CN102936223A - Synthesis method and purification method of 5-iodo-2-methylbenzimidazole - Google Patents
Synthesis method and purification method of 5-iodo-2-methylbenzimidazole Download PDFInfo
- Publication number
- CN102936223A CN102936223A CN2012104169236A CN201210416923A CN102936223A CN 102936223 A CN102936223 A CN 102936223A CN 2012104169236 A CN2012104169236 A CN 2012104169236A CN 201210416923 A CN201210416923 A CN 201210416923A CN 102936223 A CN102936223 A CN 102936223A
- Authority
- CN
- China
- Prior art keywords
- iodo
- reaction
- formula
- suc
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Abstract
The invention discloses a synthesis method and purification method of 5-iodo-2-methylbenzimidazole, relating to the field of organic synthesis. The method comprises the following steps: by using o-nitroaniline as a main raw material, simple substance iodine as an iodine source and oxydol as an oxidizer, carrying out iodination reaction in a polar solvent in the presence of sulfuric acid to obtain 4-iodo-2-nitroaniline; and in the polar solvent, carrying out hydrogenation reduction by using Raney nickel as a catalyst to obtain 4-iodo-1,2-phenylenediamine, and carrying out cyclization reaction by using slight acetic acid as a catalyst and ortho-triacetate as a cyclization reagent to obtain 5-iodo-2-methylbenzimidazole, and finally, carrying out decolorization and purification in an acetate generation mode. The synthesis method disclosed by the invention belongs to green synthesis, has the advantages of high atomic economical efficiency and less waste, and is simple to operate; the catalyst has the advantages of low price, small recovery loss and less waste, and is simple to operate; and the product decolorization and purification mode is simple and efficient, the product appears a creamy white powder solid, and the purity is higher than 99.5%.
Description
Technical field
The invention belongs to the organic synthesis field, what be specifically related to is synthetic method and the purification process thereof of 5-iodo-2-tolimidazole.
Background technology
5-iodo-2-tolimidazole, CAS accession number 2818-70-4, it is a kind of important medicine intermediate, its chemical structural formula is as follows:
The synthetic method of the existing report of 5-iodo-2-tolimidazole has three kinds:
Popov, I.I.(russian patent SU 1616911; Chemistry of Heterocyclic Compounds, 1997,33 (8), 949-953) report is take the 2-tolimidazole as raw material, at first in chloroform solvent, generate 2-tolimidazole perbromide (yield 95%) with bromine (1.0eq) reaction, after this perbromide is dry after filtration and potassiumiodide (1.0eq) in water in 60-80 ℃ of reaction, after finishing, reaction adds 10% sodium carbonate solution, add ether, divide three layers, discard water layer after the stirring, the standing over night crystallization, filter to get product 5-iodo-2-tolimidazole (yield 80%), reaction formula is as follows.The shortcoming of this method is to use the liquid bromine that high malicious highly corrosive is difficult for disposal, and bromo element is all stayed in the waste at last, not Atom economy and environmental protection; Also have the finished product purity not high.
Kamaura; M. etc. (world patent WO 2010001869) reports take 4-iodo-2-N-methyl-p-nitroaniline as raw material through making the reductive agent back flow reaction 1.5 hours with iron powder (5.0eq) after the N-acetylize in the solvent mixture of acetic acid (7.3w/w) and ethanol (2.9w/w); cold filtration after reaction finishes; filtrate is spin-dried for; silica gel column chromatography (hexane: ethyl acetate 50:50 ~ 1:99v/v); get product 5-iodo-2-tolimidazole (yield is not reported) with the hexane/ethyl acetate crystallization, reaction formula is as follows.The shortcoming of this method is to adopt the solvent mixture acetic acid/ethanol not easy to recovery of applied, uses greatly excessive iron powder, and it is more serious " to take off " phenomenon (generate by product 2-tolimidazole) of iodine in the reduction process.
(the Tetrahedron such as Byeong Hyo Kim, 2011,67 (41), 8027-8033) report is take 4-iodo-2-N-methyl-p-nitroaniline as raw material, in acetic acid (10.0eq) and ethyl acetate (17.0w/w) the solvent mixture, make reductive agent with indium powder (5.0eq), make to carry out under the cyclizing agent reflux one pot reaction with trimethyl orthoacetate (2.0eq), cooling after reaction finishes, add the ethyl acetate dilution, pass through diatomite filtration, filtrate is washed with 10% sodium hydrogen carbonate solution, through anhydrous magnesium sulfate drying, be spin-dried for after the filtration, (methyl alcohol: methylene dichloride 1:99v/v) get product 5-iodo-2-tolimidazole (yield 74%), reaction formula is as follows for silica gel column chromatography.The shortcoming of this method is to use the partially large indium powder of your recovery loss of greatly excessive and price.
