CN112500359A - Preparation method of lorazepam intermediate - Google Patents
Preparation method of lorazepam intermediate Download PDFInfo
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- CN112500359A CN112500359A CN202011504585.2A CN202011504585A CN112500359A CN 112500359 A CN112500359 A CN 112500359A CN 202011504585 A CN202011504585 A CN 202011504585A CN 112500359 A CN112500359 A CN 112500359A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
- C07D243/30—Preparation including building-up the benzodiazepine skeleton from compounds already containing hetero rings
Abstract
The invention discloses a preparation method of a lorazepam intermediate. The preparation method comprises the following steps: the 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone is used as a raw material to carry out oxidation reaction with hydrogen peroxide in an aprotic polar solvent without an acidic solvent, and after the reaction is finished, the 7-chloro-2-oxo-5- (2-chlorphenyl) -1, 4-benzodiazepine-4-oxide is obtained through post treatment. The preparation method does not need to use expensive raw materials for catalysis in the reaction process, does not need operations such as reaction quenching, solvent extraction, concentration distillation and the like in the post-treatment process, reduces the operation steps, shortens the production period, reduces the production cost, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of a lorazepam intermediate 7-chloro-2-oxo-5- (2-chlorphenyl) -1, 4-benzodiazepine-4-oxide.
Background
Lorazepam (Lorazepam) belongs to benzodiazepine sedative hypnotics, is a benzodiazepine psychotropic drug developed by Wyeth company in the United states, has the effects of tranquilizing central nerves, hypnosis, antianxiety, antiepileptic and the like, can be used as a first-line first-choice drug for resisting the status epilepticus, and is a national basic drug. Lorazepam intermediate 7-chloro-2-oxo-5- (2-chlorophenyl) -1, 4-benzodiazepine-4-oxide, CAS No.: 2955-37-5, the structural formula is:
the 7-chloro-2-oxo-5- (2-chlorophenyl) -1, 4-benzodiazepine-4-oxide is an important intermediate for preparing lorazepam and chlordiazepam, and is also the lorazepam impurity C specified in European pharmacopoeia EP 8.0.
The lorazepam intermediate 7-chloro-2-oxo-5- (2-chlorphenyl) -1, 4-benzodiazepine-4-oxide is prepared by taking 2-amino-2 ', 5-dichlorobenzophenone as a raw material and oximating with hydroxylamine hydrochloride to obtain 2-amino-2', 5-dichlorobenzophenone oxime; reacting with chloracetyl chloride to obtain 2-chloracetyl amino-2', 5-dichlorobenzophenone oxime; closing the ring in acetic acid to obtain 2-chloromethyl-4- (2-chlorphenyl) -6-chloroquinazoline-3-oxide; finally, the ring is expanded under the action of sodium hydroxide to prepare the 7-chloro-2-oxo-5- (2-chlorphenyl) -1, 4-benzodiazepine-4-oxide. Long reaction steps, complex post-treatment operation and low total reaction yield. The synthetic route is as follows:
a process for preparing 7-Chloro-5-phenyl-1, 3-dihydro-2H-1, 4-benzodiazepine-2-one-4-Oxide from 7-Chloro-5-phenyl-3H-l, 4-benzodiazepine 4-Oxide (Journal of Organic Chemistry,1961,26, 4936) by adding 30% of hydrogen peroxide solution to acetic acid solvent under acidic environment conditions, extracting with dichloromethane, washing with hydrochloric acid, and finally washing with dichloromethane is disclosed in the literature, in which 7-Chloro-2-methyl-5-phenyl-1, 3-dihydro-2H-1, 4-benzodiazepine-2-one-4-Oxide is prepared by using 7-Chloro-5-phenyl-1, 3-dihydro-2H-4-benzodiazepine-4-Oxide as a starting material, Refining diethyl ether and petroleum ether to obtain 7-chloro-5-phenyl-1, 3-dihydro-2H-1, 4-benzodiazepine-2-one-4-oxide. The reaction time of the process is over 46 hours, reaction byproducts are more, extraction and multi-solvent purification are needed after the reaction is finished, the post-treatment is complicated, and the product yield is only 19%.
