CN104961692A - Improved preparation method of 7-chlorin-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-keto-4-oxide - Google Patents
Improved preparation method of 7-chlorin-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-keto-4-oxide Download PDFInfo
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- CN104961692A CN104961692A CN201510360445.5A CN201510360445A CN104961692A CN 104961692 A CN104961692 A CN 104961692A CN 201510360445 A CN201510360445 A CN 201510360445A CN 104961692 A CN104961692 A CN 104961692A
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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
- C07D243/26—Preparation from compounds already containing the benzodiazepine skeleton
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Abstract
The invention discloses an improved preparation method of a 7-chlorin-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-keto-4-oxide. The method comprises the following steps that 7-chlorin-5-phenyl-1,3- dihydro-2H-1,4-benzodiazepine-2-ketone and 30% hydrogen peroxide are subjected to an oxidizing reaction in acetic acid under the action of a sodium tungstate dihydrate catalyst to obtain the 7-chlorin-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-keto-4-oxide. Compared with an existing preparation method, the method has the advantages that the preparation method is easy and convenient to implement, reaction conditions are gentle, and the yield is high; products can be separated and purified easily, an end product with high purity can be obtained, the environment pollution is small, and the method is suitable for industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, relate to a kind of 7-chloro-5-phenyl-1,3-dihydro-2H-1, the improvement preparation method of 4-benzodiazepine-2-ketone-4-oxide compound.
Background technology
7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound, No. CAS: 963-39-3, Chinese another name: demoxepam; Demoxepam; Oxygen is stabilized; Demoxepam; Chlordiazepoxide impurity A etc.Its structural formula is:
7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound is that preparation is peaceful, the important intermediate of oxazepan (oxazepam), and application widely.It is the chlordiazepoxide impurity II of specifying in Chinese Pharmacopoeia CP2010, is also simultaneously American Pharmacopeia USP36, the chlordiazepoxide impurity A of specifying in European Pharmacopoeia EP8.0, British Pharmacopoeia BP2013 and chlordiazepoxide impurity A.
Preparation method conventional is at present: with 2-amino-5-chlorobenzophenone for raw material, obtain 2-amino-5-chlorobenzophenone oxime with Hydrochloride Hydroxylamine Oximation; React with chloroacetyl chloride, obtain 2-chloro acetylamino-5-chlorobenzophenone oxime; In acetic acid, close ring obtain the chloro-2-chloromethyl of 6--4-phenylquinazoline-3-oxide compound; Finally under sodium hydroxide effect, ring expansion obtains 7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound.Reactions steps is long, and post-processing operation is loaded down with trivial details, and overall yield of reaction is lower.Its synthetic route is as follows:
Preparation method is below reported in document [Journal of Organic Chemistry, 1961,26,4936-4941]:
With 7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-ketone is starting raw material, in acetic acid, with the hydrogen peroxide oxidation of 2.5 equivalents, 80 DEG C are reacted 10 hours, and stirring at room temperature reacts 36 hours, shrend on the rocks is gone out, dichloromethane extraction, salt acid elution, finally obtains the chloro-5-phenyl-1 of 7-with methylene dichloride, ether and sherwood oil are refining, 3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound.Produce a large amount of waste water in technological process, need to use multi-solvents, post-processing operation is loaded down with trivial details, and the reaction times, reaction yield only had 19% more than 46 hours.
Therefore, the chloro-5-phenyl-1 of research 7-, the improvement preparation method of 3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound, optimum synthesis technique, reduce the consumption of hydrogen peroxide, reduce the generation of side reaction, improve transformation efficiency and the selectivity of reaction, improve quality and yield, reduce costs, have great importance.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of 7-chloro-5-phenyl-1,3-dihydro-2H-1, the improvement preparation method of 4-benzodiazepine-2-ketone-4-oxide compound.Compare with existing preparation method, it is easy that present method has preparation method, and reaction conditions is gentle, and yield is high; Product is easy to separation and purification, and can obtain the end product that purity is higher, environmental pollution is little, is suitable for the advantages such as suitability for industrialized production.
