CN106749053B - The preparation method of Lormetazepam rearrangement product - Google Patents
The preparation method of Lormetazepam rearrangement product Download PDFInfo
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- CN106749053B CN106749053B CN201611055712.9A CN201611055712A CN106749053B CN 106749053 B CN106749053 B CN 106749053B CN 201611055712 A CN201611055712 A CN 201611055712A CN 106749053 B CN106749053 B CN 106749053B
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- lormetazepam
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- rearrangement product
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- purified water
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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
-
- 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
Abstract
The present invention relates to a kind of preparation methods of Lormetazepam rearrangement product, belong to technical field of medicine synthesis.The preparation method is that first Lormetazepam is added in organic solvent to stir evenly, sodium hydrate solid is added to be reacted, then organic solvent is isolated by vacuum distillation, obtain residue, purified water is added into residue and carries out once washing, secondary washing is carried out with purified water again after filtering, obtains Lormetazepam rearrangement product after finally vacuum dried.The present invention, as raw material, has only just obtained Lormetazepam rearrangement product using Lormetazepam with single step reaction, and many hypertoxic or unstable raw materials of current preparation process, and reaction step is too long, and yield is too low；For the feed stock conversion of preparation method of the invention close to 100%, the waste water of yield > 97%, generation are less, have the characteristics that raw material is easy to get, to post-process simple, high income, reaction safety high.
Description
Technical field
The present invention relates to a kind of preparation methods of Lormetazepam rearrangement product, belong to technical field of medicine synthesis.
Background technique
The Benzodiazepines such as Oxazepam, Lorazepam, Lormetazepam have been widely used for treatment insomnia, suppression
Strongly fragrant disease and relevant disease.Wherein, Lormetazepam is most listed earlier than Germany, and to the quality research of its rearrangement product for raw material
Medicine production and preparation production have more important profound significance.J.Org.Chem.,Vol.40,No.10,1508-1510,
(1975) a kind of preparation method of Lormetazepam rearrangement product is disclosed, for this method using Lorazepam as primary raw material, dichloro is sub-
Sulfone, trimethoxy phosphine or triethoxy phosphine, dimethyl suflfate, sodium hydride are remaining raw material, have carried out the reaction of five steps in total and have just obtained
To Lormetazepam rearrangement product, also occur many hypertoxic intermediates in reaction, that there are reaction steps is too long, yield is low, Yi Zao
The problem of at environmental pollution, therefore, it is necessary to be improved to preparation method.
Summary of the invention
The object of the present invention is to provide a kind of preparation methods of Lormetazepam rearrangement product, solve in current preparation method
The problem of existing preparation step is too long, using poisonous reagent, pollution environment, there is raw material to be easy to get, is easy to operate, reaction safety
Property high, high income the characteristics of.
The preparation method of Lormetazepam rearrangement product of the present invention, comprising the following steps:
(1) first Lormetazepam is added in organic solvent and is stirred evenly, added sodium hydrate solid and reacted, so
Organic solvent is isolated by the way of vacuum distillation afterwards, obtains residue；Wherein, reaction equation is as follows:
(2) purified water is added into residue and carries out once washing, carry out secondary washing, vacuum with purified water again after filtering
Lormetazepam rearrangement product is obtained after drying；
Wherein, preferred technical solution is as follows:
Organic solvent in step (1) is methanol, ethyl alcohol, ethyl acetate, any one in acetonitrile, preferably acetic acid second
Ester.
The molar ratio of Lormetazepam and sodium hydrate solid is 1:1.2~1.8 in step (1).
Reaction temperature in step (1) is 20~60 DEG C, and the reaction time is 1~3h, preferably 2h.
Pressure when vacuum drying in step (2) when vacuum drying is -0.08MPa, and temperature is 80 DEG C, and drying time is
2h。
Beneficial effects of the present invention are as follows:
The present invention, as raw material, has only just obtained Lormetazepam rearrangement product using Lormetazepam with single step reaction, and mesh
Preceding preparation process many severe toxicity or unstable raw material, and reaction step is too long, yield is too low；Preparation of the invention
For the feed stock conversion of method close to 100%, the waste water of yield > 97%, generation are less, have raw material be easy to get, post-process simply,
The high feature of high income, reaction safety.
Detailed description of the invention
Fig. 1 is the hydrogen spectrogram of the Lormetazepam rearrangement product obtained using preparation method of the invention.
Fig. 2 is the carbon spectrogram of the Lormetazepam rearrangement product obtained using preparation method of the invention.
Fig. 3 is the mass spectrogram of the Lormetazepam rearrangement product obtained using preparation method of the invention.
Specific embodiment
The present invention is described further with reference to embodiments.
Embodiment 1
Lormetazepam rearrangement product the preparation method is as follows:
0.1mol Lormetazepam is added in 200mL dehydrated alcohol, is stirred evenly at room temperature, 0.12mol is then added
Solid sodium hydroxide reacts 3h at 20 DEG C, is evaporated under reduced pressure out whole ethyl alcohol, obtains residue, 200mL is added into residue
Purified water carries out once washing, carries out secondary washing with 100mL purified water again after filtering, obtained solid is in -0.08MPa, 80
It is dried in vacuo 2h at DEG C, obtains 32.39g Lormetazepam rearrangement product.It is computed, product yield 97.21%, purity is
99.78%.
