CN102775354A - Process method for synthesizing 4-aryl-5-carboxylic acid imidazole and ester thereof - Google Patents
Process method for synthesizing 4-aryl-5-carboxylic acid imidazole and ester thereof Download PDFInfo
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- CN102775354A CN102775354A CN2011101201907A CN201110120190A CN102775354A CN 102775354 A CN102775354 A CN 102775354A CN 2011101201907 A CN2011101201907 A CN 2011101201907A CN 201110120190 A CN201110120190 A CN 201110120190A CN 102775354 A CN102775354 A CN 102775354A
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Abstract
The invention discloses a preparation method for 4-aryl-5-carboxylic acid imidazole shown as formula 3. The method comprises the following step of performing a ring-closing reaction on a compound 2 and methanamide in methanoic acid or a methanoic acid-water solution, wherein R represents C6-C10 aryls or C1-C6 heterocyclic aryls, with hetero-atoms being N, O or S; R' represents C1-C5 alkyls; a temperature of the ring-closing reaction is 100 DEG C-140 DEG C; a molar quantity of the methanamide is more than that of the compound 2; the weight of the methanamide is 1-5 times that of the compound 2; a mass concentration of the methanoic acid-water solution is 85%-98%; and the weight of the methanoic acid-water solution is 1-5 times that of the compound 2.
Description
Technical field
The process method that relates to a kind of synthetic 4-aryl-5-carboxylic acid imidazoles and ester thereof that the present invention is concrete.
Background technology
Imidazoles is all very important in biochemical and medicineization, and for example Histidine is one of amino acid of needed by human, and its deacidified product-I4EA has bringing high blood pressure down, shrink effect such as uterus, is applied to pharmaceutically.Histidine, I4EA all are glyoxaline compounds.And for example treat hyperthyroid Thycapsol, the Xin Maika azoles, antifungal drug clotrimazole etc. all is an imdazole derivatives.
4-aryl-5-carboxylic acid imidazoles and ester thereof are not only a kind of useful synthetic intermediate as one type of important imidazolium compounds, and have higher using value in fields such as medicine, agricultural chemicals.For example (US2003/100576 has obtained widespread use in US2005/14765) to 4-phenyl-5-carboxylic acid imidazoles at king's evil suddenly, Lymphocytic leukemia, the exploitation of carcinoma of testis kind new medicine at present.In recent years, the ester derivative of 4-aryl-5-carboxylic acid imidazoles is in the research and the application Sino-Japan apparent active (US2008/45542) in new drug development field.The methodology of organic synthesis research of 4-aryl-5-carboxylic acid imidazoles is significant for the new pharmaceutical research and development.
The report of the compound method of existing 4-aryl-5-carboxylic acid imidazoles and ester thereof is following:
Benzoylacetic acid ester is in butyl ether, ether equal solvent, and logical nitrogen oxide gas oxidation generates the dicarbapentaborane carboxylicesters, closes ring with ammonium acetate, acetic acid, formaldehyde again.This method is used nitrogen oxide gas, the operation trouble, and toxicity is big, and environmental pollution is serious.
Two,
Ethyl benzoylacetate carries out the methylene radical oxidation with the Dess-Martin oxygenant, closes the ester that ring generates corresponding 4-phenyl-5-carboxylic acid imidazoles again.The used oxygenant Dess-Martin of this method expensive, cost is high, is inappropriate for industrial production.
Three,
This method is that isocyano-methyl acetate and cyanobenzene directly carry out ring closure reaction, but raw material isocyano-methyl acetate market value is high, and cost is very expensive.In addition, cyanobenzene is easy to get, and other aryl formonitrile HCN is not easy to obtain, and this method applicability is not high.
Summary of the invention
Technical problem to be solved by this invention is among the preparation method who overcomes existing 4-aryl-5-carboxylic acid imidazoles and ester thereof; Cost is high; Suitability is low, troublesome poeration, and toxicity is big; Be inappropriate for defectives such as suitability for industrialized production, and the process method of a kind of synthetic 4-aryl-5-carboxylic acid imidazoles and ester thereof is provided.Process method of the present invention is easy to operate, and Atom economy is high, is suitable for industriallization, is applicable to the 4-aryl-5-carboxylic acid imidazoles and the ester thereof of synthesizing series.