In recent years, technicians carry out a lot of work and make beneficial progress in the field of catalytic hydrogen peroxide oxidation reaction, and catalytic oxidation by adopting a transition metal complex is beneficial to increasing the oxidation activity of hydrogen peroxide. In the same way, in a Chinese patent CN104961692A, in an acetic acid reaction solvent under an acidic environment condition, under the action of a sodium tungstate dihydrate catalyst, 7-chloro-5-phenyl-1, 3-dihydro-2H-1, 4-benzodiazepine-2-one and 30% hydrogen peroxide are subjected to an oxidation reaction to prepare 7-chloro-5-phenyl-1, 3-dihydro-2H-1, 4-benzodiazepine-2-one-4-oxide. At present, technicians generally consider that the hydrogen peroxide oxidation reaction under the catalysis of sodium tungstate dihydrate is generally carried out under the condition of an acidic ligand, such as acetic acid, hydrochloric acid, sulfuric acid and the like, and the effects of accelerating the oxidation reaction process, reducing the consumption of hydrogen peroxide and reducing side reactions cannot be exerted under neutral and alkaline environments. Because the oxidation reaction raw material is 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone which is a lorazepam intermediate or 7-chloro-5-phenyl-1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone which is the oxidation reaction raw material in Chinese patent CN104961692A has low solubility in acetic acid, the oxidation reaction is carried out in a heterogeneous system. The process has the advantages of shortening the reaction time, reducing the consumption of hydrogen peroxide and improving the reaction yield by adding the catalyst, namely the sodium tungstate dihydrate in the oxidation reaction. However, the price of the sodium tungstate dihydrate is high, a large amount of water is required to be added in the post-reaction treatment process to promote the complete precipitation of the product and the bottom-measuring washing of the catalyst sodium tungstate dihydrate, the product precipitated in water needs to be fully dissolved by a large amount of dichloromethane, the expensive catalyst cannot be recovered, the recovery rate of the dichloromethane which is a low-boiling-point solvent with a large usage amount is low, and the factors undoubtedly increase the production cost; moreover, the excessive hydrogen peroxide is decomposed, and a genotoxic substance formaldehyde is required to be used, and the substance has a very strong carcinogenic effect and harms the production site environment.
In the oxidation process of benzodiazepine psychotics, diazepam, oxazepam, lorazepam and the like are added into an acetic acid solvent to react at a temperature of over 50 ℃ when hydrogen peroxide oxidation reaction is carried out, wherein the maximum concentration of hydrogen peroxide does not exceed 35%. For example, the literature "Quinazolines and 1,4-benzodiazepines. IV. transformations 7-Chloro-2-methyl lamino-5-phenyl-3H-l,4-benzodiazepine 4-Oxide" (Journal of Organic Chemistry,1961,26,4936 and 4941) and the Chinese patent CN104961692A all used hydrogen peroxide solution with a concentration of 30% in acetic acid solvent for reaction. The technicians generally consider that the mass concentration of hydrogen peroxide used in the oxidation reaction is in the range of 25-35%, and the concentration below the range can cause the oxidation to be weakened and the reaction rate to be slow; above this concentration range, the reaction temperature is limited, and the reaction is carried out at room temperature or lower, otherwise the oxidation reaction cannot be achieved due to the rapid decomposition of hydrogen peroxide.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of a lorazepam intermediate, namely 7-chloro-2-oxo-5- (2-chlorphenyl) -1, 4-benzodiazepine-4-oxide. The method has simple reaction and post-treatment process and low production cost, and is suitable for industrial large-scale production.
The technical scheme of the invention is realized by adopting the following process route:
in order to achieve the above object, the present invention provides a method for preparing lorazepam intermediate, 7-chloro-2-oxo-5- (2-chlorophenyl) -1, 4-benzodiazepine-4-oxide (shown in formula I), comprising the following steps:
(1) mixing 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one (shown as a formula II) with an aprotic polar solvent, stirring and heating, adding 45-55 wt% of hydrogen peroxide solution in batches for reaction under the condition of heat preservation, cooling after the reaction is finished, adding water for elutriation, filtering and washing to obtain a target product crude product;
(2) pulping and refining the crude target product in the step (1) in a mixed solvent of acetone and water to obtain the lorazepam intermediate, namely 7-chloro-2-oxo-5- (2-chlorphenyl) -1, 4-benzodiazepine-4-oxide.
