CN106946802A - A kind of preparation method of Clobazam - Google Patents
A kind of preparation method of Clobazam Download PDFInfo
- Publication number
- CN106946802A CN106946802A CN201710166922.3A CN201710166922A CN106946802A CN 106946802 A CN106946802 A CN 106946802A CN 201710166922 A CN201710166922 A CN 201710166922A CN 106946802 A CN106946802 A CN 106946802A
- Authority
- CN
- China
- Prior art keywords
- clobazam
- phenyl
- preparation
- chloro
- diketone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
Abstract
The invention discloses a kind of preparation method of Clobazam, belong to organic synthesis field.Comprise the following steps：（1）In the mixed solvent that the chlorodiphenyl amine of 2 nitro 5 is put into lower alcohol and water, Pd C catalysts are added, hydrogen, the phenylenediamine of 5 chlorine of synthesis N phenyl 1,2 is passed through；（2）By step（1）In the obtained phenylenediamine of 5 chlorine of N phenyl 1,2 input THF solvents, malonyl chloride is added portionwise, the diketone of 1 phenyl, 8 chlorine, 1,2,4,5 tetrahydrochysene, 1,5 benzodiazepine 2,4 is obtained；（3）By step（1）The obtained diketone of 1 phenyl, 8 chlorine, 1,2,4,5 tetrahydrochysene, 1,5 benzodiazepine 2,4 reacts with halide or dimethyl suflfate, obtains object Clobazam.The present invention is a kind of simple, efficient Clobazam synthetic method.
Description
Technical field
The present invention relates to a kind of preparation method of Clobazam, belong to organic synthesis field.
Background technology
Clobazam (Clobazam), chemical name：Chloro- 1- methyl -5- phenyl -1, the 5- benzodiazepines -2,4 of 7-
(3H)-diketone, a kind of benzodiazepine compound researched and developed by Ling North companies of Denmark.Trade name is Onfi, U.S.'s food and medicine
Surveillance Authority (FDA) ratifies its listing on October 21st, 2011, and principal indication is controlling for anxiety disorder and intractable epilepsy
Treat, it is better to the breaking-out of epilepsy complexity and Lin-dagger-axe syndrome (Lennox-Gaslaut).The chemical structural formula of Clobazam
For：
Chloro- 1- methyl -5- phenyl -1,5- benzodiazepines -2,4 (3 of 7- in the prior artHThe synthetic method of)-diketone：With 5-
Chloro- 2- nitros-N- phenylaniline is initiation material, and hydrogenated reduction obtains chloro- 1, the 2- phenylenediamines of N- phenyl -5-.Intermediate N benzene
With malonyl chloride cyclization reaction occurs for chloro- 1, the 2- phenylenediamines of base -5-, obtains 8- chloro-1-phenyl -1,5- benzodiazepines -2,4
(3H, 5H)-diketone.Hydrogenated sodium activation, occurs methylation reaction with iodomethane, obtains chloro- 1- methyl -5- phenyl -1, the 5- benzene of 7-
And diaza -2,4 (3H)-diketone.
Patent WO2011/100838 report Clobazam synthetic method be：With the chloro- 2- nitros of iron powder-hydrochloric acid reduction 5--N-
Phenylaniline, is made chloro- 1, the 2- phenylenediamines of N- phenyl -5-.The chloro- 1,2- phenylenediamines of intermediate N phenyl -5- are sent out with malonyl chloride
Intercrescence ring reacts, and obtains 8- chloro-1-phenyls -1,5- benzodiazepine -2,4 (3H, 5H)-diketone.Hydrogenated sodium activation, with iodine first
Methylation reaction occurs for alkane, obtains chloro- 1- methyl -5- phenyl -1, the 5- benzodiazepines -2,4 (3 of 7-H)-diketone.Although this side
Method synthetic route is short, but the post-processing operation of ferrous acid reduction is complicated, and environmental pollution is big, and gross production rate is low.
Patent US 3984398 with the chloro- 2- nitros of 5--N- phenylaniline is initiation material, with monoethyl malonate in pentachloro-
Change phosphorus in the presence of react, obtain the chloro- 2- nitros of 5--N- phenyl-N- ethoxycarbonylacetyl aniline, through hydrochloric acid and zinc powder reduction, ring
Change, methylating obtains Clobazam.Phosphorus pentachloride is used in the method, cyclization needs strong acid condition, and operational danger is larger, no
Beneficial to industrialized production.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of preparation method of Clobazam, the present invention is a kind of simple, high
Effect, can significantly improve the Clobazam synthetic method of product quality on the premise of product yield is ensured.