Therefore, the present invention relates to a kind of synthetic process method suc as formula the aryl of the 4-shown in 3-5-carboxylic acid imidazate, it comprises the following step: in the aqueous solution of formic acid or formic acid, compound 2 and methane amide are carried out ring closure reaction, get final product;
Wherein, R is C
6～C
10Aromatic base (preferred phenyl) or C
1-C
6Heterocyclic aryl, heteroatoms are N, O or S; R ' is C
1～C
5Alkyl (preferred ethyl); The temperature of ring closure reaction is 100 ℃～140 ℃ (preferred 100 ℃～135 ℃); The molar weight of described methane amide is more than compound 2; The weight of described formic acid is 1～5 times of compound 2; The mass concentration of the aqueous solution of described formic acid is 85%～98%; The weight of described aqueous formic acid is 1～5 times of compound 2.
Wherein, the consumption of described methane amide is preferable is 2～5 times of molar weight of compound 2, and better is 3～4 times.The time of described ring closure reaction can through detection reaction fully till, be generally 12～24 hours.
Above-mentioned ring closure reaction also can carry out in the presence of organic solvent, organic solvent can be this area conventional can solubilizing reaction thing 2, and to the solvent of reactionlessness.
After above-mentioned ring closure reaction finishes, can carry out the aftertreatment purifying, the preferred following post-treating method of the present invention: reaction solution is added water and organic solvent diluting according to the conventional knowledge in this area; With inorganic adjusting PH with base to 7～8, separate out solid, with solid filtering; Washing, drying gets final product.Wherein, described organic solvent is the conventional polar solvent in this area, like ETHYLE ACETATE.Described mineral alkali can be the mineral alkali of this area conventional pH of adjusting value, like in yellow soda ash, salt of wormwood, sodium hydroxide, Pottasium Hydroxide and the Lithium Hydroxide MonoHydrate one or more, and can be with the form adjusting pH value of saturated sodium carbonate solution.What the volume ratio of described organic solvent and water was preferable is 1: 1～1: 6.
Among the present invention, described compound 2 can be made by following method: compound 1 is carried out the chlorination of the α-hydrogen of carbonyl, get final product;
Wherein, the method for described chlorination and condition all can be the ordinary method and the condition of this type of reaction of this area, preferred especially following method of the present invention and condition: in the dry organic solvent, with compound 1 and dichloride sulfone (SO
2Cl
2) carry out chlorination, get final product.
Wherein, described dry organic solvent is preferable is in methylene dichloride, THF, dioxane, ether, sherwood oil, ETHYLE ACETATE, normal hexane, chloroform and the hexanaphthene one or more, preferred methylene dichloride.The volume mass of organic solvent and compound 1 than preferable be 10～30ml/g.The consumption of described dichloride sulfone is preferable is 1～2 times of molar weight of compound 1, and better is 1.1～1.2 times.The time of described chlorination can through detection reaction fully till.What the temperature of described chlorination was preferable is 10～40 ℃, and better is 25～35 ℃.
After above-mentioned chlorination finishes, can handle by the conventional post-treating method in this area, as through simple washing, drying, concentrate can high yield make pure compound 2.
The invention further relates to synthetic process method suc as formula the aryl of the 4-shown in 4-5-carboxylic acid imidazoles, it comprises the following step:
(1) makes compound 3 according to the aforementioned method for preparing compound 3;
(2) step (1) gained compound 3 is carried out the hydrolysis reaction of ester, get final product;
Wherein, the definition of R and R ' is ditto said.
Wherein, the method for the hydrolysis reaction of described ester and condition can be the ordinary method and the condition of this type of reaction of this area, and the preferred following method of the present invention: temperature of reaction is 55～75 ℃; In the organic solvent; Under the effect of inorganic strong alkali, compound 3 is carried out the hydrolysis reaction of ester, get final product.Wherein, described organic solvent is preferable is in ethanol, acetone, dioxane, THF and the methyl alcohol one or more, particular methanol.The volume mass of organic solvent and compound 3 than preferable be 10～40ml/g.Described inorganic strong alkali is preferable is in sodium hydroxide, Pottasium Hydroxide and the Lithium Hydroxide MonoHydrate one or more, preferred sodium hydroxide.The consumption of described inorganic strong alkali is preferable is 1～4 times of molar weight of compound 3.The time of the hydrolysis reaction of described ester can through detection reaction fully till, be generally 12～24 hours.What the temperature of the hydrolysis reaction of described ester was preferable is 60 ℃～65 ℃.