Preferably, the ratio of the 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one to the aprotic polar solvent in the step (1) is 1 g: 1.5ml to 3.5 ml.
Preferably, the aprotic polar solvent in step (1) is one or both of dimethylformamide and dimethylacetamide.
Preferably, the concentration of the hydrogen peroxide solution in the step (1) is 50 wt%.
Preferably, the temperature for stirring and heating in the step (1) is 40-55 ℃.
Preferably, the temperature of the heat preservation in the step (1) is 40-55 ℃.
Preferably, the mass ratio of the total mass of the hydrogen peroxide solution added in portions in the step (1) to the mass of the 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one is 1.2: 1-1.5: 1.
preferably, the addition in portions in step (1) is carried out at least twice.
Preferably, the batch addition is divided into two times, and the two times of addition are as follows: firstly, 70-80% of the total mass of the hydrogen peroxide solution is added, the reaction is carried out for 3-4 hours at the temperature of 55-65 ℃, and then the rest hydrogen peroxide solution is added at the temperature of 60-65 ℃ and the reaction is carried out for 6-9 hours at the temperature of 60-65 ℃.
Preferably, the temperature is reduced to 0 to-10 ℃ after the reaction in the step (1) is finished, and more preferably to-5 ℃.
Preferably, the mass ratio of the mass of the water added in the water adding and water precipitating in the step (1) to the mass of the 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one is 0.5: 1-2.0: 1, more preferably 0.9: 1-1.8: 1.
preferably, the water adding and water precipitating manner in the step (1) is as follows: adding water, stirring at 0-5 deg.C for 1/4-2 hr, standing for more than 2 hr, and preferably adding water, stirring at 0-5 deg.C for 0.5 hr.
Preferably, the mass ratio of the total volume of the mixed solvent of acetone and water in the step (2) to the 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one is 2.0 ml: 1.0 g-5.0 ml: 1.0 g.
Preferably, the acetone and water of step (2) are mixed according to a ratio of 4: 1-2: 1 by volume.
The reaction mechanism of the present invention: the preparation of the intermediate in the oxidation process of the benzodiazepine psychotropic drugs is generally to carry out heterogeneous reaction of a reaction substrate and hydrogen peroxide with the mass percentage concentration of about 30% in an acetic acid solvent, and the addition of a transition metal complex such as sodium tungstate dihydrate can accelerate the reaction speed and reduce the consumption of the hydrogen peroxide. The applicant of the invention uses 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone as a raw material, tries to carry out oxidation reaction at different temperatures by adding hydrogen peroxide with the concentration of about 30 percent by mass of sodium tungstate dihydrate into different solvents such as water, acid water (hydrochloric acid or sulfuric acid or acetic acid added into water), alkaline water (sodium hydroxide or potassium hydroxide or sodium carbonate added into water), acetone, methanol, ethanol, acetonitrile, dichloromethane and the like respectively, and the result shows that the better oxidation reaction result needs at least more than 20 hours and is accompanied with the generation of a plurality of byproducts with larger proportion; the reaction results in acidic aqueous solutions are clearly superior to those in water and alkaline water. The applicant of the invention finds that the oxidation reaction speed of the raw material 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone in dimethylformamide as a solvent by adopting 50% hydrogen peroxide is obviously higher than the reaction speed of the hydrogen peroxide which is about 30% and is commonly used in the field in other solvents, and further finds that: on the premise of abandoning the expensive raw material catalyst of sodium tungstate dihydrate, the method adopts 50 percent hydrogen peroxide and carries out oxidation reaction in a dimethyl formamide or dimethyl acetamide solvent, can also obviously improve the oxidation reaction speed, simultaneously removes the complicated processes of quenching by formaldehyde, acid-base neutralization, dichloromethane extraction, concentration distillation and the like, can greatly shorten the period, reduce the production cost and improve the production site environment.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the process of the invention abandons the expensive raw material catalyst-sodium tungstate dihydrate required in the prior art, and promotes the smooth proceeding of the oxidation reaction by adopting 50 percent by mass of hydrogen peroxide and dimethylformamide or dimethylacetamide as reaction solvent to replace 30 percent by mass of hydrogen peroxide and acetic acid as reaction solvent in the prior art;
(2) the process of the invention adopts dimethylformamide or dimethylacetamide as a reaction solvent to complete the oxidation reaction in a homogeneous system, and the post-treatment process adopts a direct elutriation mode to replace a complicated post-treatment process: quenching by formaldehyde, neutralizing by acid and alkali, extracting by dichloromethane, concentrating and distilling, which is favorable for greatly shortening the process period, reducing the production cost, improving the production site environment and being suitable for large-scale industrial production.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. 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.
