CN103664678B - An intermediate of N1-(4-fluorobenzyl)-4-nitrophenyl-1, 3-diamine and its prepn - Google Patents
An intermediate of N1-(4-fluorobenzyl)-4-nitrophenyl-1, 3-diamine and its prepn Download PDFInfo
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- CN103664678B CN103664678B CN201310543745.8A CN201310543745A CN103664678B CN 103664678 B CN103664678 B CN 103664678B CN 201310543745 A CN201310543745 A CN 201310543745A CN 103664678 B CN103664678 B CN 103664678B
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- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 238000002360 preparation method Methods 0.000 claims abstract description 29
- 238000006482 condensation reaction Methods 0.000 claims abstract description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 46
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 28
- 229910017604 nitric acid Inorganic materials 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 23
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- 239000000010 aprotic solvent Substances 0.000 claims description 18
- 238000006396 nitration reaction Methods 0.000 claims description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
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- 238000003756 stirring Methods 0.000 claims description 13
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- 238000001953 recrystallisation Methods 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
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- 238000000034 method Methods 0.000 abstract description 34
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 abstract description 20
- PCOBBVZJEWWZFR-UHFFFAOYSA-N ezogabine Chemical compound C1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 PCOBBVZJEWWZFR-UHFFFAOYSA-N 0.000 abstract description 19
- 229960003312 retigabine Drugs 0.000 abstract description 18
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- 239000002994 raw material Substances 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
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- 239000001961 anticonvulsive agent Substances 0.000 abstract description 3
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- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
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- 150000002466 imines Chemical class 0.000 description 4
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- 230000007613 environmental effect Effects 0.000 description 3
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
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- RNEACARJKXYVND-KQGZCTBQSA-N (2r)-2-[[(5z)-5-[(5-ethylfuran-2-yl)methylidene]-4-oxo-1,3-thiazol-2-yl]amino]-2-(4-fluorophenyl)acetic acid Chemical compound O1C(CC)=CC=C1\C=C/1C(=O)N=C(N[C@@H](C(O)=O)C=2C=CC(F)=CC=2)S\1 RNEACARJKXYVND-KQGZCTBQSA-N 0.000 description 1
- CBCKQZAAMUWICA-UHFFFAOYSA-N 1,4-phenylenediamine Chemical compound NC1=CC=C(N)C=C1 CBCKQZAAMUWICA-UHFFFAOYSA-N 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of preparation method of retigabine intermediate, be specifically related to <i>N
1intermediate of </i>-(4-luorobenzyl)-4-nitrophenyl-1,3-diamines and preparation method thereof.Intermediate of the present invention is compound (VI), and chemical structural formula is such as formula shown in VI.The present invention is nitrated by the generation of <i>N</iGreatT.Gr eaT.GT-(3-fluorophenyl) ethanamide, condensation reaction obtains new compound VI, and hydrolysis reaction occurs compound VI further can obtain <i>N
1</i>-(4-luorobenzyl)-4-nitrophenyl-1,3-diamines, <i>N
1</i>-(4-luorobenzyl)-4-nitrophenyl-1,3-diamines is the important intermediate preparing retigabine.Method of the present invention is easy and simple to handle, yield is good, with low cost, quality satisfied, and used raw material and solvent thereof all have more supplier, cheap, one-step synthesis antiepileptic drug retigabine of going forward side by side.
Description
Technical field
The present invention relates to a kind of preparation method of retigabine intermediate, be specifically related to
n 1 intermediate of-(4-luorobenzyl)-4-nitrophenyl-1,3-diamines and preparation method thereof.
Background technology
Retigabine (chemical name:
n-[2-amino-4-(4-flunamine base) phenyl] urethanum, retigabine) there is following structure (see formula I):
Formula I
The antiepileptic drug of the number of mechanisms such as a kind of neurone potassium channel openers of retigabine and GABA toughener.This medicine is by being researched and developed by GlaxoSmithKline PLC/Valeant drugmaker, on March 29th, 2011 gets permission listing in European Union's (commodity are called Trobalt), and ratify listing, for the assisting therapy of adult epilepsy partial seizure the same year by U.S. FDA (commodity are called Potiga).In addition, to be used for the treatment of II clinical trial phase of postherpetic neuralgia also underway for this product.
The synthetic method of several retigabine is disclosed, method one and method two in US Patent No. 5384330.
Method one:
The method with acid ion exchange (Nafion) for catalyzer, by p-Fluorobenzenecarboxaldehyde and 2-nitro-1, the condensation of 4-phenylenediamine first obtains imines, 2-amino-4-(4-flunamine base) oil of mirbane is obtained again through sodium borohydride reduction, yield is lower, two-step reaction total recovery only has 68%, and reaction uses this noxious solvent of dimethylbenzene, and boiling point is higher not easily to be removed.
