CN113698316B - Preparation method of labetalol hydrochloride - Google Patents
Preparation method of labetalol hydrochloride Download PDFInfo
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- CN113698316B CN113698316B CN202111030247.4A CN202111030247A CN113698316B CN 113698316 B CN113698316 B CN 113698316B CN 202111030247 A CN202111030247 A CN 202111030247A CN 113698316 B CN113698316 B CN 113698316B
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Abstract
The invention provides a preparation method of labetalol hydrochloride, belonging to the technical field of medicines. The preparation method provided by the invention comprises the steps of carrying out nucleophilic substitution reaction on 5-halogenated acetyl salicylamide serving as an initial raw material and benzylamine, then carrying out nucleophilic substitution reaction on the 5-halogenated acetyl salicylamide and 3-halogenated butylbenzene (or carrying out amine ester exchange reaction on a product of esterification reaction of the 3-hydroxybutylbenzene and p-toluenesulfonyl chloride), carrying out catalytic hydrogenation reaction, and forming salt to obtain labetalol hydrochloride. According to the preparation method provided by the invention, benzylamine is used for replacing dibenzylamine, the atom utilization rate of the raw material is high, the preparation method is environment-friendly, and the atom economy of green chemistry is reflected; the selectivity of the amine ester exchange reaction is high, and the obtained product is directly used for the next reaction; the process route is shortened by adopting a one-step method to remove the protective agent and reduce carbonyl; the preparation method is simple and convenient to operate, high in stability and controllability, high in production cost and high in yield, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a preparation method of labetalol hydrochloride.
Background
Labetalol hydrochloride (Labetalol hydrochloride) with a chemical name of 2-hydroxy-5- [ 1-hydroxy-2- [ (1-methyl-3-phenylpropyl) amino ] ethyl ] benzamide hydrochloride (the structural formula is shown in the specification) is an antihypertensive drug with a nonselective beta receptor blocking effect and a selective postsynaptic alpha 1 blocking effect, can reduce peripheral vascular resistance, has a membrane stabilizing effect but has no intrinsic sympathomimetic activity, can quickly reduce blood pressure, and is suitable for treating hypertensive emergency, such as acute aortic dissection, pheochromocytoma and gestational hypertension syndrome.
Shangyun et al (Shangyanjun, Von Juncai, Nanjing university Proc., 1980(1): 61-64) disclose a synthesis method of labetalol hydrochloride, which is prepared by condensing 5-bromoacetyl methyl salicylate as a starting material with dibenzylamine, performing amine ester exchange, hydrogenation debenzylation, condensation with 4-phenyl-2-butanone, reduction of carbonyl and salt formation, wherein the synthesis route is as follows:
the labranol hydrochloride is prepared by taking salicylamide as an initial raw material and performing Friedel-crafts reaction, bromination, dibenzylamine protection, condensation and reduction on the salicylamide 2008,25(3):276-278, and the synthetic route is as follows:
however, in the above synthesis method, dibenzylamine is used as an amino source, and the atom utilization rate of the raw material is not high.
Disclosure of Invention
In view of the above, the present invention aims to provide a preparation method of labetalol hydrochloride, which has the advantages of high atom utilization rate of raw materials, high yield and low production cost.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of labetalol hydrochloride, which comprises the following steps:
(1) carrying out a first nucleophilic substitution reaction on the compound II and benzylamine to obtain a compound III;
(2) carrying out a second nucleophilic substitution reaction on the compound III and the compound IV to obtain a compound V;
(3) carrying out catalytic hydrogenation reaction on the compound V under the action of a catalyst to obtain a compound VIII;
(4) mixing the compound VIII with a hydrochloric acid solution for salt forming reaction to obtain labetalol hydrochloride with a structure shown in a formula I;
x in the compound II and the compound IV is halogen.
