CN116041280A - Preparation method of trimetazidine hydrochloride - Google Patents

Preparation method of trimetazidine hydrochloride Download PDF

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CN116041280A
CN116041280A CN202211548894.9A CN202211548894A CN116041280A CN 116041280 A CN116041280 A CN 116041280A CN 202211548894 A CN202211548894 A CN 202211548894A CN 116041280 A CN116041280 A CN 116041280A
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trimetazidine
reaction
trimethoxybenzaldehyde
acidic
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周海峰
陈多鹏
刘义稳
刘祈星
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China Three Gorges University CTGU
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China Three Gorges University CTGU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • 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
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/827—Iridium
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to a preparation method of trimetazidine hydrochloride, which takes 2,3, 4-trimethoxybenzaldehyde and N-Boc-piperazine as raw materials, takes a complex of triphenylphosphine and metallic iridium as a catalyst, and takes the complex in H 2 In the atmosphere of (2) synthesizing trimetazidine hydrochloride by catalytic reduction. The method has the advantages of low cost, simple operation, high yield, good environmental protection and the like, and has wide application prospect.

Description

Preparation method of trimetazidine hydrochloride
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of an anti-angina cardiovascular medicine trimetazidine hydrochloride.
Background
Trimetazidine hydrochloride (Trimetazidine dihydrochloride), of formula: c (C) 14 H 24 Cl 2 N 2 O 3 The chemical name is 1- [ (2, 3, 4-trimethoxyphenyl) methyl]Piperazine hydrochloride has a structural formula shown in formula I, is a piperazine derivative, is originally developed by Shi Weiya (Server), belongs to an anti-angina cardiovascular drug, has the effects of antagonizing epinephrine, norepinephrine and vasopressin, can reduce vascular resistance, increase coronary and circulating blood flow, and promote myocardial metabolism and myocardial energy generation. Simultaneously can reduce myocardial oxygen consumption, thereby improving myocardial oxygen supply and demand balance, relieving myocardial damage inflammatory reaction, correcting heart failure, and being clinically applicable to coronary artery workCan be used for treating insufficiency, angina pectoris, and old myocardial infarction.
Figure BDA0003981302290000011
In the preparation process of trimetazidine dihydrochloride bulk drug, the impurities which are most easily generated are 1, 4-bis (2, 3, 4-trimethoxybenzyl) piperazine (shown as IV):
Figure BDA0003981302290000012
in the prior art, there have been many reports of processes for preparing trimetazidine, in which the processes using hydrogenation reductive amination are as follows:
1. in U.S. Pat. No. 3, 5142053, trimetazidine is prepared by hydroreductive amination under the catalysis of 5% Pd/C using 2,3, 4-trimethoxybenzaldehyde and piperazine as raw materials and ethanol or methyl tert-butyl ether as a reaction solvent. The method requires multiple recrystallisation to remove impurities (compounds of formula IV) and is complex to operate.
Figure BDA0003981302290000013
2. In Chinese patent CN102010386A, 2,3, 4-trimethoxybenzaldehyde and piperazine are used as raw materials, a mixed solution consisting of water and ethanol is used as a solvent, and the trimetazidine is prepared by hydrogenation and reductive amination under the catalysis of 5% Pd/C. The method successfully improves the purity of the product, reduces the content of impurities (compounds shown in formula IV), but has complex operation.
Figure BDA0003981302290000021
3.2017, wang Zhaowen et al reported that trimetazidine was prepared by hydrogenation reductive amination under Pd/C catalysis using 2,3, 4-trimethoxybenzaldehyde and piperazine as raw materials and salicylic acid-complexed palladium (sodium chloropalladate+sodium salicylate) as an active component source to prepare a Pd/C catalyst having a relatively high Pd dispersity. The method needs special Pd/C catalyst and has complex operation.