Method two:
The method is starting raw material with p-Nitroaniline, first obtains
n-(4-amino-2-nitrophenyl) urethanum, then obtain with the condensation of 4-fluorobenzaldehyde
n-[4-(4-fluorobenzylidene is amino)-2-nitrophenyl] urethanum, then obtain retigabine through imine reduction, nitroreduction, synthetic route is longer, and total recovery is lower, only has 29%.
Above-mentioned two kinds of methods all adopt and obtain imines with the condensation of 4-fluorobenzaldehyde, then obtain amine through sodium borohydride reduction, and not only process is loaded down with trivial details, and product yield is low, is unfavorable for that industrialization is produced.
Chinese patent CN10191195A discloses a kind of synthetic route of retigabine intermediate---method three.The method be with fluoro-1, the 2-dinitrobenzene of 4-for raw material, introduce 4-flunamine base by the mode of fragrant substitution reaction, but fluoro-1, the 2-dinitrobenzene of 4-is difficult to preparation, not easily obtains, limit the commercial application of the method, and the solvent DMSO boiling point of the method is higher not easily removes.
Method three:
US Patent No. 5384330 also discloses a kind of method---method four being obtained retigabine by fragrant substitution reaction.The method is the method for synthesis retigabine preferably at present, its important intermediate
n 1 -(4-luorobenzyl)-4-nitrophenyl-1,3-diamines is the key that the method prepares retigabine.
Method four:
The method is in preparation
n 1 4-flunamine base is introduced by the mode of fragrant substitution reaction, comparatively directly during-(4-luorobenzyl)-4-nitrophenyl-1,3-diamines, but the reaction times is longer, 30 hours need be reacted in DMSO, and DMSO boiling point is higher not easily removes, yield is not high simultaneously, is only 85%.
Summary of the invention
The object of the present invention is to provide one
n 1 the intermediate of-(4-luorobenzyl)-4-nitrophenyl-1,3-diamines, wherein
n 1 -(4-luorobenzyl)-4-nitrophenyl-1,3-diamines may be used for preparing retigabine.
The present invention also aims to provide a kind of simple to operate, yield is high, the low and safety and environmental protection of cost
n 1 the preparation method of-(4-luorobenzyl)-4-nitrophenyl-1,3-diamines.
In order to achieve the above object, the technical solution adopted in the present invention is as follows:
Intermediate of the present invention is compound (VI), and its chemical structural formula is as follows:
Compound (VI):
.
Preparation method of the present invention: it is characterized in that being synthesized by compound (VI)
n 1 -(4-luorobenzyl)-4-nitrophenyl-1,3-diamines.
The concrete operation step of preparation method of the present invention is as follows:
Step one: nitration reaction: by compound (III) and aprotic solvent and acid (1) mix and blend, drips acid (2) under room temperature, after dropwising, is cooled to by above-mentioned reaction solution not higher than 5 DEG C; Above-mentioned solution is added to the water, separates out white solid, filter after stirring, gained white solid sherwood oil: ethyl acetate=1.0 ~ 1.2: the mixing solutions recrystallization of 1, suction filtration, concentrate and obtain compound (IV);
Wherein said compound (III) is 1:0 ~ 5(g/mL with the mass volume ratio of aprotic solvent);
Described aprotic solvent is selected from methylene dichloride, chloroform, acetic anhydride or glycol dimethyl ether;
Described acid (1) and acid (2) are different acid, and described acid (1) is selected from concentrated nitric acid or the vitriol oil, and described acid (2) is selected from the vitriol oil or concentrated nitric acid;
Described compound (III) is 1:1 ~ 3.5 with the mol ratio of concentrated nitric acid;
Described compound (III) is 1:2 ~ 20 with the mol ratio of the vitriol oil;
Step 2: condensation reaction: described compound (IV) is added the mixing solutions containing NSC 158269 (compound V), aprotic solvent and alkali, 50 ~ 130 DEG C are refluxed 2 ~ 6 hours, and after stopped reaction, concentration of reaction solution obtains compound (VI);
Wherein said compound (IV) is 1:1 ~ 1.5 with the mol ratio of NSC 158269;
Described compound (IV) is 1:3 ~ 15(g/mL with the mass volume ratio of aprotic solvent);
Described aprotic solvent is selected from acetone, dimethyl sulfoxide (DMSO) (DMSO), dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMAC), ether, isopropyl ether, dimethylbenzene, toluene or acetonitrile;
Described compound (IV) is 1:1 ~ 2 with the mol ratio of alkali;
Described alkali is selected from salt of wormwood, triethylamine, Diisopropylamine, diisopropylethylamine or diazabicylo (DBU);
Step 3: hydrolysis reaction: be dissolved in containing alcohol and aqueous acid by compound (VI), hydrolysis temperature is be stirred to reaction solution at 50 ~ 100 DEG C to take on a red color clarification, is cooled to not higher than 10 DEG C, adjusts pH to neutral, obtain after suction filtration with alkaline solution
n 1 -(4-luorobenzyl)-4-nitrophenyl-1,3-diamines;
Wherein said alcohol is selected from ethanol, methyl alcohol or Virahol;
Described compound (VI) is 1:3 ~ 10(g/mL with the mass volume ratio of alcohol);
Described acid is selected from hydrochloric acid or sulfuric acid;
Described compound (VI) is 1:5 ~ 30 with the mol ratio of acid;
The structural formula of wherein said compound (III) is:
;
The structural formula of described compound (VI) is:
;
The structural formula of described compound (VI) is:
;
Wherein said Hal is selected from: F, Cl or Br.