Preferably, the step (2) is replaced by:
carrying out esterification reaction on the compound VI and p-toluenesulfonyl chloride to obtain a compound VII;
carrying out amine ester exchange reaction on the compound VII and the compound III to obtain a compound V;
preferably, the molar ratio of the compound II to benzylamine is 1: 0.5 to 2;
the temperature of the first nucleophilic substitution reaction is-10-35 ℃, and the time is 1-5 h.
Preferably, the molar ratio of compound III to compound IV is 1: 0.9 to 1.5;
the temperature of the second nucleophilic substitution reaction is 0-100 ℃.
Preferably, the molar ratio of the compound VI to the p-methylbenzenesulfonyl chloride is 1: 0.5 to 1.2;
the temperature of the esterification reaction is-10 to 30 ℃.
Preferably, the molar ratio of the compound III to the compound VII is 1: 1 to 1.2;
the temperature of the amine transesterification reaction is 79-83 ℃.
Preferably, the catalyst comprises palladium on carbon and/or platinum on carbon.
Preferably, the pressure of hydrogen in the catalytic hydrogenation reaction is 0.1-10 MPa, the temperature is 25-70 ℃, and the time is 4-12 h.
Preferably, the hydrochloric acid solution comprises one or more of a hydrochloric acid aqueous solution, a hydrochloric acid alcohol solution and a hydrochloric acid ester solution.
Preferably, the temperature of the salt forming reaction is-10-30 ℃, the time is 30-90 min, and the pH value is 1-3.
The invention provides a preparation method of labetalol hydrochloride, which comprises the following steps: (1) carrying out a first nucleophilic substitution reaction on the compound II and benzylamine to obtain a compound III; (2) carrying out a second nucleophilic substitution reaction on the compound III and the compound IV to obtain a compound V; (3) mixing the compound V with a catalyst to perform catalytic hydrogenation reaction to obtain a compound VIII; (4) mixing the compound VIII with a hydrochloric acid solution for salt forming reaction to obtain labetalol hydrochloride with a structure shown in a formula I; the step (2) is replaced by the following steps: carrying out esterification reaction on the compound VI and p-toluenesulfonyl chloride to obtain a compound VII; and carrying out amine transesterification on the compound VII and the compound III to obtain a compound V. The preparation method provided by the invention comprises the steps of carrying out nucleophilic substitution reaction on 5-halogenated acetyl salicylamide serving as an initial raw material and benzylamine, then carrying out nucleophilic substitution reaction on the 5-halogenated acetyl salicylamide and 3-halogenated butylbenzene (or carrying out amine ester exchange reaction on a product of esterification reaction of the 3-hydroxybutylbenzene and p-toluenesulfonyl chloride), carrying out catalytic hydrogenation reaction, and forming salt to obtain labetalol hydrochloride. According to the preparation method provided by the invention, benzylamine is used for replacing dibenzylamine, the atom utilization rate of the raw material is high, the preparation method is environment-friendly, and the atom economy of green chemistry is reflected. The further amine transesterification reaction has high selectivity, and the obtained product is directly used for the next reaction. The invention adopts a one-step method to remove the protective agent and reduce carbonyl, thus shortening the process route; the preparation method is simple and convenient to operate, high in stability and controllability, high in production cost and high in yield, and is suitable for industrial production.
Drawings
FIG. 1 is a hydrogen spectrum of labetalol hydrochloride prepared in example 1;
FIG. 2 is a carbon spectrum of labetalol hydrochloride prepared in example 1.
Detailed Description
The invention provides a preparation method of labetalol hydrochloride, which comprises the following steps:
(1) carrying out a first nucleophilic substitution reaction on the compound II and benzylamine to obtain a compound III;
(2) carrying out a second nucleophilic substitution reaction on the compound III and the compound IV to obtain a compound V;
(3) carrying out catalytic hydrogenation reaction on the compound V under the action of a catalyst to obtain a compound VIII;
(4) mixing the compound VIII with a hydrochloric acid solution for salt forming reaction to obtain labetalol hydrochloride with a structure shown in a formula I;
x in the compound II and the compound IV is halogen.
