CN103193713A - Method for preparing 2-propylimidazole-4,5-dicarboxylic acid - Google Patents
Method for preparing 2-propylimidazole-4,5-dicarboxylic acid Download PDFInfo
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- CN103193713A CN103193713A CN2013101218822A CN201310121882A CN103193713A CN 103193713 A CN103193713 A CN 103193713A CN 2013101218822 A CN2013101218822 A CN 2013101218822A CN 201310121882 A CN201310121882 A CN 201310121882A CN 103193713 A CN103193713 A CN 103193713A
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- CN
- China
- Prior art keywords
- dicarboxylic acid
- preparation
- propyl imidazole
- general structure
- compound
- 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.)
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- 238000000034 method Methods 0.000 title claims abstract description 18
- BGPZYJSOTDBJMV-UHFFFAOYSA-N 2-propyl-1h-imidazole-4,5-dicarboxylic acid Chemical compound CCCC1=NC(C(O)=O)=C(C(O)=O)N1 BGPZYJSOTDBJMV-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 239000000203 mixture Substances 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 5
- 230000035484 reaction time Effects 0.000 claims abstract description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 14
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 239000001117 sulphuric acid Substances 0.000 claims description 4
- 235000011149 sulphuric acid Nutrition 0.000 claims description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 150000003016 phosphoric acids Chemical class 0.000 claims description 2
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 2
- -1 vitriol Chemical compound 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract 1
- 238000001816 cooling Methods 0.000 description 12
- 206010013786 Dry skin Diseases 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- DPZSNGJNFHWQDC-ARJAWSKDSA-N (z)-2,3-diaminobut-2-enedinitrile Chemical compound N#CC(/N)=C(/N)C#N DPZSNGJNFHWQDC-ARJAWSKDSA-N 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- NYXKVDPOWQTTNC-UHFFFAOYSA-N 2,4-dimethyl-1h-benzimidazole Chemical compound C1=CC=C2NC(C)=NC2=C1C NYXKVDPOWQTTNC-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 239000005480 Olmesartan Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 1
- 229960005117 olmesartan Drugs 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing 2-propylimidazole-4,5-dicarboxylic acid. The method comprises the following steps of: carrying out oxidization and open loop on a compound shown by the structural general formula (A) or a salt thereof as a raw material in an acidic environment to obtain a compound shown by the structural general formula (B), wherein the reaction temperature is controlled in the range from 50 DEG C to 170 DEG C, and the reaction time is controlled for 10-16 hours; and separating to obtain a target compound of 2-propylimidazole-4,5-dicarboxylic acid. By using the technical scheme provided by the invention, a corresponding mixture is obtained by direct reaction, the mixture is directly subjected to an oxidation reaction without separation to obtain a needed target product, thus the cost of producing the target product is reduced; and by using the technical scheme provided by the invention, the yield of the 2-propylimidazole-4,5-dicarboxylic acid is improved by 20%, and the purity is improved by 10%.
Description
Technical field
The present invention relates to the medicine intermediate field, specifically relate to a kind of method of preparation 2-propyl imidazole-4,5 dicarboxylic acid.
Background technology
2-alkyl imidazole-4,5-dicarboxylic acid are a kind of important pharmaceutical intermediates, and particularly 2-propyl imidazole-4,5 dicarboxylic acid wherein is the intermediate of antihypertensive drug Olmesartan of new generation.Many documents and patent have disclosed 2-alkyl imidazole-4, the preparation method of 5-dicarboxylic acid, as Chinese patent: CN106563A with extensively offer: journal of medicalchemistry, 1996, No1,323-33 has reported 2-propyl imidazole-4, the preparation method of 5-dicarboxylic acid, described method is with Diaminomaleonitrile and former butyric acid three esters (trimethyl or triethyl), make 2-propyl group-4, the 5-dicyano imidazole, make 2-propyl imidazole-4 with hydrochloric acid hydrolysis again, the 5-dicarboxylic acid, expensive raw material Diaminomaleonitrile and former butyric acid front three/ethyl ester have all been used in related extensively offering with patent, Diaminomaleonitrile then is to prepare the raw material sources difficulty with hypertoxic prussiate.Make present production method be subjected to certain limitation, industrial application is restricted.