For reaching above-mentioned purpose, the invention provides following technical scheme:
A kind of 7-chloro-5-phenyl-1,3-dihydro-2H-1, the improvement preparation method of 4-benzodiazepine-2-ketone-4-oxide compound, the chloro-5-phenyl-1 of described 7-, 3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound is the compound that formula I indicates, and chemical structural formula is as follows:
。
The chloro-5-phenyl-1 of a kind of 7-, 3-dihydro-2H-1, the improvement preparation method of 4-benzodiazepine-2-ketone-4-oxide compound, the chloro-5-phenyl-1 of 7-that formula I indicates, 3-dihydro-2H-1, the preparation method of 4-benzodiazepine-2-ketone-4-oxide compound, comprise the steps: the chloro-5-phenyl-1 of 7-, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone (II) is in acetic acid, under the effect of tungstate dihydrate acid sodium catalyst, with 30% hydrogen peroxide generation oxidizing reaction, obtain the chloro-5-phenyl-1 of 7-, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone-4-oxide compound (I), reaction equation is as follows:
。
The chloro-5-phenyl-1 of a kind of 7-, 3-dihydro-2H-1, the improvement preparation method of 4-benzodiazepine-2-ketone-4-oxide compound, formula II oxidation is prepared in the reaction of formula I, and the ratio of described tungstate dihydrate acid sodium and the weight consumption of formula II is 0.01 ~ 0.12.
The chloro-5-phenyl-1 of a kind of 7-, 3-dihydro-2H-1, the improvement preparation method of 4-benzodiazepine-2-ketone-4-oxide compound, formula II oxidation is prepared in the reaction of formula I, and the ratio of 30% described hydrogen peroxide and the weight consumption of formula II is 0.42:1 ~ 0.84:1.
The chloro-5-phenyl-1 of a kind of 7-, 3-dihydro-2H-1, the improvement preparation method of 4-benzodiazepine-2-ketone-4-oxide compound, formula II oxidation is prepared in the reaction of formula I, and the volumetric usage of described acetic acid and the ratio of formula II weight consumption are 3:1 ~ 7:1.
A kind of 7-chloro-5-phenyl-1,3-dihydro-2H-1, the improvement preparation method of 4-benzodiazepine-2-ketone-4-oxide compound, formula II oxidation is prepared in the reaction of formula I, and described oxidizing reaction temperature is 70 ~ 100 DEG C.
The present invention compared with prior art tool has the following advantages:
1) method is easy, and reaction conditions is gentle, and process easily controls, and side reaction is few, and feed stock conversion is high.
2) adopt tungstate dihydrate acid sodium to be catalyzer, add the activity of hydrogen peroxide, reduce the consumption of hydrogen peroxide; Decrease the consumption of acetic acid simultaneously, reduce cost.Catalytic activity and selectivity high.
3) byproduct of reaction is water, and product is easy to separation and purification, and can obtain the end product that purity is higher, yield is high, pollutes little, is suitable for suitability for industrialized production.
Embodiment
Embodiment 1:
Add 7-chloro-5-phenyl-1,3-dihydro-2H-1 successively, 4-benzodiazepine-2-ketone 27.07g, tungstate dihydrate acid sodium 0.27g, water 10 ml and acetic acid 162ml, stir and be warming up to 50-60 DEG C.Under stirring, in 50 ~ 60 DEG C, in 1 hour, slowly drip 30% hydrogen peroxide 22.74g.After dropwising, be warming up to 90 ~ 100 DEG C, insulation reaction 6 hours.In cooling with under stirring, add the hydrogen peroxide that Formaldehyde decomposition is excessive; Add 10% aqueous sodium carbonate and be neutralized to pH=8 ~ 9.Dichloromethane extraction water layer, merges organic layer, dry, is evaporated to dry, ethyl alcohol recrystallization, obtains 7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound 24.12g, yield 84.1%, HPLC purity 99.0%.
Embodiment 2:
Add 7-chloro-5-phenyl-1,3-dihydro-2H-1 successively, 4-benzodiazepine-2-ketone 27.07g, tungstate dihydrate acid sodium 0.97g, water 10 ml and acetic acid 189ml, stir and be warming up to 50-60 DEG C.Under stirring, in 50 ~ 60 DEG C, in 1 hour, slowly drip 30% hydrogen peroxide 17.05g.After dropwising, be warming up to 70 ~ 80 DEG C, insulation reaction 4 hours.In cooling with under stirring, add the hydrogen peroxide that Formaldehyde decomposition is excessive; Add 10% aqueous sodium carbonate and be neutralized to pH=8 ~ 9.Dichloromethane extraction water layer, merges organic layer, dry, is evaporated to dry, ethyl alcohol recrystallization, obtains 7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound 23.91g, yield 83.4%, HPLC purity 99.5%.