In the present invention, all the raw material components are commercially available products well known to those skilled in the art unless otherwise specified.
The compound II and benzylamine are subjected to a first nucleophilic substitution reaction to obtain a compound III. In the present invention, X in the compound II preferably includes chlorine or bromine; the compound II preferably comprises 5-bromoacetylsalicylamide or 5-chloroacetylsalicylamide. In the present invention, the molar ratio of the compound II to benzylamine is preferably 1: 0.5 to 2, more preferably 1: 1 to 1.5. In the present invention, the first nucleophilic substitution reaction is preferably performed under basic conditions; the first nucleophilic substitution reaction of the compound II and benzylamine is preferably carried out by mixing benzylamine, an alkaline reagent and an organic solvent, and then dropwise adding the compound II solution for mixing. In the invention, the alkaline reagent preferably comprises an organic base or an inorganic base, and the inorganic base preferably comprises one or more of potassium carbonate, sodium hydroxide and potassium hydroxide; the organic base preferably comprises triethylamine. In the present invention, the molar ratio of the compound II to the basic agent is preferably 1: 0.8 to 3, more preferably 1: 1-2, more preferably 1: 1 to 1.6. In the present invention, the organic solvent preferably includes one or more of tetrahydrofuran, an ether solvent, an aromatic hydrocarbon solvent and a chlorinated hydrocarbon solvent; the ether solvent preferably comprises one or more of diethyl ether, ethylene glycol dimethyl ether, isopropyl ether and tertiary butyl ether; the aromatic hydrocarbon solvent preferably comprises one or more of benzene, toluene and xylene; the chlorinated hydrocarbon solvent preferably comprises dichloromethane; in the present invention, the amount of the organic solvent is not particularly limited, and the first nucleophilic substitution reaction can be smoothly performed. In the present invention, the solvent in the compound II solution is preferably the same as the aforementioned organic solvent, and is not described herein again; the concentration of the compound II solution is preferably 0.1-2 g/L, more preferably 0.5-1.5 g/L, and further preferably 1 g/L; the preferable temperature of the dropwise addition is-10-35 ℃, and the more preferable temperature is 0-25 ℃; the dropping speed is not particularly limited in the invention, and the dropping can be carried out dropwise. The speed and time of the mixing are not particularly limited, and the raw materials can be uniformly mixed. In the invention, the temperature of the first nucleophilic substitution reaction is preferably-10-35 ℃, and more preferably 0-25 ℃; the time of the first nucleophilic substitution reaction is preferably 1-5 h, and more preferably 2-3 h. In the present invention, the reaction occurring during the first nucleophilic substitution reaction is as follows:
after the first nucleophilic substitution reaction, the method preferably further comprises the step of carrying out post-treatment on a system of the first nucleophilic substitution reaction, wherein the post-treatment comprises the steps of sequentially carrying out water washing and extraction, sequentially carrying out saturated sodium bicarbonate washing, saturated salt water washing, anhydrous sodium sulfate drying and filtering on an obtained organic phase, and concentrating an obtained filtrate to constant weight to obtain a compound III. In the present invention, the ratio of the mass of the compound II to the volume of water for washing is preferably 1 g: 1-5 mL, more preferably 1 g: 2-4 mL, more preferably 1 g: 3mL of the solution. In the present invention, the organic solvent for extraction preferably includes an ester solvent and/or a chlorinated alkane solvent, and the ester solvent preferably includes ethyl acetate and/or isopropyl acetate; the chloroalkane solvent preferably comprises one or more of dichloromethane, trichloromethane and 1, 2-dichloroethane; the extraction frequency is preferably 1-3 times, and more preferably 2 times; the ratio between the mass of the compound II and the volume of the organic solvent for a single extraction is preferably 1 g: 1-5 mL, more preferably 1 g: 2-4 mL, more preferably 1 g: 3 mL. In the present invention, the concentration is preferably performed by distillation under reduced pressure; in the present invention, the vacuum distillation conditions are not particularly limited, and the concentration may be carried out to a constant weight. In the present invention, the compound III was used in the next reaction without purification.
