CN112028844A - Preparation method of lorazepam intermediate - Google Patents
Preparation method of lorazepam intermediate Download PDFInfo
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- CN112028844A CN112028844A CN201910476064.1A CN201910476064A CN112028844A CN 112028844 A CN112028844 A CN 112028844A CN 201910476064 A CN201910476064 A CN 201910476064A CN 112028844 A CN112028844 A CN 112028844A
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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
- C07D243/28—Preparation including building-up the benzodiazepine skeleton from compounds containing no hetero rings
Abstract
The invention provides a preparation method of a lorazepam intermediate, wherein the lorazepam intermediate is 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone-4-oxide, and the preparation method comprises the following steps: (1) 2-amino-2 ', 5-dichlorobenzophenone and chloroacetyl chloride are subjected to acylation reaction to prepare 2-chloroacetylamino-2', 5-dichlorobenzophenone; (2) reacting 2-chloroacetamido-2', 5-dichlorobenzophenone with urotropine and ammonium acetate to prepare 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone; and (3) carrying out oxidation reaction on 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one and hydrogen peroxide to prepare 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one-4-oxide. The preparation method is simple and convenient, the reaction condition is mild, the yield is high, the product quality is good, and the cost is low.
Description
Technical Field
The invention relates to the field of medicines and chemical industry, in particular to a preparation method of a lorazepam intermediate.
Background
The compound is 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one-4-oxide, the CAS number is 2955-37-5, and the structure is shown in the formula I.
The 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone-4-oxide is an important intermediate for preparing lorazepam and chlordiazepam, and has wide application. In particular, 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepin-2-one-4-oxide is lorazepam impurity B identified in the european pharmacopoeia, british pharmacopoeia.
Currently, the conventional preparation method of 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one-4-oxide is as follows: the method comprises the steps of taking 2-amino-2 ', 5-dichlorobenzophenone as a raw material, oximating the raw material with hydroxylamine hydrochloride to obtain 2-amino-2', 5-dichlorobenzophenone oxime, reacting the obtained product with chloroacetyl chloride in dichloromethane to obtain 3-oxide, and finally performing ring expansion under the action of sodium hydroxide to obtain the 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one-4-oxide. However, the post-treatment operation of such a method is complicated, and the total reaction yield is as low as 50.61% (Journal of Pharmaceutical Research 2017, Vol.36, No.8, 485-) 489).
Specifically, in the above-mentioned method,
(1) in the oxime forming reaction, the post-treatment needs three steps of distilling ethanol, adjusting pH value by using dilute hydrochloric acid and purifying normal hexane;
(2) in the cyclization reaction, post-treatment needs to be carried out by extraction, drying and concentration;
(3) in the ring expansion reaction, the post-treatment requires adjusting the pH by dilute hydrochloric acid, and the obtained solid is purified by ethanol reflux and hot filtration.
Therefore, a preparation method of a lorazepam intermediate, namely 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one-4-oxide, is still needed to improve the conversion rate of the reaction, improve the quality and yield, simplify the operation and reduce the cost.
Disclosure of Invention
In view of the above, the invention aims to provide a preparation method of a lorazepam intermediate aiming at the defects in the prior art, wherein the lorazepam intermediate is 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone-4-oxide.
The purpose of the invention is realized by the following technical scheme.
The invention provides a preparation method of a lorazepam intermediate, wherein the lorazepam intermediate is 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone-4-oxide shown in a formula I, and the preparation method comprises the following steps:
(1) acylating 2-amino-2 ', 5-dichlorobenzophenone shown in formula II with chloroacetyl chloride to obtain 2-chloroacetylamino-2', 5-dichlorobenzophenone shown in formula III;
(2) reacting 2-chloroacetamido-2', 5-dichlorobenzophenone shown in formula III with urotropine and ammonium acetate to prepare 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone shown in formula IV; and
(3) carrying out oxidation reaction on 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone shown in a formula IV and hydrogen peroxide to prepare 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone-4-oxide shown in a formula I;
the preparation method provided by the invention is characterized in that the molar ratio of the 2-amino-2', 5-dichlorobenzophenone to the chloroacetyl chloride in the step (1) is 1: 1.05-1.5.
