CN107118161A - The synthetic method of the carboxylic acid of 2 n-propyl, 4 tolimidazole 6 - Google Patents
The synthetic method of the carboxylic acid of 2 n-propyl, 4 tolimidazole 6 Download PDFInfo
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- CN107118161A CN107118161A CN201710313540.9A CN201710313540A CN107118161A CN 107118161 A CN107118161 A CN 107118161A CN 201710313540 A CN201710313540 A CN 201710313540A CN 107118161 A CN107118161 A CN 107118161A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
Abstract
The present invention relates to a kind of synthetic method of the carboxylic acid of 2 n-propyl, 4 tolimidazole 6.3,5 dimethyl nitrobenzenes are through nitric acid/concentrated sulfuric acid nitration reaction, the dinitro benzene of II 3,5 dimethyl of generation intermediate product 1,2；Intermediate product II is in ethanol solution, Pd/C catalytic hydrogenations, obtains the phenylenediamine of III 3,5 dimethyl of intermediate product 1,2；Intermediate product III reacts with n-butyric acie in poly phosphoric acid solution, obtains the dimethylbenzimidazole of IV 2 n-propyl of intermediate product 4,6；Intermediate product IV reacts through cobalt salt air oxidation in liquid phase in acetum, obtains the carboxylic acid of 2 n-propyls of product V, 4 tolimidazole 6.The present invention is simple to operate, and raw material is easy to get, solvent for use energy recovery, and product content is up to more than 95%, and high income is up to 73.2%, and pollution is few, is suitable for industrialized production.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, and in particular to a kind of telmisartan intermediate 2- n-propyls -4- methylbenzenes
And the synthetic method of imidazoles -6- carboxylic acids.
Background technology
Telmisartan (telmisartan), as a class novel hypertension II receptor antagonist depressor, it is unique
New bisbenzimidazole structure, it is ensured that height receptor affinity and superior pharmacokinetic properties, at the same again have first
The mechanism of action entered, steady decompression, does not rebound, long-acting efficient, better tolerance, targeting selection, Small side effects, and it is all that adaptability is good etc.
Many advantages, are clinically used for the treatment of essential hypertension, have good efficacy to hyperpietic.
Over twenties years, domestic and foreign scholars have done substantial amounts of research in the production technology and technology of Telmisartan, propose
Many new technologies and new technology, mainly using toluene derivative and benzimidizole derivatives as two class synthetic routes of raw material.
2- n-propyl -4- tolimidazole -6- carboxylic acids are an important intermediates for synthesizing Telmisartan.1993
(Med.Chem., 1993,36 (25) such as RIES:4040-4051) using 3- methyl-PABA methyl esters as initiation material, with
N-butyryl chloride carries out acylation reaction under chlorobenzene, and nitration reaction, nitrification production are then carried out with the nitration mixture of fuming nitric aicd and the concentrated sulfuric acid
Thing hydrogenate obtaining 3- methyl -4- butanamide base -5- Methyl anthranilates under palladium/charcoal catalysis.Again in glacial acetic acid
The lower backflow cyclization of effect forms core benzimidazole, through sodium hydroxide hydrolysis, obtains 2- n-propyl -4- tolimidazoles -6-
Carboxylic acid.
Hubei Inst. of Chemistry Cao Wei et al. (Gansu oil and chemical industry, 2010, (2)：18-22) to 2- n-propyls -4-
Research is optimized in the synthesis technique of methyl -6- carboxy benzimidazoles, it is determined that with the positive butyrylamino -5- nitros of 3- methyl -4-
Methyl benzoate is raw material, target product is made by reduction, cyclization, hydrolysis 3 steps reaction, total recovery is 76.3%.
A kind of CN101983962A, preparation technology of telmisartan active pharmaceutical ingredient, disclosure of which has：With 3- methyl-
4- Nitro-benzoic acids are initiation material, 4-Amino-3-methylbenzoic acid methyl esters are obtained through esterification, reduction, through acylation, smoke nitre
Sour nitrification, reduction, cyclization, hydrolysis obtain 2- n-propyl -4- tolimidazole -6- carboxylic acids.