Thereby the advantage of rear two kinds of methods is can Main By product 2-tolimidazole effectively be removed by crystallization mode to obtain sterling.The synthetic method of the existing report of intermediate 4-iodo-2-N-methyl-p-nitroaniline is to obtain through iodination reaction from the relatively cheap o-Nitraniline of price, and having of iodination reagent bibliographical information is a variety of, such as I
2/ Ag
2SO
4/ EtOH (Synthetic Communications, 1992,22 (22), 3215-3219), ICl/NaOAc/HOAc (Tetrahedron, 2004,60 (1), 81-92), HIO
3/ I
2/ HOAc (Bioorganic ﹠amp; Medicinal Chemistry, 2005,13 (23), 6324-6335), KIO
4/ KI/NaCl/HOAc(Tetrahedron Letters, 2006,47 (28), 4793-4796), KI/H
2O
2/ HOAc(Synthetic Communications, 2008,38 (22), 3894-3902), I
2/ H
2SO
4/ (NH
4)
2S
2O
8/ MeOH (JP2012153656), there is respectively following shortcoming in above iodate method:
(1) use expensive Sulfuric acid disilver salt (1.0eq), raw materials cost is too high.
(2) iodine monochloride is the more labile liquid of kind of less stable, and in use not easy to operate, market supply is limited.
(3) the large HIO of raw materials cost accounting
3/ I
2All use 0.5eq, have 0.5eq " I " not to be utilized, raw materials cost is high.
(4) the large KIO of raw materials cost accounting
4/ KI all uses 1.0eq, only has half " iodine " to be utilized, and raw materials cost is high; React complete rear non-product solid and cause too much the aftertreatment difficulty.
(5) solubleness of potassiumiodide in reaction system is limited, and along with the product " double team " of easily being separated out and can not the attend fully reaction is carried out in reaction, " double team " scale effect is more obvious; By-product sylvite increases the saltiness of waste.
(6) adding of solid oxidizing agent ammonium persulphate need to be carried out in batches, and is more loaded down with trivial details than dripping liquid oxidizer in the operation; The by-product monoammonium sulfate increases the salts contg of waste water.
Summary of the invention
The object of the present invention is to provide a kind of new preparation process of 5-iodo-2-tolimidazole, by changing reaction conditions so that this technique have raw materials cost consume low, reduce waste kind and quantity, easy and simple to handle, be easy to suitability for industrialized production, product purity high.
Further purpose of the present invention is to provide a kind of purification process of 5-iodo-2-tolimidazole.
In order to realize technical purpose of the present invention, technical scheme of the present invention is:
A kind of synthetic method suc as formula the 5-iodo-2-tolimidazole shown in the D, it is characterized in that: take the o-Nitraniline shown in the formula A as main raw material, in solvent, in the presence of sulfuric acid, take iodine as propiodal, hydrogen peroxide is oxygenant, temperature of reaction is carried out iodination reaction and is generated suc as formula the 4-iodo-2-N-methyl-p-nitroaniline shown in the B, filtration, drying at 0-60 ℃; In solvent, make catalyzer with Raney's nickel, temperature of reaction 0-60 ℃, carry out the hydro-reduction reaction and generate suc as formula the 4-iodo-1 shown in the C, 2-phenylenediamine, filter, add a small amount of Glacial acetic acid, drip ortho-acetic acid front three (second) ester, temperature of reaction 0-60 ℃, carry out ring closure reaction, again through precipitation, decolouring, crystallization, washing, the dry product that obtains.
Chemical equation of the present invention is as follows:
The concrete steps of described method comprise:
(1) vitriol oil is added dropwise in the solvent, adds suc as formula the o-Nitraniline shown in the A, stirring and dissolving, add again iodine, stirring and dissolving, temperature control drips hydrogen peroxide, drips to finish rear insulation reaction 2-12 hour, add the entry dilution, cooling is filtered, with 5% S-WAT or sodium thiosulfate solution washing, drying obtains suc as formula the 4-iodo-2-N-methyl-p-nitroaniline shown in the B.