The compound III and the compound IV are subjected to a second nucleophilic substitution reaction to obtain a compound V. In the present invention, the second nucleophilic substitution reaction is preferably performed under basic conditions; the second nucleophilic substitution reaction of the compound III and the compound IV is preferably carried out by mixing the compound III, an alkaline reagent and an organic solvent and then adding the compound IV. In the present invention, the molar ratio of the compound III to the compound IV is preferably 1: 0.9 to 1.5, more preferably 1: 1 to 1.2. In the invention, the alkaline reagent preferably comprises one or more of potassium carbonate, triethylamine, sodium hydroxide and potassium hydroxide; the molar ratio of said compound III to the alkaline agent is preferably 1: 0.9 to 2.5, more preferably 1: 1-2, more preferably 1: 1.5. in the present invention, the organic solvent preferably includes one or more of N, N-Dimethylformamide (DMF), dichloromethane, acetonitrile and tetrahydrofuran; the dosage of the organic solvent is not specially limited, and the second nucleophilic substitution reaction can be smoothly carried out; in the embodiment of the present invention, the ratio of the mass of the compound III to the volume of the organic solvent is preferably 1 g: 3-8 mL, more preferably 1 g: 5-6 mL. The speed and time of the mixing are not particularly limited, and the raw materials can be uniformly mixed. In the invention, the temperature of the second nucleophilic substitution reaction is preferably 0-100 ℃, and more preferably 40-80 ℃; the time of the second nucleophilic substitution reaction is preferably determined by TLC detection until the compound III is completely reacted; the reaction that occurs during the second nucleophilic substitution reaction is as follows:
after the second nucleophilic substitution reaction, the method preferably further comprises the step of carrying out post-treatment on a system of the second nucleophilic substitution reaction, wherein the post-treatment comprises the steps of sequentially returning to room temperature, washing and extracting, drying and filtering the obtained organic phase anhydrous sodium sulfate, and concentrating the obtained filtrate to constant weight to obtain the compound V. In the present invention, the ratio of the mass of the compound III to the volume of water for washing is preferably 1 g: 2-6 mL, more preferably 1 g: 4-5 mL. In the present invention, the organic solvent for extraction preferably includes an ester solvent and/or a chlorinated alkane solvent, and the ester solvent preferably includes ethyl acetate and/or isopropyl acetate; the chloroalkane solvent preferably comprises one or more of dichloromethane, trichloromethane and 1, 2-dichloroethane; the extraction frequency is preferably 1-3 times, and more preferably 2 times; the ratio of the mass of the compound III to the volume of the organic solvent for a single extraction is preferably 1 g: 3-8 mL, more preferably 1 g: 5-6 mL. In the present invention, the concentration is preferably performed by distillation under reduced pressure; in the present invention, the vacuum distillation conditions are not particularly limited, and the concentration may be carried out to a constant weight. In the present invention, the compound V is used in the next reaction without purification.