After above-mentioned esterification finishes, can handle by the conventional post-treating method in this area, as through simple extraction, acidolysis, separate out solid, with the solid washing, dry can high yield make pure compound 4.
Among the present invention, the preparing method's of compound 4 synthetic route preferable as follows:
Wherein, the definition of R and R ' is ditto said; The method and the condition in each step are all ditto said.This route is different fully with prior art, and overall yield is high, is suitable for industriallization.
On the basis of this area general knowledge, above-mentioned each optimum condition, but arbitrary combination promptly get each preferred embodiments of the present invention.
Agents useful for same of the present invention and raw material are all commercially available to be got.
Positive progressive effect of the present invention is: process method of the present invention is easy to operate, and aftertreatment is simple, and Atom economy is high, and highly versatile is applicable to the 4-aryl-5-carboxylic acid imidazoles and the ester thereof of synthesizing series to be suitable for industriallization.
Embodiment
Mode through embodiment further specifies the present invention below, but does not therefore limit the present invention among the described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example according to ordinary method and condition, or is selected according to catalogue.
The preparation of embodiment 1 alpha-chloro ethyl benzoylacetate
Take by weighing the 12g ethyl benzoylacetate,, add 8.42 dichloride sulfones with the dissolving of 120ml methylene dichloride.The gained mixture is warmed up to 32 ℃ of stirring reactions, when no bubble produces, promptly reacts completely.After reaction finished, system was cooled to room temperature, with the saturated sodium bicarbonate aqueous solution washing, and saturated common salt washing, drying.Concentrate 14.0g product 2, productive rate 99%.
1H?NMR(300MHz，CDCl
3)：δ8.1(m，2H)，7.6(m，1H)，7.5(m，2H)，5.6(s，1H)，4.3(m，2H)，1.2(m，3H)
The preparation of embodiment 24-phenyl-5-carboxylic acid imidazate
Add 12.2g alpha-chloro ethyl benzoylacetate in the there-necked flask of 100ml, 15g formic acid, 4.8g methane amide.The gained mixture is warmed up to 135 ℃ of stirring reaction 48h, adds the 2.4g methane amide, and 135 ℃ are continued reaction 24h, react completely.After reaction finished, system was cooled to room temperature, filtered and removed inorganic salt, and filtrating adds 40ml water, 10ml ETHYLE ACETATE, and saturated aqueous sodium carbonate 40ml, mixture stirs, and filters the solid of separating out, washing, drying.Re-crystallizing in ethyl acetate promptly gets 8.1g product 4-phenyl-5-carboxylic acid imidazate 3, productive rate 69%.
1H?NMR(300MHz，d6-DMSO)：δ7.9(m，3H)，7.1(m，3H)，4.2(m，2H)，1.3(m，3H)
The preparation of embodiment 34-phenyl-5-carboxylic acid imidazoles
In the there-necked flask of 100ml, 1.84g sodium hydroxide is dissolved in the mixing solutions of 18ml water and 36ml methyl alcohol.Add 5g4-phenyl-5-carboxylic acid imidazate, the gained mixture is warmed up to 65 ℃ of stirring reaction 12h.After reaction finished, system was cooled to room temperature, the 25ml ethyl acetate extraction once, water is transferred PH 2-3 with 6N hydrochloric acid, separates out a large amount of solids, filters, solid is washed, drying.Promptly get 4.05g 4-phenyl-5-carboxylic acid imidazoles 4, faint yellow solid, productive rate 93%.
1H?NMR(300MHz，d6-DMSO)：δ12.9(br，1H)，7.8(m，3H)，7.3(m，3H)
Claims (11)
1. synthetic process method suc as formula the aryl of the 4-shown in 3-5-carboxylic acid imidazate, it comprises the following step: in the aqueous solution of formic acid or formic acid, compound 2 and methane amide are carried out ring closure reaction, get final product;
Wherein, R is C
6～C
10Aromatic base or C
1-C
6Heterocyclic aryl, heteroatoms are N, O or S; R ' is C
1～C
5Alkyl; The temperature of ring closure reaction is 100 ℃～140 ℃; The molar weight of described methane amide is more than compound 2; The weight of described formic acid is 1～5 times of compound 2; The mass concentration of the aqueous solution of described formic acid is 85%～98%; The weight of described aqueous formic acid is 1～5 times of compound 2.