Other has bibliographical information to use the 2-alkyl benzimidazole to be raw material production 2-alkyl imidazole-4, the 5-dicarboxylic acid, and this method is than using Diaminomaleonitrile and former butyric acid front three/ethyl ester cost that bigger improvement is arranged, but still higher, products obtained therefrom content is on the low side,
Summary of the invention
At the deficiencies in the prior art, the invention provides a kind of is starting raw material with 2-alkyl-4-tolimidazole and 2-alkyl-5-tolimidazole mixture, under acidic conditions, uses oxygenant to be oxidized to 2-alkyl imidazole-4, the preparation method of 5-dicarboxylic acid.
For achieving the above object, the invention provides following technical scheme:
A kind of preparation 2-propyl imidazole-4, the method of 5 dicarboxylic acid, be raw material with the compound or its salt shown in the general structure (A), in sour environment, the control temperature of reaction is in 50～170 ℃ of scopes, and the control reaction times obtained the compound shown in the general structure (B) at 10～16 hours with oxygenant oxidation open loop, separate and obtain target compound 2-alkyl imidazole 4,5-dicarboxylic acid;
Wherein, described general structure (A) is the mixture of compound or its salt I and II;
Described I, its general structure is:
Described II, its general structure is:
Described R1 is: the alkyl of 1～4 carbon atom;
The salt of compound is shown in the described general structure (A): a kind of in hydrochloride, vitriol, nitrate, phosphoric acid salt, phosphite or the hydrobromate;
The blending ratio of described I and II is any ratio of the two;
Described I is preferably: 2-alkyl-4-tolimidazole;
Described II is preferably: 2-alkyl-5-tolimidazole;
Described oxygenant is: the zeroth order hydrogen peroxide;
According to molar ratio computing, described oxygenant consumption is 1～10 times of raw material consumption;
Described sour environment is: concentration is 98% sulphuric acid soln;
By mass ratio, the amount ratio of sulphuric acid soln and raw material is 10～30 ﹕ 1.
Adopting technical scheme provided by the invention, is raw material with the mixture described in the aforesaid general structure, and direct reaction obtains corresponding mixture, and this mixture need not to separate equally, directly carries out oxidizing reaction, obtains required target product.Simultaneously, described I and II all contain a sub-methyl of power supply in its general formula, the oxidation of phenyl ring is easier to be carried out, reaction conditions has further reduced the cost of productive target product than using on the phenyl ring the not 2-alkyl benzimidazole milder of methylic available technology adopting; Adopt technical scheme provided by the invention, its yield improves 20%, and purity improves 10%.
Embodiment
Below by specific embodiment, the present invention is explained in detail:
Embodiment 1
10g2-propyl group-3-tolimidazole and 2-propyl group-4-tolimidazole (mass ratio 1:1) mixture are dissolved in the sulfuric acid of 200g98%, and cooling adds the 200g30% hydrogen peroxide down, finish, 120 ℃ of reactions of temperature control 12 hours after reacting completely, add the 1000g frozen water, crystallization is placed in cooling, filter, 80 ℃ of dryings obtain 6.5g2-propyl imidazole-4, the 5-dicarboxylic acid, content 97.2%.
Embodiment 2
10g2-propyl group-3-tolimidazole and 2-propyl group-4-tolimidazole (mass ratio 2:3) mixture are dissolved in the sulfuric acid of 200g98%, and cooling adds the 200g30% hydrogen peroxide down, finish, 120 ℃ of reactions of temperature control 12 hours after reacting completely, add the 1000g frozen water, crystallization is placed in cooling, filter, 80 ℃ of dryings obtain 6.7g2-propyl imidazole-4, the 5-dicarboxylic acid, content 97.3%.
By embodiment 1 and embodiment 2 as can be known, though the ratio of the raw material of mixture in two embodiment is inequality, be not influence substantially to the content of target product.Therefore really described I as claimed in claim and the blending ratio of II are any ratio of the two.
