CN105837522A - Preparation method of 1,5-benzodiazepine-one derivative - Google Patents
Preparation method of 1,5-benzodiazepine-one derivative Download PDFInfo
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- CN105837522A CN105837522A CN201610228575.8A CN201610228575A CN105837522A CN 105837522 A CN105837522 A CN 105837522A CN 201610228575 A CN201610228575 A CN 201610228575A CN 105837522 A CN105837522 A CN 105837522A
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- 0 **C1=C(**)[Tl]=CC=C1 Chemical compound **C1=C(**)[Tl]=CC=C1 0.000 description 3
- FYERMRPJPNMBKD-UHFFFAOYSA-N BC(C(C)=O)C(N)=O Chemical compound BC(C(C)=O)C(N)=O FYERMRPJPNMBKD-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
Abstract
The invention discloses a preparation method of 1,5-benzodiazepine-one derivative. The preparation method is characterized by including using substituted o-phenyl binitro compound as raw material, reacting with substituted aniline, reacting with malonic acid monoester, and performing cyclization to obtain the target compound. The method has simple step, easily available and cheap raw material, is easy to operate and realize industrialization, and can improve the yield and purity.
Description
Technical field:
The present invention relates to one 1, the preparation method of 5-Benzodiazepine ketone derivatives, belong to chemosynthesis technical field.
Background technology:
1,5-benzodiazepine ketone is the seven member ring heterocyclic compounds thing that a class has physiologically active and pharmacologically active widely,
A lot of compounds, as clinical medicine, have the highest researching value and application prospect.Existing synthetic route
WO2011100838 is to replace o-fluoronitrobenzene, reacts with substituted aniline, after then nitro is reduced into amido again with malonyl
Chlorine reaction prepares target compound, and it is expensive that this route replaces the o-fluoronitrobenzene market price, and also having is exactly to use acyl chlorides, instead
Answering condition harsh, environmental pollution is big, is not suitable for industrialized production.
Summary of the invention:
Key problem in technology to be solved by this invention is to overcome above weak point, designs a kind of brand-new 1,5-benzo two
The synthetic route of Azone derivative.
The technical scheme that the present invention takes for achieving the above object is as follows:
A kind of 1, the preparation method of 5-Benzodiazepine ketone derivatives, it is characterised in that: to replace adjacent benzene dinitro chemical combination
Thing is raw material, reacts with substituted aniline, and product reacts with malonic acid monoester again, and then cyclization obtains compound shown in formula (I)；
In formula: R1For hydrogen, o-, m-, contraposition replaces halogen atom, alkoxyl or alkyl；R2Halogen is replaced former for o-, m-, contraposition
Son, alkoxyl or alkyl；R3For alkyl or aryl.
The reaction equation that the present invention relates to is as follows:
In formula: R1For hydrogen, o-, m-, contraposition replaces halogen atom, alkoxyl or alkyl；R2Halogen is replaced former for o-, m-, contraposition
Son, alkoxyl or alkyl；R3For alkyl or aryl.
Above-mentioned one 1, the preparation method of 5-Benzodiazepine ketone derivatives, use following being preferably provided with, it is possible to obtain
Preferably yield and purity:
(1), adjacent dinitro compound directly react with substituted aniline, reaction dissolvent is: methyl alcohol, ethanol or propyl alcohol, temperature
Scope 10-60 DEG C, the amount of adjacent dinitro compound and the material of substituted aniline ratio for 0.8-1.2, react post processing direct
Filtration under diminished pressure, washing, it is dried to obtain formula (II)；
(2), the formula (II) step (1) prepared is reacted with replacement malonic acid monoester and is obtained formula (III), compound formula (II)
With replace the amount ratio of malonic acid monoester material for 0.8-1.2, react solvent for use: benzene,toluene,xylene, dichloromethane or chlorine
Imitative, chlorination reagent is: phosphorus pentachloride, thionyl chloride, phosphorus trichloride or POCl3, and recrystallization solvent is: toluene and petroleum ether
Mixed liquor or dimethylbenzene and petroleum ether mixed liquor；
(3) formula (III) the direct cyclization of step, by step (2) prepared obtains target compounds of formula (I), and reaction temperature is
0-60 DEG C, anti-solvent-applied is: ethanol, methyl alcohol or propyl alcohol.
Further it is provided in:
In step (1), reaction dissolvent is ethanol, and reaction temperature is room temperature, and the reaction time is 5-10h.
In step (2), chlorination reagent selects phosphorus pentachloride.
In step (2), recrystallization solvent is: toluene and petroleum ether mixed liquor, its volume ratio is between 0.2-1.5.
In step (3), solvent selects ethanol, and reaction temperature is room temperature.
Beneficial effects of the present invention is as follows:
The synthetic route of the present invention, to replace adjacent benzene dinitro compound as raw material, is reacted with substituted aniline, then with the third two
Acid monoester reacts, and then a step completes cyclization and obtains target compound.The method uses the adjacent dinitro of replacement straight with substituted aniline
Connecing reaction, then react with malonic acid monoester, then cyclization obtains target compound.This route raw material is cheap and easy to get, it is easy to operation
Industrialize with realization, and there is outstanding yield and purity.