Further, the aprotic solvent described in preparation method's step one of the present invention is glycol dimethyl ether, and described compound (III) is 1:2 ~ 4(g/L with the mass volume ratio of glycol dimethyl ether).
Further, the acid (1) described in preparation method's step one of the present invention is concentrated nitric acid, and described compound (III) is 1:2.0 ~ 2.5 with the mol ratio of concentrated nitric acid; Acid (2) is the vitriol oil, and described compound (III) is 1:6.5 ~ 8.0 with the mol ratio of the vitriol oil.
Further, the compound (IV) described in preparation method's step 2 of the present invention is 1:1.05 ~ 1.3 with the mol ratio of NSC 158269.
Further, the aprotic solvent described in preparation method's step 2 of the present invention is acetonitrile, and described compound (IV) is 1:8 ~ 12(g/mL with the mass volume ratio of acetonitrile); Described alkali is triethylamine, and described compound (IV) is 1:1.2 ~ 1.8 with the mol ratio of triethylamine.
Further, in preparation method's step 2 of the present invention 70 ~ 80 DEG C of back flow reaction.
Further, in preparation method's step 3 of the present invention, ethanol elected as by wherein said alcohol, and described compound (VI) is 1:6 ~ 8(g/mL with the mass volume ratio of ethanol); Hydrochloric acid is elected in described acid as, and described compound (VI) is 1:17 ~ 23 with the mol ratio of hydrochloric acid;
Described hydrolysis temperature is 70 ~ 80 DEG C.
Further, the alkali described in preparation method's step 3 of the present invention is selected from sodium hydroxide, potassium hydroxide or ammoniacal liquor.
The present invention's synthesis
n 1 -(4-luorobenzyl)-4-nitrophenyl-1,3-diamines can prepare retigabine further, and its method can adopt preparation method disclosed in US Patent No. 5384330.
Concentrated nitric acid of the present invention refers to that massfraction is about 65%, and density is about 1.4g/cm
3concentrated nitric acid; The mol ratio of compound of the present invention (III) and concentrated nitric acid, refers to the ratio of the amount of substance of the nitric acid contained in the amount of substance of compound (III) and concentrated nitric acid.When the nitric acid that working concentration improves further, as nitrosonitric acid can also realize preparation method of the present invention, be the method identical with the present invention.
The vitriol oil of the present invention refers to the sulphuric acid soln being more than or equal to 98%; The mol ratio of compound of the present invention (III) and the vitriol oil, refers to the ratio of the amount of substance of the sulfuric acid contained in the amount of substance of compound (III) and the vitriol oil.In nitration reaction of the present invention, the effect of sulfuric acid sloughs the intramolecular water of nitric acid to make generation nitro positive ion as electrophilic reagent attack phenyl ring, the sulphuric acid soln that therefore can realize this object should think identical with the vitriol oil of indication of the present invention, is the method identical with the present invention.
Beneficial effect of the present invention is:
The present invention is by the important intermediate of compound (VI) synthesis retigabine
n 1 -(4-luorobenzyl)-4-nitrophenyl-1,3-diamines, it is advantageous that: compound (VI) easily prepare, its raw material also easily obtains, with low cost, and obtain the key of higher yields and do not lie in the use of expensive catalyst or increase the factors such as energy consumption, and be the ingenious selection of solvent and feed way, the uniqueness of purification process uses; Setting-up point is relatively low, and the reaction times is short, thus more can meet the requirement of energy-conserving and environment-protective.Compound (VI) is a kind of new compound of a kind of the present invention synthesis, and its feature is: yellow solid, is soluble in acetonitrile, fusing point 170 ~ 173 DEG C.
