CN107445845A - The method of one kind synthesis Clofazimine key intermediate N (4 chlorphenyl) 1,2 phenylenediamine - Google Patents
The method of one kind synthesis Clofazimine key intermediate N (4 chlorphenyl) 1,2 phenylenediamine Download PDFInfo
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- CN107445845A CN107445845A CN201710738472.0A CN201710738472A CN107445845A CN 107445845 A CN107445845 A CN 107445845A CN 201710738472 A CN201710738472 A CN 201710738472A CN 107445845 A CN107445845 A CN 107445845A
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- chlorphenyls
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/60—Preparation of compounds containing amino groups bound to a carbon skeleton by condensation or addition reactions, e.g. Mannich reaction, addition of ammonia or amines to alkenes or to alkynes or addition of compounds containing an active hydrogen atom to Schiff's bases, quinone imines, or aziranes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
- C07C209/32—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups
- C07C209/36—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst
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Abstract
The invention provides a kind of method of synthesis Clofazimine key intermediate N (4 chlorphenyl) 1,2 phenylenediamine.Specifically include：1), using o-fluoronitrobenzene and parachloroanilinum as raw material, the catalyst by the use of organic base as condensation reaction reacts in organic solvent；After reaction terminates, through being conventionally treated the condensation aniline of intermediate N (4 chlorphenyl) 2 nitro 1；2), resulting condensation intermediate, in organic solvent, by the use of metallic nickel as catalyst, catalytic hydrogen reduction is carried out；Through being conventionally treated the phenylenediamine crude products of N (4 chlorphenyl) 1,2 after reduction；3) crude product, obtained recrystallizes by organic solvent, obtains final finished.
Description
Technical field
The invention belongs to organic synthesis field, is in particular a kind of Clofazimine key intermediate N- (4- chlorobenzenes
Base) -1,2- phenylenediamines synthetic method.
Background technology
Clofazimine (structural formula is as follows), is called clofazimine, is to develop in the sixties in 20th century.The compound
It is desirable to be used as anti-tuberculosis drugs earliest, but early stage research shows the effect very little of its antituberculosis.Afterwards, the chemical combination
Thing is used for the treatment of leprosy and achieves good effect.Nowadays the compound has as a few of leprosy
Medicine is imitated, is widely used in the combined chemotherapy and II type lepra reactions of MB type leprosies.
Trend occurred frequently is presented in tuberculosis at present, particularly multiple drug-resistance tuberculosis always, and this serious threat the strong of the mankind
Health.But in terms of the drug discovery of antituberculosis, but never obtain big progress.Some are as the anti-of a line or two wires
Medicine for tuberculosis is used for being up to over half a century, problems, such as treatment cycle length in clinical practice be present, to resistance to
Multiple medicine tuberculotherapy is invalid, while not strong etc. to the effect of the mycobacterium tuberculosis of latent form.In order to during effectively avoiding treatment
Endodontic failure caused by the drug resistance of appearance, the administering drug combinations therapy of a variety of antituberculotics is clinically generally used at present.
In this therapy, research shows that Clofazimine can play good therapeutic action.In WHO in 2014 to tubercular drugs
In directive document, Clofazimine is classified as the 5th class, it is allowed to in the administering drug combinations of antituberculosis.
With the expansion of Clofazimine usage amount, fast, being efficiently synthesized the compound just becomes very necessary.It is the simplest
Just the synthetic route of Clofazimine, it is by two molecule N- (4- chlorphenyls) -1,2- phenylenediamines condensation.That is N- (4-
Chlorphenyl) key intermediate that is synthesized as Clofazimine of -1,2- phenylenediamines, its cost, quality are by the synthesis to Clofazimine
There is direct influence.
The method of synthesis N- (4- chlorphenyls) -1,2- phenylenediamines is usually to utilize o-chloronitrobenzene or o-fluoronitrobenzene at present
It is condensed in the presence of an inorganic base with parachloroanilinum, recycles metal/acid system to be reduced (as follows) afterwards.