The patent (WO, 2010149360) of the applications of HanseImami in 2010 report using cheap o-toluidine for
Beginning raw material, is acylated, Br/H by n-butyryl chloride2O2System bromination, palladium chtalyst introduce cyano group, mixed acid nitrification, iron powder-glacial acetic acid
The reaction of totally 6 steps synthesizes 2- n-propyl -4- tolimidazole -6- carboxylic acids for reduction system cyclization, concentrated hydrochloric acid hydrolysis, and total recovery is
4%.The route initiation material o-toluidine is cheap, route is shorter, and shortcoming is introduced into cyano group and needs to use ferrous cyanogen
Change potassium toxic articles, and solvent DMF reclaims difficult, post-processes cumbersome；The eroding chemical such as sulfuric acid and concentrated hydrochloric acid, operability compared with
Difference, it is seriously polluted.The technique is not suitable for industrialized production.
The patent (WO, 201081670) of Buechime applications is reported using 2- methyl -6- nitroanilines as raw material, is passed through
HBr/H2O2Bromination, Na2S2O4Reduce cyclization, catalysis is introduced carbonyl and sodium hydroxide hydrolysis totally 4 steps reaction synthesis 2- n-propyls-
4- tolimidazole -6- carboxylic acids.4 step reaction yields are up to 54%.But it is big that reducing agent requirement is made of sodium hydrosulfite.In addition,
Due to Na2S2O4Meet water and easily decompose to give off SO2Gaseous contamination environment, therefore its commercial Application is restricted.
Fudan University's hippology into (Fudan University's Master's thesis, 2012) using 2- methyl -6- nitroanilines cheap and easy to get as
Raw material, through NBS brominations, n-butyryl chloride, acylated, iron powder/ammonium chloride reduce in second alcohol and water, added in acetic aid medium at 100 DEG C
Hot cyclization, Pd (dppf) Cl2Carbonyl is inserted at 100 DEG C of catalysis, totally 6 steps obtain 2- n-propyl -4- methylbenzenes to sodium hydroxide hydrolysis
And imidazoles -6- carboxylic acids, total recovery is up to 62%.This route has high income, and cost is low, pollutes small, technological reaction mild condition, behaviour
Make simple and practical, with preferable industrial applications prospect.But carbonyl reaction is inserted in catalysis needs 100 DEG C of temperature, carbon monoxide pressure
1.5MPa high pressure and heavy metal palladium catalysis.
The content of the invention
The purpose of the present invention is to be directed to the above-mentioned state of the art, it is desirable to provide a kind of product yield and purity are high, environmental pollution
Small, cost is low, the synthesis of the 2- n-propyl -4- tolimidazole -6- carboxylic acids with huge economic benefit and social benefit
Method.
The implementation of the object of the invention is that the synthetic method of 2- n-propyl -4- tolimidazole -6- carboxylic acids is synthesized
Method is carried out in four steps：
The first step, with 3,5- dimethyl nitrobenzenes for raw material, through nitric acid/concentrated sulfuric acid nitration reaction, hydrolyzes, filters, generation
3,5- dimethyl -1,2- the dinitro benzenes of intermediate product II；
Second step, by the intermediate product 3 obtained by the first step, 5- dimethyl -1,2- dinitro benzene dissolves in ethanol, Pd/C
Catalytic hydrogenation, realizes that nitro becomes the reaction of amino, through filtering, concentration, obtains intermediate product III 3,5- dimethyl -1,2- benzene
Diamines；
3rd step, by the intermediate product 3 obtained by second step, 5- dimethyl -1,2- phenylenediamine is in poly phosphoric acid solution, and just
Butyric acid reacts, and through activated carbon decolorizing, filtering, sodium hydroxide is neutralized to pH8, obtains 2- n-propyl -4, the 6- diformazans of intermediate product IV
Base benzimidazole；
4th step, by intermediate product 2- n-propyl -4,6- dimethylbenzimidazoles obtained by the 3rd step in acetum,
Reacted through cobalt salt air oxidation in liquid phase, realize that 6 methyl become the reaction of carboxyl, concentrated, alkaline hydrolysis, filtering, acidolysis is produced
Product V 2- n-propyl -4- tolimidazole -6- carboxylic acids；
Specific reaction is carried out by following formula:
The present invention, for initiation material, is nitrified, palladium/carbon catalytic hydrogenation with 3,5- dimethyl nitrobenzenes through concentrated nitric acid/concentrated sulfuric acid,
Polyphosphoric acids cyclization, the air oxidation under cobalt catalysis, obtains 2- n-propyl -4- tolimidazole -6- carboxylic acids, simple to operate,
Raw material is easy to get, solvent for use energy recovery, and high income is up to 73.2%, and pollution is few, and the present invention is suitable for industrialized production.