According to the preparation method provided by the invention, the acylation reaction in the step (1) is carried out in an organic solvent.
Examples of suitable organic solvents include, but are not limited to: dichloromethane, ethyl acetate, acetone and tetrahydrofuran.
The preparation method provided by the invention is characterized in that the mass-to-volume ratio of the 2-amino-2', 5-dichlorobenzophenone to the organic solvent in the step (1) is 1: 5-15 g/ml, and preferably 1:8 g/ml.
According to the preparation method provided by the invention, the acylation reaction in the step (1) is carried out at the temperature of 0-30 ℃. In some embodiments, the acylation in step (1) is carried out at a temperature of 5 to 20 ℃.
According to the preparation method provided by the invention, the reaction time of the acylation reaction in the step (1) is 0.5-2 hours, and preferably 1 hour.
According to the preparation method provided by the invention, the acylation reaction in the step (1) is carried out in the presence of an acid-binding agent.
Examples of suitable acid scavengers include, but are not limited to: anhydrous potassium carbonate, sodium carbonate and triethylamine. In some embodiments, the acid scavenger is preferably anhydrous potassium carbonate.
According to the preparation method provided by the invention, no special requirement is imposed on the amount of the acid binding agent. In some embodiments, the molar ratio of the acid scavenger to 2-amino-2', 5-dichlorobenzophenone is 1.1-2.5: 1.
The preparation method provided by the invention, wherein the step (1) further comprises the following steps: the product of the acylation reaction is purified.
According to the preparation method provided by the invention, in the step (1), the product of the acylation reaction is purified by a method comprising the following steps:
(101) adding water into the acylation reaction product, stirring and filtering, and drying and filtering the product to obtain the 2-chloroacetamido-2', 5-dichlorobenzophenone.
According to the preparation method provided by the invention, the stirring in the step (101) is carried out at the temperature of 10-20 ℃ for 0.5-2 hours.
According to the preparation method provided by the invention, in the step (101), impurities such as inorganic salts are dissolved in water by stirring and removed by filtration.
According to the preparation method provided by the invention, the drying temperature in the step (101) is 70-80 ℃.
The preparation method provided by the invention is characterized in that the molar ratio of the 2-chloroacetamido-2', 5-dichlorobenzophenone, the urotropine and the ammonium acetate in the step (2) is 1: 1-2.5. In some embodiments, the molar ratio of 2-chloroacetamido-2', 5-dichlorobenzophenone, urotropin, and ammonium acetate in step (2) is 1:2.2: 2.2.
According to the preparation method provided by the invention, the reaction in the step (2) is carried out in ethanol or ethanol water solution with the ethanol concentration of 90-99 wt%.
According to the preparation method provided by the invention, in the step (2), the mass-to-volume ratio of the 2-chloroacetamido-2', 5-dichlorobenzophenone to the ethanol or the ethanol aqueous solution is 1: 5-15 g/ml, and preferably 1:10 g/ml.
According to the preparation method provided by the invention, the reaction in the step (2) is carried out under reflux conditions.
According to the preparation method provided by the invention, the reaction time of the reaction in the step (2) is 3-6 hours, and preferably 4-5 hours.
The preparation method provided by the invention, wherein the step (2) further comprises the following steps: purifying the reaction product of 2-chloroacetamido-2', 5-dichlorobenzophenone, urotropine and ammonium acetate.
The preparation method provided by the invention is characterized in that the reaction product of 2-chloroacetamido-2', 5-dichlorobenzophenone, urotropine and ammonium acetate is purified in the step (2) by a method comprising the following steps:
(201) distilling the reaction product of 2-chloroacetamido-2', 5-dichlorobenzophenone, urotropine and ammonium acetate to remove 70-90%, preferably 80% of ethanol;
(202) adding water into the distilled product obtained in the step (201), stirring for dissolving, and filtering;
(203) drying the filtered product obtained in step (202) to obtain 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one.
According to the preparation method provided by the invention, in the step (202), the impurities are dissolved in the water by stirring and are removed by filtration.
The preparation method provided by the invention is characterized in that the drying temperature in the step (203) is 70-80 ℃.