The present invention, when carrying out nitration reaction, nitratedly under the condition of nitration mixture obtains compound (IV), and W-response at room temperature can complete, and avoid the energy dissipation that common low-temp reaction causes, and security is high, is easy to carry out industrialization production.For the further optimization of nitration reaction, in the selection of solvent, spent glycol dme substitutes the toxic solvents such as chloroform, and the operating environment that the volatilization avoiding toxic agent causes is polluted and operator's damage, and security and the feature of environmental protection improve further.Moreover the present invention, in order of addition(of ingredients), is optimized for the method adding concentrated nitric acid after first adding the vitriol oil further, reaction preference and yield are all significantly improved.
The present invention is when carrying out condensation reaction, compound (IV) and 4-flunamine are carried out condensation reaction and obtains compound (VI), introduce 4-flunamine base by the mode of fragrant substitution reaction, this method is compared with to obtain the method that then imines reduce more direct with the condensation of 4-fluorobenzaldehyde; The present invention with carry out condensation with the fluoro-2-N-methyl-p-nitroaniline of 5-with 4-flunamine in aforesaid method four and compare, because kharophen is electron-donating weak to phenyl ring, make the reaction times can shorten to 4 hours by 30 hours, if count hydrolysis reaction interior, the total recovery obtaining compound (II) can be increased to 93% by 85%.Solvent acetonitrile is as reaction solvent simultaneously, and its boiling point meets temperature of reaction minimum requirements, is again recrystallization solvent, kills two birds with one stone for product.
The present invention is when being hydrolyzed reaction, and with the mixed solvent of water, ethanol for reaction solvent, be hydrolyzed in acid condition, thus be more conducive to the dissolving of raw material, the reaction times is short, reacts completely.If selection hydrolyzed under basic conditions, because material dissolution is poor, product is that free alkali is not soluble yet, and reaction is difficult to carry out.
The raw material of preparation method of the present invention is easy to get, and without the need to using noxious solvent and expensive catalyzer, economic environmental protection, cost is lower, and aftertreatment is simple, but is greatly improved by the purification process overall yield of reaction of specific solvent, ratio of components and uniqueness.
Accompanying drawing explanation
Fig. 1 is the magnetic resonance detection collection of illustrative plates of compound (VI) in embodiment 1.
Embodiment
Embodiment 1
The chemical structural formula of compound (VI):
.
The fusing point of compound (VI) is 170 ~ 173 DEG C; Hydrogen spectrum signature is:
1h NMR (500MHz, CDCl
3) δ: 11.0 [s, 1H, Ar-
nH-C (=O) CH
3], 8.12 (dd,
j=6.5,4.0 Hz, 2H, ArH), 7.30 (dd,
j=8.5,5.0 Hz, 2H, ArH), 7.05 (t,
j=8.5 Hz, 2H, ArH), 6.27 (dd,
j=9.5,2.5 Hz, 1H, ArH), 5.00 (s, 1H, Ar-
cH 2 -NH-Ar), 4.41 (d,
j=5.5 Hz, Ar-CH
2-
nH-Ar), 2.26 [s, 3H ,-(C=O) CH
3].The feature of magnetic resonance detection is: ESI-MS m/z: 304 [M+H]
+, specifically as shown in Figure 1.
Embodiment 2
Synthesized by compound (VI)
n 1 the method of-(4-luorobenzyl)-4-nitrophenyl-1,3-diamines.
It specifically reacts:
Step one: nitration reaction: will
n-(3-fluorophenyl) ethanamide (compound III, Hal=F) (76.5 g, 0.5 mol), glycol dimethyl ether (200 mL), concentrated nitric acid (65 mL, 1.1 mol) be added to 1L reaction flask successively, stir, under room temperature, drip the vitriol oil (200 mL, 3.6 mol), within 1.5 hours, drip off, be added drop-wise to by reaction solution in trash ice, adularescent solid is separated out.Add 1L water again, stir after 15 minutes and filter, filter cake washes with water, obtains white solid 88g, and by gained crude product sherwood oil: ethyl acetate=1.1: 1 recrystallization, suction filtration, mother liquor concentrations obtains white solid
n-(the fluoro-2-nitrophenyl of 5-) ethanamide (compounds Ⅳ, Hal=F) 74.2 g, yield 75%.
Compound (IV): mp 86 ~ 87 DEG C.
