw materials are easy to obtain, the operation is simple and the reaction condition is mild, and therefore, the method has a certain potential industrial prospect.
2. According to the invention, two cheap and easily available reagents, namely 4-bromophenol and methyl acrylate, are selected as initial raw materials, and are coupled with the methyl acrylate through Heck reaction under the catalysis of palladium acetate, so that methyl propionate fragments in a target product can be constructed with high selectivity and economy, and the product yield is greatly improved.
3. The esmolol hydrochloride synthesized by the invention has the characteristics of quick response, quick play of drug effect after intravenous injection or intravenous drip, and adjustment of dosage at any time according to clinical needs so as to achieve maximum treatment effect and minimum toxic and side effects.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments or the description of the prior art will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a schematic structural formula of a methyl p-hydroxycinnamate organic compound according to example 1 of the present invention.
FIG. 2 is a schematic structural diagram of an organic compound of methyl 3- [4- (allyloxy) phenyl ] propionate according to example 2 of the present invention.
FIG. 3 is a schematic structural diagram of an organic compound 4- (oxiranylmethoxy) -phenylpropionic acid methyl ester in example 3 according to the invention.
Fig. 4 is a structural formula of esmolol hydrochloride organic compound in example 4 of the present invention.
FIG. 5 is an SEM image of a methyl 3- [4- (allyloxy) phenyl ] propanoate intermediate of example 2 of the invention.
FIG. 6 is a bar graph of percent yield of the products of inventive example 1 and comparative example 1, comparative example 2.
FIG. 7 is a bar graph of percent yield of the products of inventive example 2 and comparative example 3, comparative example 4.
FIG. 8 is a bar graph of percent yield of the products of inventive example 3 and comparative example 5, comparative example 6.
Fig. 9 is a bar graph of percent yield of the products of inventive example 4 and comparative examples 7, 8.
Detailed Description
In order to make the technical problems, technical schemes and beneficial effects to be solved by the present invention more clear, the present invention is further described in detail below with reference to the accompanying drawings and examples. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the present patent.
Example 1
S1, sequentially adding 3g of p-bromophenol, 96mL of acetonitrile, 0.8g of tri (o-methylphenyl) phosphine, 0.3g of palladium acetate, 25mL of triethylamine and nitrogen into a 250mL single-port bottle, replacing air in the reaction bottle, injecting 6g of methyl acrylate into the reaction bottle by using a syringe, and carrying out a nitrogen protection heating reflux reaction for 4 hours. To this was added 80mL of ethyl acetate for dissolution, 240mL of water was added, stirring was performed for 10min, pH was adjusted to 3 with 6mol/L hydrochloric acid, the organic phase was separated, the aqueous phase was extracted 2 times with 100mL of ethyl acetate, the organic phases were combined, extracted 1 time with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to flash column chromatography with ethyl acetate/petroleum ether to give methyl p-hydroxycinnamate as a white solid. In the step, two cheap and easily available reagents, namely 4-bromophenol and methyl acrylate, are selected as initial raw materials, and are coupled with the methyl acrylate through Heck reaction under the catalysis of palladium acetate, so that a methyl propionate fragment in a target product can be constructed with high selectivity and economy. The reaction solution was concentrated under reduced pressure on a rotary evaporator to promote separation of the organic phase from the aqueous phase. The dosage of methyl acrylate is 2 times of the mole number of p-bromophenol, and the reaction is carried out for 4.0 hours in the presence of alkali, which is favorable for C-C bond coupling to generate p-hydroxy methyl cinnamate.
S2, sequentially adding 4g of the methyl p-hydroxy cinnamate prepared in the step S1, 80mL of methanol, 0.5g of 5% palladium/carbon in a 250mL single-port bottle, replacing air in the reaction bottle with hydrogen, stirring for 3h at normal temperature and normal pressure under the hydrogen atmosphere, monitoring the reaction by TLC, after the reaction of the methyl p-hydroxy cinnamate is finished, carrying out suction filtration, leaching the palladium/carbon with 3mL of methanol, and concentrating the filtrate under reduced pressure on a rotary evaporator to obtain white solid methyl p-hydroxy phenylpropionate. In the step, hydrogen is selected as a reducing gas, palladium/carbon is used as a catalyst to reduce C=C in the methyl hydroxycinnamate, so that the reaction efficiency is greatly improved, meanwhile, the relative molecular mass of the hydrogen is very small, and the hydrogen can freely pass through various cell membranes and has no influence on the hemodynamics of an organism, and the conventional indexes such as body temperature, blood pressure, pH value, oxygen partial pressure and the like.
S3, sequentially adding 3g of methyl p-hydroxyphenylpropionate obtained in the step S2, 100mL of acetone, 5g of potassium carbonate and 0.3g of potassium iodide into a reaction bottle, replacing air in the reaction bottle with nitrogen, sucking 5g of allyl bromide by a syringe, injecting the allyl bromide into the reaction bottle, reacting for 8 hours at room temperature, monitoring the reaction by TLC, completely reacting the methyl p-hydroxyphenylpropionate, carrying out suction filtration, eluting a filter cake with a small amount of acetone, concentrating the filtrate under reduced pressure on a rotary evaporator, and carrying out flash column chromatography on the residue by ethyl acetate/petroleum ether to obtain pale yellow oily substance which is methyl 3- [4- (allyloxy) phenyl ] propionate. The methyl p-hydroxyphenylpropionate is etherified with allyl bromide under the action of potassium carbonate, and an intermediate is obtained.