The preparation method provided by the invention is characterized in that in the step (3), the 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one and H in hydrogen peroxide2O2The molar ratio of (A) to (B) is 1: 2-6.
According to the preparation method provided by the invention, the concentration of the hydrogen peroxide is 30-33 wt%.
According to the preparation method provided by the invention, the oxidation reaction in the step (3) is carried out in acetic acid.
The preparation method provided by the invention is characterized in that the mass-to-volume ratio of the 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one to the acetic acid in the step (3) is 1: 4-12 g/ml, preferably 1: 6-8 g/ml.
According to the preparation method provided by the invention, the reaction temperature of the oxidation reaction in the step (3) is 50-100 ℃, preferably 75-85 ℃, and further preferably 80-85 ℃.
According to the preparation method provided by the invention, the reaction time of the oxidation reaction in the step (3) is 2-5 hours.
According to the preparation method provided by the invention, the step (3) further comprises the following steps:
(301) adding sodium bisulfite solution into the product of the oxidation reaction to decompose the residual hydrogen peroxide;
(302) adding water into the product obtained in the step (301), stirring and filtering;
(303) drying the filtered product obtained in step (302) to obtain 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one-4-oxide.
According to the preparation method provided by the invention, the concentration of the sodium bisulfite solution is 20-30 wt%.
According to the preparation method provided by the invention, the amount of the sodium bisulfite solution added in the step (301) is enough to completely decompose the residual hydrogen peroxide.
The preparation method provided by the invention is characterized in that the ratio of the volume of the water added in the step (302) to the weight of the 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one in the step (3) is 2-4: 1ml: g, preferably 3:1ml: g.
The preparation method provided by the invention is characterized in that the drying temperature in the step (303) is 70-80 ℃.
The preparation method provided by the invention has the following advantages:
(1) the invention designs a process route, takes 2-amino-2 ', 5-dichlorobenzophenone and chloracetyl chloride as raw materials, firstly carries out acylation reaction with the chloracetyl chloride to prepare the 2-chloracetyl-amino-2', 5-dichlorobenzophenone; then 2-chloroacetamido-2', 5-dichlorobenzophenone reacts with urotropine and ammonium acetate to prepare 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone; then, the 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one and hydrogen peroxide are subjected to oxidation reaction to prepare a lorazepam intermediate, namely 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one-4-oxide. The preparation method has the advantages of simple operation, mild reaction conditions, easy process control, less side reactions and high yield.
(2) In the preparation method, the reaction products in each step are easy to separate and purify, and the final product with higher purity can be obtained.
(3) The preparation method of the invention has little environmental pollution, particularly adopts reagents such as water to purify products of each step of reaction, has easily obtained raw materials and little pollution, and is suitable for 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. The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. 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.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
Example 1: preparation of 2-chloroacetylamino-2', 5-dichlorobenzophenone (III)
Adding 150g of 2-amino-2', 5-dichlorobenzophenone (II), 124.6g of anhydrous potassium carbonate and 1200ml of ethyl acetate into a 3L dry three-necked bottle, cooling to about 10 ℃ through an ice water bath, dropwise adding 82.8g of chloroacetyl chloride, controlling the temperature to be 10-20 ℃ in the dropwise adding process, stirring and reacting at the temperature of 10 +/-5 ℃ after the dropwise adding is finished, monitoring the reaction progress through thin-layer chromatography (TLC), and displaying that the reaction is complete after stirring and reacting for 1 hour.
After completion of the reaction, 1000ml of water was added to the reaction flask, stirred for 30 minutes, and filtered with suction. The filtered product was air-dried at 80 ℃ for 4 hours to give 185.5g of a pale yellow solid powder.
The light yellow solid powder was analyzed by nmr hydrogen spectroscopy and was found to be 2-chloroacetamido-2', 5-dichlorobenzophenone (formula III) in a calculated yield of 96.21%.
Example 2: preparation of 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one (IV)
To a 3L reaction flask were added 180g of 2-chloroacetamido-2', 5-dichlorobenzophenone (III) prepared in example 1, 162g of urotropin, 89g of ammonium acetate and 1800ml of 95% ethanol, and heated to reflux. After refluxing for about 30 minutes, the solid dissolved to give a yellow clear solution. The reflux reaction was continued and the progress of the reaction was monitored by Thin Layer Chromatography (TLC), and after 3 hours of reflux reaction, the reaction was complete.