Described solvent is the solvent mixture of methyl alcohol or ethanol and water, and weight ratio is 1.5 ~ 6.0.
Described solvent can recovery in next batch.
The described vitriol oil, iodine, hydrogen peroxide and be respectively 0.1 ~ 3.0,0.5 ~ 0.6,0.2 ~ 5.0 suc as formula the mol ratio of the o-Nitraniline shown in the A.
Add the water yield, washing when described solvent, aftertreatment and be respectively 2.5 ~ 10.0,1.0 ~ 10.0,0.5 ~ 5.0 with 5% S-WAT or sodium thiosulfate solution and suc as formula the weight ratio of the o-Nitraniline shown in the A.
Can again add S-WAT or Sulfothiorine after described S-WAT or sodium thiosulfate solution are used for washing for next batch, reuse 4 ~ 8 times.
The insulation reaction temperature was 0-60 ℃ after described dropping hydrogen peroxide and dropping finished.
(2) will be suspended in the solvent suc as formula the 4-iodo-2-N-methyl-p-nitroaniline shown in the B, add Raney's nickel, extract air, add under the hydrogen certain pressure temperature control reaction 2 ~ 12 hours, filter after reaction finishes, must be suc as formula the 4-iodo-1 shown in the C, the solution of 2-phenylenediamine;
(3) add a small amount of Glacial acetic acid, temperature control drips the mixed solution of ortho-acetic acid three esters and solvent, dropwises insulation reaction 0.5 ~ 5 hour, after reaction finishes, and must be suc as formula the 5-iodo-2-tolimidazole shown in the D.
A kind of purification process for preparing suc as formula the 5-iodo-2-tolimidazole method shown in the D, the decompression desolvation adds aqueous acetic acid, rising temperature for dissolving, add activated carbon decolorizing, filter, cooling drips 30% aqueous sodium hydroxide solution and regulates the pH value greater than 11, solid is separated out, wash with water, drying must be suc as formula the 5-iodo-2-tolimidazole sterling shown in the D.
Described solvent is methyl alcohol or ethanol.
Described solvent can recovery in next batch.
Described ortho-acetic acid three esters are trimethyl orthoacetate or triethly orthoacetate.
Described hydrogen pressure is 0.01 ~ 0.3MPa.
Glacial acetic acid in the described ring closure reaction, ortho-acetic acid three esters are respectively 0.5% ~ 5.0%, 1.0 ~ 3.0 with mol ratio suc as formula the 4-iodo-2-N-methyl-p-nitroaniline shown in the B.
The solvent of described dilution ortho-acetic acid three esters is methyl alcohol or ethanol, with the weight ratio of ortho-acetic acid three esters be 0 ~ 1.0.
Described decolouring aqueous acetic acid is the mixed solution of Glacial acetic acid and water, and weight ratio is 0.1 ~ 0.5.
Described reaction is respectively 5.0 ~ 10.0,2.0% ~ 30.0%, 4.0 ~ 15.0,0.05 ~ 0.20,3.0 ~ 10.0 with solvent, Raney's nickel, aqueous acetic acid, gac, bath water and suc as formula the weight ratio of the 4-iodo-2-N-methyl-p-nitroaniline shown in the B.
Beneficial effect:
(1) iodination reagent adopts iodine/hydrogen peroxide/sulfuric acid system, and is more green, Atom economy good, do not waste more expensive propiodal, and is easy and simple to handle, adopt single organic solvent, can recovery, waste is few.
(2) one step of reduction adopts single organic solvent, does not use acetic acid, goes back original reagent and adopts that price is relatively cheap, consumption is few, reclaim the little Raney's nickel of loss in this reaction system, and easy and simple to handle, waste is few.
(3) product decolouring, purifying mode are simply efficient, outward appearance rice white powdery solid, and purity is greater than 99.5%.
Description of drawings
Fig. 1 is the HPLC collection of illustrative plates of intermediate 4-iodo-2-N-methyl-p-nitroaniline.
Fig. 2 is intermediate 4-iodo-1, the HPLC collection of illustrative plates of 2-phenylenediamine after reaction finishes.
Fig. 3 is the HPLC collection of illustrative plates of product 5-iodo-2-tolimidazole.
Fig. 4 is intermediate 4-iodo-2-N-methyl-p-nitroaniline
1H-NMR.