S4, taking 3g of methyl 3- [4- (allyloxy) phenyl ] propionate prepared in the step S3, sequentially adding 150mL of methylene dichloride and 4g of m-chloroperoxybenzoic acid into a reaction bottle, carrying out reflux reaction for 3h at 40 ℃, monitoring by TLC, cooling the reaction liquid to room temperature, adding 150mL of 1mol/L sodium thiosulfate solution to quench the reaction, stirring for 15min, standing for layering, separating out an organic phase, continuously extracting an aqueous phase with 140mL of methylene dichloride for 2 times, combining the organic phase, extracting for 1 time by using saturated sodium bicarbonate, drying by using anhydrous sodium sulfate, carrying out suction filtration, concentrating, and carrying out flash column chromatography on the residue by using ethyl acetate/petroleum ether silica gel to obtain an off-white solid which is 4- (ethylene oxide methoxy) -methyl phenylpropionate. The m-chloroperoxybenzoic acid selected in the step is favorable for efficiently converting the electron-rich olefin into the ethylene oxide, and is characterized by mild reaction conditions, and the olefin can be oxidized into the epoxy in a low-boiling point solvent such as methylene dichloride.
S5, 2g of the methyl 4- (oxiranylmethoxy) -phenylpropionate prepared in the step S4 is taken and dissolved in 42mL of methanol, 4g of isopropylamine is added, heating reflux is carried out for 5h, TLC monitoring is carried out, the reaction liquid is decompressed and concentrated on a rotary evaporator to obtain yellowish solid which is methyl 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate. The isopropylamine added in the step is favorable for substitution reaction with ethylene oxide methoxy to generate methyl ethylamino, so that important intermediate of methyl 4- { [3- (1-methyl ethylamino) -2-hydroxy ] propoxy } phenylpropionate is further obtained, and meanwhile, no byproducts are generated in the step, so that the yield of the product is improved.
S6, 2g of methyl 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate prepared in the step S5 is dissolved in 40mL of methyl tertiary butyl ether, nitrogen is used for replacing air in a reaction bottle, the reaction liquid is cooled to-5 ℃, 3mol/L of hydrogen chloride methanol solution is slowly added dropwise, then the reaction is carried out for 1h at-5 ℃, a large amount of off-white solid is generated in the system, suction filtration is carried out, a filter cake is leached by cold tertiary butyl methyl ether, and phosphorus pentoxide is dried in vacuum to obtain white solid which is esmolol hydrochloride. In the new synthetic route of the step, the traditional methanol is not used as a solvent, but methyl tertiary butyl ether is used as a solvent to dissolve methyl 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate, and 3mol/L hydrogen chloride methanol solution is dropwise added at the temperature of minus 5 ℃ until no solid is separated out, so that the yield of the final product esmolol hydrochloride can be effectively improved.
Comparative example 1: the procedure of example 1 was repeated except that the alkali agent triethylamine used in step S1 was replaced with sodium carbonate.
Comparative example 2: the respective steps were the same as in example 1 except that the solvent acetonitrile used in step S1 was changed to tetrahydrofuran.
Fig. 1 is a simplified structural formula of methyl p-hydroxycinnamate organic compound according to the present invention in example 1, fig. 6 is a bar graph of the yield percentage of the products according to the present invention in example 1 and comparative examples 1 and 2, and table 1 is the yield percentage of the products according to the present invention in example 1 and comparative examples 1 and 2 and the impurity content percentage. As can be seen from FIG. 6 and Table 1, in example 1, when triethylamine is used as a base and acetonitrile is used as a solvent, the synthesized esmolol hydrochloride has the best performance, the product yield is higher than that of comparative examples 1 and 2, and the generated byproducts are the least. As can be seen from fig. 1, acetonitrile as a solvent is more favorable for dissolution of methyl acrylate, promoting substitution of bromide ions to produce methyl p-hydroxycinnamate. The result shows that the solubility of methyl acrylate is poor, the alkalinity of a triethylamine solvent is strong, the stronger alkaline environment is favorable for inserting palladium into a halogen-carbon bond, a pi complex is generated by the action of palladium atoms and olefin, the coordinated olefin is inserted into the palladium-carbon bond in a cis mode, the coupling reaction of methyl acrylate and p-bromophenol is promoted, and an intermediate is obtained.