Embodiment 3
10g2-ethyl-3-tolimidazole and 2-ethyl-4-tolimidazole (mass ratio 1:1) mixture are dissolved in the sulfuric acid of 200g98%, and cooling adds the 200g30% hydrogen peroxide down, finish, 120 ℃ of reactions of temperature control 12 hours after reacting completely, add the 1000g frozen water, crystallization is placed in cooling, filter, 80 ℃ of dryings obtain 6.4g2-ethyl imidazol(e)-4, the 5-dicarboxylic acid, content 98.0%
Embodiment 4
10g2,3-dimethylbenzimidazole and 2,4-dimethylbenzimidazole (mass ratio 1:1) mixture is dissolved in the sulfuric acid of 200g98%, cooling adds the 200g30% hydrogen peroxide down, finishes, 120 ℃ of reactions of temperature control 12 hours after reacting completely, add the 1000g frozen water, crystallization is placed in cooling, filter, 80 ℃ of dryings obtain 6.2g2-ethyl imidazol(e)-4, the 5-dicarboxylic acid, content 98.0%
Embodiment 5
Adopt the method identical with embodiment 1, oxygenant is used the 150g50% hydrogen peroxide instead, and after the crystallization, 80 ℃ of dryings obtain 6.4g2-propyl imidazole-4,5-dicarboxylic acid, content 97.5%.
Embodiment 6
15.6g2-propyl group-3-tolimidazole and 2-propyl group-4-tolimidazole vitriol (mass ratio 1:1) mixture is dissolved in the sulfuric acid of 200g98%, cooling adds the 200g30% hydrogen peroxide down, finish, 120 ℃ of reactions of temperature control 12 hours after reacting completely, add the 1000g frozen water, crystallization is placed in cooling, filter, 80 ℃ of dryings obtain 6.5g2-propyl imidazole-4, the 5-dicarboxylic acid, content 97.6%.
Comparative example
10g2-propyl group benzoglyoxaline is dissolved in the sulfuric acid of 200g98%, and cooling adds the 200g30% hydrogen peroxide down, finish, 120 ℃ of reactions of temperature control 12 hours after reacting completely, add the 1000g frozen water, crystallization is placed in cooling, filter, 80 ℃ of dryings obtain 4.5g2-propyl imidazole-4, the 5-dicarboxylic acid, content 90.5%.
Claims (9)
1. one kind prepares 2-propyl imidazole-4, the method of 5 dicarboxylic acid, it is characterized in that: be raw material with the compound or its salt shown in the general structure (A), in sour environment, the control temperature of reaction is in 50 ~ 170 ℃ of scopes, and the control reaction times obtained the compound shown in the general structure (B) at 10 ~ 16 hours with oxygenant oxidation open loop, separate and obtain target compound 2-alkyl imidazole 4,5-dicarboxylic acid;
Wherein, described general structure (A) is compound or its salt
With
Mixture;
Described
, its general structure is:
Described R1 is: the alkyl of 1 ~ 4 carbon atom.
2. a kind of preparation 2-propyl imidazole-4 according to claim 1, the method of 5 dicarboxylic acid is characterized in that: the salt of compound is shown in the described general structure (A): a kind of in hydrochloride, vitriol, nitrate, phosphoric acid salt, phosphite or the hydrobromate.
3. the method for a kind of preparation 2-propyl imidazole-4,5 dicarboxylic acid according to claim 1 is characterized in that: the blending ratio of described I and II is any ratio of the two.
4. according to the method for claim 1 or 3 described a kind of preparation 2-propyl imidazole-4,5 dicarboxylic acid, it is characterized in that: described I is preferably: 2-alkyl-4-tolimidazole.
5. according to the method for claim 1 or 3 described a kind of preparation 2-propyl imidazole-4,5 dicarboxylic acid, it is characterized in that: described II is preferably: 2-alkyl-5-tolimidazole.
6. the method for a kind of preparation 2-propyl imidazole-4,5 dicarboxylic acid according to claim 1, it is characterized in that: described oxygenant is: the zeroth order hydrogen peroxide.