Fig. 5 is intermediate 4-iodo-1, the 2-phenylenediamine
1H-NMR.
Fig. 6 is product 5-iodo-2-tolimidazole
1H-NMR.
Embodiment
Below in conjunction with specific examples technical scheme of the present invention is described further, but does not limit the present invention.
Of the present invention to intermediate 4-iodo-2-N-methyl-p-nitroaniline, 4-iodo-1,2-phenylenediamine and be the HPLC method to the detection method of product 5-iodo-2-tolimidazole, its concrete testing conditions is as follows:
Method one:
Plant and instrument HPLC
Moving phase/flow velocity 0.02M NaH
2PO
4(pH 3.0) damping fluid: acetonitrile=40:60/0.8mL/min
Chromatographic column/column temperature Inertsil ODS-3,250mm * 4.6 μ m * 5 μ m/40 ℃
Wavelength 240nm
Method two:
Plant and instrument HPLC
Moving phase/flow velocity 0.05M NaH
2PO
4(pH 3.0) damping fluid: acetonitrile=40:60/0.8mL/min
Chromatographic column/column temperature Kromasil 100-5C18,250 * 4.6mm * 5 μ m/40 ℃
Wavelength 240nm
Iodination reaction: in 3L four-hole reaction flask, add 720g methyl alcohol and 180g water, be added dropwise to the 163g vitriol oil, drip to finish and drop into the 150g o-Nitraniline, drop into again 138g iodine, stirring and dissolving after the stirring and dissolving, temperature control drips 615g 30% hydrogen peroxide in 35 ℃, drip Bi Jixu and stirred 5 hours at 35 ℃, add 633 gram water after reaction finishes, be cooled to 5 ℃, suction filtration, solid washs with 75g 5% sodium thiosulfate solution, and 60 ℃ of vacuum-dryings get 275.3 grams suc as formula the 4-iodo-2-N-methyl-p-nitroaniline shown in the B, as shown in Figure 1, the reddish-brown crystal, yield 96.0%, HPLC purity 99.4%.
1H-NMR(such as Fig. 4, CDCl
3, 500MHz, δ 5.4 (s, br, 2H), 6.6 (d, J=8.5Hz, 1H), 7.6 (dd, J=8.5Hz, 2.0Hz, 1H), 8.4 (d, J=2.0Hz, 1H)).
Reduction reaction: in the 500mL forcer, add 150g methyl alcohol, 30g 4-iodo-2-N-methyl-p-nitroaniline and 0.6g Raney's nickel, extract air, displacement enters hydrogen to pressure to 0.15MPa, slowly intensification and control temperature of reaction are at 60 ℃, and insulation reaction 8 hours is after reaction finishes, be cooled to 10 ℃, displacement enters nitrogen, filters, must be suc as formula the 4-iodo-1 shown in the C, the methanol solution of 2-phenylenediamine, as shown in Figure 2.
Ring closure reaction: in above-mentioned 4-iodo-1, add the 0.34g Glacial acetic acid in the methanol solution of 2-phenylenediamine, 0 ℃ of solution that slowly drips 35g triethly orthoacetate and 17.5g methyl alcohol of temperature control, dripped complete insulation reaction 4 hours, desolvation after reaction finishes adds 300g 23% aqueous acetic acid, be warming up to 50 ℃ of dissolvings, add the 3.6g gac, insulated and stirred 2 hours is filtered, filtrate is cooled to 30 ℃, drip 30% sodium hydroxide and regulate pH extremely 11, be cooled to 10 ℃, filter, solid 150g water washing, 70 ℃ of vacuum-dryings get 22.3g suc as formula the 5-iodo-2-tolimidazole shown in the D, as shown in Figure 3, the rice white powdery solid, two-step reaction yield 76.0%, HPLC purity 99.8%, moisture 0.07%.
1H-NMR(such as Fig. 6, DMSO-d
6, 500MHz, δ 2.5 (s, 3H), 7.3 (d, J=8.5Hz, 1H), 7.4 (dd, J=8.5Hz, 1.5Hz, 1H), 7.8 (d, J=1.5Hz, 1H), 12.3 (s, 1H)).