Embodiment
Synthetic method of the present invention is carried out in four steps：
The first step, with 3,5- dimethyl nitrobenzenes for raw material, through nitric acid/concentrated sulfuric acid nitration reaction, hydrolyzes, filters, generation
3,5- dimethyl -1,2- the dinitro benzenes of intermediate product II.
Specially：95% fuming nitric aicd and 98% concentrated sulfuric acid are configured to preserve at mixed acid, 0 DEG C；In reaction vessel
It is middle add 98% the concentrated sulfuric acid and 3,5- dimethyl nitrobenzene, be cooled to -10 DEG C under stirring, be added dropwise 95% fuming nitric aicd and
The mixed acid that 98% concentrated sulfuric acid is configured to, control charging rate makes reaction temperature be not higher than -5 DEG C.After completion of dropping, continue ice
Bath stirring 3 hours, reactant mixture is added slowly to hydrolyze in trash ice, maintains temperature to be no more than 5 DEG C, is stirred vigorously, to a large amount of
Faint yellow solid is separated out；Filtering, filter cake uses frozen water respectively, and saturated sodium bicarbonate solution, clear water washing is dried, obtains intermediate product
II, faint yellow solid 3,5- dimethyl -1,2- dinitro benzenes.
The volume ratio for the mixed acid that described 95% fuming nitric aicd and 98% concentrated sulfuric acid are prepared is 1:2, mixed acid and 3,
The amount ratio of 5- dimethyl nitrobenzenes is 3ml:1g.
Second step, by the intermediate product 3 obtained by the first step, 5- dimethyl -1,2- dinitro benzene dissolves in ethanol, Pd/C
Catalytic hydrogenation, realizes that nitro becomes the reaction of amino, through filtering, concentration, obtains intermediate product III 3,5- dimethyl -1,2- benzene
Diamines；
Specially：Intermediate product 3 into autoclave obtained by the addition first step, 5- dimethyl -1,2- dinitro benzenes,
Then 5%Pd/C catalyst is added, methanol solvate carries out 6h hydrogenation reactions, reaction terminates in temperature 60 C, pressure 0.5Mpa
Afterwards, decrease temperature and pressure drives kettle, and catalyst is recovered by filtration, and removes solvent, and crystallization obtains intermediate product III 3,5- dimethyl -1,2-
Phenylenediamine；
The catalyst is that 5%Pd/C and intermediate product 3,5- dimethyl -1,2- dinitro benzenes amount ratio are 1g：10g.
3rd step, by the intermediate product 3 obtained by second step, 5- dimethyl -1,2- phenylenediamine is in poly phosphoric acid solution, and just
Butyric acid reacts, and through activated carbon decolorizing, filtering, sodium hydroxide is neutralized to pH8, obtains 2- n-propyl -4, the 6- diformazans of intermediate product IV
Base benzimidazole；
Specially：The product 3 added in reaction vessel in the middle of second step preparation, 5- dimethyl -1,2- phenylenediamines are added
Butyric acid, polyphosphoric acids is into reaction bulb.120-125 DEG C is warming up to, is reacted 16 hours；60 DEG C are cooled to, is added water, activated carbon,
Stirring and dissolving is filtered to micro-boiling while hot after about 30min.Filtrate is cooled down, sodium hydroxide is added into reaction solution under agitation
Solution is neutralized to pH 10；Suction filtration is cooled down, the solid of precipitation is filtered out, is washed with cold water, dry crude product；Crude product ethanol weight
Crystallization, separates out and is dried at suction filtration after crystal, 100 DEG C, obtain intermediate compound IV 2- n-propyl -4,6- dimethylbenzimidazoles.