Examples 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one was prepared according to the preparation method described in Chinese patent CN 112028844A.
Example 1
Adding 30g of 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one and 75ml of dimethylformamide into a reaction bottle in sequence, stirring, dissolving and heating to 40 ℃, and then dropwise adding 30g of hydrogen peroxide with the concentration of 50 wt% at the temperature of 40-55 ℃. After the dropwise addition, the reaction is carried out for 3 hours at the temperature of 55-65 ℃. After the heat preservation reaction is finished, 10g of hydrogen peroxide with the mass percentage concentration of 50% is dripped again at the temperature of 60-65 ℃, and the heat preservation reaction is continued for 6 hours at the temperature of 60-65 ℃ after the dripping is finished. Cooling to-5 ℃, dropwise adding 30g of water, continuing stirring at the temperature of 0-5 ℃ for 0.5 hour after adding, standing for 2 hours, filtering, and washing with water to obtain a crude product of 7-chloro-2-oxo-5- (2-chlorophenyl) -1, 4-benzodiazepine-4-oxide. The crude product was added to a mixed solvent of 90ml of acetone and 30ml of water and slurried to give 27.2g of 7-chloro-2-oxo-5- (2-chlorophenyl) -1, 4-benzodiazepine-4-oxide in an HPLC purity of 99.3% and a yield of 86.08%.
Example 2
Adding 30g of 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one and 105ml of dimethylacetamide into a reaction bottle in sequence, stirring, dissolving and heating to 40 ℃, and then dropwise adding 30g of 50% hydrogen peroxide at the controlled temperature of 40-55 ℃. After the dropwise addition, the reaction is carried out for 3 hours at the temperature of 55-65 ℃. After the heat preservation reaction is finished, 10g of hydrogen peroxide with the mass percentage concentration of 50% is dripped again at the temperature of 60-65 ℃, and the heat preservation reaction is continued for 7 hours at the temperature of 60-65 ℃ after the dripping is finished. Cooling to-5 ℃, dropwise adding 50g of water, continuing stirring at the temperature of 0-5 ℃ for 0.5 hour after the water is added, standing for 2 hours, filtering, and washing with water to obtain a crude product of 7-chloro-2-oxo-5- (2-chlorophenyl) -1, 4-benzodiazepine-4-oxide. The crude product was added to a mixed solvent of 60ml of acetone and 15ml of water and refined by beating to obtain 27.5g of 7-chloro-2-oxo-5- (2-chlorophenyl) -1, 4-benzodiazepine-4-oxide with an HPLC purity of 99.1% and a yield of 87.03%.
Example 3
Adding 30g of 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one and 105ml of dimethylacetamide into a reaction bottle in sequence, stirring, dissolving and heating to 40 ℃, and then dropwise adding 30g of 50% hydrogen peroxide at the controlled temperature of 40-55 ℃. After the dropwise addition, the reaction is carried out for 3 hours at the temperature of 55-65 ℃. After the heat preservation reaction is finished, 15g of hydrogen peroxide with the mass percentage concentration of 50% is dripped again at the temperature of 60-65 ℃, and the heat preservation reaction is continued for 6.5 hours at the temperature of 60-65 ℃ after the dripping is finished. Cooling to-5 ℃, dropwise adding 54g of water, continuing stirring at the temperature of 0-5 ℃ for 0.5 hour after the water is added, standing for 2 hours, filtering, and washing with water to obtain a crude product of 7-chloro-2-oxo-5- (2-chlorophenyl) -1, 4-benzodiazepine-4-oxide. The crude product was added to a mixed solvent of 60ml of acetone and 15ml of water and refined by beating to obtain 27.7g of 7-chloro-2-oxo-5- (2-chlorophenyl) -1, 4-benzodiazepine-4-oxide with an HPLC purity of 99.6% and a yield of 87.66%.