After the reaction was complete, about 1350ml of ethanol were removed by atmospheric distillation. To the distillate was added 500ml of water, stirred at room temperature for 30 minutes, and filtered with suction. The filtered product was air-dried at 80 ℃ for 4 hours to obtain 136.28g of an off-white solid powder.
The white solid powder is analyzed by nuclear magnetic resonance hydrogen spectrum, and the result shows that the white solid powder is 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone (IV), and the calculated yield is 85.1%.
Example 3: preparation of 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one-4-oxide (I)
To a 2L three-necked flask were added 130g of 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepin-2-one (IV) prepared in example 2, 1040ml of glacial acetic acid and 193.2g of 30% by weight hydrogen peroxide, and the mixture was stirred, heated to 65 ℃ and the solid was gradually dissolved. Heating was continued to 80 ℃ and the reaction was stirred with constant temperature, the progress of the reaction was monitored by Thin Layer Chromatography (TLC), and after 4 hours, the reaction was complete.
After the reaction is finished, cooling, adding 30 weight percent sodium bisulfite solution while stirring to decompose excessive hydrogen peroxide, and then obtaining the offwhite turbid liquid in the reaction bottle. 260ml of water was added thereto, stirred for 1 hour and filtered with suction. The filtered product was air-dried at 80 ℃ for 4 hours to give 118.64g of a beige solid powder.
Analysis of the beige solid powder by nmr hydrogen spectroscopy showed that the beige solid powder was 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one-4-oxide (I) in a calculated yield of 86.72% and a further total yield of 71% was calculated combining examples 1 and 2.
Example 4: preparation of 2-chloroacetylamino-2', 5-dichlorobenzophenone (III)
150g of 2-amino-2', 5-dichlorobenzophenone (II), 124.6g of anhydrous potassium carbonate and 1500ml of dichloromethane are added into a 3L dry three-necked bottle, the temperature is reduced to about 10 ℃ through an ice water bath, 82.8g of chloroacetyl chloride is dropwise added, the temperature is controlled to be 10-20 ℃ in the dropwise adding process, the reaction is stirred at the temperature of 15 +/-5 ℃ after the dropwise adding is finished, the reaction progress is monitored through Thin Layer Chromatography (TLC), and the reaction is shown to be complete after the stirring reaction is carried out for 1 hour.
After completion of the reaction, 1000ml of water was added to the reaction flask, stirred for 30 minutes, separated by extraction, and the dichloromethane layer was concentrated to dryness. 450ml of ethanol is added into the dried product, the mixture is heated to 60 ℃, stirred for 30 minutes and filtered by suction. The filtered product was air-dried at 80 ℃ for 4 hours to give 184.1g of a pale yellow solid powder.
The light yellow solid powder was analyzed by nmr hydrogen spectroscopy and was found to be 2-chloroacetamido-2', 5-dichlorobenzophenone (formula III) in a calculated yield of 95.48%.
Example 5: preparation of 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one (IV)
To a 3L reaction flask were added 180g of 2-chloroacetamido-2', 5-dichlorobenzophenone (III) prepared in example 4, 162g of urotropin, 89g of ammonium sulfate and 1800ml of 95% ethanol, and heated to reflux. After refluxing for about 30 minutes, the solid dissolved to give a yellow clear solution. The reflux reaction was continued and the progress of the reaction was monitored by Thin Layer Chromatography (TLC), and after 3 hours of reflux reaction, the reaction was complete.
After the reaction was complete, about 1260ml of ethanol was removed by atmospheric distillation. To the distillate was added 500ml of water, stirred at room temperature for 30 minutes, and filtered with suction. The filtered product was air-dried at 80 ℃ for 4 hours to obtain 132.52g of an off-white solid powder.
The white solid powder is analyzed by nuclear magnetic resonance hydrogen spectrum, and the result shows that the white solid powder is 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone (IV), and the calculated yield is 82.7%.