TABLE 1
Detecting items Example 1 Comparative example 2 Comparative example 3
Product yield (%) 89.2±0.4 76.6±0.2 75.3±0.3
Impurity content (%) 0.25±0.30 0.37±0.20 0.46±0.20
Example 2
S1, 6g of p-bromophenol, 100mL of acetonitrile, 1.0g of tri (o-methylphenyl) phosphine, 0.6g of palladium acetate, 30mL of triethylamine and nitrogen are sequentially added into a 250mL single-port bottle, air in the reaction bottle is replaced by nitrogen, 12g of methyl acrylate is injected into the reaction bottle by a syringe, and the reaction is carried out for 6 hours under nitrogen protection and heating reflux. To this was added 100mL of ethyl acetate for dissolution, 270mL of water was added, stirring was carried out for 15min, pH was adjusted to 4.00 with 8mol/L hydrochloric acid, the organic phase was separated, the aqueous phase was extracted 2 times with 120mL of ethyl acetate, the organic phases were combined, extracted 1 time with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to flash column chromatography with ethyl acetate/petroleum ether to give methyl p-hydroxycinnamate as a white solid. In the step, two cheap and easily available reagents, namely 4-bromophenol and methyl acrylate, are selected as initial raw materials, and are coupled with the methyl acrylate through Heck reaction under the catalysis of palladium acetate, so that a methyl propionate fragment in a target product can be constructed with high selectivity and economy. The reaction solution was concentrated under reduced pressure on a rotary evaporator to promote separation of the organic phase from the aqueous phase. The dosage of methyl acrylate is 2 times of the mole number of p-bromophenol, and the reaction is carried out for 6.0h in the presence of alkali, which is favorable for C-C bond coupling to generate p-hydroxy methyl cinnamate.
S2, sequentially adding 6g of the methyl p-hydroxy cinnamate prepared in the step S1, 100mL of methanol, 0.8g of 5% palladium/carbon in a 250mL single-port bottle, replacing air in a reaction bottle with hydrogen, stirring for 5h at normal temperature and normal pressure under the hydrogen atmosphere, monitoring the reaction by TLC, after the reaction of the methyl p-hydroxy cinnamate is finished, carrying out suction filtration, leaching the palladium/carbon with 5mL of methanol, and concentrating the filtrate under reduced pressure on a rotary evaporator to obtain white solid methyl p-hydroxy phenylpropionate. In the step, hydrogen is selected as a reducing gas, palladium/carbon is used as a catalyst to reduce C=C in the methyl hydroxycinnamate, so that the reaction efficiency is greatly improved, meanwhile, the relative molecular mass of the hydrogen is very small, and the hydrogen can freely pass through various cell membranes and has no influence on the hemodynamics of an organism, and the conventional indexes such as body temperature, blood pressure, pH value, oxygen partial pressure and the like.
S3, 6g of methyl p-hydroxyphenylpropionate obtained in the step S2, 110mL of acetone, 7g of potassium carbonate and 0.6g of potassium iodide are sequentially added into a reaction bottle, nitrogen is used for replacing air in the reaction bottle, 7g of allyl bromide is sucked by a syringe and is injected into the reaction bottle, reaction is carried out for 10 hours at room temperature, TLC monitors the reaction, methyl p-hydroxyphenylpropionate is completely reacted, suction filtration is carried out, a small amount of acetone is used for leaching a filter cake, the filtrate is decompressed and concentrated on a rotary evaporator, and the residue is subjected to ethyl acetate/petroleum ether flash column chromatography to obtain pale yellow oily substance, namely methyl 3- [4- (allyloxy) phenyl ] propionate. The methyl p-hydroxyphenylpropionate is etherified with allyl bromide under the action of potassium carbonate, and an intermediate is obtained.
S4, taking 6g of methyl 3- [4- (allyloxy) phenyl ] propionate prepared in the step S3, sequentially adding 170mL of methylene dichloride and 7g of m-chloroperoxybenzoic acid into a reaction bottle, carrying out reflux reaction for 5h at 40 ℃, monitoring by TLC, cooling the reaction liquid to room temperature, adding 200mL of 1mol/L sodium thiosulfate solution to quench the reaction, stirring for 20min, standing for layering, separating out an organic phase, continuously extracting an aqueous phase with 160mL of methylene dichloride for 2 times, combining the organic phase, extracting for 1 time by using saturated sodium bicarbonate, drying by using anhydrous sodium sulfate, carrying out suction filtration, concentrating, and carrying out flash column chromatography on the residue by using ethyl acetate/petroleum ether silica gel to obtain an off-white solid which is 4- (ethylene oxide methoxy) -methyl phenylpropionate. The m-chloroperoxybenzoic acid selected in the step is favorable for efficiently converting the electron-rich olefin into the ethylene oxide, and is characterized by mild reaction conditions, and the olefin can be oxidized into the epoxy in a low-boiling point solvent such as methylene dichloride.
S5, dissolving 3g of the methyl 4- (oxiranylmethoxy) -phenylpropionate prepared in the step S4 in 50mL of methanol, adding 7g of isopropylamine, heating and refluxing for 8h, monitoring by TLC, and concentrating the reaction liquid on a rotary evaporator under reduced pressure to obtain a yellowish solid which is methyl 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate. The isopropylamine added in the step is favorable for substitution reaction with ethylene oxide methoxy to generate methyl ethylamino, so that important intermediate of methyl 4- { [3- (1-methyl ethylamino) -2-hydroxy ] propoxy } phenylpropionate is further obtained, and meanwhile, no byproducts are generated in the step, so that the yield of the product is improved.