In first step condensation reaction, usually using inorganic base, as sodium acetate (Chem.Ber., 1902,35,957),
Potassium carbonate (Bioorg.And Med.Chem.Lett., 2005,15,1923；Bioorg. And Med.Chem.Lett.,
2017,27,90), potassium fluoride (WO 20123190；Molecules, 1012,17,4545；J.Med.Chem.,2012,55,
8409；Chinese J.Chem., 2013,31,1473), the mixed system (WO 2012151512 of potassium fluoride and potassium carbonate；
ACS Med.Chem.Lett., 2016,7,145；Chinese J.Chem., 2012,23,707) and sodium hydrogen
(Bioorg.And Med.Chem.Lett.,2017,16,4475).Those described above alkali, all exists in actual applications
Needs higher reaction temperature (being more than 160 degree), and the longer reaction time (is more than 20 hours), and reaction yield is low (to be less than
50%), the shortcomings of security difference.
The reduction reaction of second step is generally adopted by metal/lewis acid system or low-valent metal chloride is gone back
Former.Relatively common such as iron powder, zinc powder, titanium chloride etc., the Part Methods in the above documents it can be seen that.In addition
Also reduced using palladium carbon/hydrogen (Chinese J.Chem., 2013,31,1473).Using metal/lewis acid body
System is reduced, and metal needs are significantly excessive, and substantial amounts of metallic residue can be produced after the completion of reaction, and pollution is huge.Use palladium carbon
Catalytic hydrogen reduction is carried out as catalyst, although more cleaning, catalyst is sufficiently expensive, can cause the cost of raw material to the greatest extent
It is higher.
The content of the invention
For above-mentioned weak point of the prior art, the present invention is new by selecting on the basis of original synthetic route
Condensation reagent and reducing catalyst, there is provided a kind of side of safe and efficient synthesis N- (4- chlorphenyls) -1,2- phenylenediamines
Method.
Specifically, the synthetic method comprises the following steps：
1), using o-fluoronitrobenzene and parachloroanilinum as raw material, the catalyst by the use of organic base as condensation reaction is organic
Condensation reaction is carried out in solvent；After reaction terminates, through being conventionally treated condensation intermediate N (4- chlorphenyls) -2- nitros -1-
Aniline；
2), above-mentioned resulting condensation intermediate, in organic solvent, by the use of metallic nickel as catalyst, is catalyzed
Hydro-reduction；Through conventional treatment after reduction, N- (4- chlorphenyls) -1,2- phenylenediamine crude products can be obtained.
3), the crude product recrystallizes through organic solvent, obtains final certified products.
In above-mentioned steps：
Used organic base is usually organic amine compound, and such as triethylamine, diisopropyl ethyl amine, dimethyl are different
Propyl group amine, 4- methyl morpholines, Isosorbide-5-Nitrae-diazabicyclo [2,2,2] octane (DABCO), 1,8- diazabicyclos [5,4,0] ten
One -7- alkene (DBU), -7- alkene (DBN) of 1,5- diazabicyclos [4,3,0] 11,1- crassitudes etc..They were being used
Can be in journey it is a certain, can also two or more be used in mixed way, to reach more preferably catalytic effect.
When used organic base is as catalyst, the amount and the mol ratio of raw materials used parachloroanilinum that are usually added into exist
Between 0.8~2, between preferably 1~1.3.
Solvent prioritizing selection aprotic, polar type solvent used in condensation reaction, such as DMF, DMAC, DMSO, dioxy six
Ring etc..Can be a certain or their mixed system in use.
Condensation reaction is usually to be carried out between 80 degree~150 degree, preferably 100~120 degree.Reaction process is entered using HPLC
Row monitoring.