Iodination reaction: in 3L four-hole reaction flask, add 900g methyl alcohol and 600g water, be added dropwise to the 326g vitriol oil, drip to finish and drop into the 150g o-Nitraniline, drop into again 165g iodine after the stirring and dissolving, stirring and dissolving, temperature control drips Bi Jixu and stirred 12 hours at 0 ℃ in 0 ℃ of dropping 25g 30% hydrogen peroxide, after finishing, reaction adds 633 gram water, suction filtration, solid washs with 750g 5% sodium sulfite aqueous solution, 60 ℃ of vacuum-dryings, get 271.0g suc as formula the 4-iodo-2-N-methyl-p-nitroaniline shown in the B, the reddish-brown crystal, yield 94.5%, HPLC purity 99.2%.
Reduction reaction: in the 500mL forcer, add 300g methyl alcohol, 30g 4-iodo-2-N-methyl-p-nitroaniline and 4.5g Raney's nickel, extract air, displacement enters hydrogen to pressure to 0.01MPa, the control temperature of reaction is at 35 ℃, insulation reaction 8 hours, reaction is cooled to 10 ℃ after finishing, displacement enters nitrogen, filter, must be suc as formula the 4-iodo-1 shown in the C, the methanol solution of 2-phenylenediamine.
Ring closure reaction: in above-mentioned 4-iodo-1, add the 0.04g Glacial acetic acid in the methanol solution of 2-phenylenediamine, 35 ℃ of solution that slowly drip 41g trimethyl orthoacetate and 20.5g methyl alcohol of temperature control, dripped complete insulation reaction 2 hours, desolvation after reaction finishes adds 450g 9.1% aqueous acetic acid, is warming up to 50 ℃ of dissolvings, add the 6g gac, insulated and stirred 2 hours is filtered, and filtrate is cooled to 30 ℃, drip 30% sodium hydroxide and regulate pH extremely 11, be cooled to 10 ℃, filter solid 150g water washing, 70 ℃ of vacuum-dryings, get 22.8g suc as formula the 5-iodo-2-tolimidazole shown in the D, rice white powdery solid, two-step reaction yield 77.8%, HPLC purity 99.8%, moisture 0.08%.
Iodination reaction: in 2L four-hole reaction flask, add 321g ethanol and 54g water, be added dropwise to the 11g vitriol oil, drip to finish and drop into the 150g o-Nitraniline, drop into again 152g iodine after the stirring and dissolving, stirring and dissolving, temperature control drips 250g 30% hydrogen peroxide in 60 ℃, dripping Bi Jixu stirred 3 hours at 60 ℃, add 633 gram water after reaction finishes, be cooled to 5 ℃, suction filtration, solid washs with the 375g5% sodium sulfite aqueous solution, 60 ℃ of vacuum-dryings get 272.4g suc as formula the 4-iodo-2-N-methyl-p-nitroaniline shown in the B, reddish-brown crystal, yield 95.0%, HPLC purity 99.2%.
Reduction reaction: in the 500mL forcer, add 240g ethanol, 30g 4-iodo-2-N-methyl-p-nitroaniline and 9g Raney's nickel, extract air, displacement enters hydrogen to pressure to 0.3MPa, and the control temperature of reaction is at 0 ℃, insulation reaction 12 hours, after reaction finished, displacement entered nitrogen, filtered, must be suc as formula the 4-iodo-1 shown in the C, the methanol solution of 2-phenylenediamine.
Ring closure reaction: in above-mentioned 4-iodo-1, add the 0.15g Glacial acetic acid in the methanol solution of 2-phenylenediamine, 60 ℃ of solution that slowly drip 20g triethly orthoacetate and 10g ethanol of temperature control, dripped complete insulation reaction 0.5 hour, desolvation after reaction finishes adds 120g 33% aqueous acetic acid, is warming up to 50 ℃ of dissolvings, add the 1.5g gac, insulated and stirred 2 hours is filtered, and filtrate is cooled to 30 ℃, drip 30% sodium hydroxide and regulate pH extremely 11, be cooled to 10 ℃, filter solid 150g water washing, 70 ℃ of vacuum-dryings, get 21.2g suc as formula the 5-iodo-2-tolimidazole shown in the D, rice white powdery solid, two-step reaction yield 72.3%, HPLC purity 99.8%, moisture 0.06%.