S6, 5g of methyl 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate prepared in the step S5 is dissolved in 50mL of methyl tertiary butyl ether, nitrogen is used for replacing air in a reaction bottle, the reaction liquid is cooled to-5 ℃, 5mol/L of hydrogen chloride methanol solution is slowly added dropwise, then the reaction is carried out for 3 hours at the temperature of-5 ℃, a large amount of off-white solid is generated in the system, suction filtration is carried out, a filter cake is leached by cold tertiary butyl methyl ether, and phosphorus pentoxide is dried in vacuum to obtain white solid which is esmolol hydrochloride. In the new synthetic route of the step, the traditional methanol is not used as a solvent, but methyl tertiary butyl ether is used as a solvent to dissolve methyl 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate, and 5mol/L hydrogen chloride methanol solution is dropwise added at the temperature of minus 5 ℃ until no solid is separated out, so that the yield of the final product esmolol hydrochloride can be effectively improved.
Comparative example 3: the steps are the same as in example 2, except that no potassium carbonate is added in step S3.
Comparative example 4: the respective steps were the same as in example 2 except that allyl bromide used in step S3 was changed to allyl chloride.
FIG. 2 is a simplified structural formula of the methyl 3- [4- (allyloxy) phenyl ] propionate organic compound of example 2 of the present invention, FIG. 5 is an SEM image of the methyl 3- [4- (allyloxy) phenyl ] propionate intermediate of example 2 of the present invention, and FIG. 7 is a bar graph of the percent yield of the products of example 2 of the present invention and comparative examples 3 and 4. Table 2 shows the yields and impurity percentages of the products of example 2 and comparative examples 3 and 4. As can be seen from fig. 7 and table 2, the esmolol hydrochloride product synthesized in example 2 has the best performance, and the added potassium carbonate solvent and allyl bromide reaction substrate have wide applicability, and the steric hindrance effect and the electronic effect have less influence on the reaction. The liquid is dropped on the conductive substrate, and the SEM is dried and tested, as can be seen from FIG. 5, the methyl 3- [4- (allyloxy) phenyl ] propionate intermediate prepared by etherification of allyl bromide and hydroxyl has a synergistic effect is in a nanowire structure, and the structure enables the intermediate to be more stable, so that the ester group is not easy to hydrolyze, and the yield of the target product is improved.
TABLE 2
Detecting items Example 2 Comparative example 3 Comparative example 4
Product yield (%) 90.3±0.4 82.6±0.2 81.3±0.3
Impurity content (%) 0.19±0.30 0.34±0.20 0.42±0.20
Example 3
S1, sequentially adding 4g of p-bromophenol, 97mL of acetonitrile, 0.9g of tri (o-methylphenyl) phosphine, 0.4g of palladium acetate, 26mL of triethylamine and nitrogen into a 250mL single-port bottle, replacing air in the reaction bottle, injecting 7g of methyl acrylate into the reaction bottle by using a syringe, and carrying out a nitrogen protection heating reflux reaction for 5h. 85mL of ethyl acetate was added thereto for dissolution, 250mL of water was added thereto, stirring was carried out for 12 minutes, pH was adjusted to 3 with 7mol/L hydrochloric acid, the organic phase was separated, the aqueous phase was extracted 2 times with 105mL of ethyl acetate, the organic phases were combined, extracted 1 time with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to flash column chromatography with ethyl acetate/petroleum ether to obtain methyl p-hydroxycinnamate as a white solid. In the step, two cheap and easily available reagents, namely 4-bromophenol and methyl acrylate, are selected as initial raw materials, and are coupled with the methyl acrylate through Heck reaction under the catalysis of palladium acetate, so that a methyl propionate fragment in a target product can be constructed with high selectivity and economy. The reaction solution was concentrated under reduced pressure on a rotary evaporator to promote separation of the organic phase from the aqueous phase. The dosage of methyl acrylate is 2 times of the mole number of p-bromophenol, and the reaction is carried out for 5 hours in the presence of alkali, so that the coupling of C-C bonds is facilitated to generate the p-hydroxy methyl cinnamate.
S2, sequentially adding 4g of the methyl p-hydroxy cinnamate prepared in the step S1, 85mL of methanol, 0.6g of 5% palladium/carbon in a 250mL single-port bottle, replacing air in the reaction bottle with hydrogen, stirring for 4h at normal temperature and normal pressure under the hydrogen atmosphere, monitoring the reaction by TLC, after the reaction of the methyl p-hydroxy cinnamate is finished, carrying out suction filtration, leaching the palladium/carbon with 3mL of methanol, and concentrating the filtrate under reduced pressure on a rotary evaporator to obtain white solid methyl p-hydroxy phenylpropionate. In the step, hydrogen is selected as a reducing gas, palladium/carbon is used as a catalyst to reduce C=C in the methyl hydroxycinnamate, so that the reaction efficiency is greatly improved, meanwhile, the relative molecular mass of the hydrogen is very small, and the hydrogen can freely pass through various cell membranes and has no influence on the hemodynamics of an organism, and the conventional indexes such as body temperature, blood pressure, pH value, oxygen partial pressure and the like.