, can be remaining more generally because parachloroanilinum reactivity is poor, therefore select o-fluoronitrobenzene excessive,
And parachloroanilinum is slowly added in the reaction system containing o-fluoronitrobenzene and organic base, parachloroanilinum is improved with this
Conversion ratio.Nonetheless, parachloroanilinum still has remaining close to 10% when reaction is close to terminal, but it does not influence subsequently
Purifying products.
After the completion of reaction, after reaction system cools to 50~60 degree, the protons such as a certain amount of water or methanol, ethanol are added
Type polar solvent, followed by cooling to stirred crystallization within 20 degree.Isolated condensation intermediate N (4- chlorphenyls) -2- afterwards
Nitro -1- aniline.
In reduction step, used catalyst is metallic nickel, and the metallic nickel can be load-type nickel, skeleton nickel (thunder
Buddhist nun's nickel) or nickel nano-cluster or amorphous alloy nickel.Wherein preferred security performance is high, low-cost load-type nickel is made
For catalyst.
The 5%~20% of body weight, excellent among the condensation of the generally required reduction of amount used in the type catalyst
Select between 5~8%.
The reduction reaction can be carried out in many organic solvents, toluene, methanol, ethanol, DMF etc., selected solvent
It is main to need to consider condensation product intermediate and final products solubility and the difficulty or ease of post processing.
For the sake of safety, used Hydrogen Vapor Pressure is typically maintained within 5 kilograms during reduction；Reaction temperature typically 50~
Between 80 degree.
Course of reaction is monitored using HPLC, is reacted and is disappeared with condensation product intermediate for terminal.
After reaction terminates, heat filtering isolates metalNicatalyst, and the catalyst may be reused after methanol washs
More than three times, its catalytic activity is without being decreased obviously.
Mother liquor after heat filtering it is concentrated go out a certain amount of reaction dissolvent after, cool within 20 degree and crystallize.Centrifuge afterwards
N- (4- chlorphenyls) -1,2- phenylenediamine products are isolated, at this moment for the product purity typically more than 98%, color is taupe.
Organic solvent, toluene, methanol, ethanol etc. such as are reused to the product, once recrystallized, can be with
Purity is obtained more than 99.5%, single impurity is less than 0.1%, and color is argenteous N- (4- chlorphenyls) -1,2- phenylenediamines
Finished product.
Since then, using above-mentioned technical proposal, by using organic base as the catalyst of condensation reaction and by using
Catalyst of the metallic nickel as reduction reaction so that synthesis N- (4- chlorphenyls)-this compound of 1,2- phenylenediamines is safer,
Convenient, low stain；The technical scheme cost can be lower simultaneously, and quality can be more readily available control.In general, the technical side
Case is adapted to big production application.
Embodiment
The present invention is further described with reference to specific embodiment.
Condensation reaction：
Embodiment one：
In drying, clean stress reaction bottle, 104 grams of o-fluoronitrobenzenes and 200 grams of DMF are put into, stir lower input 88
Gram triethylamine, 120 degree are warming up under nitrogen protection afterwards, pressure rise is less than 1 kilogram.86 grams of parachloroanilinum are dissolved in 100
Gram DMF in be prepared into solution, the solution is slowly added drop-wise in above-mentioned reaction system afterwards.During dropwise addition temperature can on
Rise, should be by cooling down controlling reaction temperature within 125 degree.
Reaction is persistently carried out 8 hours between 120~130 degree, HPLC monitoring reaction process.When parachloroanilinum content is not under
During drop, reaction terminates, at this moment parachloroanilinum about residue 18%.Then cool to 60 degree.
Lower 300 grams of the deionized water toward 50~60 degree of addition in reaction solution of stirring, is stirred 30 minutes.It is slow cooling to afterwards
Crystallized in 20 degree.
Filter to isolate crystalline solid.The solid washs after appropriate amount of deionized water is washed, then with a small amount of cold methanol.Filter
And 103 grams of condensation product intermediate N (4- chlorphenyls) -2- nitro -1- aniline are obtained after drying, yield 62%, HPLC purity is more than
98%.