Below in conjunction with the drawings and specific embodiments, the invention will be further described.
Accompanying drawing illustrates:
Fig. 1 is the H spectrogram of the 1,5-Benzodiazepine ketone derivatives that the present invention synthesizes；
Fig. 2 is the C13 spectrogram of the 1,5-Benzodiazepine ketone derivatives that the present invention synthesizes.
Detailed description of the invention:
Embodiment 1: prepare compound II (N-(5-chloro-2-nitrobenzophenone) aniline.
Under room temperature, by 3,4-dinitrofluorobenzene (30g, 90% content, FW=202) is dissolved in 95% ethanol (165mL), dropping
Aniline (42mL), this reaction is stirred at room temperature, and obtains Orange red solid, direct filtration under diminished pressure, washing, dries.Obtain product
(30.0g, productivity about 90%).
Reaction equation is as follows:
Embodiment 2: prepare compound III (2-(N-(5-chloro-2-nitrobenzophenone)-N-phenylcarbamoyl acetic acid acid second
Ester).
Starting compound (N-(5-chloro-2-nitrobenzophenone) aniline) (17g, FW=248) is dissolved in solvent, adds the third two
Acid mono ethyl ester (12.8g, FW=132), under room temperature, is dividedly in some parts PCl5(15.2g) FW=208), it is stirred at room temperature 1 after adding little
Time, it is then heated to backflow only reaction completely.Stop heating, to adding mixture of ice and water, be that reaction system is cooled to room temperature.Point
From organic phase, aqueous phase toluene (30mL) extracts 2 times.Merging organic phase, wash with saturated sodium carbonate solution, anhydrous sodium sulfate is done
Dry.Concentrate.Dimethylbenzene and petroleum ether recrystallization (the solid petroleum ether of precipitation) obtain (shallow) slightly yellow solid (20g, FW
=362, productivity 80%) compound III.
Reaction equation is as follows:
Embodiment 3: prepare compound I (8-chloro-1-phenyl-1-H-benzo [b] [1,4] nitrogen Zhuo-2,4-(3H, 5H)-two
Ketone.
The above-mentioned compound III prepared is dissolved in the mixed liquor (100mL, 1:1) of ethanol and concentrated hydrochloric acid, in cold bath
Under (5-10 DEG C) be dividedly in some parts activation Zn powder (7.5g), after adding, cold bath automatic heating is to room temperature, and slightly yellow solid starts molten
Solve, and gradually separate out white solid.Continuing stirring 2 hours, by system suction filtration, filter cake, with a small amount of absolute methanol washing, obtains
White products compound I (4.5g, FW=286, productivity 57%).
Reaction equation is as follows:
Product confirms: the product (compound I) embodiment 1 prepared carries out nuclear magnetic resonance spectroscopy, obtains H spectrogram, C13Spectrogram
As shown in Figure 1 and Figure 2.
Embodiment 1-1～1-5:
Preparation method is with embodiment 1, and difference is: adjusts solvent, reaction temperature and the time in preparation method, and detects
It is on reaction effect yield and the impact of purity, and result is as shown in table 1.
Table 1,
As shown in table 1: different reaction conditions is for the preparation method of the present invention, and solvent has considerable influence, solvent to change into
Propyl alcohol, reaction yield substantially reduces.Reaction temperature is at 0-60 DEG C, when other conditions do not change, it has been found that the rising meeting of temperature
Reducing productivity, can find that product purity reduces at liter high-temperature, productivity also reduces.
Embodiment 2-1～2-4:
Preparation method is with embodiment 2, and difference is: adjusts the chlorination reagent in preparation method, and detects it to reaction effect
Really yield and the impact of purity, result is as shown in table 2.
| Sequence number | Chlorination reagent | Yield |
| 2-1 | Phosphorus pentachloride | 80% |
| 2-2 | Phosphorus trichloride | 78% |
| 2-3 | Thionyl chloride | 75% |
| 2-4 | POCl3 | 68% |
As shown in table 2: change chlorination reagent has certain impact to the yield of reaction, but impact is not very big, selects pentachloro-
When changing phosphorus, effect is optimal.
Embodiment 3-1～3-4:
Preparation method is with embodiment 3, and difference is: adjust the solvent in preparation method and reaction temperature, and it is right to detect it
Reaction effect yield and the impact of purity, result is as shown in table 3.
| Sequence number | Solvent | Reaction temperature | Yield |
| 3-1 | Ethanol | Room temperature | 57% |
| 3-2 | Methyl alcohol | Room temperature | 50% |
| 3-3 | Propyl alcohol | Room temperature | 38% |
| 3-4 | Ethanol | 60 | 53% |
As shown in table 3: to change solvent bigger on the yield impact of reaction, it is not the brightest for changing the temperature impact on reacting
Aobvious, optimal combination is: solvent selects ethanol, when reaction temperature is room temperature, best results.