S3, taking 4g of methyl p-hydroxyphenylpropionate obtained in the step S2, 105mL of acetone, 5g of potassium carbonate and 0.4g of potassium iodide, sequentially adding into a reaction bottle, replacing air in the reaction bottle with nitrogen, sucking 5g of allyl bromide by a syringe, injecting into the reaction bottle, reacting for 8 hours at room temperature, monitoring the reaction by TLC, completely reacting the methyl p-hydroxyphenylpropionate, carrying out suction filtration, eluting a filter cake with a small amount of acetone, concentrating the filtrate under reduced pressure on a rotary evaporator, and carrying out flash column chromatography on the residue by ethyl acetate/petroleum ether to obtain pale yellow oily substance which is methyl 3- [4- (allyloxy) phenyl ] propionate. The methyl p-hydroxyphenylpropionate is etherified with allyl bromide under the action of potassium carbonate, and an intermediate is obtained.
S4, taking 4g of methyl 3- [4- (allyloxy) phenyl ] propionate prepared in the step S3, sequentially adding 155mL of methylene dichloride and 5g of m-chloroperoxybenzoic acid into a reaction bottle, carrying out reflux reaction for 4h at 40 ℃, monitoring by TLC, cooling the reaction liquid to room temperature, adding 160mL of 1mol/L sodium thiosulfate solution to quench the reaction, stirring for 16min, standing for layering, separating an organic phase, continuously extracting an aqueous phase with 145mL of methylene dichloride for 2 times, combining the organic phases, extracting for 1 time by using saturated sodium bicarbonate, drying by using anhydrous sodium sulfate, carrying out suction filtration, concentrating, and carrying out flash column chromatography on the residue by using ethyl acetate/petroleum ether silica gel to obtain an off-white solid which is 4- (ethylene oxide methoxy) -methyl phenylpropionate. The m-chloroperoxybenzoic acid selected in the step is favorable for efficiently converting the electron-rich olefin into the ethylene oxide, and is characterized by mild reaction conditions, and the olefin can be oxidized into the epoxy in a low-boiling point solvent such as methylene dichloride.
S5, 2g of the methyl 4- (oxiranylmethoxy) -phenylpropionate prepared in the step S4 is dissolved in 44mL of methanol, 5g of isopropylamine is added, heating reflux is carried out for 6h, TLC monitoring is carried out, the reaction liquid is decompressed and concentrated on a rotary evaporator to obtain yellowish solid, namely, methyl 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate. The isopropylamine added in the step is favorable for substitution reaction with ethylene oxide methoxy to generate methyl ethylamino, so that important intermediate of methyl 4- { [3- (1-methyl ethylamino) -2-hydroxy ] propoxy } phenylpropionate is further obtained, and meanwhile, no byproducts are generated in the step, so that the yield of the product is improved.
S6, 3g of methyl 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate prepared in the step S5 is dissolved in 43mL of methyl tertiary butyl ether, nitrogen is used for replacing air in a reaction bottle, the reaction liquid is cooled to-5 ℃, 4mol/L of hydrogen chloride methanol solution is slowly added dropwise, then the reaction is carried out for 1h at-5 ℃, a large amount of off-white solid is generated in the system, suction filtration is carried out, a filter cake is leached by cold tertiary butyl methyl ether, and phosphorus pentoxide is dried in vacuum to obtain white solid which is esmolol hydrochloride. In the new synthetic route of the step, the traditional methanol is not used as a solvent, but methyl tertiary butyl ether is used as a solvent to dissolve methyl 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate, and 4mol/L hydrogen chloride methanol solution is dropwise added at the temperature of minus 5 ℃ until no solid is separated out, so that the yield of the final product esmolol hydrochloride can be effectively improved.
Comparative example 5: the steps are the same as in example 3 except that the intermediate chloroperoxybenzoic acid in step S4 is replaced with hydrogen peroxide.
Comparative example 6: the procedure of example 3 was repeated except that the intermediate chloroperoxybenzoic acid in step S4 was replaced with peroxyacetic acid.
FIG. 3 is a schematic structural diagram of an organic compound 4- (oxiranylmethoxy) -phenylpropionic acid methyl ester in example 3 according to the invention. FIG. 8 is a bar graph of percent yield of the products of inventive example 3 and comparative example 5, comparative example 6. Table 3 shows the yields and impurity percentages of the products of example 3 and comparative example 5 and comparative example 6. As can be seen from fig. 8 and table 3, esmolol hydrochloride synthesized in example 3 has a superior yield and a low impurity content, and as can be seen from fig. 3, m-chloroperoxybenzoic acid has the effect of oxidizing c=c to form an epoxy ethyl group. The result shows that the type of the oxidant has a decisive effect on the generation of target products, the oxidation performance is too strong or weak, the yield of the 4- (oxiranemethoxy) -methyl phenylpropionate intermediate is reduced, and the peroxyacetic acid serving as the oxidant has stronger oxidation performance, so that the generation of byproducts is possibly caused, and the utilization rate of raw materials is reduced. The m-chloroperoxybenzoic acid is favorable for efficiently converting the electron-rich olefin into the ethylene oxide, and can oxidize the olefin into the epoxy under mild reaction conditions.