Example 6: preparation of 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one-4-oxide (I)
To a 2L three-necked flask were added 130g of 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepin-2-one (IV) prepared in example 5, 1040ml of glacial acetic acid, and 193.2g of 30% by weight hydrogen peroxide, and the mixture was stirred, heated to 65 ℃ and the solid was gradually dissolved. Heating was continued to 85 ℃ and the reaction was stirred with constant temperature and progress of the reaction was monitored by Thin Layer Chromatography (TLC) and after 4 hours the reaction was complete.
After the reaction is finished, cooling, adding 30 weight percent sodium bisulfite solution while stirring to decompose excessive hydrogen peroxide, and then obtaining the offwhite turbid liquid in the reaction bottle. 260ml of water was added thereto, stirred for 1 hour and filtered with suction. The filtered product was air-dried at 80 ℃ for 4 hours to give 117.86g of a beige solid powder.
Analysis of the beige solid powder by nmr hydrogen spectroscopy showed that the beige solid powder was 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one-4-oxide (I) in a calculated yield of 86.15% and a further total yield of 68.03% was calculated combining examples 4 and 5.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of a lorazepam intermediate, wherein the lorazepam intermediate is 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one-4-oxide shown in a formula I, and the preparation method comprises the following steps:
(1) acylating 2-amino-2 ', 5-dichlorobenzophenone shown in formula II with chloroacetyl chloride to obtain 2-chloroacetylamino-2', 5-dichlorobenzophenone shown in formula III;
(2) reacting 2-chloroacetamido-2', 5-dichlorobenzophenone shown in formula III with urotropine and ammonium acetate to prepare 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone shown in formula IV;
(3) carrying out oxidation reaction on 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone shown in a formula IV and hydrogen peroxide to prepare 7-chloro-5- (2-chlorphenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone-4-oxide shown in a formula I;
2. the preparation method according to claim 1, wherein the molar ratio of the 2-amino-2', 5-dichlorobenzophenone to the chloroacetyl chloride in the step (1) is 1:1.05 to 1.5;
preferably, the acylation reaction in the step (1) is carried out in an organic solvent;
more preferably, the organic solvent is one or more of dichloromethane, ethyl acetate, acetone and tetrahydrofuran;
more preferably, the mass-to-volume ratio of the 2-amino-2', 5-dichlorobenzophenone to the organic solvent in the step (1) is 1: 5-15 g/ml, preferably 1:8 g/ml.
3. The production method according to claim 1 or 2, wherein the acylation reaction in the step (1) is carried out at a temperature of 0 to 30 ℃, preferably 5 to 20 ℃;
preferably, the reaction time of the acylation reaction in the step (1) is 0.5 to 2 hours, preferably 1 hour;
preferably, the acylation reaction in the step (1) is carried out in the presence of an acid-binding agent;
more preferably, the acid-binding agent is one or more selected from anhydrous potassium carbonate, sodium carbonate and triethylamine; further preferably, the acid-binding agent is anhydrous potassium carbonate;
more preferably, the molar ratio of the acid-binding agent to the 2-amino-2', 5-dichlorobenzophenone is 1.1-2.5: 1.
4. The production method according to any one of claims 1 to 3, wherein the step (1) further comprises the steps of: purifying the product of the acylation reaction;
preferably, the purification of the product of the acylation reaction in step (1) is carried out by a method comprising the steps of:
(101) adding water into the acylation reaction product, stirring and filtering, and drying and filtering the product to obtain 2-chloroacetamido-2', 5-dichlorobenzophenone;
more preferably, the stirring in the step (101) is carried out at a temperature of 10 to 20 ℃ for 0.5 to 2 hours;
more preferably, the drying temperature in the step (101) is 70-80 ℃.
5. The production method according to any one of claims 1 to 4, wherein the molar ratio of 2-chloroacetamido-2', 5-dichlorobenzophenone, urotropin and ammonium acetate in the step (2) is 1:1 to 2.5, preferably 1:2.2: 2.2;
preferably, the reaction in the step (2) is carried out in ethanol or ethanol water solution with the ethanol concentration of 90-99 wt%;
preferably, the mass-to-volume ratio of the 2-chloroacetamido-2', 5-dichlorobenzophenone to the ethanol or the ethanol aqueous solution in the step (2) is 1: 5-15 g/ml, preferably 1:10 g/ml.