1H NMR (500 MHz , CDCl
3) δ: 10.59 [ s , 1H , Ar-
NH-(C=O)-CH
3] , 8.65 (dd ,
J = 11.5, 3.0 Hz, 1H, ArH) , 8.29 (dd ,
J= 9.5, 6.0 Hz , 1H , ArH) , 6.87 (m , 1H, ArH) , 2.31[s , 3H , -(C=O)-
CH 3 ]。ESI-MS m/z : 199 [M+H]
+。
Step 2: condensation reaction: by compound (IV, Hal=F) (50 g, 0.25 mol), acetonitrile (500 mL), NSC 158269 (38 g, 0.3 mol), triethylamine (38 g, 0.38 mol) join in 1L reaction flask, reflux 4 hours, stopped reaction, reaction solution is concentrated into dry, and acetonitrile-triethylamine recrystallization obtains yellow solid
n-{ 5-[(4-luorobenzyl) amine]-2-nitrophenyl } ethanamide (compound VI) 72.6 g, yield 95%.
Compound VI: mp 170 ~ 173 DEG C.
1H NMR (500MHz, CDCl
3) δ: 11.0 [s , 1H , Ar-
NH-C(=O)CH
3] , 8.12 (dd ,
J= 6.5 , 4.0 Hz , 2H , ArH) , 7.30 (dd ,
J = 8.5, 5.0 Hz , 2H , ArH) , 7.05 (t ,
J= 8.5 Hz , 2H , ArH) , 6.27 (dd ,
J= 9.5, 2.5 Hz, 1H, ArH) , 5.00 (s , 1H , Ar-CH
2-
NH-Ar) , 4.41 (d ,
J= 5.5 Hz , Ar-
CH 2 -NH-Ar) , 2.26 [s , 3H, -(C=O)CH
3]。ESI-MS m/z : 304 [M+H]
+。
Step 3: hydrolysis reaction: by compound (VI) (60.6 g, 0.1 mol) be dissolved in ethanol (400 mL), water (120 mL), concentrated hydrochloric acid (160 mL) are added in 1L reaction flask, stir 1 hour at 70 ~ 80 DEG C, reaction solution takes on a red color after clarification, be cooled to 10 DEG C, use 4 molL
-1sodium hydroxide solution adjusts pH to neutral, suction filtration, and filter cake washes with water, and suction filtration is dry, obtains yellow solid
n 1 -(4-luorobenzyl)-4-nitrophenyl-1,3-diamines (II) 51.2 g, yield 98%, mp 112 ~ 113 DEG C.
The method of the present embodiment is most preferred embodiment of the present invention.
The compound (II) that the present invention obtains can conveniently by the method for patent US5384330 report, and nitroreduction, amidation occur further, obtains antiepileptic drug retigabine, concrete reaction scheme is as follows.
The selection of embodiment 3 ~ 7 pairs of step one nitration reaction conditions
Embodiment 3: will
n-(3-fluorophenyl) ethanamide (III, Hal=F) (76.5 g, 0.5 mol), chloroform (200 mL), concentrated nitric acid (65 mL, 1.1 mol) are added to 1L reaction flask successively, stir, less than-20 DEG C drip the vitriol oil (200 mL, 3.6 mol), within 1.5 hours, drip off, after thin-layer chromatography display reacts completely, separatory, is added drop-wise in trash ice by lower floor's organic phase, and adularescent solid is separated out.Add 1L water again, stir after 15 minutes and filter, filter cake washes with water, obtains white solid 81g, and by gained crude product sherwood oil: ethyl acetate=1.1: 1 recrystallization, suction filtration, mother liquor concentrations obtains white solid
n-(the fluoro-2-nitrophenyl of 5-) ethanamide (compounds Ⅳ, Hal=F) 57.4g, yield 58 %, mp 86 ~ 87 DEG C.
Embodiment 4: will
n-(3-fluorophenyl) ethanamide (III, Hal=F) (76.5 g, 0.5 mol), acetic anhydride (200 mL), concentrated nitric acid (65 mL, 1.1 mol) be added to 1L reaction flask successively, stir, under room temperature, drip the vitriol oil (200 mL, 3.6 mol), within 1.5 hours, drip off, be added drop-wise to by reaction solution in trash ice, adularescent solid is separated out.Add 1L water again, stir after 15 minutes and filter, filter cake washes with water, obtains white solid 77g, and by gained crude product sherwood oil: ethyl acetate=1.1: 1 recrystallization, suction filtration, mother liquor concentrations obtains white solid
n-(the fluoro-2-nitrophenyl of 5-) ethanamide (IV) 51.4g, yield 52 %, mp 86 ~ 87 DEG C.