Middle product 3,5- dimethyl -1,2- phenylenediamines and the amount ratio of butyric acid are 8g:9g, the consumption with polyphosphoric acids
Than for 40g:80g, the amount ratio with activated carbon is 20g:1g, the amount ratio with ethanol is 4g:50ml.
4th step, by intermediate product 2- n-propyl -4,6- dimethylbenzimidazoles obtained by the 3rd step in acetum,
Reacted through cobalt salt air oxidation in liquid phase, realize that 6 methyl become the reaction of carboxyl, concentrated, alkaline hydrolysis, filtering, acidolysis is produced
Product V 2- n-propyl -4- tolimidazole -6- carboxylic acids.
Specifically, adding intermediate product IV 2- n-propyl -4,6- dimethylbiphenyls obtained by the 3rd step in reaction vessel
Imidazoles, adds catalyst 2 ethyl hexanoic acid cobalt, co-catalyst HP, glacial acetic acid；It is 110 in temperature
DEG C, oxygen pressure 1MPa reacts 2h；After reaction stops, decrease temperature and pressure drives kettle, and decompression abjection acetic acid is precipitated, suction filtration is obtained
Crude product, crude product is neutralized with 10% sodium hydrate aqueous solution arrives pH=8-9, plus activated carbon removes color, and filtering, filtrate is acidified to pH through 6N
=3, filter, drying obtains off-white color crystalline solid 2- n-propyl -4- tolimidazole -6- carboxylic acids (V)；
The catalyst 2 ethyl hexanoic acid cobalt, co-catalyst HP and 2- n-propyls -4,6- two
The amount ratio of tolimidazole is 0.5g：20g；
The amount ratio of glacial acetic acid and 2- n-propyl -4,6- dimethylbenzimidazoles is 15ml：20g.
With specific embodiment, the invention will be further described below
The first step, synthesis 3,5- dimethyl -1,2- dinitro benzenes
95% fuming nitric aicd 20mL and 98% concentrated sulfuric acid 40mL is configured to be cooled to -10 DEG C under mixed acid, stirring
Preserve.To equipped with the addition 100ml concentrated sulfuric acids, 20g3,5- dimethyl nitrobenzenes in churned mechanically 500ml three-necked flasks.Stirring
It is lower that -10 DEG C are cooled to cryostat, the mixed acid of fuming nitric aicd and 98% concentrated sulfuric acid is added dropwise in batches, controls charging rate, makes
Reaction temperature is not higher than -5 DEG C.After charging is finished, continue ice bath and stir 3 hours., will be anti-after question response mixture is darkened
Answer liquid to be added slowly to hydrolyze in trash ice, maintain temperature to be no more than 5 DEG C, be stirred vigorously, it is seen that a large amount of faint yellow solids are separated out.Cross
Filter, filter cake uses frozen water respectively, and saturated sodium bicarbonate solution, clear water washing is dried, obtains 21g intermediate product II, faint yellow solid 3,
5- dimethyl -1,2- dinitro benzenes, yield 92.8%, 132.7-134.7 DEG C of fusing point.
Infrared spectrum IR INSTRUMENT MODEL Perkin-Elmer Spectrum (KBr, cm-1):3088(Ar-H)；2919(CH3-
H)；1547,1441(Ar-C)；1547,1362 (N=O)；1441,1362(-CH3)；1040(C-N)；876-763(Ar-H).
Nuclear magnetic resonance nmr INSTRUMENT MODEL Varian Mercury 400,1H-NMR(CDCl3):7.79(S,1H,Ar-H)；
7.43(S,1H,Ar-H)；2.50(S,3H,Ar-CH3)；2.40(S,3H,Ar-CH3)。
Mass spectrometer Xevo TQ.MS:M/z=196.02 (M+)；
Second step, synthesis 3,5- dimethyl -1,2- phenylenediamines
After determining that reactor is air tight, the addition 15g 3 into autoclave, 5- dimethyl -1,2- dinitro benzenes, then
Add 1.5g 5%Pd/C catalyst, then the addition 300ml methanol into high-pressure bottle.The nitrogen of certain pressure is first passed through, is emptied
Air in reactor, it is continuous to arrange three times, then the hydrogen displacement nitrogen of certain pressure is passed through, it is continuous to replace three times.Finally 60
DEG C, react under reaction pressure 0.5Mpa and 6h.Decrease temperature and pressure drives kettle, with raw material, product and accessory substance in gas chromatographic detection kettle
Content, be recovered by filtration catalyst, remove solvent, crystallization obtains 10.5g intermediate products III 3,5- dimethyl -1,2- benzene two
Amine, is more than 98%, yield 98.8%, 73.9-74.6 DEG C of fusing point through GC detection purity.