Embodiment 2
Lormetazepam rearrangement product the preparation method is as follows:
0.15mol Lormetazepam is added in 300mL ethyl acetate, is stirred evenly at room temperature, 0.225mol is then added
Solid sodium hydroxide reacts 3h at 40 DEG C, is evaporated under reduced pressure out whole ethyl acetate, obtains residue, be added into residue
200mL purified water carry out once washing, carry out secondary washing with 100mL purified water again after filtering, obtained solid in-
0.08MPa, 2h is dried in vacuo at 80 DEG C, obtain 48.73g Lormetazepam rearrangement product.It is computed, the product yield of the present embodiment
It is 97.5%, purity 99.85%.
Embodiment 3
0.2mol Lormetazepam is added in 400mL acetonitrile, is stirred evenly at room temperature, 0.36mol solid is then added
Sodium hydroxide reacts 1h at 60 DEG C, is evaporated under reduced pressure out whole acetonitriles, obtains residue, and 200mL purifying is added into residue
Water carries out once washing, carries out secondary washing with 100mL purified water again after filtering, obtained solid is at -0.08MPa, 80 DEG C
It is dried in vacuo 2h, obtains 64.91g Lormetazepam rearrangement product.It is computed, product yield 97.4%, purity 99.67%.
Claims (5)
1. a kind of preparation method of Lormetazepam rearrangement product, it is characterised in that: the following steps are included:
(1) first Lormetazepam is added in organic solvent and is stirred evenly, added sodium hydrate solid and reacted, then led to
It crosses vacuum distillation and isolates organic solvent, obtain residue；
(2) purified water is added into residue and carries out once washing, carry out secondary washing with purified water again after filtering, be dried in vacuo
After obtain Lormetazepam rearrangement product；
The molecular formula of the Lormetazepam rearrangement product is as follows:
2. the preparation method of Lormetazepam rearrangement product according to claim 1, it is characterised in that: having in step (1)
Solvent is methanol, ethyl alcohol, ethyl acetate, any one in acetonitrile.
3. the preparation method of Lormetazepam rearrangement product according to claim 1, it is characterised in that: chloromethane in step (1)
It is 1:1.2~1.8 that west, which is dissolved with the molar ratio of sodium hydrate solid,.
4. the preparation method of Lormetazepam rearrangement product according to claim 1, it is characterised in that: anti-in step (1)
Answering temperature is 20~60 DEG C, and the reaction time is 1~3h.
5. the preparation method of Lormetazepam rearrangement product according to claim 1, it is characterised in that: vacuum in step (2)
Pressure when dry is -0.08MPa, and temperature is 80 DEG C, drying time 2h.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611055712.9A CN106749053B (en) | 2016-11-25 | 2016-11-25 | The preparation method of Lormetazepam rearrangement product |
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| CN201611055712.9A CN106749053B (en) | 2016-11-25 | 2016-11-25 | The preparation method of Lormetazepam rearrangement product |
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| CN106749053A CN106749053A (en) | 2017-05-31 |
| CN106749053B true CN106749053B (en) | 2019-06-21 |
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| CN201611055712.9A Active CN106749053B (en) | 2016-11-25 | 2016-11-25 | The preparation method of Lormetazepam rearrangement product |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3915961A (en) * | 1972-12-21 | 1975-10-28 | American Home Prod | 5-Aryl-1H-1,4-benzodiazepine-2(3H)-one-3-phosphonic acids, derivatives and processes for their use |
-
2016
- 2016-11-25 CN CN201611055712.9A patent/CN106749053B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3915961A (en) * | 1972-12-21 | 1975-10-28 | American Home Prod | 5-Aryl-1H-1,4-benzodiazepine-2(3H)-one-3-phosphonic acids, derivatives and processes for their use |
Non-Patent Citations (2)
| Title |
|---|
| Special features of the alkylation of 7-bromo-5-(2-chlorophenyl)- 3-hydroxy-1,2-dihydro-3H-1,4-benzo- diazepin-2-one with alkyl tosylates;Pavlovsky, V. I.，等;《 Chemistry of Heterocyclic Compounds (New York, NY, United States) 》;20091231;第45卷(第11期);1379-1387 |
| Use of (2,3-Dihydro-2-oxo-1 fl-1,4-benzodiazepin-3-yl) - phosphonic Acid Esters as Novel "Wittig Reagents";John H. Sellstedt;《J. Org. Chem.》;19751231;第40卷(第10期);1508-1510 |
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Inventor after: Zhang Fuqiang Inventor after: Chang Sen Inventor after: Wang Furong Inventor after: Xu Haojie Inventor after: Cheng Chunlei Inventor before: Zhang Fuqiang Inventor before: Chang Sen Inventor before: Wang Furong |
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