Figure BDA0003981302290000022
4. In chinese patent CN106397357a, 2,3, 4-trimethoxybenzaldehyde and piperazine salt are used as raw materials, and hydrogenation reductive amination is performed under the catalysis of Ni to synthesize trimetazidine, and the method uses Ni catalyst with high risk.
Figure BDA0003981302290000023
Disclosure of Invention
The invention aims to provide a novel method for synthesizing trimetazidine hydrochloride, which is an anti-angina drug, and the process route is as follows:
Figure BDA0003981302290000024
the steps are as follows:
step (1), reacting 2,3, 4-trimethoxybenzaldehyde (III) with N-Boc-piperazine in a solvent and in the presence of a catalyst to obtain N-Boc-trimetazidine (II);
step (2), removing the tertiary butoxy carbonyl protecting group of the N-Boc-trimetazidine (II) under the acidic condition and salifying to obtain trimetazidine hydrochloride (I)
The specific reaction route is as follows:
Figure BDA0003981302290000025
the solvent in the step (1) comprises one or a mixture of trifluoroethanol, methanol and ethanol.
The catalyst in the step (1) is a complex ([ Ir (cod) Cl) of triphenylphosphine and metallic iridium] 2 -PPh 3 )。
In the step (1)2,3, 4-trimethoxybenzaldehyde, N-Boc-piperazine and catalyst ([ Ir (cod) Cl)] 2 -PPh 3 ) The molar ratio of (2) is 1: 1-2: 0.0001 to 0.0004.
Charging H at 0-50deg.C in the reaction process of step (1) 2 Controlling the pressure to be 0.1-10 MPa for reaction for 15-30 h.
And (3) recrystallizing the N-Boc-trimetazidine (II) obtained in the step (1) in one or more solvents selected from petroleum ether, normal hexane, dichloromethane, ethyl acetate, methanol, ethanol and water.
The conditions for removing the tert-butoxycarbonyl protecting group in the step (2) are acidic, and the acidic solvent used comprises an organic solvent containing hydrogen chloride, such as acidic ethanol, acidic isopropanol or acidic ethyl acetate.
The acidic solvent may also be an organic acid of hydrochloric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, or chloroacetic acid.
The reaction temperature of the step (2) is 0-40 ℃ and the reaction time is 1-10 h. The reaction temperature of the step (2) is 0-40 ℃ and the reaction time is 1-10 h.
Compared with the prior art, the invention has the main innovation point that the complex ([ Ir (cod) Cl) of triphenylphosphine and metallic iridium is adopted by taking 2,3, 4-trimethoxybenzaldehyde and N-Boc-piperazine as raw materials] 2 -PPh 3 ) As a catalyst in H 2 In the atmosphere of (2), the trimetazidine hydrochloride (I) is synthesized by catalytic reduction, and has the following advantages: the complex of triphenylphosphine and iridium is simple and easy to obtain, the minimum dosage can reach 0.01mol% (S/C=10000), and the method has the advantages of low dosage of organic solvent, simple operation, high yield and mild condition, and is more suitable for industrial application.
Detailed Description
The following examples further illustrate the present invention, but the present invention is not limited to the following examples.