Embodiment 5: will
n-(3-fluorophenyl) ethanamide (III, Hal=F) (76.5 g, 0.5 mol), glycol dimethyl ether (200 mL), the vitriol oil (200 mL, 3.6 mol) be added to 1L reaction flask successively, stir, under room temperature, drip concentrated nitric acid (65 mL, 1.1 mol), within 1.5 hours, drip off, be added drop-wise to by reaction solution in trash ice, adularescent solid is separated out.Add 1L water again, stir after 15 minutes and filter, filter cake washes with water, obtains white solid 87g, and by gained crude product sherwood oil: ethyl acetate=1.1: 1 recrystallization, suction filtration, mother liquor concentrations obtains white solid
n-(the fluoro-2-nitrophenyl of 5-) ethanamide (IV) 68.3 g, yield 69 %, mp 86 ~ 87 DEG C.
Embodiment 6: will
n-(3-chloro-phenyl-) ethanamide (III, Hal=Cl) (84.8 g, 0.5 mol), glycol dimethyl ether (200 mL), concentrated nitric acid (65 mL, 1.1 mol) be added to 1L reaction flask successively, stir, under room temperature, drip the vitriol oil (200 mL, 3.6 mol), within 1.5 hours, drip off, with reference to above-mentioned 1) method, obtain
n-(the chloro-2-nitrophenyl of 5-) ethanamide 67.3 g, yield 63%, mp 114 ~ 115 DEG C.
Embodiment 7: will
n-(3-bromophenyl) ethanamide (III, Hal=Br) (107 g, 0.5 mol), glycol dimethyl ether (200 mL), concentrated nitric acid (65 mL, 1.1 mol) be added to 1L reaction flask successively, stir, under room temperature, drip the vitriol oil (200 mL, 3.6 mol), within 1.5 hours, drip off, with reference to the method for embodiment 2, obtain white solid
n-(the bromo-2-nitrophenyl of 5-) ethanamide (compounds Ⅳ, Hal=Br) 85.4 g, yield 66%, mp 138 ~ 140 DEG C.
From the above results: more known by embodiment 2,6,7, compound (III, Hal=F, Cl, Br) all to go forward side by side one-step synthesis target compound (II) as nitration reaction raw material, although fluorine, chlorine, bromine are ortho-para directing group, but with compound (III, Hal=Cl, Br) compare, with
n-(3-fluorophenyl) ethanamide (compound III, Hal=F) is raw material, and using fluorine as seeking group, yield and the selectivity of reaction are the highest.More known by embodiment 2,3, the aprotic solvent such as glycol dimethyl ether, chloroform, acetic anhydride all can be used as the solvent of nitration reaction, selectivity due to nitration reaction is determined by multiple factors such as the concentration of nitryl positive ion in reaction solution, the polarity of different nitration product and the polarity of reaction solvent, chloroform polarity is relatively little, a nonhomogeneous system can be formed after adding nitration mixture, simultaneous temperature needs to ensure less than-20 DEG C, otherwise can cause because temperature is too high the by product that activation energy is relatively high
n-(the fluoro-4-nitrophenyl of 3-) ethanamide too much produces.Acetic anhydride polarity is moderate, and yield is general, and uses because it also limit it by public security department's control.By screening, we find with glycol dimethyl ether to be that solvent can more be conducive to improving selectivity under the prerequisite ensureing yield, it also avoid low-temp reaction simultaneously, can realize, thus be more conducive to industrialization under normal temperature.More known by embodiment 2,5, no matter adding the vitriol oil after first adding concentrated nitric acid or adding concentrated nitric acid after first adding the vitriol oil all to make nitration reaction carry out smoothly, consider the optionally influence factor of nitration reaction, we add the vitriol oil and the concentration of nitryl positive ion in reaction solution can be made to maintain a constant level for a long time after first adding concentrated nitric acid under finding normal temperature, and nitration product corresponding to the concentration of this nitryl positive ion is just
n-(the fluoro-2-nitrophenyl of 5-) ethanamide (compounds Ⅳ, Hal=F), makes the by product that in nitration product, activation energy and polarity are all relatively high like this
nthe generation of-(3-fluoro-4-nitrophenyl) ethanamide drops to minimum, thus improves product yield.
The selection of embodiment 8 ~ 10 pairs of step 2 condensation reaction conditions
Embodiment 8: by compound (IV) (Hal=F) (50 g, 0.25 mol), DMF (500 mL), NSC 158269 (38 g, 0.3 mol), salt of wormwood (52 g, 0.38 mol) join in 1 L reaction flask, reflux 4 hours, after thin-layer chromatography display reacts completely, stopped reaction, reaction solution cools, add water 1 L, have solid to separate out, suction filtration obtains yellow solid
n-{ 5-[(4-luorobenzyl) amine]-2-nitrophenyl } ethanamide (VI) 68 g, yield 90%, mp 170 ~ 173 DEG C.
Embodiment 9: by compound (IV) (Hal=F) (50 g, 0.25 mol), acetone (500 mL), NSC 158269 (38 g, 0.3 mol), triethylamine (38 g, 0.38 mol) join in 1L reaction flask, reflux 10 hours, thin-layer chromatography display reaction solution Raw residue is still more, and reaction not exclusively.