Embodiment two：
In reaction bulb, 87 grams of o-fluoronitrobenzenes and 200 grams of DMAC are put into, stir 94 grams of diisopropylethylamine of lower input,
120 degree are warming up under nitrogen protection afterwards.71 grams of parachloroanilinum are dissolved in 100 grams of DMAC and are prepared into solution, afterwards will
The solution is slowly added drop-wise in above-mentioned reaction system.Temperature can rise during dropwise addition, should be existed by cooling down controlling reaction temperature
Within 125 degree.
Reaction is persistently carried out 8 hours between 120~125 degree, HPLC monitoring reaction process.When parachloroanilinum content is not under
During drop, reaction terminates, at this moment parachloroanilinum about residue 11%.Cool to 60 degree.
Afterwards with processing mode in embodiment one, finally 100 grams of condensation product intermediate N (4- chlorphenyls) -2- nitros -
1- aniline, yield 72%, HPLC purity are more than 98%.
Embodiment three：
In reaction bulb, 92 grams of o-fluoronitrobenzenes and 200 grams of DMSO are put into, stir 117 grams of DBU of lower input, afterwards nitrogen
120 degree are warming up under protection.75 grams of parachloroanilinum are dissolved in 100 grams of DMSO and are prepared into solution, it is afterwards that the solution is slow
Slowly it is added drop-wise in above-mentioned reaction system.Temperature can rise during dropwise addition, should by cool down controlling reaction temperature 125 degree with
It is interior.
Reaction is persistently carried out 5 hours between 120~125 degree, HPLC monitoring reaction process.When parachloroanilinum content is not under
During drop, reaction terminates, at this moment parachloroanilinum about residue 12%.Cool to 80 degree.
Afterwards with processing mode in embodiment one, finally 100 grams of condensation product intermediate N (4- chlorphenyls) -2- nitros -
1- aniline, yield 68%, HPLC purity are more than 98%.
Reduction reaction：
Example IV：
In hydriding reactor, 100 grams of N- (4- chlorphenyls) -2- nitro -1- aniline and 800 grams of toluene, nitrogen displacement are put into
Afterwards, 10 grams of nickel-metal catalysts are put into.Stirring is opened, 60 degree is warming up to, is passed through hydrogen to 3 kilograms of pressure.Remain above-mentioned and hold
Continue and be passed through hydrogen between 60~70 degree, until not reabsorbing hydrogen, reaction process is controlled in HPLC.When condensation product intermediate disappear,
Reaction is reached home.
Reaction system with nitrogen, heat filtering remove Raney nickel.Gained filtrate decompression is evaporated off concentrating out about 600 grams
After toluene, it is slow cooling in 20 degree and crystallizes.Solid is filtered to isolate, solid is washed with appropriate cold toluene, drying.Finally obtain
72 grams of N- (4- chlorphenyls) -1,2- phenylenediamine crude products, yield 82%, purity are more than 98%, and color is taupe.
Embodiment five：
In hydriding reactor, 100 grams of N- (4- chlorphenyls) -2- nitro -1- aniline and 200 grams of DMF, nitrogen displacement are put into
Afterwards, 10 grams of nickel-metal catalysts are put into.Stirring is opened, 60 degree is warming up to, is passed through hydrogen to 3 kilograms of pressure.Continue 60~70
Hydrogen is passed through between degree, until not reabsorbing hydrogen, reaction process is controlled in HPLC.When the disappearance of condensation product intermediate, it is reacted to up to eventually
Point.
Reaction system with nitrogen, heat filtering remove Raney nickel.Gained filtrate decompression is evaporated off concentrating out about 100 grams
After DMF, 200 grams of deionized waters are added, is slow cooling in 20 degree and crystallizes afterwards.Filter to isolate solid, solid with going in right amount
After ion water washing, then washed with cold toluene, dried.81 grams of N- (4- chlorphenyls) -1,2- phenylenediamine crude products are finally obtained, are received
Rate 92%, purity are more than 98%, and color is taupe.