Embodiment 3:
Add 7-chloro-5-phenyl-1,3-dihydro-2H-1 successively, 4-benzodiazepine-2-ketone 27.07g, tungstate dihydrate acid sodium 0.33g, water 10 ml and acetic acid 135ml, stir and be warming up to 50-60 DEG C.Under stirring, in 50 ~ 60 DEG C, in 1 hour, slowly drip 30% hydrogen peroxide 12.53g.After dropwising, be warming up to 80 ~ 90 DEG C, insulation reaction 7 hours.In cooling with under stirring, add the hydrogen peroxide that Formaldehyde decomposition is excessive; Add 10% aqueous sodium carbonate and be neutralized to pH=8 ~ 9.Dichloromethane extraction water layer, merges organic layer, dry, is evaporated to dry, ethyl alcohol recrystallization, obtains 7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound 25.21g, yield 87.9%, HPLC purity 99.2%.
Embodiment 4:
Add 7-chloro-5-phenyl-1,3-dihydro-2H-1 successively, 4-benzodiazepine-2-ketone 27.07g, tungstate dihydrate acid sodium 3.25g, water 10 ml and acetic acid 81ml, stir and be warming up to 50-60 DEG C.Under stirring, in 50 ~ 60 DEG C, in 1 hour, slowly drip 30% hydrogen peroxide 11.37g.After dropwising, be warming up to 90 ~ 100 DEG C, insulation reaction 9 hours.In cooling with under stirring, add the hydrogen peroxide that Formaldehyde decomposition is excessive; Add 10% aqueous sodium carbonate and be neutralized to pH=8 ~ 9.Dichloromethane extraction water layer, merges organic layer, dry, is evaporated to dry, ethyl alcohol recrystallization, obtains 7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound 23.65g, yield 82.5%, HPLC purity 99.1%.
Embodiment 5:
Add 7-chloro-5-phenyl-1,3-dihydro-2H-1 successively, 4-benzodiazepine-2-ketone 27.07g, tungstate dihydrate acid sodium 2.27g, water 10 ml and acetic acid 162ml, stir and be warming up to 50-60 DEG C.Under stirring, in 50 ~ 60 DEG C, in 1 hour, slowly drip 30% hydrogen peroxide 19.49g.After dropwising, be warming up to 80 ~ 90 DEG C, insulation reaction 5 hours.In cooling with under stirring, add the hydrogen peroxide that Formaldehyde decomposition is excessive; Add 10% aqueous sodium carbonate and be neutralized to pH=8 ~ 9.Dichloromethane extraction water layer, merges organic layer, dry, is evaporated to dry, ethyl alcohol recrystallization, obtains 7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound 25.38g, yield 88.5%, HPLC purity 99.3%.
Embodiment recited above is only be described the preferred embodiment for the present invention; not the spirit and scope of the present invention are limited; under the prerequisite not departing from design philosophy of the present invention; the various distortion that in this area, common engineering technical personnel make technical scheme of the present invention and improvement, all should belong to protection scope of the present invention.
Claims (6)
1. the chloro-5-phenyl-1 of 7-, 3-dihydro-2H-1, the improvement preparation method of 4-benzodiazepine-2-ketone-4-oxide compound, it is characterized in that: the chloro-5-phenyl-1 of described 7-, 3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound is the compound that formula I indicates, and chemical structural formula is as follows:
。
2. the chloro-5-phenyl-1 of a kind of 7-as claimed in claim 1, 3-dihydro-2H-1, the improvement preparation method of 4-benzodiazepine-2-ketone-4-oxide compound, it is characterized in that: the chloro-5-phenyl-1 of 7-that formula I indicates, 3-dihydro-2H-1, the preparation method of 4-benzodiazepine-2-ketone-4-oxide compound, comprise the steps: the chloro-5-phenyl-1 of 7-, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone (II) is in acetic acid, under the effect of tungstate dihydrate acid sodium catalyst, with 30% hydrogen peroxide generation oxidizing reaction, obtain the chloro-5-phenyl-1 of 7-, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone-4-oxide compound (I), reaction equation is as follows:
。
3. the chloro-5-phenyl-1 of a kind of 7-as claimed in claim 2,3-dihydro-2H-1, the improvement preparation method of 4-benzodiazepine-2-ketone-4-oxide compound, it is characterized in that: formula II oxidation is prepared in the reaction of formula I, the ratio of described tungstate dihydrate acid sodium and the weight consumption of formula II is 0.01 ~ 0.12.