TABLE 3 Table 3
Detecting items Example 3 Comparative example 5 Comparative example 6
Product yield (%) 89.3±0.4 73.1±0.2 70.2±0.3
Impurity content (%) 0.23±0.30 0.36±0.20 0.59±0.20
Example 4
S1, sequentially adding 5g of p-bromophenol, 98mL of acetonitrile, 0.9g of tri (o-methylphenyl) phosphine, 0.5g of palladium acetate, 28mL of triethylamine and nitrogen into a 250mL single-port bottle, replacing air in the reaction bottle, injecting 11g of methyl acrylate into the reaction bottle by using a syringe, and carrying out a nitrogen protection heating reflux reaction for 5h. To this was added 90mL of ethyl acetate for dissolution, 260mL of water was added, stirring was carried out for 14min, pH was adjusted to 4 with 7mol/L hydrochloric acid, the organic phase was separated, the aqueous phase was extracted 2 times with 110mL of ethyl acetate, the organic phases were combined, extracted 1 time with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to flash column chromatography with ethyl acetate/petroleum ether to give methyl p-hydroxycinnamate as a white solid. In the step, two cheap and easily available reagents, namely 4-bromophenol and methyl acrylate, are selected as initial raw materials, and are coupled with the methyl acrylate through Heck reaction under the catalysis of palladium acetate, so that a methyl propionate fragment in a target product can be constructed with high selectivity and economy. The reaction solution was concentrated under reduced pressure on a rotary evaporator to promote separation of the organic phase from the aqueous phase. The dosage of methyl acrylate is 2 times of the mole number of p-bromophenol, and the reaction is carried out for 5 hours in the presence of alkali, so that the coupling of C-C bonds is facilitated to generate the p-hydroxy methyl cinnamate.
S2, sequentially adding 5g of the methyl p-hydroxy cinnamate prepared in the step S1, 90mL of methanol, 0.7g of 5% palladium/carbon in a 250mL single-port bottle, replacing air in the reaction bottle with hydrogen, stirring for 4h at normal temperature and normal pressure under the hydrogen atmosphere, monitoring the reaction by TLC, after the reaction of the methyl p-hydroxy cinnamate is finished, carrying out suction filtration, leaching the palladium/carbon with 4mL of methanol, and concentrating the filtrate under reduced pressure on a rotary evaporator to obtain white solid methyl p-hydroxy phenylpropionate. In the step, hydrogen is selected as a reducing gas, palladium/carbon is used as a catalyst to reduce C=C in the methyl hydroxycinnamate, so that the reaction efficiency is greatly improved, meanwhile, the relative molecular mass of the hydrogen is very small, and the hydrogen can freely pass through various cell membranes and has no influence on the hemodynamics of an organism, and the conventional indexes such as body temperature, blood pressure, pH value, oxygen partial pressure and the like.
S3, sequentially adding 5g of methyl p-hydroxyphenylpropionate obtained in the step S2, 105mL of acetone, 6g of potassium carbonate and 0.5g of potassium iodide into a reaction bottle, replacing air in the reaction bottle with nitrogen, sucking 6g of allyl bromide by a syringe, injecting the allyl bromide into the reaction bottle, reacting for 9 hours at room temperature, monitoring the reaction by TLC, completely reacting the methyl p-hydroxyphenylpropionate, carrying out suction filtration, eluting a filter cake with a small amount of acetone, concentrating the filtrate under reduced pressure on a rotary evaporator, and carrying out flash column chromatography on the residue by ethyl acetate/petroleum ether to obtain pale yellow oily substance which is methyl 3- [4- (allyloxy) phenyl ] propionate. The methyl p-hydroxyphenylpropionate is etherified with allyl bromide under the action of potassium carbonate, and an intermediate is obtained.
S4, taking 5g of methyl 3- [4- (allyloxy) phenyl ] propionate prepared in the step S3, sequentially adding 160mL of methylene dichloride and 6g of m-chloroperoxybenzoic acid into a reaction bottle, carrying out reflux reaction for 4h at 40 ℃, monitoring by TLC, cooling the reaction liquid to room temperature, adding 190mL of 1mol/L sodium thiosulfate solution to quench the reaction, stirring for 18min, standing for layering, separating out an organic phase, continuously extracting an aqueous phase with 150mL of methylene dichloride for 2 times, combining the organic phase, extracting with saturated sodium bicarbonate for 1 time, drying with anhydrous sodium sulfate, carrying out suction filtration, concentrating, and carrying out flash column chromatography on the residue by ethyl acetate/petroleum ether silica gel to obtain an off-white solid which is 4- (ethylene oxide methoxy) -methyl phenylpropionate. The m-chloroperoxybenzoic acid selected in the step is favorable for efficiently converting the electron-rich olefin into the ethylene oxide, and is characterized by mild reaction conditions, and the olefin can be oxidized into the epoxy in a low-boiling point solvent such as methylene dichloride.
S5, dissolving 3g of the methyl 4- (oxiranylmethoxy) -phenylpropionate prepared in the step S4 in 48mL of methanol, adding 6g of isopropylamine, heating and refluxing for 7h, monitoring by TLC, and concentrating the reaction liquid on a rotary evaporator under reduced pressure to obtain a yellowish solid which is methyl 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate. The isopropylamine added in the step is favorable for substitution reaction with ethylene oxide methoxy to generate methyl ethylamino, so that important intermediate of methyl 4- { [3- (1-methyl ethylamino) -2-hydroxy ] propoxy } phenylpropionate is further obtained, and meanwhile, no byproducts are generated in the step, so that the yield of the product is improved.