6. The production method according to any one of claims 1 to 5, wherein the reaction in step (2) is carried out under reflux conditions;
preferably, the reaction time of the reaction in the step (2) is 3 to 6 hours, preferably 4 to 5 hours.
7. The production method according to any one of claims 1 to 6, wherein the step (2) further comprises the steps of: purifying the reaction product of 2-chloroacetamido-2', 5-dichlorobenzophenone, urotropine and ammonium acetate;
preferably, the step (2) is a step of purifying the reaction product of 2-chloroacetamido-2', 5-dichlorobenzophenone, urotropine and ammonium acetate by a method comprising the following steps:
(201) distilling the reaction product of 2-chloroacetamido-2', 5-dichlorobenzophenone, urotropine and ammonium acetate to remove 70-90%, preferably 80% of ethanol;
(202) adding water into the distilled product obtained in the step (201), stirring for dissolving, and filtering;
(203) drying the filtered product obtained in the step (202) at the temperature of 70-80 ℃ to obtain 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one.
8. The production method according to any one of claims 1 to 7, wherein in the step (3), 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepin-2-one is reacted with H in hydrogen peroxide2O2The molar ratio of (A) to (B) is 1: 2-6;
preferably, the concentration of the hydrogen peroxide is 30-33 wt%;
preferably, the oxidation reaction in step (3) is carried out in acetic acid;
preferably, the mass-to-volume ratio of the 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one to the acetic acid in the step (3) is 1: 4-12 g/ml, and preferably 1: 6-8 g/ml.
9. The production method according to any one of claims 1 to 8, wherein the oxidation reaction in the step (3) is carried out at a reaction temperature of 50 to 100 ℃, preferably 75 to 85 ℃, and more preferably 80 to 85 ℃;
preferably, the reaction time of the oxidation reaction in the step (3) is 2 to 5 hours.
10. The production method according to any one of claims 1 to 9, wherein the step (3) further comprises the steps of:
(301) adding sodium bisulfite solution into the product of the oxidation reaction to decompose the residual hydrogen peroxide;
(302) adding water into the product obtained in the step (301), stirring and filtering;
(303) drying the filtered product obtained in step (302) to obtain 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one-4-oxide;
preferably, the ratio of the volume of water added in the step (302) to the weight of the 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1, 4-benzodiazepine-2-one in the step (3) is 2-4: 1ml: g, preferably 3:1ml: g;
preferably, the drying temperature in the step (303) is 70-80 ℃.
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| CN112500359A (en) * | 2020-12-18 | 2021-03-16 | 华中药业股份有限公司 | Preparation method of lorazepam intermediate |
| CN113816913A (en) * | 2021-09-28 | 2021-12-21 | 华中药业股份有限公司 | Preparation method of oxazepam intermediate |
| CN114702451A (en) * | 2022-03-29 | 2022-07-05 | 国药集团国瑞药业有限公司 | Preparation method of clonazepam and intermediate thereof |
| CN115215809A (en) * | 2022-08-02 | 2022-10-21 | 华中药业股份有限公司 | Preparation method of oxazepam key intermediate |
| CN115304554A (en) * | 2022-09-19 | 2022-11-08 | 公安部物证鉴定中心 | Preparation method of 2' -chlorodiazepam-D3 |
| WO2024036115A1 (en) * | 2022-08-08 | 2024-02-15 | Purdue Research Foundation | Continuous flow synthesis of lorazepam |
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| CN115215809A (en) * | 2022-08-02 | 2022-10-21 | 华中药业股份有限公司 | Preparation method of oxazepam key intermediate |
| WO2024036115A1 (en) * | 2022-08-08 | 2024-02-15 | Purdue Research Foundation | Continuous flow synthesis of lorazepam |
| CN115304554A (en) * | 2022-09-19 | 2022-11-08 | 公安部物证鉴定中心 | Preparation method of 2' -chlorodiazepam-D3 |
| CN115304554B (en) * | 2022-09-19 | 2023-07-07 | 公安部物证鉴定中心 | Preparation method of 2' -clonazepam-D3 |
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