Example 1
Catalyst ([ Ir (cod) Cl)] 2 -PPh 3 ) Is prepared from
2.00mg (3. Mu. Mol) of [ Ir (cod) Cl are added to the test tube] 2 ，3.50mg(13.2μmol)PPh 3 (2 mL) trifluoroethanolSealing, stirring at room temperature for 30min to obtain catalyst triphenylphosphine and iridium complex ([ Ir (cod) Cl)] 2 -PPh 3 )。
Example 2
Preparation method 1 of N-Boc-trimetazidine (II)
To a hydrogenation reactor, 1.18g (6 mmol) of 2,3, 4-trimethoxybenzaldehyde, 1.34g (7.2 mmol) of N-Boc-piperazine, (200. Mu.L) of the prepared catalyst ([ Ir (cod) Cl) were successively added] 2 -PPh 3 ) (8.3 mL) trifluoroethanol, sealing, purging the reaction system with nitrogen, and then introducing H into the reaction system 2 The hydrogen pressure is kept at 10MPa, and then the reaction system is reacted for 24 hours at 25-30 ℃. Sampling, rapid HPLC detection, and waiting for the content of the raw material 2,3, 4-trimethoxybenzaldehyde<1, i.e., the end point of the reaction was reached. After the reaction, concentrating under reduced pressure, removing trifluoroethanol to obtain a light yellow liquid, namely an N-Boc-trimetazidine crude product, recrystallizing the N-Boc-trimetazidine crude product by using methanol-water (1:2), and filtering to obtain a white solid (2.05 g), namely an N-Boc-trimetazidine refined product, wherein the yield is 93.2% and the purity is 99.0%.
Example 3
Preparation method 2 of N-Boc-trimetazidine (II)
To a hydrogenation reactor, 1.18g (6 mmol) of 2,3, 4-trimethoxybenzaldehyde, 1.34g (7.2 mmol) of N-Boc-piperazine, (250. Mu.L) of the prepared catalyst ([ Ir (cod) Cl) were successively added] 2 -PPh 3 ) (8.3 mL) trifluoroethanol, sealing, purging the reaction system with nitrogen, and then introducing H into the reaction system 2 The hydrogen pressure is kept at 10MPa, and then the reaction system is reacted for 24 hours at 25-30 ℃. Sampling, rapid HPLC detection, and waiting for the content of the raw material 2,3, 4-trimethoxybenzaldehyde<1, i.e., the end point of the reaction was reached. After the reaction, concentrating under reduced pressure, removing trifluoroethanol to obtain a light yellow liquid, namely an N-Boc-trimetazidine crude product, recrystallizing the N-Boc-trimetazidine crude product by using methanol-water (1:2), and filtering to obtain a white solid (2.06 g), namely an N-Boc-trimetazidine refined product, wherein the yield is 93.7% and the purity is 98.9%.
Example 4
Preparation method 3 of N-Boc-trimetazidine (II)
To a hydrogenation reactor, 1.18g (6 mmol) of 2,3, 4-trimethoxybenzaldehyde, 1.34g (7.2 mmol) of N-Boc-piperazine, (800. Mu.L) of the prepared catalyst ([ Ir (cod) Cl) were successively added] 2 -PPh 3 ) (8.3 mL) trifluoroethanol, sealing, purging the reaction system with nitrogen, and then introducing H into the reaction system 2 The hydrogen pressure is kept at 10MPa, and then the reaction system is reacted for 24 hours at 25-30 ℃. Sampling, rapid HPLC detection, and waiting for the content of the raw material 2,3, 4-trimethoxybenzaldehyde<1, i.e., the end point of the reaction was reached. After the reaction, concentrating under reduced pressure, removing trifluoroethanol to obtain a light yellow liquid, namely an N-Boc-trimetazidine crude product, recrystallizing the N-Boc-trimetazidine crude product by using methanol-water (1:2), and filtering to obtain a white solid (2.03 g), namely an N-Boc-trimetazidine refined product, wherein the yield is 92.3% and the purity is 99.1%.
Example 5
Preparation method 4 of N-Boc-trimetazidine (II)
To a hydrogenation reactor, 1.18g (6 mmol) of 2,3, 4-trimethoxybenzaldehyde, 1.34g (7.2 mmol) of N-Boc-piperazine, (200. Mu.L) of the prepared catalyst ([ Ir (cod) Cl) were successively added] 2 -PPh 3 ) (8.3 mL) trifluoroethanol, sealing, purging the reaction system with nitrogen, and then introducing H into the reaction system 2 The hydrogen pressure is kept at 7MPa, and then the reaction system is reacted for 24 hours at 25-30 ℃. Sampling, rapid HPLC detection, and waiting for the content of the raw material 2,3, 4-trimethoxybenzaldehyde<1, i.e., the end point of the reaction was reached. After the reaction, concentrating under reduced pressure, removing trifluoroethanol to obtain a light yellow liquid, namely an N-Boc-trimetazidine crude product, recrystallizing the N-Boc-trimetazidine crude product by using methanol-water (1:2), and filtering to obtain a white solid (2.06 g), namely an N-Boc-trimetazidine refined product, wherein the yield is 93.7% and the purity is 98.5%.