Claims (10)
1. synthetic method suc as formula the 5-iodo-2-tolimidazole shown in the D, its step is as follows:
(1) iodination reaction:
Take the o-Nitraniline shown in the formula A as raw material, in solvent, add sulfuric acid, take iodine as propiodal, hydrogen peroxide is oxygenant, temperature of reaction is carried out iodination reaction and is generated suc as formula the 4-iodo-2-N-methyl-p-nitroaniline shown in the B at 0-60 ℃;
(2) hydro-reduction reaction:
In solvent, make catalyzer with Raney's nickel, temperature of reaction 0-60 ℃, carry out the hydro-reduction reaction and generate suc as formula the 4-iodo-1 shown in the C, 2-phenylenediamine;
(3) annulation:
Add Glacial acetic acid, and add trimethyl orthoacetate or triethly orthoacetate, temperature of reaction 0-60 ℃, carry out annulation, obtain suc as formula the 5-iodo-2-tolimidazole shown in the D.
2. synthetic method according to claim 1 is characterized in that: the concrete steps of described method comprise,
(1) iodination reaction:
The vitriol oil is added in the solvent, add suc as formula the o-Nitraniline shown in the A, stirring and dissolving adds iodine again, stirring and dissolving, and temperature control drips hydrogen peroxide, drips to finish rear insulation reaction 2-12 hour, obtains suc as formula the 4-iodo-2-N-methyl-p-nitroaniline shown in the B;
(2) hydro-reduction reaction:
To be suspended in the solvent suc as formula the 4-iodo-2-N-methyl-p-nitroaniline shown in the B, add Raney's nickel, extract air, add under the hydrogen certain pressure temperature control reaction 2 ~ 12 hours, filter after reaction finishes, must be suc as formula the 4-iodo-1 shown in the C, the solution of 2-phenylenediamine;
(3) annulation:
Add Glacial acetic acid, temperature control adds the mixed solution of trimethyl orthoacetate or triethly orthoacetate and solvent, dropwises insulation reaction 0.5 ~ 5 hour, and reaction must be suc as formula the 5-iodo-2-tolimidazole shown in the D after finishing.
3. synthetic method according to claim 1 and 2 is characterized in that: described step (1) iodination reaction, and aftertreatment is for adding the entry dilution, cooling is filtered, with 5% S-WAT or sodium thiosulfate solution washing, drying obtains suc as formula the 4-iodo-2-N-methyl-p-nitroaniline shown in the B.
4. synthetic method according to claim 1 and 2, it is characterized in that: described step (2) hydro-reduction reaction, solvent, Raney's nickel, aqueous acetic acid, gac, bath water and be respectively 5.0 ~ 10.0,2.0% ~ 30.0%, 4.0 ~ 15.0,0.05 ~ 0.20,3.0 ~ 10.0 suc as formula the weight ratio of the 4-iodo-2-N-methyl-p-nitroaniline shown in the B.
5. synthetic method according to claim 1 and 2, it is characterized in that: described step (3) annulation, the solvent of dilution trimethyl orthoacetate or triethly orthoacetate is methyl alcohol or ethanol, with the weight ratio of trimethyl orthoacetate or triethly orthoacetate be 0 ~ 1.0.
6. synthetic method according to claim 1 and 2 is characterized in that: described step (1) iodination reaction, and solvent is the solvent mixture of methyl alcohol or ethanol and water, weight ratio is 1.5 ~ 6.0;
Described sulfuric acid, iodine, hydrogen peroxide and be respectively 0.1 ~ 3.0,0.5 ~ 0.6,0.2 ~ 5.0 suc as formula the mol ratio of the o-Nitraniline shown in the A;
Temperature is 0-60 ℃ when adding hydrogen peroxide.
7. synthetic method according to claim 1 and 2 is characterized in that: the reaction of described step (2) hydro-reduction, and solvent is methyl alcohol or ethanol, and weight ratio is 5.0 ~ 10.0, and hydrogen pressure is 0.01 ~ 0.3MPa.
8. synthetic method according to claim 1 and 2, it is characterized in that: described step (3) annulation, Glacial acetic acid, trimethyl orthoacetate or triethly orthoacetate and be respectively 0.5% ~ 5.0%, 1.0 ~ 3.0 suc as formula the mol ratio of the 4-iodo-2-N-methyl-p-nitroaniline shown in the B.
One kind with any one preparation of claim 1 to 8 suc as formula the purification process of the 5-iodo-2-tolimidazole method shown in the D, it is characterized in that: the method for described purifying 5-iodo-2-tolimidazole adds aqueous acetic acid, rising temperature for dissolving for the decompression desolvation, add activated carbon decolorizing, filter, cooling drips 30% aqueous sodium hydroxide solution and regulates the pH value between 11 and 14, solid is separated out, wash with water, drying obtains suc as formula the 5-iodo-2-tolimidazole shown in the D.