Claims (6)
1. one kind 1, the preparation method of 5-Benzodiazepine ketone derivatives, it is characterised in that: to replace adjacent benzene dinitro compound
For raw material, reacting with substituted aniline, product reacts with malonic acid monoester again, and then cyclization obtains compound shown in Formulas I；
Formulas I
In formula: R1For hydrogen, o-, m-, contraposition replaces halogen atom, alkoxyl or alkyl；R2Halogen atom, alkane is replaced for o-, m-, contraposition
Epoxide or alkyl；R3For alkyl or aryl.
The preparation method of the most according to claim 1 a kind of 1,5-Benzodiazepine ketone derivatives, it is characterised in that include
Following steps:
(1), adjacent dinitro compound directly react with substituted aniline, reaction dissolvent is: methyl alcohol, ethanol or propyl alcohol, temperature range
10-60 DEG C, adjacent dinitro compound directly amount ratio with the material of substituted aniline is: 0.8-1.2, react post processing direct
Filtration under diminished pressure, washing, it is dried to obtain Formula II compound；
(2) the Formula II compound, by step (1) prepared reacts with replacement malonic acid monoester and obtains formula III compound, and reaction is used
Solvent: benzene,toluene,xylene, dichloromethane or chloroform, Formula II compound with the amount ratio of the material replacing malonic acid monoester is
0.8-1.2, chlorination reagent is: phosphorus pentachloride, thionyl chloride, phosphorus trichloride or POCl3, and recrystallization solvent is: toluene and stone
Oil ether mixed liquor or dimethylbenzene and petroleum ether mixed liquor；
(3) the formula III compound one direct cyclization of step, by step (2) prepared obtains target compound Formulas I, and reaction temperature is 0-
60 DEG C, anti-solvent-applied is: ethanol, methyl alcohol or propyl alcohol；
Formula II formula III
Formulas I
In formula: R1For hydrogen, o-, m-, contraposition replaces halogen atom, alkoxyl or alkyl；R2Halogen atom, alkane is replaced for o-, m-, contraposition
Epoxide or alkyl；R3For alkyl or aryl.
The preparation method of the most according to claim 2 a kind of 1,5-Benzodiazepine ketone derivatives, it is characterised in that: step
(1) in, reaction dissolvent is propyl alcohol, and reaction temperature is room temperature, and the reaction time is 10 h.
The preparation method of the most according to claim 2 a kind of 1,5-Benzodiazepine ketone derivatives, it is characterised in that: step
(2), in, chlorination reagent selects phosphorus pentachloride.
The preparation method of the most according to claim 2 a kind of 1,5-Benzodiazepine ketone derivatives, it is characterised in that: step
(2) in, recrystallization solvent is: toluene and petroleum ether mixed liquor, its volume ratio is between 0.2-1.5.
The preparation method of the most according to claim 2 a kind of 1,5-Benzodiazepine ketone derivatives, it is characterised in that: step
(3), in, solvent selects ethanol, and reaction temperature is room temperature.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749052A (en) * | 2016-11-30 | 2017-05-31 | 济南科汇医药科技有限公司 | The preparation method of Clobazam |
| CN112724091A (en) * | 2021-01-21 | 2021-04-30 | 三峡大学 | Method for industrially producing clobazam |
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| US3984398A (en) * | 1966-12-14 | 1976-10-05 | Roussel-Uclaf | 1,5-Benzodiazepine-2,4-diones |
| CN1113236A (en) * | 1994-04-29 | 1995-12-13 | 伊莱利利公司 | Non-peptidyl tachykinin receptor antagonists |
| KR20140140455A (en) * | 2013-05-29 | 2014-12-09 | 희성소재 (주) | Benzodiimidazole-based compound and organic light emitting device using the same |
-
2016
- 2016-06-14 CN CN201610228575.8A patent/CN105837522A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3984398A (en) * | 1966-12-14 | 1976-10-05 | Roussel-Uclaf | 1,5-Benzodiazepine-2,4-diones |
| CN1113236A (en) * | 1994-04-29 | 1995-12-13 | 伊莱利利公司 | Non-peptidyl tachykinin receptor antagonists |
| KR20140140455A (en) * | 2013-05-29 | 2014-12-09 | 희성소재 (주) | Benzodiimidazole-based compound and organic light emitting device using the same |
Non-Patent Citations (2)
| Title |
|---|
| ANTHONY G.BORE1 ET AL.: "THE SYNTHESIS OF 7-CHLORO-5-PENTADEUTERIOPHENYL-l-METHYL-lH-l,5-BENZODIAZEPINE-2,4(3H,5H)DIONE ([2H5]CLOBAZAM)", 《JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICAL》 * |
| MYEONG SEOP KIM ET AL.: "Asymmetric synthesis and receptor activity of chiral simplified resiniferatoxin (sRTX) analogues as transient receptor potential vanilloid 1 (TRPV1) ligands", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749052A (en) * | 2016-11-30 | 2017-05-31 | 济南科汇医药科技有限公司 | The preparation method of Clobazam |
| CN106749052B (en) * | 2016-11-30 | 2020-09-01 | 济南科汇医药科技有限公司 | Preparation method of clobazam |
| CN112724091A (en) * | 2021-01-21 | 2021-04-30 | 三峡大学 | Method for industrially producing clobazam |
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Application publication date: 20160810 |