Example 6
Preparation method 5 of N-Boc-trimetazidine (II)
To a hydrogenation reactor, 1.18g (6 mmol) of 2,3, 4-trimethoxybenzaldehyde, 1.34g (7.2 mmol) of N-Boc-piperazine, (200. Mu.L) of the prepared catalyst ([ Ir (cod) Cl) were successively added] 2 -PPh 3 ) (8.3 mL) trifluoroethanol, sealing, purging the reaction system with nitrogen, and then introducing H into the reaction system 2 The hydrogen pressure is kept at 4MPa, and then the reaction system is reacted for 24 hours at 25-30 ℃. Sampling, rapid HPLC detection, and waiting for the content of the raw material 2,3, 4-trimethoxybenzaldehyde<1, i.e., the end point of the reaction was reached. After the reaction, concentrating under reduced pressure, removing trifluoroethanol to obtain a light yellow liquid, namely an N-Boc-trimetazidine crude product, recrystallizing the N-Boc-trimetazidine crude product by using methanol-water (1:2), and filtering to obtain a white solid (2.00 g), namely an N-Boc-trimetazidine refined product, wherein the yield is 91.0% and the purity is 98.4%.
Example 7
Preparation method 6 of N-Boc-trimetazidine (II)
To a hydrogenation reactor, 1.18g (6 mmol) of 2,3, 4-trimethoxybenzaldehyde, 1.34g (7.2 mmol) of N-Boc-piperazine, (200. Mu.L) of the prepared catalyst ([ Ir (cod) Cl) were successively added] 2 -PPh 3 ) (8.3 mL) trifluoroethanol, sealing, purging the reaction system with nitrogen, and then introducing H into the reaction system 2 The hydrogen pressure is kept at 2MPa, and then the reaction system is reacted for 24 hours at 25-30 ℃. Sampling, rapid HPLC detection, and waiting for the content of the raw material 2,3, 4-trimethoxybenzaldehyde<1, i.e., the end point of the reaction was reached. After the reaction, concentrating under reduced pressure, removing trifluoroethanol to obtain a light yellow liquid, namely an N-Boc-trimetazidine crude product, recrystallizing the N-Boc-trimetazidine crude product by using methanol-water (1:2), and filtering to obtain a white solid (2.05 g), namely an N-Boc-trimetazidine refined product, wherein the yield is 93.2% and the purity is 99.0%.
Example 8
Preparation method 7 of N-Boc-trimetazidine (II)
To a hydrogenation reactor, 1.18g (6 mmol) of 2,3, 4-trimethoxybenzaldehyde, 1.12g (6 mmol) of N-Boc-piperazine, (200. Mu.L) of the prepared catalyst ([ Ir (cod) Cl) were successively added] 2 -PPh 3 ) (8.3 mL) trifluoroethanol, sealing, purging the reaction system with nitrogen, and then introducing H into the reaction system 2 The hydrogen pressure is kept at 2MPa, and then the reaction system is reacted for 24 hours at 25-30 ℃. Sampling, rapid HPLC detection, and waiting for the content of the raw material 2,3, 4-trimethoxybenzaldehyde<1, i.e., the end point of the reaction was reached. Concentrating under reduced pressure after the reaction is finished, and removing trifluoroethanol to obtain light yellow liquid, namely N-Boc-kojiThe crude product of the metazine is recrystallized by methanol-water (1:2), and filtered to obtain white solid (1.96 g), namely the refined product of the N-Boc-trimetazidine, with the yield of 89.1 percent and the purity of 98.2 percent.