2. the method for claim 1 is characterized in that: among the R, and described C
6～C
10Aromatic base is a phenyl; And/or, among the R ', described C
1～C
5Alkyl is an ethyl.
3. the method for claim 1, it is characterized in that: the temperature of described ring closure reaction is 100 ℃～135 ℃.
4. the method for claim 1 is characterized in that: the consumption of described methane amide is 2～5 times of molar weight of compound 2.
5. method as claimed in claim 4 is characterized in that: the consumption of described methane amide is 3～4 times of molar weight of compound 2.
6. the method for claim 1 is characterized in that: the time of described ring closure reaction through detection reaction fully till.
7. the method for claim 1 is characterized in that: ring closure reaction carries out following post-treating method after finishing: reaction solution is added water and organic solvent diluting, with inorganic adjusting PH with base to 7～8, separate out solid, with solid filtering, wash, drying gets final product; Wherein, described organic solvent is the conventional polar solvent in this area; The volume ratio of described organic solvent and water is 1: 1～1: 6.
8. the method for claim 1, it is characterized in that: described compound 2 is made by following method: compound 1 is carried out the chlorination of the α-hydrogen of carbonyl, get final product;
9. method as claimed in claim 8 is characterized in that: described chlorination comprises the following step: in the dry organic solvent, compound 1 and dichloride sulfone are carried out chlorination, get final product; Wherein, described dry organic solvent is one or more in methylene dichloride, THF, dioxane, ether, sherwood oil, ETHYLE ACETATE, normal hexane, chloroform and the hexanaphthene; The consumption of described dichloride sulfone is 1～2 times of molar weight of compound 1; The time of described chlorination is with till complete through detection reaction; The temperature of described chlorination is 10～40 ℃.
10. synthetic process method suc as formula the aryl of the 4-shown in 4-5-carboxylic acid imidazoles, it comprises the following step:
(1) makes compound 3 according to each described preparation method of claim 1～9;
(2) step (1) gained compound 3 is carried out the hydrolysis reaction of ester, get final product;
Wherein, each is said for the definition of R and R ' such as claim 1～9.
11. method as claimed in claim 10 is characterized in that: the hydrolysis reaction of described ester comprises the following step: temperature of reaction is 55～75 ℃, in the organic solvent, under the effect of inorganic strong alkali, compound 3 is carried out the hydrolysis reaction of ester, gets final product; Wherein, described organic solvent is one or more in ethanol, acetone, dioxane, THF and the methyl alcohol; Described inorganic strong alkali is one or more in sodium hydroxide, Pottasium Hydroxide and the Lithium Hydroxide MonoHydrate; The consumption of described inorganic strong alkali is 1～4 times of molar weight of compound 3; The time of the hydrolysis reaction of described ester through detection reaction fully till; The temperature of the hydrolysis reaction of described ester is 60 ℃～65 ℃.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4560696A (en) * | 1981-07-31 | 1985-12-24 | Zambon S.P.A. | Analgesic, antipyretic or anti-inflammatory imidazole compounds |
| US20080045542A1 (en) * | 2005-02-03 | 2008-02-21 | Aventis Pharma S.A. | Substituted Pyrroles and Imidazoles, Compositions Containing Same, Manufacturing Process Therefor and Use Thereof |
| CN101429082A (en) * | 2008-09-08 | 2009-05-13 | 华东师范大学 | Method for quick synthesis of alpha-single chloro-ketone compounds |
-
2011
- 2011-05-10 CN CN2011101201907A patent/CN102775354A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4560696A (en) * | 1981-07-31 | 1985-12-24 | Zambon S.P.A. | Analgesic, antipyretic or anti-inflammatory imidazole compounds |
| US20080045542A1 (en) * | 2005-02-03 | 2008-02-21 | Aventis Pharma S.A. | Substituted Pyrroles and Imidazoles, Compositions Containing Same, Manufacturing Process Therefor and Use Thereof |
| CN101429082A (en) * | 2008-09-08 | 2009-05-13 | 华东师范大学 | Method for quick synthesis of alpha-single chloro-ketone compounds |
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Application publication date: 20121114 |