Infrared spectrum IR INSTRUMENT MODEL Perkin-Elmer Spectrum (KBr, cm-1):3392,3299(Ar-NH2)；
2916(Ar-CH3)；912(Ar-H).
Nuclear magnetic resonance nmr INSTRUMENT MODEL Varian Mercury 400,1H-NMR(CDCl3):6.23(S,1H,Ar-H)；
6.12(S,1H,Ar-H)；4.11(br,4H,Ar-NH2)；2.03(S,3H,Ar-CH3)；1.99(S,3H,Ar-CH3)。
Mass spectrometer Xevo TQ.MS:M/z=136.08 (M+)。
3rd step, synthesis 2- n-propyl -4,6- dimethylbenzimidazoles
40g3 is taken, 5- dimethyl -1,2- phenylenediamines, 45g butyric acid, 80g polyphosphoric acids is added in reaction bulb.It is warming up to 120-
125 DEG C, react 16 hours.60 DEG C are cooled to, is added water after 500g, 2g activated carbons, about stirring and dissolving to micro-boiling, 30min while hot
Filtering.Filtrate is cooled down, 10% sodium hydroxide solution is added into reaction solution under agitation, pH to 10 or so is neutralized.Cooling
Suction filtration, the solid of precipitation is filtered out, and is washed with cold water, dry crude product.
Crude product is placed in 1000mL beakers, 500mL ethanol is added, dissolved by heating.It is cooled to room temperature, is taken out after separating out crystal
Filter, finally dries at 100 DEG C, obtains 51g intermediate product IV 2- n-propyl -4,6- dimethylbenzimidazoles.Detect pure through HPLC
Degree is more than 98%, yield 90%, 167.7-170.2 DEG C of fusing point.
Infrared spectrum IR INSTRUMENT MODEL Perkin-Elmer Spectrum (KBr, cm-1):3249(Ar-CH3)；2962(-
CH3)；2931(-CH2-)；1652 (C=N).
Nuclear magnetic resonance nmr INSTRUMENT MODEL Varian Mercury 400,1H-NMR(CDCl3):7.99,8.31(S,3H,Ar-
CH3)；6.74(S,1H,Ar-NH-)；2.27(q,2H,-CH2-)；2.13,2.16(S,3H,Ar-CH3)；1.55(dq,2H,-
CH2-)；0.9(dt,3H,Ar-CH3)。
Mass spectrometer Xevo TQ.MS:M/z=188.19 (M+)。
3rd step, synthesis 2- n-propyl -4- tolimidazole -6- carboxylic acids
After determining that reactor is air tight, 20g 2- n-propyl -4,6- dimethylbenzimidazoles are added into autoclave,
Catalyst 2 ethyl hexanoic acid cobalt 0.5g, co-catalyst HP 0.5g, glacial acetic acid 15ml.It is in temperature
110 DEG C, oxygen pressure is in 1MPa, and the reaction time is in 2h.After reaction stops, decrease temperature and pressure drives kettle, and decompression abjection acetic acid is sunk
Form sediment, obtained precipitation is subjected to suction filtration, crude product is neutralized with 10% sodium hydrate aqueous solution arrives pH=8-9, plus activated carbon removes color, mistake
Filter, filtrate is acidified to pH=3 through 6N, is filtrated to get off-white color crystalline solid V 2- n-propyl -4- tolimidazole -6- carboxylics
Acid.
2- n-propyl -4,6- dimethylbenzimidazole conversion per pass is up to 40%, 2- n-propyl -4- methyl benzo miaows
The selectivity of azoles -6- carboxylic acids is up to 100%.Product through ethyl alcohol recrystallization, obtain 20.6g 2- n-propyl -4- tolimidazoles -
6- carboxylic acids, HPLC detection purity is more than 98%, total recovery 88.8%, 257.7-259.3 DEG C of fusing point.