Example 9
Preparation method 8 of N-Boc-trimetazidine (II)
To a hydrogenation reactor, 1.18g (6 mmol) of 2,3, 4-trimethoxybenzaldehyde, 1.14g (6.12 mmol) of N-Boc-piperazine, (200. Mu.L) of the prepared catalyst ([ Ir (cod) Cl) were successively added] 2 -PPh 3 ) (8.3 mL) trifluoroethanol, sealing, purging the reaction system with nitrogen, and then introducing H into the reaction system 2 The hydrogen pressure is kept at 2MPa, and then the reaction system is reacted for 24 hours at 25-30 ℃. Sampling, rapid HPLC detection, and waiting for the content of the raw material 2,3, 4-trimethoxybenzaldehyde<1, i.e., the end point of the reaction was reached. After the reaction, concentrating under reduced pressure, removing trifluoroethanol to obtain a light yellow liquid, namely an N-Boc-trimetazidine crude product, recrystallizing the N-Boc-trimetazidine crude product by using methanol-water (1:2), and filtering to obtain a white solid (1.98 g), namely an N-Boc-trimetazidine refined product, wherein the yield is 90.1% and the purity is 98.1%.
Example 10
Preparation method 9 of N-Boc-trimetazidine (II)
To a hydrogenation reactor, 1.18g (6 mmol) of 2,3, 4-trimethoxybenzaldehyde, 1.17g (6.3 mmol) of N-Boc-piperazine, (200. Mu.L) of the prepared catalyst ([ Ir (cod) Cl) were successively added] 2 -PPh 3 ) (8.3 mL) trifluoroethanol, sealing, purging the reaction system with nitrogen, and then introducing H into the reaction system 2 The hydrogen pressure is kept at 2MPa, and then the reaction system is reacted for 24 hours at 25-30 ℃. Sampling, rapid HPLC detection, and waiting for the content of the raw material 2,3, 4-trimethoxybenzaldehyde<1, i.e., the end point of the reaction was reached. After the reaction, concentrating under reduced pressure, removing trifluoroethanol to obtain a light yellow liquid, namely an N-Boc-trimetazidine crude product, recrystallizing the N-Boc-trimetazidine crude product by using methanol-water (1:2), and filtering to obtain a white solid (1.99 g), namely an N-Boc-trimetazidine refined product, wherein the yield is 90.5%, and the purity is 99.1%.
Example 11
Preparation method 10 of N-Boc-trimetazidine (II)
To a hydrogenation reactor, 1.18g (6 mmol) of 2,3, 4-trimethoxybenzaldehyde, 1.21g (6.48 mmol) of N-Boc-piperazine, (200. Mu.L) of the prepared catalyst ([ Ir (cod) Cl) were successively added] 2 -PPh 3 ) (8.3 mL) trifluoroethanol, sealing, purging the reaction system with nitrogen, and then introducing H into the reaction system 2 The hydrogen pressure is kept at 2MPa, and then the reaction system is reacted for 24 hours at 25-30 ℃. Sampling, rapid HPLC detection, and waiting for the content of the raw material 2,3, 4-trimethoxybenzaldehyde<1, i.e., the end point of the reaction was reached. After the reaction, concentrating under reduced pressure, removing trifluoroethanol to obtain a light yellow liquid, namely an N-Boc-trimetazidine crude product, recrystallizing the N-Boc-trimetazidine crude product by using methanol-water (1:2), and filtering to obtain a white solid (2.06 g), namely an N-Boc-trimetazidine refined product, wherein the yield is 93.7% and the purity is 98.1%.