Embodiment six：
The separated nickel-metal catalyst out of reduction step, is washed with a small amount of methanol, is filtered dry.Afterwards according to example IV
Or five feed intake, almost same yield and the N- of quality (4- chlorphenyls) -1,2- phenylenediamine crude products are finally obtained.The catalyst is through set
With three times, it is found that its catalytic activity is not decreased obviously.
Recrystallization process：
Embodiment seven：
In reaction bulb, 100 grams of N- (4- chlorphenyls) -1,2- phenylenediamines and 225 grams of methanol are put into, are risen after nitrogen displacement
Temperature is slow cooling in 20 degree and crystallized to 60 degree of backflow dissolved clarifications afterwards.Solid is filtered to isolate, solid is washed with appropriate cold methanol
Wash, dry.86 grams of N- (4- chlorphenyls) -1,2- phenylenediamine finished products, yield 86% are finally obtained, purity is more than 99.5%, face
Color is silvery white.
Embodiment eight：
In reaction bulb, 100 grams of N- (4- chlorphenyls) -1,2- phenylenediamines and 200 grams of toluene are put into, are risen after nitrogen displacement
Temperature is slow cooling in 20 degree and crystallized to 80 degree of backflow dissolved clarifications afterwards.Solid is filtered to isolate, solid is washed with appropriate cold toluene
Wash, dry.88 grams of N- (4- chlorphenyls) -1,2- phenylenediamine finished products, yield 88% are finally obtained, purity is more than 99.5%, face
Color is silvery white.
The technical scheme provided above the embodiment of the present invention is described in detail, specific case used herein
The principle and embodiment of the embodiment of the present invention are set forth, the explanation of above example is only applicable to help and understands this
The principle of inventive embodiments；Meanwhile for those of ordinary skill in the art, according to the embodiment of the present invention, in specific embodiment party
There will be changes in formula and application, in summary, this specification content should not be construed as limiting the invention.
Claims (7)
1. the method for one kind synthesis Clofazimine key intermediate N- (4- chlorphenyls) -1,2- phenylenediamines, it is characterised in that including
Following steps：
1), using o-fluoronitrobenzene and parachloroanilinum as raw material, the catalyst by the use of organic base as condensation reaction is in organic solvent
Middle reaction；After reaction terminates, through being conventionally treated condensation intermediate N (4- chlorphenyls) -2- nitro -1- aniline；
2), resulting condensation intermediate, in organic solvent, by the use of metallic nickel as catalyst, catalytic hydrogen reduction is carried out；
Through being conventionally treated N- (4- chlorphenyls) -1,2- phenylenediamine crude products after reduction；
3) N- (4- chlorphenyls) -1, the 2- phenylenediamines crude product, obtained recrystallizes by organic solvent, obtains final finished.
2. a kind of synthesis Clofazimine key intermediate N- (4- chlorphenyls) -1,2- phenylenediamines according to claim 1
Method, it is characterised in that：In the step 1), used organic base is organic amine compound, including triethylamine, diisopropyl
Base ethylamine, dimethyl isopropyl amine, 4- methyl morpholines, Isosorbide-5-Nitrae-diazabicyclo [2,2,2] octane (DABCO), 1,8- phenodiazines
Miscellaneous bicyclic [5,4,0] 11-7- alkene (DBU) ,-7- alkene (DBN) of 1,5- diazabicyclos [4,3,0] 11,1- crassitudes,
One of which can be used, it is possible to use two or more is used in mixed way.
3. a kind of synthesis Clofazimine key intermediate N- (4- chlorphenyls) -1,2- phenylenediamines according to claim 1
Method, it is characterised in that：In the step 1), the mol ratio of amount and raw materials used parachloroanilinum that organic base adds for 0.8~
2：1.