In the present invention, the compound V can also be prepared by the following method:
carrying out esterification reaction on the compound VI and p-toluenesulfonyl chloride to obtain a compound VII;
carrying out amine ester exchange reaction on the compound VII and the compound III to obtain a compound V;
the invention carries out esterification reaction on a compound VI and p-methylbenzenesulfonyl chloride to obtain a compound VII. In the present invention, the esterification reaction is preferably carried out under an alkaline condition; preferably, the esterification reaction of the compound VI (3-hydroxybutylbenzene) and p-methylbenzenesulfonyl chloride is carried out by dissolving the compound VI in an organic solvent, adding an alkaline reagent and mixing with the p-methylbenzenesulfonyl chloride, and carrying out the esterification reaction. In the present invention, the molar ratio of the compound VI to the p-methylbenzenesulfonyl chloride is preferably 1: 0.5 to 1.2, more preferably 1: 0.8 to 1. In the present invention, the organic solvent preferably includes one or more of N, N-Dimethylformamide (DMF), dichloromethane, acetonitrile and tetrahydrofuran; the amount of the organic solvent is not particularly limited, and the esterification reaction can be smoothly carried out; in the present embodiment, the ratio of the mass of the compound VI to the volume of the organic solvent is preferably 1 g: 4-9 mL, more preferably 1 g: 5-7 mL. In the invention, the alkaline reagent preferably comprises an inorganic base and/or an organic base, and the inorganic base preferably comprises one or more of potassium carbonate, sodium hydroxide and potassium hydroxide; the organic base preferably comprises triethylamine. In the present invention, the molar ratio of the compound VI to the basic agent is preferably 1: 1 to 1.5, more preferably 1: 1.2 to 1.3. In the invention, the adding temperature of the alkaline reagent and the p-methylbenzenesulfonyl chloride is preferably-10-30 ℃, and more preferably-5 ℃. The speed and time of the mixing are not particularly limited, and the raw materials can be uniformly mixed. In the invention, the temperature of the esterification reaction is preferably-10-30 ℃, and more preferably 0-10 ℃; the esterification reaction time is preferably determined by TLC detection until the compound VI is completely reacted; the reactions that occur during the esterification reaction are as follows:
after the esterification reaction, the method preferably further comprises the step of carrying out post-treatment on the system of the esterification reaction, wherein the post-treatment comprises water washing, drying the obtained organic phase anhydrous sodium sulfate, filtering, and concentrating the obtained filtrate to constant weight to obtain a compound VII. In the present invention, the ratio of the mass of the compound VI to the volume of water for washing is preferably 1 g: 0.8-2 mL, more preferably 1 g: 1-1.5 mL. In the present invention, the concentration is preferably performed by distillation under reduced pressure; in the present invention, the vacuum distillation conditions are not particularly limited, and the concentration may be carried out to a constant weight. In the present invention, the compound VII was used in the next reaction without purification.
After the compound VII is obtained, the compound VII and the compound III are subjected to amine ester exchange reaction to obtain a compound V. In the present invention, the amine transesterification reaction is preferably carried out under basic conditions; the amine transesterification of the compound VII and the compound III is preferably carried out by mixing the compound VII, the compound III, a basic reagent and an organic solvent. In the present invention, the molar ratio of the compound III to the compound VII is preferably 1: 1 to 1.2, more preferably 1: 1.1. in the invention, the alkaline reagent preferably comprises one or more of potassium carbonate, triethylamine, sodium hydroxide and potassium hydroxide; the molar ratio of said compound III to the alkaline agent is preferably 1: 2-3.5, more preferably 1: 2.5 to 3. In the present invention, the organic solvent preferably includes acetonitrile and/or N, N-Dimethylformamide (DMF); the dosage of the organic solvent is not specially limited, and the amine ester exchange reaction can be smoothly carried out; in the embodiment of the present invention, the ratio of the mass of the compound III to the volume of the organic solvent is preferably 1 g: 5-10 mL, more preferably 1 g: 8-9 mL. In the invention, the temperature of the amine ester exchange reaction is preferably 30-85 ℃, more preferably 50-80 ℃, and further preferably 60-70 ℃; the time of the amine transesterification reaction is preferably determined by TLC detection until the compound III is completely reacted; the reactions that occur during the amine transesterification reaction are as follows:
after the amine transesterification reaction, the method preferably further comprises the step of carrying out post-treatment on the amine transesterification reaction system, wherein the post-treatment comprises the steps of cooling to room temperature, filtering, and concentrating the obtained filtrate to constant weight to obtain the compound V. The cooling method of the present invention is not particularly limited, and a cooling method known to those skilled in the art may be used. In the present invention, the concentration is preferably performed by distillation under reduced pressure; in the present invention, the vacuum distillation conditions are not particularly limited, and the concentration may be carried out to a constant weight. In the present invention, the compound V is used in the next reaction without purification.