Example 4
Adding 30g of 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one, 45ml of dimethylformamide and 50ml of dimethylacetamide into a reaction bottle in sequence, stirring, dissolving and heating to 40 ℃, and then dropwise adding 30g of hydrogen peroxide with the mass percentage concentration of 50% at the temperature of 40-55 ℃. After the dropwise addition, the reaction is carried out for 3 hours at the temperature of 55-65 ℃. After the heat preservation reaction is finished, 10g of hydrogen peroxide with the mass percentage concentration of 50% is dripped again at the temperature of 60-65 ℃, and the heat preservation reaction is continued for 7 hours at the temperature of 60-65 ℃ after the dripping is finished. Cooling to 0 ℃, dropwise adding 50g of water, continuing stirring at the temperature of 0-5 ℃ for 0.5 hour after the water is added, standing for 2 hours, filtering, and washing with water to obtain a crude product of 7-chloro-2-oxo-5- (2-chlorophenyl) -1, 4-benzodiazepine-4-oxide. The crude product was added to a mixed solvent of 40ml of acetone and 20ml of water and refined by beating to obtain 27.3g of 7-chloro-2-oxo-5- (2-chlorophenyl) -1, 4-benzodiazepine-4-oxide with an HPLC purity of 99.2% and a yield of 86.39%.
Example 5
Adding 30g of 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one and 105ml of dimethylacetamide into a reaction bottle in sequence, stirring, dissolving and heating to 45 ℃, and then dropwise adding 27g of 50% hydrogen peroxide at the controlled temperature of 45-55 ℃. After the dropwise addition, the reaction is carried out for 4 hours at the temperature of 55-65 ℃. After the heat preservation reaction is finished, 9g of hydrogen peroxide with the mass percentage concentration of 50% is dripped again at the temperature of 60-65 ℃, and the heat preservation reaction is continued for 9 hours at the temperature of 60-65 ℃ after the dripping is finished. Cooling to-5 ℃, dropwise adding 25g of water, stirring for 0.5 hour at the temperature of 0-5 ℃ after adding, standing for 2 hours, filtering, and washing with water to obtain a crude product of 7-chloro-2-oxo-5- (2-chlorophenyl) -1, 4-benzodiazepine-4-oxide. The crude product was added to a mixed solvent of 60ml of acetone and 15ml of water and refined by beating to obtain 26.5g of 7-chloro-2-oxo-5- (2-chlorophenyl) -1, 4-benzodiazepine-4-oxide with an HPLC purity of 99.5% and a yield of 83.86%.
Example 6
Adding 30g of 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one and 75ml of dimethylformamide into a reaction bottle in sequence, stirring, dissolving and heating to 45 ℃, and then dropwise adding 30g of 50% hydrogen peroxide at the controlled temperature of 45-55 ℃. After the dropwise addition, the reaction is carried out for 3 hours at the temperature of 55-65 ℃. After the heat preservation reaction is finished, 10g of hydrogen peroxide with the mass percentage concentration of 50% is dripped again at the temperature of 60-65 ℃, and the heat preservation reaction is continued for 6 hours at the temperature of 60-65 ℃ after the dripping is finished. Cooling to-10 ℃, dropwise adding 60g of water, continuing stirring at the temperature of 0-5 ℃ for 0.5 hour after adding, standing for 2 hours, filtering, and washing with water to obtain a crude product of 7-chloro-2-oxo-5- (2-chlorophenyl) -1, 4-benzodiazepine-4-oxide. The crude product was added to a mixed solvent of 120ml of acetone and 30ml of water and refined by beating to obtain 27.1g of 7-chloro-2-oxo-5- (2-chlorophenyl) -1, 4-benzodiazepine-4-oxide with an HPLC purity of 99.0% and a yield of 85.75%.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes, which are made by the present specification, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (10)
1. A preparation method of a lorazepam intermediate is characterized by comprising the following steps:
(1) mixing 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one with an aprotic polar solvent, stirring and heating, adding 45-55 wt% of hydrogen peroxide solution in batches under a heat preservation condition for reaction, cooling after the reaction is finished, adding water for elutriation, filtering and washing to obtain a target product crude product;
(2) pulping and refining the crude target product in the step (1) in a mixed solvent of acetone and water to prepare the lorazepam intermediate, namely 7-chloro-2-oxo-5- (2-chlorphenyl) -1, 4-benzodiazepine-4-oxide.