Example 12
Preparation method 11 of N-Boc-trimetazidine (II)
To a hydrogenation reactor, 1.18g (6 mmol) of 2,3, 4-trimethoxybenzaldehyde, 1.23g (6.6 mmol) of N-Boc-piperazine, (200. Mu.L) of the prepared catalyst ([ Ir (cod) Cl) were successively added] 2 -PPh 3 ) (8.3 mL) trifluoroethanol, sealing, purging the reaction system with nitrogen, and then introducing H into the reaction system 2 The hydrogen pressure is kept at 2MPa, and then the reaction system is reacted for 24 hours at 25-30 ℃. Sampling, rapid HPLC detection, and waiting for the content of the raw material 2,3, 4-trimethoxybenzaldehyde<1, i.e., the end point of the reaction was reached. After the reaction, concentrating under reduced pressure, removing trifluoroethanol to obtain a light yellow liquid, namely an N-Boc-trimetazidine crude product, recrystallizing the N-Boc-trimetazidine crude product by using methanol-water (1:2), and filtering to obtain a white solid (2.05 g), namely an N-Boc-trimetazidine refined product, wherein the yield is 93.2% and the purity is 99.1%.
Example 13
Preparation method 12 of N-Boc-trimetazidine (II)
To a hydrogenation reactor, 1.18g (6 mmol) of 2,3, 4-trimethoxybenzaldehyde, 1.23g (6.6 mmol) of N-Boc-piperazine, (200. Mu.L) of the prepared catalyst ([ Ir (cod) Cl) were successively added] 2 -PPh 3 ) (8.3 mL) trifluoroethanol, sealed and purged with nitrogen gasSweeping the reaction system, and then introducing H into the reaction system 2 The hydrogen pressure is kept at 2MPa, and then the reaction system is reacted for 30 hours at 25-30 ℃. Sampling, rapid HPLC detection, and waiting for the content of the raw material 2,3, 4-trimethoxybenzaldehyde<1, i.e., the end point of the reaction was reached. After the reaction, concentrating under reduced pressure, removing trifluoroethanol to obtain a light yellow liquid, namely an N-Boc-trimetazidine crude product, recrystallizing the N-Boc-trimetazidine crude product by using methanol-water (1:2), and filtering to obtain a white solid (2.05 g), namely an N-Boc-trimetazidine refined product, wherein the yield is 93.2% and the purity is 98.3%.
Example 14
Preparation method 13 of N-Boc-trimetazidine (II)
To a hydrogenation reactor, 1.18g (6 mmol) of 2,3, 4-trimethoxybenzaldehyde, 1.23g (6.6 mmol) of N-Boc-piperazine, (200. Mu.L) of the prepared catalyst ([ Ir (cod) Cl) were successively added] 2 -PPh 3 ) (8.3 mL) trifluoroethanol, sealing, purging the reaction system with nitrogen, and then introducing H into the reaction system 2 The hydrogen pressure is kept at 2MPa, and then the reaction system is reacted for 15 hours at 25-30 ℃. After the reaction, concentrating under reduced pressure, removing trifluoroethanol to obtain a light yellow liquid, namely an N-Boc-trimetazidine crude product, recrystallizing the N-Boc-trimetazidine crude product by using methanol-water (1:2), and filtering to obtain a white solid (1.11 g), namely an N-Boc-trimetazidine refined product, wherein the yield is 50.5%, and the purity is 98.7%.
Example 15
Preparation method 14 of N-Boc-trimetazidine (II)
To a hydrogenation reactor, 1.18g (6 mmol) of 2,3, 4-trimethoxybenzaldehyde, 1.23g (6.6 mmol) of N-Boc-piperazine, (200. Mu.L) of the prepared catalyst ([ Ir (cod) Cl) were successively added] 2 -PPh 3 ) (3.5 mL) trifluoroethanol, sealing, purging the reaction system with nitrogen, and then introducing H into the reaction system 2 The hydrogen pressure is kept at 2MPa, and then the reaction system is reacted for 24 hours at 25-30 ℃. Sampling, rapid HPLC detection, and waiting for the content of the raw material 2,3, 4-trimethoxybenzaldehyde<1, i.e., the end point of the reaction was reached. After the reaction, concentrating under reduced pressure to remove trifluoroethanol to obtain a pale yellow liquid, namely a crude product of N-Boc-trimetazidine, and using methanol-water (1:2) to carry out the reaction on the N-Boc-trimetazidineThe crude product of the tazidine is recrystallized and filtered to obtain white solid (1.97 g), namely the refined product of the N-Boc-trimetazidine, with the yield of 89.6 percent and the purity of 99.0 percent.