After the compound V is obtained, the compound V is subjected to catalytic hydrogenation reaction under the action of a catalyst to obtain a compound VIII. In the present invention, the compound V is subjected to catalytic hydrogenation reaction under the action of a catalyst, preferably, the compound V, the catalyst and an organic solvent are mixed, and the catalytic hydrogenation reaction is carried out in the presence of hydrogen. In the present invention, the catalyst preferably comprises palladium on carbon and/or platinum on carbon; the mass fraction of palladium in the palladium on carbon is preferably 10% (10% palladium on carbon); the mass fraction of platinum in the platinum carbon is preferably 10% (10% platinum carbon); the mass ratio of the compound V to the catalyst is preferably 1: 0.05 to 0.5, more preferably 1: 0.1 to 0.2. In the present invention, the organic solvent preferably includes an alcohol solvent, and more preferably includes one or more of methanol, ethanol, and isopropanol; the dosage of the organic solvent is not specially limited, and the catalytic hydrogenation reaction can be smoothly carried out; in the embodiment of the present invention, the ratio of the mass of the compound V to the volume of the organic solvent is preferably 1 g: 3-10 mL, more preferably 1 g: 5-6 mL. In the invention, the hydrogen pressure of the catalytic hydrogenation reaction is preferably 0.1-10 MPa, and more preferably 2-5 MPa; the temperature of the catalytic hydrogenation reaction is preferably 25-70 ℃, and more preferably 40-50 ℃; the time of the catalytic hydrogenation reaction is preferably 6-12 h, and more preferably 8-10 h; the catalytic hydrogenation reaction is preferably carried out in a hydrogenation reaction kettle; the reactions that occur during the catalytic hydrogenation reaction are as follows:
after the catalytic hydrogenation reaction, the invention preferably further comprises carrying out post-treatment on the system of the catalytic hydrogenation reaction, wherein the post-treatment comprises cooling to room temperature, filtering to remove the catalyst, and concentrating the obtained filtrate to constant weight to obtain the compound VIII. The cooling method of the present invention is not particularly limited, and a cooling method known to those skilled in the art may be used. In the present invention, the concentration is preferably performed by distillation under reduced pressure; in the present invention, the vacuum distillation conditions are not particularly limited, and the concentration may be carried out to a constant weight. In the present invention, the compound VIII is used in the next reaction without purification.
After the compound VIII is obtained, the compound VIII and a hydrochloric acid solution are mixed for salt forming reaction, and the labetalol hydrochloride with the structure shown in the formula I is obtained. In the invention, the hydrochloric acid solution preferably comprises one or more of a hydrochloric acid aqueous solution, a hydrochloric acid alcohol solution and a hydrochloric acid ester solution; the hydrochloric acid alcohol solution preferably comprises one or more of hydrochloric acid ethanol solution, hydrochloric acid methanol solution and hydrochloric acid isopropanol solution; the ester hydrochloride solution preferably comprises ethyl acetate hydrochloride solution; the concentration of the hydrochloric acid solution is preferably 5-25 wt%, more preferably 8-20 wt%, and further preferably 10-15 wt%; the dosage of the hydrochloric acid solution is not specially limited, and the pH value of the system can be ensured to be 1-3; the pH value is more preferably 2 in the invention, the temperature of the salt forming reaction is preferably-10-30 ℃, and more preferably 0-10 ℃; the time of the salt forming reaction is preferably 30-90 min, and more preferably 60-70 min; the reactions occurring during the salt-forming reaction are as follows:
after the salt-forming reaction, the method preferably further comprises the step of carrying out post-treatment on the system of the salt-forming reaction, wherein the post-treatment comprises solid-liquid separation, and the obtained solid product is washed by an organic solvent and then dried to obtain the labetalol hydrochloride. The solid-liquid separation mode is not particularly limited, and a solid-liquid separation mode known to those skilled in the art can be adopted, such as suction filtration. In the invention, the organic solvent for washing the organic solvent preferably comprises an alcohol solvent, and the alcohol solvent preferably comprises one or more of isopropanol, methanol, ethanol and n-butanol; the organic solvent is preferably washed by rinsing. In the present invention, the drying temperature is preferably room temperature to 80 ℃, and more preferably 50 ℃; the drying time is preferably 6-24 hours, and more preferably 12 hours.