Infrared spectrum IR INSTRUMENT MODEL Perkin-Elmer Spectrum (KBr, cm-1):3425(O-H)；2965(Ar-
CH3)；1650 (C=N).
Nuclear magnetic resonance nmr INSTRUMENT MODEL Varian Mercury 400,1H-NMR(CDCl3):12.59(b,1H,Ar-
COOH)；7.93(S,1H,Ar-H)；7.61(S,1H,Ar-H)；3.55(b,1H,Ar-NH-)；2.88(t,2H,-CH2-)；2.55
(S,3H,Ar-CH3)；1.81(m,2H,-CH2-)；1.02(t,3H,Ar-CH3)。
Mass spectrometer Xevo TQ.MS:M/z=218.25 (M+)。
Claims (5)
- The synthetic method of 1.2- n-propyl -4- tolimidazole -6- carboxylic acids, it is characterised in that：Synthetic method is carried out in four steps：The first step, with 3,5- dimethyl nitrobenzenes for raw material, through nitric acid/concentrated sulfuric acid nitration reaction, is hydrolyzed, filtering, in the middle of generation 3,5- dimethyl -1,2- the dinitro benzenes of product II；Second step, by the intermediate product 3 obtained by the first step, 5- dimethyl -1,2- dinitro benzene dissolves in ethanol, Pd/C catalysis Hydrogenation, realizes that nitro becomes the reaction of amino, through filtering, concentration, obtains intermediate product III 3,5- dimethyl -1,2- benzene two Amine；3rd step, by the intermediate product 3 obtained by second step, 5- dimethyl -1,2- phenylenediamines are in poly phosphoric acid solution, with positive fourth Acid reaction, through activated carbon decolorizing, filtering, sodium hydroxide is neutralized to pH8, obtains intermediate product IV 2- n-propyl -4,6- dimethyl Benzimidazole；4th step, by intermediate product 2- n-propyl -4,6- dimethylbenzimidazoles obtained by the 3rd step in acetum, through cobalt Salt air oxidation in liquid phase reacts, and realizes that 6 methyl become the reaction of carboxyl, concentrated, alkaline hydrolysis, filtering, acidolysis is obtaining V 2- just Propyl group -4- tolimidazole -6- carboxylic acids；Specific reaction is carried out by following formula:
- 2. the synthetic method of 2- n-propyls -4- tolimidazole -6- carboxylic acids according to claim 1, it is characterised in that： First step reaction is specially to be configured to 95% fuming nitric aicd and 98% concentrated sulfuric acid to preserve at mixed acid, 0 DEG C；In reaction vessel It is middle add 98% the concentrated sulfuric acid and 3,5- dimethyl nitrobenzene, be cooled to -10 DEG C under stirring, be added dropwise 95% fuming nitric aicd and The mixed acid that 98% concentrated sulfuric acid is prepared, control charging rate makes reaction temperature be not higher than -5 DEG C.After completion of dropping, continue ice bath Stirring 3 hours, reactant mixture is added slowly to hydrolyze in trash ice, maintains temperature to be no more than 5 DEG C, is stirred vigorously, to a large amount of light Yellow solid is separated out；Filtering, filter cake uses frozen water respectively, and saturated sodium bicarbonate solution, clear water washing is dried, obtains intermediate product II, Faint yellow solid 3,5- dimethyl -1,2- dinitro benzenes；The volume ratio for the mixed acid that described 95% fuming nitric aicd and 98% concentrated sulfuric acid are prepared is 1:2, mixed acid and 3,5- bis- The amount ratio of methyl nitrobenzene is 3ml:1g.