4. a kind of synthesis Clofazimine key intermediate N- (4- chlorphenyls) -1,2- phenylenediamines according to claim 1
Method, it is characterised in that：In the step 1), used solvent is aprotic, polar type solvent, including DMF, DMAC,
DMSO, dioxane, can be a certain or their mixed system in use.
5. a kind of synthesis Clofazimine key intermediate N- (4- chlorphenyls) -1,2- phenylenediamines according to claim 1
Method, it is characterised in that：In the step 2), used catalyst is metallic nickel, and the metallic nickel can be load-type nickel, bone
Frame nickel or nickel nano-cluster or amorphous alloy nickel.
6. a kind of synthesis Clofazimine key intermediate N- (4- chlorphenyls) -1,2- phenylenediamines according to claim 1
New method, it is characterised in that：In the step 2), the usage amount of metalNicatalyst is body weight among the condensation of required reduction
The 5%~20% of amount.
7. a kind of synthesis Clofazimine key intermediate N- (4- chlorphenyls) -1,2- phenylenediamines according to claim 1
New method, it is characterised in that：In the step 3), recrystallization solvent is toluene, methanol, ethanol, acetone, ethyl acetate；Can be with
Select one of which or their mixed system.
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| CN201710738472.0A CN107445845A (en) | 2017-08-24 | 2017-08-24 | The method of one kind synthesis Clofazimine key intermediate N (4 chlorphenyl) 1,2 phenylenediamine |
| PCT/CN2017/100965 WO2019037161A1 (en) | 2017-08-24 | 2017-09-08 | Method for synthesizing key clofazimine intermediate n-(4-chlorphenyl)-1,2-phenylenediamine |
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| CN201710738472.0A CN107445845A (en) | 2017-08-24 | 2017-08-24 | The method of one kind synthesis Clofazimine key intermediate N (4 chlorphenyl) 1,2 phenylenediamine |
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| CN109293587A (en) * | 2018-11-07 | 2019-02-01 | 浙江华海立诚药业有限公司 | The preparation method of Clofazimine and its intermediate |
| WO2020166984A1 (en) * | 2019-02-15 | 2020-08-20 | 에스티팜 주식회사 | Intermediate for producing phenazine derivative, and method for producing same |
| CN112521339A (en) * | 2020-11-20 | 2021-03-19 | 山西立业制药有限公司 | Preparation method of chlorphenazine |
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| BRPI0609417A2 (en) * | 2005-04-13 | 2011-10-18 | Neurosearch As | compound or an n-oxide thereof, or any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt of the same pharmaceutical composition, use of the chemical compound |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109293587A (en) * | 2018-11-07 | 2019-02-01 | 浙江华海立诚药业有限公司 | The preparation method of Clofazimine and its intermediate |
| CN109293587B (en) * | 2018-11-07 | 2023-06-16 | 浙江华海立诚药业有限公司 | Preparation method of clofazimine and intermediate thereof |
| WO2020166984A1 (en) * | 2019-02-15 | 2020-08-20 | 에스티팜 주식회사 | Intermediate for producing phenazine derivative, and method for producing same |
| KR20200099718A (en) * | 2019-02-15 | 2020-08-25 | 에스티팜 주식회사 | Intermediates for the production of phenazine derivative and methods for their preparation |
| KR102219563B1 (en) * | 2019-02-15 | 2021-02-24 | 에스티팜 주식회사 | Intermediates for the production of phenazine derivative and methods for their preparation |
| CN113454057A (en) * | 2019-02-15 | 2021-09-28 | St制药株式会社 | Intermediate for preparing phenazine derivative and preparation method thereof |
| CN112521339A (en) * | 2020-11-20 | 2021-03-19 | 山西立业制药有限公司 | Preparation method of chlorphenazine |
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Application publication date: 20171208 |