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
(1) Preparation of 2-hydroxy-5- {2- [ (phenylmethyl) amino ] acetyl } -benzamide (Compound III)
Adding 500mL of tetrahydrofuran, 42g of benzylamine and 59g of triethylamine into a four-neck flask, cooling to-10 ℃, dropwise adding 200mL of tetrahydrofuran solution of a compound II (X ═ Br, 5-bromoacetyl salicylamide) with the concentration of 0.5g/L, controlling the temperature to be not more than-5 ℃, after dropwise adding, keeping the temperature and stirring for 1h, heating to room temperature, keeping the temperature for a first nucleophilic reaction for 2h, adding 200mL of water for washing, extracting with ethyl acetate for 2 times (300 mL each time), washing the obtained organic layer with 100mL of saturated sodium bicarbonate for 1 time, washing the obtained organic layer with 100mL of saturated saline for 1 time, drying the organic layer with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate under reduced pressure to constant weight to obtain a compound III (100.62g, the yield of 91.0%), and directly using the compound III in the next reaction without purification.
(2) Preparation of 5- [ N-benzyl-N- (4-phenylbutan-2-yl) glycyl ] 2-hydroxybenzamide (Compound V)
Adding 300mL of acetonitrile, 36.5g of potassium carbonate and 50.0g of compound III into a four-neck flask, stirring for 30min at room temperature, adding 41.05g of compound IV (X ═ Br, 3-bromobutyl benzene), heating to 60 ℃, performing a second nucleophilic substitution reaction, detecting by TLC until the compound III disappears, finishing the reaction, cooling to room temperature, adding 200mL of water for washing, extracting with dichloromethane for 2 times (300 mL for a single time), drying the obtained organic layer with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate under reduced pressure to constant weight to obtain compound V (62.25g, yield 84.98%), and directly using the compound V in the next reaction without purification.
(3) Preparation of labetalol (Compound VIII)
Adding 300mL of methanol, 50g of compound V and 5.0g of 10% palladium carbon into a hydrogenation reaction kettle, carrying out catalytic hydrogenation reaction for 8h at 50 ℃ and under the hydrogen pressure of 0.5Mpa, cooling to room temperature, filtering to remove 10% palladium carbon, and concentrating the obtained filtrate under reduced pressure to constant weight to obtain compound VIII (38.11g, yield 96.68%).
(4) Preparation of labetalol hydrochloride (having structure shown in formula I)
Adding 100mL of isopropanol and 35g of compound VIII into a four-neck flask, cooling to 10 ℃, then dropwise adding a hydrochloric acid isopropanol solution until the pH value is 2.0, carrying out heat preservation and salt formation reaction for 1h, carrying out suction filtration, washing the obtained solid product isopropanol, and drying at 50 ℃ for 12h to obtain labetalol hydrochloride (35.21g, yield 90.65%).
The hydrogen spectrogram and the carbon spectrogram of the labetalol hydrochloride prepared in the embodiment are shown in the figure 1 and the figure 2, and as can be seen from the figures 1-2, the labetalol hydrochloride with the structure shown in the formula I is successfully prepared.
Example 2
Other preparation conditions were the same as in example 1, differing from example 1 only in that: step (1) replaced 5-bromoacetylsalicylamide with 5-chloroacetylsalicylamide (i.e. X ═ Cl in compound II) to give compound III (93.48g, yield 84.54%).
Example 3
Other preparation conditions were the same as in example 1, differing from example 1 only in that: step (2) replaced 5-bromoacetylsalicylamide with 5-chloroacetylsalicylamide (i.e. X ═ Cl in compound IV) to give compound V (61.16g, yield 83.49%).