Example 16
Preparation method 15 of N-Boc-trimetazidine (II)
To a hydrogenation reactor, 1.18g (6 mmol) of 2,3, 4-trimethoxybenzaldehyde, 1.23g (6.6 mmol) of N-Boc-piperazine, (200. Mu.L) of the prepared catalyst ([ Ir (cod) Cl) were successively added] 2 -PPh 3 ) (4.7 mL) trifluoroethanol, sealing, purging the reaction system with nitrogen, and then introducing H into the reaction system 2 The hydrogen pressure is kept at 2MPa, and then the reaction system is reacted for 24 hours at 25-30 ℃. Sampling, rapid HPLC detection, and waiting for the content of the raw material 2,3, 4-trimethoxybenzaldehyde<1, i.e., the end point of the reaction was reached. After the reaction, concentrating under reduced pressure, removing trifluoroethanol to obtain a light yellow liquid, namely an N-Boc-trimetazidine crude product, recrystallizing the N-Boc-trimetazidine crude product by using methanol-water (1:2), and filtering to obtain a white solid (2.05 g), namely an N-Boc-trimetazidine refined product, wherein the yield is 93.2% and the purity is 98.4%.
Example 17
Preparation method 16 of N-Boc-trimetazidine (II)
Into a hydrogenation reactor, 5.89g (30 mmol) of 2,3, 4-trimethoxybenzaldehyde, 6.03g (32.4 mmol) of N-Boc-piperazine and (1 mL) of the prepared catalyst ([ Ir (cod) Cl) were sequentially added] 2 -PPh 3 ) (23.5 mL) trifluoroethanol, sealing, purging the reaction system with nitrogen, and then introducing H into the reaction system 2 The hydrogen pressure is kept at 2MPa, and then the reaction system is reacted for 24 hours at 25-30 ℃. Sampling, rapid HPLC detection, and waiting for the content of the raw material 2,3, 4-trimethoxybenzaldehyde<1, i.e., the end point of the reaction was reached. After the reaction, concentrating under reduced pressure, removing trifluoroethanol to obtain a light yellow liquid, namely an N-Boc-trimetazidine crude product, recrystallizing the N-Boc-trimetazidine crude product by using methanol-water (1:2), and filtering to obtain a white solid (10.23 g), namely an N-Boc-trimetazidine refined product, wherein the yield is 93.1% and the purity is 99.1%.
Example 18
Preparation of ethyl acetate solution of HCl
200mL (3.43 mol) of ethanol is added into a reaction bottle, the mixture is stirred in an ice-water bath, the strict temperature is controlled to be not more than 10 ℃, 203mL (2.86 mol) of acetyl chloride is added dropwise, and the mixture is reacted in the ice-water bath for 10min after the addition, thus obtaining the ethyl acetate solution of HCl.
Example 19
Preparation method 1 of trimetazidine hydrochloride (I)
To 2.01g (5.48 mmol) of N-Boc-trimetazidine essence was added (20 mL) of ethyl acetate, a self-made ethyl acetate solution of HCl was added dropwise until the pH was about 1, and if the pH was not reached, a multi-drop HCl ethyl acetate solution was added, the reaction was stirred at 25 to 30℃for 2 to 4 hours, the reaction was completed, suction filtration was performed, the solid was washed with ethyl acetate, and vacuum-dried overnight at 35℃to give a white solid (1.74 g), trimetazidine hydrochloride, yield 93.59%,97.5%.