- 3. the synthetic method of 2- n-propyls -4- tolimidazole -6- carboxylic acids according to claim 1, it is characterised in that： Second step reaction is specially that the intermediate product 3,5- dimethyl -1,2- dinitros obtained by the first step are added into autoclave Benzene, then adds 5%Pd/C catalyst, and methanol solvate carries out 6h hydrogenation reactions, reaction knot in temperature 60 C, pressure 0.5Mpa Shu Hou, decrease temperature and pressure drives kettle, and catalyst is recovered by filtration, and removes solvent, and crystallization obtains intermediate product III, off-white powder 3,5- Dimethyl -1,2- phenylenediamines；The catalyst is that 5%Pd/C and intermediate product II 3,5- dimethyl -1,2- dinitro benzenes amount ratio are 1g：10g.
- 4. the synthetic method of 2- n-propyls -4- tolimidazole -6- carboxylic acids according to claim 1, it is characterised in that： Three-step reaction is specially that intermediate product 3 prepared by second step is added in reaction vessel, 5- dimethyl -1,2- phenylenediamines, plus Enter butyric acid, polyphosphoric acids is into reaction bulb.120-125 DEG C is warming up to, is reacted 16 hours；60 DEG C are cooled to, is added water, activity Filtered while hot after charcoal, about stirring and dissolving to micro-boiling, 30min.Filtrate is cooled down, hydroxide is added into reaction solution under agitation Sodium solution is neutralized to pH 10；Suction filtration is cooled down, the solid of precipitation is filtered out, is washed with cold water, dry crude product；Crude product ethanol Recrystallization, separates out and is dried at suction filtration after crystal, 100 DEG C, obtain intermediate compound IV, white crystal 2- n-propyl -4,6- dimethylbiphenyls Imidazoles；The amount ratio of intermediate product III 3,5- dimethyl -1,2- phenylenediamines and butyric acid is 8g:9g, the amount ratio with polyphosphoric acids For 40g:80g, the amount ratio with activated carbon is 20g:1g, the amount ratio with ethanol is 4g:50ml.
- 5. the synthetic method of 2- n-propyls -4- tolimidazole -6- carboxylic acids according to claim 1, it is characterised in that： Four-step reaction is specially that the intermediate product 2- n-propyl -4,6- dimethylbiphenyl miaows obtained by the 3rd step are added in reaction vessel Azoles, catalyst 2 ethyl hexanoic acid cobalt, co-catalyst HP, glacial acetic acid；It is 110 DEG C, oxygen in temperature Pressure 1MPa, reacts 2h；After reaction stops, decrease temperature and pressure drives kettle, and decompression abjection acetic acid is precipitated, suction filtration, obtains crude product, slightly Product are neutralized with 10% sodium hydrate aqueous solution arrives pH=8-9, plus activated carbon removes color, and filtering, filtrate is acidified to pH=3, mistake through 6N Filter, drying, obtains product V, off-white color crystalline solid 2- n-propyl -4- tolimidazole -6- carboxylic acids；The catalyst 2 ethyl hexanoic acid cobalt, co-catalyst HP and 2- n-propyl -4,6- dimethyl The amount ratio of benzimidazole is 0.5g：20g；The amount ratio of glacial acetic acid and 2- n-propyl -4,6- dimethylbenzimidazoles is 15ml：20g.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111689903A (en) * | 2020-07-17 | 2020-09-22 | 浙江金立源药业有限公司 | Synthesis method of 2-n-propyl-4-methyl-6- (1-methylbenzimidazole-2-yl) benzimidazole |
| CN114621096A (en) * | 2020-12-11 | 2022-06-14 | 余购粮 | Synthetic method of 3, 5-dimethyl-1, 2-phenylenediamine dihydrochloride |
| CN114621101A (en) * | 2020-12-11 | 2022-06-14 | 李冰坚 | Refining method of 3, 5-dimethyl-1, 2-phenylenediamine dihydrochloride |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111689903A (en) * | 2020-07-17 | 2020-09-22 | 浙江金立源药业有限公司 | Synthesis method of 2-n-propyl-4-methyl-6- (1-methylbenzimidazole-2-yl) benzimidazole |
| CN114621096A (en) * | 2020-12-11 | 2022-06-14 | 余购粮 | Synthetic method of 3, 5-dimethyl-1, 2-phenylenediamine dihydrochloride |
| CN114621101A (en) * | 2020-12-11 | 2022-06-14 | 李冰坚 | Refining method of 3, 5-dimethyl-1, 2-phenylenediamine dihydrochloride |
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