10. purification process according to claim 8, it is characterized in that: described is the mixed solution of Glacial acetic acid and water with aqueous acetic acid, and weight ratio is 0.1 ~ 0.5; Described reaction is respectively 5.0 ~ 10.0,2.0% ~ 30.0%, 4.0 ~ 15.0,0.05 ~ 0.20,3.0 ~ 10.0 with solvent, Raney's nickel, aqueous acetic acid, gac, bath water and suc as formula the weight ratio of the 4-iodo-2-N-methyl-p-nitroaniline shown in the B.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012104169236A CN102936223A (en) | 2012-11-02 | 2012-11-02 | Synthesis method and purification method of 5-iodo-2-methylbenzimidazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012104169236A CN102936223A (en) | 2012-11-02 | 2012-11-02 | Synthesis method and purification method of 5-iodo-2-methylbenzimidazole |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102936223A true CN102936223A (en) | 2013-02-20 |
Family
ID=47695157
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012104169236A Pending CN102936223A (en) | 2012-11-02 | 2012-11-02 | Synthesis method and purification method of 5-iodo-2-methylbenzimidazole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102936223A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103724276A (en) * | 2013-12-13 | 2014-04-16 | 成都丽璟科技有限公司 | Novel method for preparing benzimidazole compounds from nitroaniline |
| CN104447356A (en) * | 2014-11-11 | 2015-03-25 | 常州大学 | Synthesis method of 3-fluoro-N-dimethyl o-phenylenediamine |
| CN115232074A (en) * | 2022-08-22 | 2022-10-25 | 湖南复瑞生物医药技术有限责任公司 | Synthesis method of 1-alkyl substituted-2-methyl-5-bromobenzimidazole |
| CN117050011A (en) * | 2023-10-11 | 2023-11-14 | 湖南工程学院 | Method for synthesizing 2-methylquinoline by using vinyl acetate as raw material |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1379764A (en) * | 1999-10-15 | 2002-11-13 | 弗·哈夫曼-拉罗切有限公司 | Benzodiazepine derivatives |
| EP0647137B1 (en) * | 1992-06-22 | 2008-08-13 | The Regents Of The University Of California | Glycine receptor antagonists and the use thereof |
| TW201202222A (en) * | 2010-05-28 | 2012-01-16 | Presidio Pharmaceuticals Inc | Inhibitors of HCV NS5A |
-
2012
- 2012-11-02 CN CN2012104169236A patent/CN102936223A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0647137B1 (en) * | 1992-06-22 | 2008-08-13 | The Regents Of The University Of California | Glycine receptor antagonists and the use thereof |
| CN1379764A (en) * | 1999-10-15 | 2002-11-13 | 弗·哈夫曼-拉罗切有限公司 | Benzodiazepine derivatives |
| TW201202222A (en) * | 2010-05-28 | 2012-01-16 | Presidio Pharmaceuticals Inc | Inhibitors of HCV NS5A |
Non-Patent Citations (7)
| Title |
|---|
| B. N. FEITELS: "Some Benximinaxole Derivatives", 《JOURNAL OF THE CHEMICAL SOCIETY》, 1 January 1952 (1952-01-01), pages 2389 - 2398 * |
| CECILIO áLVAREZ-TOLEDANO: "Unusual nucleophilic versus electrophilic aromatic substitution on nitroanilines", 《JOURNAL OF MOLECULAR CATALYSIS A: CHEMICAL》, vol. 164, 9 June 2000 (2000-06-09), pages 85 - 89 * |
| EMILY J. HANAN: "Mild and General One-Pot Reduction and Cyclization of Aromatic and Heteroaromatic 2-Nitroamines to Bicyclic 2H-Imidazoles", 《SYNLETT》, no. 18, 14 October 2010 (2010-10-14), pages 2759 - 2764 * |
| J. GERALD WILSON AND FREDERICK C. HUNT: "Iminodiacetic Acid Derivatives of Benzimidazole. Synthesis of N-(Benzimidazol-2-ylmethy1)iminodiacetic Acids", 《AUST. J. CHEM.》, 31 December 1983 (1983-12-31), pages 2317 - 2325 * |
| K. SURESH KUMAR REDDY: "Iodination of Aromatic Compounds Using Potassium Iodide and Hydrogen Peroxide", 《SYNTHETIC COMMUNICATIONS》, vol. 38, no. 22, 15 November 2008 (2008-11-15), pages 3894 - 3902 * |