Embodiment 10: will
n-(the chloro-2-nitrophenyl of 5-) ethanamide (compound (IV), Hal=Cl) (53.5 g, 0.25 mol), DMF (500 mL), NSC 158269 (38 g, 0.3 mol), salt of wormwood (52 g, 0.38 mol) join in 1L reaction flask, with reference to the method for embodiment 8, obtain yellow solid
n-{ 5-[(4-luorobenzyl) amine]-2-nitrophenyl } ethanamide (VI) 40 g, yield 53%, mp 170 ~ 173 DEG C.
Embodiment 11: will
n-(the bromo-2-nitrophenyl of 5-) ethanamide (compound (IV), Hal=Br) (64.7 g, 0.25 mol), DMF (500 mL), NSC 158269 (38 g, 0.3 mol), salt of wormwood (52 g, 0.38 mol) joins in 1L reaction flask, the method with reference to embodiment 8 obtains yellow solid
n-{ 5-[(4-luorobenzyl) amine]-2-nitrophenyl } ethanamide (VI) 44.6 g, yield 59%, mp 170 ~ 173 DEG C.
From the above results: by embodiment 2,10,11 known, compound (IV, Hal=F, Cl, Br) all can obtain with NSC 158269 condensation
n-{ 5-[(4-luorobenzyl) amine]-2-nitrophenyl } ethanamide (VI), although fluorine, chlorine, bromine all can be used as leavings group, the leaving capability of fluorine is the strongest, namely with
n-(the fluoro-2-nitrophenyl of 5-) ethanamide is raw material, and temperature of reaction is minimum, shortest time, and yield is also the highest.By embodiment 2,8,9 known, the aprotic solvent such as acetone, DMF, acetonitrile all can be used as the solvent of condensation reaction, wherein acetone makes temperature of reaction be not enough to make condensation reaction complete because boiling point is lower, though and DMF can ensure that condensation reaction is carried out completely, its high boiling point can make again aftertreatment become difficult, acetonitrile moderate boiling point, just reach temperature requirement, acetonitrile is as reaction solvent simultaneously, is again recrystallization solvent for product, kill two birds with one stone, therefore reaction solvent selects acetonitrile.
Claims (10)
1. one kind
n 1 the intermediate of-(4-luorobenzyl)-4-nitrophenyl-1,3-diamines, it is characterized in that described intermediate is compound VI, its chemical structural formula is as follows:
Compound VI:
.
2. one kind
n 1 the preparation method of-(4-luorobenzyl)-4-nitrophenyl-1,3-diamines: it is characterized in that being synthesized by compound VI
n 1 -(4-luorobenzyl)-4-nitrophenyl-1,3-diamines; The structural formula of described compound VI is:
.
3. according to claim 2
n 1 the preparation method of-(4-luorobenzyl)-4-nitrophenyl-1,3-diamines: it is characterized in that its concrete operation step is as follows:
Step one: nitration reaction: by compound III and aprotic solvent and sour 1 mix and blend, drips acid 2 under room temperature, after dropwising, is cooled to by above-mentioned reaction solution not higher than 5 DEG C; Be added to the water by above-mentioned solution, separate out white solid, filter, gained white solid sherwood oil: ethyl acetate=1.0 ~ 1.2: the mixing solutions recrystallization of 1, suction filtration after stirring, filtrate is concentrated obtains compounds Ⅳ;
Wherein said compound III and the mass volume ratio of aprotic solvent are 1:0 ~ 5g/mL;
Described aprotic solvent is selected from methylene dichloride, chloroform, acetic anhydride or glycol dimethyl ether;
Described acid 1 and acid 2 are different acid, and described acid 1 is selected from concentrated nitric acid or the vitriol oil, and described acid 2 is selected from the vitriol oil or concentrated nitric acid;
Described compound III and the mol ratio of concentrated nitric acid are 1:1 ~ 3.5;
Described compound III and the mol ratio of the vitriol oil are 1:2 ~ 20;
Step 2: condensation reaction: described compounds Ⅳ is added the mixing solutions containing compound V, aprotic solvent and alkali, 50 ~ 130 DEG C are refluxed 2 ~ 6 hours, and after stopped reaction, concentration of reaction solution obtains compound VI; Described compound V is NSC 158269;
The mol ratio of wherein said compounds Ⅳ and NSC 158269 is 1:1 ~ 1.5;
The mass volume ratio of described compounds Ⅳ and aprotic solvent is 1:3 ~ 15g/mL;
Described aprotic solvent is selected from acetone, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, ether, isopropyl ether, dimethylbenzene, toluene or acetonitrile;
The mol ratio of described compounds Ⅳ and alkali is 1:1 ~ 2;
Described alkali is selected from salt of wormwood, triethylamine, Diisopropylamine, diisopropylethylamine or diazabicylo;
Step 3: hydrolysis reaction: be dissolved in by compound VI containing alcohol and aqueous acid, hydrolysis temperature is be stirred to reaction solution at 50 ~ 100 DEG C to take on a red color clarification, is cooled to not higher than 10 DEG C, adjusts pH to neutral, obtain after suction filtration with alkaline solution
n 1 -(4-luorobenzyl)-4-nitrophenyl-1,3-diamines;
Wherein said alcohol is selected from ethanol, methyl alcohol or Virahol;
Described compound VI is 1:3 ~ 10g/mL with the mass volume ratio of alcohol;
Described acid is selected from hydrochloric acid or sulfuric acid;
Described compound VI is 1:5 ~ 30 with the mol ratio of acid;
The structural formula of wherein said compound III is:
;
The structural formula of described compounds Ⅳ is:
;
The structural formula of described compound VI is:
Wherein said Hal is selected from: F, Cl or Br.