Example 20
Preparation method 2 of trimetazidine hydrochloride (I)
To 2.01g (5.48 mmol) of N-Boc-trimetazidine fine product was added (20 mL) of isopropanol, HCl gas was introduced for 1.5 hours until the pH was about 1, if the pH was not reached, the time for introducing HCl gas could be prolonged, the reaction was stirred at 25 to 30℃for 2 to 4 hours, the reaction was completed, suction filtration was performed, the solid was washed with isopropanol (5 mL), and dried under vacuum at 35℃overnight to give a white solid, trimetazidine hydrochloride (1.72 g), yield 92.52%, purity 97.8%.
Example 21
Preparation method 3 of trimetazidine hydrochloride (I)
2.01g (5.48 mmol) of N-Boc-trimetazidine is added with (20 mL) of absolute ethyl alcohol, 4M HCl ethanol solution is added dropwise until the pH is about 1, if the pH is less than the pH at which HCl ethanol solution can be added dropwise, stirring is carried out at 25-30 ℃ for 2-4 h, the reaction is finished, stirring is carried out at 0 ℃ for 1-2 h, suction filtration is carried out, the solid is washed by ethanol, and vacuum drying is carried out at 35 ℃ for overnight, thus obtaining white solid, namely trimetazidine hydrochloride (1.22 g), the yield is 65.62%, and the purity is 96.5%.

Claims (9)

1. A synthesis method of trimetazidine hydrochloride is characterized in that the structural formula of the compound is shown as formula I,
Figure FDA0003981302280000011
the method comprises the following steps:
step (1), reacting 2,3, 4-trimethoxybenzaldehyde (III) with N-Boc-piperazine in a solvent and in the presence of a catalyst to obtain N-Boc-trimetazidine (II);
step (2), removing the tertiary butoxy carbonyl protecting group of the N-Boc-trimetazidine (II) under the acidic condition and salifying to obtain trimetazidine hydrochloride (I)
The specific reaction route is as follows:
Figure FDA0003981302280000012
2. the method of claim 1, wherein the solvent in step (1) comprises one or a mixture of trifluoroethanol, methanol and ethanol.
3. The synthesis method according to claim 1, wherein the catalyst in the step (1) is a complex ([ Ir (cod) Cl) of triphenylphosphine and metallic iridium] 2 -PPh 3 )。
4. The synthesis method according to claim 3, wherein 2,3, 4-trimethoxybenzaldehyde, N-Boc-piperazine and catalyst ([ Ir (cod) Cl) in the step (1)] 2 -PPh 3 ) The molar ratio of (2) is 1: 1-2: 0.0001 to 0.0004.
5. The synthesis method according to claim 1, wherein H is charged at a temperature of 0 to 50℃during the reaction in step (1) 2 Controlling the pressure to be 0.1-10 MPa for reaction for 15-30 h.
6. The synthesis method of claim 1, wherein the N-Boc-trimetazidine (ii) obtained in the step (1) is recrystallized in one or more solvents selected from petroleum ether, N-hexane, dichloromethane, ethyl acetate, methanol, ethanol and water.
7. The synthesis method according to claim 1, wherein the conditions for removing the t-butoxycarbonyl protecting group in the step (2) are acidic, and the acidic solvent used comprises an organic solvent containing hydrogen chloride, such as acidic ethanol, acidic isopropanol or acidic ethyl acetate.
8. The method of claim 1, wherein the acidic solvent is an organic acid selected from the group consisting of hydrochloric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and chloroacetic acid.
9. The synthesis method according to claim 1, wherein the reaction temperature in the step (2) is 0-40 ℃ and the reaction time is 1-10 h.
CN202211548894.9A 2022-12-05 2022-12-05 Preparation method of trimetazidine hydrochloride Pending CN116041280A (en)

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