| SUBHASH B. JUNNE: "Microwave Assisted Iodination of Aromatic Amines by Using Iodineand Iodic Acid Combination as a Iodinating agent", 《INTERNATIONAL JOURNAL OF CHEMTECH RESEARCH》, vol. 1, no. 4, 31 December 2009 (2009-12-31), pages 1005 - 1007 * |
| 李琴: "5-碘-2-甲基苯并咪唑的合成和", 《现代化工》, vol. 31, 30 June 2011 (2011-06-30), pages 257 - 258 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103724276A (en) * | 2013-12-13 | 2014-04-16 | 成都丽璟科技有限公司 | Novel method for preparing benzimidazole compounds from nitroaniline |
| CN104447356A (en) * | 2014-11-11 | 2015-03-25 | 常州大学 | Synthesis method of 3-fluoro-N-dimethyl o-phenylenediamine |
| CN104447356B (en) * | 2014-11-11 | 2016-07-06 | 常州大学 | A kind of synthetic method of the fluoro-N-dimethyl o-phenylenediamine of 3- |
| CN115232074A (en) * | 2022-08-22 | 2022-10-25 | 湖南复瑞生物医药技术有限责任公司 | Synthesis method of 1-alkyl substituted-2-methyl-5-bromobenzimidazole |
| CN117050011A (en) * | 2023-10-11 | 2023-11-14 | 湖南工程学院 | Method for synthesizing 2-methylquinoline by using vinyl acetate as raw material |
| CN117050011B (en) * | 2023-10-11 | 2024-01-23 | 湖南工程学院 | Method for synthesizing 2-methylquinoline by using vinyl acetate as raw material |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103524440A (en) | Preparation method of gout curative medicine Lesinurad and midbody of Lesinurad | |
| CN106279074A (en) | A kind of compound and preparation method thereof and the purposes in synthesis Bu Waxitan | |
| CN103965181A (en) | Preparation method of flumioxazin | |
| CN102936223A (en) | Synthesis method and purification method of 5-iodo-2-methylbenzimidazole | |
| CN103319414A (en) | Improved telmisartan preparation process | |
| CN102311424A (en) | Method for synthesizing chlorantraniliprole key intermediate | |
| CN103896855A (en) | Method for synthesizing 4-(1-bromoethyl) -5-fluoro-6-chloropyrimidine | |
| CN105294583A (en) | Synthesizing method of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid | |
| CN103204801A (en) | Synthesis method for N-Boc-3-piperidone | |
| CN102491974A (en) | Method for synthesizing 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-formamidine hydrochloride | |
| CN102558069B (en) | Method for preparing intermediate in process of preparing bendamustine hydrochloride | |
| CN102304090A (en) | Method for preparing 5-substituted thiophenyl-benzimidazol-2-N-methoxycarbonyl compound | |
| CN103626697B (en) | A kind of preparation method of the cyanopyridine of 2 chlorine, 4 trifluoromethyl 3 | |
| CN102351790A (en) | Method for synthesizing 7-bromo-6-chloro-4-quinazolinone | |
| CN103880745A (en) | Chemical synthesis method of 6-bromo-1,2,3,4-tetrahydroisoquinolyl-1-formic acid | |
| CN104649966A (en) | Method for synthesizing organic intermediate 5-cyano-3-methylpyridine formic acid | |
| CN101696185B (en) | Synthesizing method of 6-nitro-S-(-)-indoline-2-carboxylic acid | |
| CN104610267A (en) | Method for efficiently synthetizing 6-alkylpyrazol-[1,5-c]-quinazoline skeleton compounds under no catalytic condition | |
| CN104974057A (en) | Preparation method and important intermediate of bromfenac sodium | |
| CN102827080B (en) | Novel synthetic method of ivabradine and novel intermediate product of ivabradine | |
| CN102391254A (en) | Preparation method of Candesartan | |
| CN103880730A (en) | Chemical synthesis method of 7-nitroindole-3-tert butyl formate | |
| CN106083631B (en) | A kind of preparation method of equal amido phenenyl acid | |
| CN102408353A (en) | Preparation method of candesartan intermediate | |
| CN102516123A (en) | Method for preparing candesartan intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20130220 |