4. according to claim 3
n 1 -(4-luorobenzyl)-4-nitrophenyl-1, the preparation method of 3-diamines intermediate, it is characterized in that the aprotic solvent described in step one is glycol dimethyl ether, described compound III and the mass volume ratio of glycol dimethyl ether are 1:2 ~ 4g/mL.
5. according to claim 3
n 1 the preparation method of-(4-luorobenzyl)-4-nitrophenyl-1,3-diamines intermediate, it is characterized in that the acid 1 described in step one is concentrated nitric acid, described compound III and the mol ratio of concentrated nitric acid are 1:2.0 ~ 2.5; Acid 2 is the vitriol oil, and described compound III and the mol ratio of the vitriol oil are 1:6.5 ~ 8.0.
6. according to claim 3
n 1 the preparation method of-(4-luorobenzyl)-4-nitrophenyl-1,3-diamines intermediate, is characterized in that the mol ratio of the compounds Ⅳ described in step 2 and NSC 158269 is 1:1.05 ~ 1.3.
7. according to claim 3
n 1 the preparation method of-(4-luorobenzyl)-4-nitrophenyl-1,3-diamines intermediate, it is characterized in that the aprotic solvent described in step 2 is acetonitrile, the mass volume ratio of described compounds Ⅳ and acetonitrile is 1:8 ~ 12g/mL;
Described alkali is triethylamine, and the mol ratio of described compounds Ⅳ and triethylamine is 1:1.2 ~ 1.8.
8. according to claim 3
n 1 the preparation method of-(4-luorobenzyl)-4-nitrophenyl-1,3-diamines intermediate, is characterized in that in step 2 70 ~ 80 DEG C of back flow reaction.
9. according to any one in claim 3 ~ 7
n 1 the preparation method of-(4-luorobenzyl)-4-nitrophenyl-1,3-diamines intermediate, is characterized in that ethanol elected as by alcohol wherein said in step 3, and described compound VI is 1:6 ~ 8g/mL with the mass volume ratio of ethanol; Hydrochloric acid is elected in described acid as, and described compound VI is 1:17 ~ 23 with the mol ratio of hydrochloric acid; Described hydrolysis temperature is 70 ~ 80 DEG C.
10. according to any one in claim 3 ~ 7
n 1 the preparation method of-(4-luorobenzyl)-4-nitrophenyl-1,3-diamines intermediate, is characterized in that the alkali described in step 3 is selected from sodium hydroxide, potassium hydroxide or ammoniacal liquor.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5384330A (en) * | 1992-01-08 | 1995-01-24 | Asta Medica Aktiengesellschaft | Pharmaceutically active 1,2,4-triamino-benzene derivatives, processes for their preparation and pharmaceutical compositions containing them |
| CN101921195A (en) * | 2010-08-02 | 2010-12-22 | 北京德众万全医药科技有限公司 | Simple method for synthesizing intermediate of retigabine |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5384330A (en) * | 1992-01-08 | 1995-01-24 | Asta Medica Aktiengesellschaft | Pharmaceutically active 1,2,4-triamino-benzene derivatives, processes for their preparation and pharmaceutical compositions containing them |
| CN101921195A (en) * | 2010-08-02 | 2010-12-22 | 北京德众万全医药科技有限公司 | Simple method for synthesizing intermediate of retigabine |
Non-Patent Citations (1)
| Title |
|---|
| 瑞替加滨的合成工艺改进;王玮等;《中国新药杂志》;20140219;第23卷(第2期);第232-234页 * |
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