S6, 4g of methyl 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate prepared in the step S5 is dissolved in 48mL of methyl tertiary butyl ether, nitrogen is used for replacing air in a reaction bottle, the temperature of the reaction liquid is reduced to minus 5 ℃, 4mol/L of hydrogen chloride methanol solution is slowly added dropwise, then the reaction is carried out for 2 hours at minus 5 ℃, a large amount of off-white solid is generated in the system, suction filtration is carried out, a filter cake is leached by cold tertiary butyl methyl ether, and phosphorus pentoxide is dried in vacuum to obtain white solid which is esmolol hydrochloride. In the new synthetic route of the step, the traditional methanol is not used as a solvent, but methyl tertiary butyl ether is used as a solvent to dissolve methyl 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate, and 4mol/L hydrogen chloride methanol solution is dropwise added at the temperature of minus 5 ℃ until no solid is separated out, so that the yield of the final product esmolol hydrochloride can be effectively improved.
Comparative example 7: the respective steps were the same as in example 4 except that methyl t-butyl ether as a solvent used in step S6 was replaced with methanol.
Comparative example 8: the procedure of example 4 was repeated except that the solvent methyl t-butyl ether used in step S6 was changed to ethyl acetate.
Fig. 4 is a simplified structural formula of esmolol hydrochloride organic compound in example 4 of the present invention, and fig. 9 is a bar chart of the percent yield of the products in example 4 and comparative examples 7 and 8 of the present invention. Table 4 shows the product yields and the impurity content percentages in example 4 and comparative examples 7 and 8. It can be seen from fig. 9 and table 4 that the product yield of example 4 is higher than that of comparative examples 7 and 8. The result shows that the reaction effect of leaching the filter cake by adopting tertiary butyl methyl ether is far higher than that of methanol and ethyl acetate, and the methanol has a certain solubility to esmolol hydrochloride, so that the yield is generally lower than 80%. Meanwhile, the polymers are arranged in para position, and the polymer has excellent selectivity and degradability, so that the medicine has minimum toxic and side effects.
TABLE 4 Table 4
Detecting items Example 4 Comparative example 7 Comparative example 8
Product yield (%) 85.3±0.4 75.1±0.2 76.2±0.3
Impurity content (%) 0.26±0.30 0.42±0.20 0.36±0.20
The above embodiments are merely illustrative of the preparation process of the present invention, and not intended to limit the scope of the present invention, and various modifications and improvements made by those skilled in the art to the technical solution of the present invention should fall within the protection scope defined by the claims of the present invention without departing from the design spirit of the present invention.

Claims (9)

1. The preparation of esmolol hydrochloride and the preparation thereof is characterized in that: the preparation method comprises the following specific steps:
s1, sequentially adding 3-6g of p-bromophenol, 96-100mL of acetonitrile, 0.8-1.0g of tri (o-methylphenyl) phosphine, 0.3-0.6g of palladium acetate and 25-30mL of triethylamine into a 250mL single-port bottle, replacing air in the reaction bottle with nitrogen, injecting 6-12g of methyl acrylate into the reaction bottle by using an injector, and carrying out nitrogen protection heating reflux reaction for 4-6h; adding 80-100mL of ethyl acetate to dissolve, adding 240-270mL of water, stirring for 10-15min, regulating pH to 3.00-4.00 with 6-8mol/L of hydrochloric acid, separating an organic phase, extracting an aqueous phase with 100-120mL of ethyl acetate for 2 times, combining the organic phases, extracting with saturated sodium chloride for 1 time, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and subjecting the residue to ethyl acetate/petroleum ether flash column chromatography to obtain white solid methyl p-hydroxycinnamate;
S2, sequentially adding 4-6g of methyl p-hydroxy cinnamate prepared in the step S1 into a 250mL single-port bottle, 80-100mL of methanol, 0.5-0.8g of 5% palladium/carbon, replacing air in a reaction bottle with hydrogen, stirring at normal temperature and normal pressure for 3-5h under the hydrogen atmosphere, performing TLC monitoring reaction, after the reaction of the methyl p-hydroxy cinnamate is finished, performing suction filtration, eluting the palladium/carbon with 3-5mL of methanol, and concentrating the filtrate on a rotary evaporator under reduced pressure to obtain white solid methyl p-hydroxyphenylpropionate;
s3, taking 3-6g of methyl p-hydroxyphenylpropionate obtained in the step S2, sequentially adding 100-110mL of acetone, 5-7g of potassium carbonate and 0.3-0.6g of potassium iodide into a reaction bottle, replacing air in the reaction bottle by nitrogen, sucking 5-7g of allyl bromide by a syringe, injecting the allyl bromide into the reaction bottle, reacting for 8-10 hours at room temperature, monitoring the reaction by TLC, completely reacting the methyl p-hydroxyphenylpropionate, filtering, leaching a filter cake by a small amount of acetone, concentrating the filtrate under reduced pressure on a rotary evaporator, and carrying out flash column chromatography on the residue by ethyl acetate/petroleum ether to obtain light yellow oily substance which is methyl 3- [4- (allyloxy) phenyl ] propionate;