The technical solution used in the present invention is：A kind of preparation method of Clobazam, comprises the following steps：
（1）In the mixed solvent that 2- nitro -5- chlorodiphenyls amine is put into lower alcohol and water, Pd-C catalyst is added, hydrogen is passed through,
Synthesize the chloro- 1,2- phenylenediamines of N- phenyl -5-.
（2）By step（1）In obtained chloro- 1, the 2- phenylenediamines input THF solvents of N- phenyl -5-, malonyl is added portionwise
Chlorine, obtains tetrahydrochysene -1,5- benzodiazepine -2, the 4- diketone of 1- phenyl -8- chloro- 1,2,4,5-.
（3）By step（2）The obtained chloro- 1,2,4,5- tetrahydrochysenes -1,5- benzodiazepines -2,4- diketone of 1- phenyl -8-
Reacted with halide, obtain object Clobazam.
It is preferred that catalyst be H2/Pd-C。
It is preferred that lower alcohol be ethanol.
It is preferred that the chloro- 1,2- phenylenediamines of N- phenyl -5- and malonyl chloride mol ratio be 1.0: 1.05.
It is preferred that the chloro- 1,2,4,5- tetrahydrochysenes -1,5- benzodiazepines -2,4- diketone of 1- phenyl -8- methylating reagent
For halide.
It is preferred that the chloro- 1,2,4,5- tetrahydrochysenes -1,5- benzodiazepines -2,4- diketone of 1- phenyl -8- methylating reagent
For iodine
Methane.
It is preferred that the chloro- 1,2,4,5- tetrahydrochysenes -1,5- benzodiazepines -2,4- diketone of 1- phenyl -8- methylation reaction
Temperature is between 45 DEG C.
It is preferred that the chloro- 1,2,4,5- tetrahydrochysenes -1,5- benzodiazepines -2,4- diketone of 1- phenyl -8- methyl choline hydrogenation.
The present invention with the chloro- 2- nitros of 5--N- phenylaniline (2) is initiation material, and ring is acylated through catalytic hydrogenation, malonyl chloride
Close, N- methylates obtained Clobazam.Raw material is cheap, be easy to get, and mild condition is easy to operate, and synthetic route is as follows：
Embodiment
Embodiment
A kind of preparation method of Clobazam, comprises the following steps：
（1）The synthesis of the chloro- 1,2- phenylenediamines of N- phenyl -5-
In high-pressure hydrogenation kettle, sequentially add the chloro- 2- nitros of compound 5--N- phenylaniline (20 g, 80.43 mmol),
Raney- nickel (0.6 g), ethanol（80 mL）And dichloromethane（20 mL）.Finish, in 1 bar Hydrogen Vapor Pressures, stir at room temperature
1.5 h are reacted, stop reaction, ice-water bath cooling and stirring has solid precipitation, and suction filtration, filter cake uses the mL of water 30 and petroleum ether 30 successively
ML is washed, vacuum drying, obtains chloro- 1, the 2- phenylenediamines of white solid N- phenyl -5- (15.83 g), mp.102.5~104.8 DEG C.
MS-ESI(m/z)：219.1[M+H]+, 241.1 [M+Na]+, 217.0 [M-H]-。1H-NMR (500MHz, DMSO-d 6), δ (ppm)：
4.91 (s, 2H ,-NH2), 6.70~6.82 (m, 5H, Ar-H), 6.95 (s, 1H ,-NH-), 7.15~7.21 (m, 3H, Ar-H),
（2）8- chloro-1-phenyls -1,5- benzodiazepine -2,4 (1H, 3HThe synthesis of)-diketone
Nitrogen is protected, in 1L four round flask, adds 150 mL tetrahydrofurans, controls 5~10 DEG C of temperature, N- is slowly added dropwise
Chloro- 1, the 2- phenylenediamines of phenyl -5- (30 g, 0.137mol) tetrahydrofuran (300 mL) solution and malonyl chloride (20.3 g,
Tetrahydrofuran (100 mL) solution 0.141mol), drop finishes, and 1 h is stirred at 5~10 DEG C, stops reaction.It is concentrated under reduced pressure, with two
Chloromethanes（650mL）Dissolution residual substance, adds petroleum ether（800mL）, precipitation is separated out, suction filtration is washed, and vacuum drying obtains white
Solid 8- chloro-1-phenyls -1,5- benzodiazepine -2,4 (1H, 3H)-diketone (33.38 g), 303~304.5 DEG C of mp..