2. The preparation method of the lorazepam intermediate, according to claim 1, wherein the ratio of the 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one and the aprotic polar solvent in step (1) is 1 g: 1.5ml to 3.5 ml.
3. The preparation method of lorazepam intermediate, according to claim 1, wherein the mass ratio of the total mass of the added hydrogen peroxide solution in the step (1) to the mass of 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one is 1.2: 1-1.5: 1.
4. the preparation method of the lorazepam intermediate, according to claim 1, wherein the mass ratio of the total volume of the mixed solvent of acetone and water in the step (2) to the mass of the 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one is 2.0 ml: 1.0 g-5.0 ml: 1.0 g.
5. The preparation method of lorazepam intermediate according to claim 1, wherein the aprotic polar solvent of step (1) is one or both of dimethylformamide and dimethylacetamide; the concentration of the hydrogen peroxide solution in the step (1) is 50 wt%; the temperature for stirring and heating in the step (1) is 40-55 ℃.
6. The preparation method of the lorazepam intermediate according to claim 1, wherein the temperature of the heat preservation in the step (1) is 40-55 ℃; adding the batch in the step (1) at least twice.
7. The preparation method of the lorazepam intermediate according to claim 6, wherein the batch addition is divided into two times, and the two times are added in a manner that: firstly, 70-80% of the total mass of the hydrogen peroxide solution is added, the reaction is carried out for 3-4 hours at the temperature of 55-65 ℃, and then the rest hydrogen peroxide solution is added at the temperature of 60-65 ℃ and the reaction is carried out for 6-9 hours at the temperature of 60-65 ℃.
8. The preparation method of the lorazepam intermediate, according to claim 1, wherein the mass ratio of the mass of the water added in the step (1) to the mass of the 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one in the water-adding elutriation is 0.5: 1-2.0: 1; after the reaction in the step (1) is finished, cooling to 0-minus 10 ℃.
9. The preparation method of the lorazepam intermediate, according to claim 1, wherein the mass ratio of the mass of the water added in the step (1) to the mass of the 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one in the water-adding elutriation is 0.9: 1-1.8: 1; and (2) after the reaction in the step (1) is finished, cooling to-5 ℃.
10. The preparation method of the lorazepam intermediate according to claim 1, wherein the water is added in the step (1) for water precipitation in a manner that: adding water, stirring for 1/4-2 hours at 0-5 ℃, and standing for more than 2 hours; and (3) mixing the acetone and the water in the step (2) according to a ratio of 4: 1-2: 1 by volume.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113816913A (en) * | 2021-09-28 | 2021-12-21 | 华中药业股份有限公司 | Preparation method of oxazepam intermediate |
| CN113816914A (en) * | 2021-09-28 | 2021-12-21 | 华中药业股份有限公司 | Preparation method of lorazepam intermediate |
| CN115215809A (en) * | 2022-08-02 | 2022-10-21 | 华中药业股份有限公司 | Preparation method of oxazepam key intermediate |
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| CN113816913A (en) * | 2021-09-28 | 2021-12-21 | 华中药业股份有限公司 | Preparation method of oxazepam intermediate |
| CN113816914A (en) * | 2021-09-28 | 2021-12-21 | 华中药业股份有限公司 | Preparation method of lorazepam intermediate |
| CN113816914B (en) * | 2021-09-28 | 2024-04-09 | 华中药业股份有限公司 | Preparation method of lorazepam intermediate |
| CN115215809A (en) * | 2022-08-02 | 2022-10-21 | 华中药业股份有限公司 | Preparation method of oxazepam key intermediate |
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