s4, taking 3-6g of methyl 3- [4- (allyloxy) phenyl ] propionate prepared in the step S3, sequentially adding 150-170mL of methylene dichloride and 4-7g of m-chloroperoxybenzoic acid into a reaction bottle, carrying out reflux reaction for 3-5h at 40 ℃, monitoring by TLC, cooling the reaction liquid to room temperature, adding 150-200mL of 1mol/L sodium thiosulfate solution for quenching reaction, stirring for 15-20min, standing for layering, separating out an organic phase, continuously extracting the aqueous phase with 140-160mL of methylene dichloride for 2 times, combining the organic phase, extracting with saturated sodium bicarbonate for 1 time, drying with anhydrous sodium sulfate, carrying out suction filtration and concentration, and carrying out flash column chromatography on the residue by ethyl acetate/petroleum ether silica gel to obtain an off-white solid which is 4- (oxirane methoxy) -phenylpropionate;
S5, 2-3g of the 4- (oxiranemethoxy) -phenylpropionate prepared in the step S4 is taken and dissolved in 42-50mL of methanol, 4-7g of isopropylamine is added, heating reflux is carried out for 5-8h, TLC monitoring is carried out, the reaction of the 4- (oxiranemethoxy) -phenylpropionate is finished, and the reaction solution is decompressed and concentrated on a rotary evaporator to obtain yellowish solid which is 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate;
s6, 2-5g of methyl 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate prepared in the step S5 is dissolved in 40-50mL of methyl tertiary butyl ether, air in a reaction bottle is replaced by nitrogen, the temperature of the reaction liquid is reduced to-5 ℃, 3-5mol/L of hydrogen chloride methanol solution is slowly added dropwise, then the reaction is carried out for 1-3h at-5 ℃, a large amount of off-white solid is generated in the system, suction filtration is carried out, a filter cake is leached by cold tertiary butyl methyl ether, and phosphorus pentoxide is dried in vacuum to obtain white solid which is esmolol hydrochloride.
2. The preparation of esmolol hydrochloride and its formulation as claimed in claim 1, wherein: in the step S1, 3g of p-bromophenol, 96mL of acetonitrile, 0.8g of tris (o-methylphenyl) phosphine, 0.3g of palladium acetate, 25mL of triethylamine and nitrogen were sequentially added to a 250mL single-port flask to replace air in the reaction flask, and 6g of methyl acrylate was injected into the reaction flask by a syringe.
3. The preparation of esmolol hydrochloride and its formulation as claimed in claim 2, wherein: in the step S1, reflux reaction is performed for 4 hours under the protection of nitrogen, 80mL of ethyl acetate is added to the solution for dissolution, 240mL of water is added, stirring is performed for 10min, and 6mol/L hydrochloric acid is used for regulating the pH to 3.
4. The preparation of esmolol hydrochloride and its formulation as claimed in claim 2, wherein: 4g of the methyl p-hydroxy cinnamate prepared in the step S1 is added into the step S2.
5. The preparation of esmolol hydrochloride and its formulation as claimed in claim 3, wherein: the preparation of esmolol hydrochloride and its preparation as claimed in claim 4, wherein: in the step S3, 3g of methyl p-hydroxyphenylpropionate obtained in the step S2, 100mL of acetone, 5g of potassium carbonate and 0.3g of potassium iodide are sequentially added into a reaction bottle, and nitrogen replaces air in the reaction bottle.
6. The preparation of esmolol hydrochloride and its preparation as claimed in claim 5, wherein: in the step S3, 5g of allyl bromide is sucked by a syringe and injected into a reaction bottle, the reaction is carried out for 8 hours at room temperature, TLC monitors the reaction, and the reaction of methyl p-hydroxyphenylpropionate is complete and suction filtration is carried out.
7. The preparation of esmolol hydrochloride and its formulation as claimed in claim 6, wherein: in the step S4, 3g of methyl 3- [4- (allyloxy) phenyl ] propionate prepared in the step S3, 150mL of methylene dichloride and 4g of m-chloroperoxybenzoic acid are sequentially added into a reaction bottle, and reflux reaction is carried out for 3h at 40 ℃.
8. The preparation of esmolol hydrochloride and its formulation as claimed in claim 7, wherein: in the step S5, 2g of the methyl 4- (oxiranylmethoxy) -phenylpropionate obtained in the step S4 is dissolved in 42mL of methanol, 4g of isopropylamine is added, and the mixture is heated and refluxed for 5 hours.
9. The preparation of esmolol hydrochloride and its formulation as claimed in claim 7, wherein: in step S6, 2g of methyl 4- { [3- (1-methylethylamino) -2-hydroxy ] propoxy } phenylpropionate prepared in step S5 was taken and dissolved in 40mL of methyl tert-butyl ether.
CN202311239543.4A 2023-09-25 2023-09-25 Esmolol hydrochloride and preparation of preparation thereof Pending CN117304043A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117209387A (en) * 2023-09-15 2023-12-12 中国海洋大学 Salifying and purifying process of esmolol hydrochloride

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117209387A (en) * 2023-09-15 2023-12-12 中国海洋大学 Salifying and purifying process of esmolol hydrochloride

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