ESI-MS(m/z)：309.1[M+Na]+, 595.0 [2M+Na]+。
（3）Chloro- 1- methyl -5- phenyl -1, the 5- benzodiazepines -2,4 (3 of 7-H)-diketone（Clobazam）Synthesis
In 500mL there-necked flasks, compound 8- chloro-1-phenyls -1,5- benzodiazepine -2,4 (1 is sequentially addedH, 3H)-two
Ketone (10 g, 34.9 mmol), sodium hydride 60% (2.98 g, 74.8 mmol), tetrahydrofuran (150 mL), nitrogen protection, room
Temperature 1 h of lower stirring, is slowly added dropwise tetrahydrofuran (200 mL) solution of iodomethane (7.4g, 52.1 mmol), drop finishes, and heating rises
Temperature stirs 1.5 h to 45 DEG C, stops reaction.It is concentrated to dryness under decompression, adds CH2Cl2And water, organic layer salt water washing, nothing
Aqueous sodium persulfate is dried, filtering, is concentrated under reduced pressure, residue CH2Cl2With methyl tertiary butyl ether(MTBE) processing, filter, vacuum drying obtains white
Chloro- 1- methyl -5- phenyl -1, the 5- benzodiazepines -2,4 (3 of color solid 7-H)-diketone（Clobazam）(7.8 g), mp.
168.5~169.7 DEG C.MS-ESI(m/z)：323.2[M+Na]+, 623.0 [2M+Na]+。1H-NMR (500MHz, DMSO-d 6), δ
（ppm）：7.62 (d, 1H, Ar-H, 7.38~7.47 (m, 4H, Ar-H), 7.27 (d, 1H, Ar-H), 6.84 (d, 1H, Ar-H),
3.71 (d, 1H ,-CH2-), 3.37 (d, 3H, N-CH3), 3.17 (d, 1H ,-CH2-)。
Claims (9)
1. a kind of preparation method of Clobazam, it is characterised in that comprise the following steps：
（1）In the mixed solvent that 2- nitro -5- chlorodiphenyls amine is put into lower alcohol and water, Pd-C catalyst is added, hydrogen is passed through,
Synthesize the chloro- 1,2- phenylenediamines of N- phenyl -5-；
（2）By step（1）In obtained chloro- 1, the 2- phenylenediamines input THF solvents of N- phenyl -5-, malonyl chloride is added portionwise, obtains
To the chloro- 1,2,4,5- tetrahydrochysenes -1,5- benzodiazepines -2,4- diketone of 1- phenyl -8-；
（3）By step（2）The obtained chloro- 1,2,4,5- tetrahydrochysenes -1,5- benzodiazepines -2,4- diketone of 1- phenyl -8- and halogen
Reacted for methane or dimethyl suflfate, obtain object Clobazam.
2. the preparation method of a kind of Clobazam according to claim 1, it is characterised in that described catalyst is H2/Pd-C
Or H2/Raney-Ni。
3. the preparation method of a kind of Clobazam according to claim 1, it is characterised in that the lower alcohol is methanol, second
One kind in alcohol or isopropanol.
4. a kind of preparation method of Clobazam according to claim 1, it is characterised in that the amount of malonyl chloride is：N- benzene
The chloro- 1,2- phenylenediamines of base -5-: malonyl chloride=1.0: 1.0~1.2（Mol ratio）.
5. a kind of preparation method of Clobazam according to claim 1, it is characterised in that 1- phenyl -8- chloro- 1,2,4,5-
Tetrahydrochysene -1,5- benzodiazepine -2,4- diketone reacts with halide or dimethyl suflfate, obtains object Clobazam.
6. the preparation method of a kind of Clobazam according to claim 4, it is characterised in that iodomethane, bromomethane and chloromethane
One kind in alkane.
7. a kind of preparation method of Clobazam according to claim 4, it is characterised in that with dimethyl suflfate to methylate
Reagent.
8. a kind of preparation method of Clobazam according to claim 4, it is characterised in that the substitution reaction temperature on nitrogen-atoms
Degree is between 25 DEG C~120 DEG C.