4. the chloro-5-phenyl-1 of a kind of 7-as claimed in claim 2,3-dihydro-2H-1, the improvement preparation method of 4-benzodiazepine-2-ketone-4-oxide compound, it is characterized in that: formula II oxidation is prepared in the reaction of formula I, and the ratio of 30% described hydrogen peroxide and the weight consumption of formula II is 0.42:1 ~ 0.84:1.
5. the chloro-5-phenyl-1 of a kind of 7-as claimed in claim 2,3-dihydro-2H-1, the improvement preparation method of 4-benzodiazepine-2-ketone-4-oxide compound, it is characterized in that: formula II oxidation is prepared in the reaction of formula I, and the volumetric usage of described acetic acid and the ratio of formula II weight consumption are 3:1 ~ 7:1.
6. the chloro-5-phenyl-1 of a kind of 7-as claimed in claim 2,3-dihydro-2H-1, the improvement preparation method of 4-benzodiazepine-2-ketone-4-oxide compound, is characterized in that: formula II oxidation is prepared in the reaction of formula I, and described oxidizing reaction temperature is 70 ~ 100 DEG C.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110840898A (en) * | 2019-11-19 | 2020-02-28 | 湖南洞庭药业股份有限公司 | Light-stabilized pharmaceutical composition, preparation method and pharmaceutical application thereof |
| CN112028844A (en) * | 2019-06-03 | 2020-12-04 | 北京益民药业有限公司 | Preparation method of lorazepam intermediate |
| CN112500359A (en) * | 2020-12-18 | 2021-03-16 | 华中药业股份有限公司 | Preparation method of lorazepam intermediate |
Citations (2)
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| US3136815A (en) * | 1959-12-10 | 1964-06-09 | Hoffmann La Roche | Amino substituted benzophenone oximes and derivatives thereof |
| CN102558197A (en) * | 2012-01-11 | 2012-07-11 | 浙江医药股份有限公司新昌制药厂 | Preparation method of levofloxacin-N-oxide |
-
2015
- 2015-06-26 CN CN201510360445.5A patent/CN104961692A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3136815A (en) * | 1959-12-10 | 1964-06-09 | Hoffmann La Roche | Amino substituted benzophenone oximes and derivatives thereof |
| CN102558197A (en) * | 2012-01-11 | 2012-07-11 | 浙江医药股份有限公司新昌制药厂 | Preparation method of levofloxacin-N-oxide |
Non-Patent Citations (2)
| Title |
|---|
| L.H.STERNBACH ET AL.: "Quinazolines and 1,4-Benzodiazepines. IV. Transformations of 7-Chloro-2-methylamino-5-phenyl-3H-l,4-benzodiazepin4e-Oxide", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| 冯晓亮等: "2, 3-二甲基-4-氯吡啶-N-氧化物的合成工艺改进", 《合成化学》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112028844A (en) * | 2019-06-03 | 2020-12-04 | 北京益民药业有限公司 | Preparation method of lorazepam intermediate |
| CN110840898A (en) * | 2019-11-19 | 2020-02-28 | 湖南洞庭药业股份有限公司 | Light-stabilized pharmaceutical composition, preparation method and pharmaceutical application thereof |
| CN110840898B (en) * | 2019-11-19 | 2022-05-13 | 湖南洞庭药业股份有限公司 | Light-stabilized pharmaceutical composition, preparation method and pharmaceutical application thereof |
| CN112500359A (en) * | 2020-12-18 | 2021-03-16 | 华中药业股份有限公司 | Preparation method of lorazepam intermediate |
| CN112500359B (en) * | 2020-12-18 | 2022-06-03 | 华中药业股份有限公司 | Preparation method of lorazepam intermediate |
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