Example 4
Other preparation conditions were the same as in example 1, differing from example 1 only in that: x ═ Cl in compound II in step (1), to give compound III (93.48g, yield 84.54%); in the compound IV in the step (2), X ═ Cl gave compound V (61.16g, yield 83.49%).
Example 5
(1) Compound III was prepared according to example 1, step (1).
(2) Preparation of 4-phenylbutan-2-yl 4-methylbenzenesulfonate (Compound VII)
500mL of dichloromethane and 80.05g of compound VI (3-hydroxybutylbenzene) are added into a four-neck flask, 70.16g of triethylamine is added after the temperature is reduced to-10 ℃, the temperature is controlled not to exceed 5 ℃, 106.75g of p-methylbenzenesulfonyl chloride is added, esterification reaction is carried out after the temperature is raised to room temperature, after reaction is finished after TLC detection of disappearance of the compound VI, 100mL of water is added for washing, the obtained organic layer anhydrous sodium sulfate is dried and filtered, the obtained filtrate is concentrated under reduced pressure to constant weight, and the compound VII (154.60g, yield 95.32%) is obtained.
(3) 800mL of acetonitrile, 95.67g of compound III, 139.41g of potassium carbonate and 112.64g of compound VII were added to a four-necked flask, and the mixture was uniformly mixed, heated to 81 ℃ and subjected to amine transesterification, TLC detection was performed until the compound III disappeared, the reaction was completed, cooled to room temperature and filtered, and the obtained filtrate was concentrated under reduced pressure to a constant weight to obtain compound V (119.13g, yield 85.0%).
(4) Labetalol was prepared according to example 1, step (3).
(5) Labetalol hydrochloride was prepared according to example 1, step (4).
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. The preparation method of labetalol hydrochloride is characterized by comprising the following steps:
(1) carrying out a first nucleophilic substitution reaction on the compound II and benzylamine to obtain a compound III;
(2) carrying out a second nucleophilic substitution reaction on the compound III and the compound IV to obtain a compound V;
(3) carrying out catalytic hydrogenation reaction on the compound V under the action of a catalyst to obtain a compound VIII;
(4) mixing the compound VIII with a hydrochloric acid solution for salt forming reaction to obtain labetalol hydrochloride with a structure shown in a formula I;
x in the compound II and the compound IV is halogen.
2. The method of claim 1, wherein the step (2) is replaced with:
carrying out esterification reaction on the compound VI and p-toluenesulfonyl chloride to obtain a compound VII;
carrying out amine ester exchange reaction on the compound VII and the compound III to obtain a compound V;
3. the method according to claim 1, wherein the molar ratio of the compound II to benzylamine is 1: 0.5-2;
the temperature of the first nucleophilic substitution reaction is-10-35 ℃, and the time is 1-5 h.
4. The preparation method according to claim 1, wherein the molar ratio of the compound III to the compound IV is 1: 0.9-1.5;
the temperature of the second nucleophilic substitution reaction is 0-100 ℃.
5. The preparation method according to claim 2, wherein the molar ratio of the compound VI to the p-methylbenzenesulfonyl chloride is 1: 0.5-1.2;
the temperature of the esterification reaction is-10 to 30 ℃.
6. The preparation method according to claim 2, wherein the molar ratio of the compound III to the compound VII is 1: 1-1.2;
the temperature of the amine transesterification reaction is 79-83 ℃.
7. The method according to claim 1, wherein the catalyst is palladium on carbon and/or platinum on carbon.
8. The preparation method according to claim 1 or 7, wherein the hydrogen pressure of the catalytic hydrogenation reaction is 0.1-10 MPa, the temperature is 25-70 ℃, and the time is 4-12 h.
9. The preparation method according to claim 1, wherein the hydrochloric acid solution is one or more of an aqueous hydrochloric acid solution, an alcoholic hydrochloric acid solution and an ester hydrochloric acid solution.
10. The preparation method according to claim 1, wherein the temperature of the salt forming reaction is-10 to 30 ℃, the time is 30 to 90min, and the pH value is 1 to 3.
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