9. the preparation method of a kind of Clobazam according to claim 4, it is characterised in that alkali sodium hydride, sodium alkoxide, alcohol
Potassium.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710166922.3A CN106946802A (en) | 2017-03-20 | 2017-03-20 | A kind of preparation method of Clobazam |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710166922.3A CN106946802A (en) | 2017-03-20 | 2017-03-20 | A kind of preparation method of Clobazam |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106946802A true CN106946802A (en) | 2017-07-14 |
Family
ID=59472969
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710166922.3A Pending CN106946802A (en) | 2017-03-20 | 2017-03-20 | A kind of preparation method of Clobazam |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106946802A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112724091A (en) * | 2021-01-21 | 2021-04-30 | 三峡大学 | Method for industrially producing clobazam |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5990146A (en) * | 1997-08-20 | 1999-11-23 | Warner-Lambert Company | Benzimidazoles for inhibiting protein tyrosine kinase mediated cellular proliferation |
| WO2011100838A1 (en) * | 2010-02-16 | 2011-08-25 | Boehringer Ingelheim International Gmbh | Derivatives of 1-phenyl-1,5-dihydro-benzo[b] [1.4]diazepine-2.4-dione as inhibitors of hiv replication |
| WO2016151464A1 (en) * | 2015-03-24 | 2016-09-29 | Piramal Enterprises Limited | An improved process for the preparation of clobazam and its intermediate |
-
2017
- 2017-03-20 CN CN201710166922.3A patent/CN106946802A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5990146A (en) * | 1997-08-20 | 1999-11-23 | Warner-Lambert Company | Benzimidazoles for inhibiting protein tyrosine kinase mediated cellular proliferation |
| WO2011100838A1 (en) * | 2010-02-16 | 2011-08-25 | Boehringer Ingelheim International Gmbh | Derivatives of 1-phenyl-1,5-dihydro-benzo[b] [1.4]diazepine-2.4-dione as inhibitors of hiv replication |
| WO2016151464A1 (en) * | 2015-03-24 | 2016-09-29 | Piramal Enterprises Limited | An improved process for the preparation of clobazam and its intermediate |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112724091A (en) * | 2021-01-21 | 2021-04-30 | 三峡大学 | Method for industrially producing clobazam |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102050687B (en) | Method for preparing aromatic primary amine by taking ammonia water as ammonia source in water phase system | |
| CN102300850A (en) | Methods For The Preparation Of Fungicides | |
| CN106187808A (en) | The preparation method of AHU-377, AHU-377 intermediate and the preparation method of AHU-377 intermediate | |
| JP7038263B2 (en) | Method for Producing Morpholine Quinazoline Compound and its Intermediate | |
| CN110423190A (en) | A kind of method of iron complex catalysis ketone alpha-alkyl | |
| CN105753731B (en) | A kind of preparation method of the methoxybenzoyl aniline of 3 amino 4 | |
| CN106905125A (en) | A kind of method that ketone α alkyl of cobalt catalysis is combined to ketones derivant | |
| CN109180498A (en) | A kind of preparation method replacing Armeen | |
| CN103044491B (en) | Dimethyl carbonate synthesis method by using methanol and carbon dioxide | |
| CN107098822A (en) | A kind of preparation method for preparing the hydroxy acetophenone of 3 amino of Pranlukast key intermediate 2 | |
| CN106946802A (en) | A kind of preparation method of Clobazam | |
| CN116023296B (en) | Preparation method of fluvoxamine maleate | |
| CN106831441B (en) | A kind of preparation method of cinacalcet hydrochloride | |
| CN101130499B (en) | Method for synthesizing nitryl arylamine compounds | |
| CN101012170A (en) | N-arylation method in water solution | |
| CN109776617B (en) | Acetone coordination binuclear palladium compound and preparation method and application thereof | |
| JP2022140364A (en) | Method for preparing 4-(perfluoropropane-2-yl)-2-trifluoromethyl aniline and use thereof | |
| CN107674037A (en) | The method of one kind 5 methyl 2 (triazoles of 2H 1,2,3) benzoic acid of synthesis | |
| CN107915694A (en) | 1 [2 (2,4 3,5-dimethylphenyl sulfydryl) phenyl] piperazine hydrochloride and preparation method thereof | |
| CN107029759B (en) | Ruthenium trichloride reacts the application prepared in imines with alcohol compound in catalysis nitrobenzene compounds | |
| CN109851551A (en) | A method of synthesis 3- bromine isonicotinic acid intermediate | |
| CN113004248A (en) | Method for synthesizing carbazole compound by catalyzing hydrocarbon amination reaction with cobalt | |
| CN107667093A (en) | Benzo [h] quinoline part and its complex compound | |
| CN113968792A (en) | Novel method for synthesizing 2-chloro-5-aminophenol | |
| CN103130704B (en) | It is a kind of to prepare 4- (2- ethoxy) -1,3- dihydro -2H- indol-2-one new method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170714 |