7. a kind of method of preparation 2-propyl imidazole-4,5 dicarboxylic acid according to claim 1 or 5, it is characterized in that: according to molar ratio computing, described oxygenant consumption is 1 ~ 10 times of raw material consumption.
8. the method for a kind of preparation 2-propyl imidazole-4,5 dicarboxylic acid according to claim 1, it is characterized in that: described sour environment is: concentration is 98% sulphuric acid soln.
9. the method for a kind of preparation 2-propyl imidazole-4,5 dicarboxylic acid according to claim 7, it is characterized in that: by mass ratio, the amount ratio of sulphuric acid soln and raw material is 10 ~ 30 ﹕ 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013101218822A CN103193713A (en) | 2013-04-09 | 2013-04-09 | Method for preparing 2-propylimidazole-4,5-dicarboxylic acid |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013101218822A CN103193713A (en) | 2013-04-09 | 2013-04-09 | Method for preparing 2-propylimidazole-4,5-dicarboxylic acid |
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| CN103193713A true CN103193713A (en) | 2013-07-10 |
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| CN2013101218822A Pending CN103193713A (en) | 2013-04-09 | 2013-04-09 | Method for preparing 2-propylimidazole-4,5-dicarboxylic acid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104262260A (en) * | 2014-09-10 | 2015-01-07 | 黄冈鲁班药业有限公司 | Preparation method and application high-purity olmesartan medoxomil intermediate 2-propylimidazolyl-4,5-dicarboxylic acid |
| CN111471016B (en) * | 2020-04-17 | 2023-08-15 | 湖南华腾医药有限公司 | Synthesis method of 2-propylimidazole-4, 5-dicarboxylic acid |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4550176A (en) * | 1983-01-20 | 1985-10-29 | Basf Aktiengesellschaft | Preparation of imidazole-4,5-dicarboxylic acid |
| CN1045776A (en) * | 1989-03-22 | 1990-10-03 | 美国氰胺公司 | Make sequential oxidation of substd quinolines become substituted pyridines-2, the method for 3-dicarboxylic acid |
| CN1752077A (en) * | 2005-10-17 | 2006-03-29 | 浙江省医学科学院 | A new preparation method of 2-n-propylimidazole-4,5-dicarboxylic acid |
| CN1830966A (en) * | 2005-03-11 | 2006-09-13 | 常州伊思特化工有限公司 | Method for preparing 2-alkyl imidazole 4,5-dicarboxylic acid |
-
2013
- 2013-04-09 CN CN2013101218822A patent/CN103193713A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4550176A (en) * | 1983-01-20 | 1985-10-29 | Basf Aktiengesellschaft | Preparation of imidazole-4,5-dicarboxylic acid |
| CN1045776A (en) * | 1989-03-22 | 1990-10-03 | 美国氰胺公司 | Make sequential oxidation of substd quinolines become substituted pyridines-2, the method for 3-dicarboxylic acid |
| CN1830966A (en) * | 2005-03-11 | 2006-09-13 | 常州伊思特化工有限公司 | Method for preparing 2-alkyl imidazole 4,5-dicarboxylic acid |
| CN1752077A (en) * | 2005-10-17 | 2006-03-29 | 浙江省医学科学院 | A new preparation method of 2-n-propylimidazole-4,5-dicarboxylic acid |
Non-Patent Citations (1)
| Title |
|---|
| ZHAN ZHOU,等: "Luminescent terbium(III) complex-based titania sensing material for fluoride and its photocatalytic properties", 《PHOTOCHEMICAL & PHOTOBIOLOGICAL SCIENCES》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104262260A (en) * | 2014-09-10 | 2015-01-07 | 黄冈鲁班药业有限公司 | Preparation method and application high-purity olmesartan medoxomil intermediate 2-propylimidazolyl-4,5-dicarboxylic acid |
| CN111471016B (en) * | 2020-04-17 | 2023-08-15 | 湖南华腾医药有限公司 | Synthesis method of 2-propylimidazole-4, 5-dicarboxylic acid |
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Application publication date: 20130710 |