CN101550106A - Industrialized preparation method of N-alkyl substituted-imidazole-5-carboxylic-acid/ester compound - Google Patents
Industrialized preparation method of N-alkyl substituted-imidazole-5-carboxylic-acid/ester compound Download PDFInfo
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- CN101550106A CN101550106A CNA2008100432194A CN200810043219A CN101550106A CN 101550106 A CN101550106 A CN 101550106A CN A2008100432194 A CNA2008100432194 A CN A2008100432194A CN 200810043219 A CN200810043219 A CN 200810043219A CN 101550106 A CN101550106 A CN 101550106A
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Abstract
The invention relates to an industrialized preparation method of an N-alkyl substituted-imidazole-5-carboxylic-acid/ester compound, which uses conventional and easily-obtained cranuric chloride as a raw material to react with DMF to generate a gold reagent, and react with alkyl-substituted glycinate to obtain N-alkyl substituted-imidazole-5-carboxylic ester under an alkali condition a loop closure way. N-alkyl substituted-imidazole-5-carboxylic acid can be obtained by hydrolysis. The invention solves the problems of long line, low yield, difficult purification and no scale production of the prior art and can realize the scale industrialized production.
Description
Technical field:
The present invention relates to a kind of industrial method of effectively synthetic N-alkyl substituted-imidazole-5-carboxylic-acid/ester compound.
Background technology:
Glyoxaline compound is the most frequently used pharmaceutical intermediate, and N-alkyl substituted-imidazole-5-carboxylic-acid/ester compound is a wherein important class, but does not up to the present effectively prepare the industrial preparative method of this product.Once reported following preparation method in the document, method one is a raw material with N-alkyl replacement-imidazoles, and butyllithium is handled, and pulls out active hydrogen, feeds carbonic acid gas, and the generation carboxylic acid (J.Am.Chem.Soc, 79,1957,4922-4926); Method two, the reflux decarboxylation in aceticanhydride of 1-N-alkyl replacement-imidazoles-4,5-dicarboxylic acid gets target product (Synthesis; EN; 10,1988,767-771).
Document synthetic route 1:
R＝methyl，ethyl
Said synthesis route 1 is not suitable for the technical scale batch reaction, this be because:
(a) the raw material that uses expensive, the cost height for example, must be used n-Butyl Lithium;
(b) reaction needed is carried out at low temperatures, inconvenient operation;
(c) product 2 and product 3 generation ratios are nearly 1: 1, and target product 3 is difficult to purifying.
Document synthetic route 2:
Said synthesis route 2 is not suitable for the technical scale batch reaction, this be because:
(a) step is long;
(b) compound 7 solubleness in water is very good, but in organic solvent the non-constant of solubleness, be difficult to separate;
(c) by product that generates of reaction difficulty remove, product purity is not high.
Summary of the invention:
The industrialized process for preparing that the purpose of this invention is to provide the N-alkyl substituted-imidazole-5-carboxylic-acid/ester compound that a kind of whole yield is higher, preparation cost is lower.It is long mainly to solve among existing N-alkyl substituted-imidazole-5-carboxylic-acid acid/ester compound preparation technology route, and yield is low, purification difficult, technical problem that can't large-scale production.
Technical scheme of the present invention:
The present invention is a raw material with cyanuric chloride conventional, that be easy to get, with N, dinethylformamide (DMF) effect generates N-(((dimethylin) methylene amido) methene)-N-alkyl dimethyl ammonium chloride (gold reagent), obtain N-alkyl substituted-imidazole-5-carboxylic-acid ester with the alkyl substituted glycine ester at alkaline condition ShiShimonoseki ring again, hydrolysis can obtain the N-alkyl substituted-imidazole-5-carboxylic-acid.
Concrete synthesis technique of the present invention is as follows:
In above-mentioned technological process, we at first use cyanuric chloride and the DMF reaction generates N-(((dimethylin) methylene amido) methene)-N-alkyl dimethyl ammonium chloride (gold reagent).Gold reagent obtains N-alkyl substituted-imidazole-5-carboxylic-acid ester with the alkyl substituted glycine ester at alkaline condition ShiShimonoseki ring again, and ester is hydrolyzed and obtains carboxylic acid.
In the gold reagent preparation: cyanuric chloride and DMF be as reaction substrate, and reaction solvent is selected from a kind of in methyl tertiary butyl ether, dioxane or the tetrahydrofuran (THF), and temperature of reaction is 0 ℃-100 ℃, and preferred initial reaction temperature is 50 ℃-60 ℃; The reaction postcooling filters and directly gets product.
In ring closure reaction, alkali is to be selected from a kind of in sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide or the sodium hydrogen, and catalyzer is a dimethyl oxalate, and reaction solvent is to be selected from a kind of in methyl tertiary butyl ether, tetrahydrofuran (THF) or the dioxane.Temperature of reaction is 0 ℃-100 ℃, and preferred initial reaction temperature is room temperature (20 ℃-30 ℃).In described ring closure reaction, processing feature is molecular distillation thereafter, temperature 50-200 ℃, and vacuum tightness 0.5mmHg-10mmHg.
In hydrolysis reaction, the used alkali of hydrolysis reaction is selected from a kind of in sodium hydroxide, potassium hydroxide or the lithium hydroxide, and reaction solvent is selected from a kind of in water, methyl alcohol, ethanol, acetone or the tetrahydrofuran (THF), and temperature is a room temperature to 78 ℃.
Alkyl substituted glycine ester wherein, simple alkyl-substituted compound such as methylglycine ester, ethyl glycine ester or benzyl glycinate etc. can directly be buied from the market, complicated alkyl-substituted compound can conveniently obtain by halogenated alkane or aldehyde compound and glycinate reaction, can also react with bromoethyl acetate by alkyl ammonia obtain.The preferred alkyl substituting group is the C1-C20 alkyl in the alkyl substituted glycine ester.Preferred alkyl substituent is the C1-C10 alkyl.
Beneficial effect of the present invention:
Reaction process of the present invention is selected rationally; adopted that economy is easy to get, cyanuric chloride that can large-scale production is a raw material; generate gold reagent with the DMF effect; obtain N-alkyl substituted-imidazole-5-carboxylic-acid ester with the alkyl substituted glycine ester at alkaline condition ShiShimonoseki ring again; hydrolysis can obtain the N-alkyl substituted-imidazole-5-carboxylic-acid, and its overall yield reaches 50～70%.The present invention reacts easy control, and preparation cost is lower, and intermediate can purify by recrystallization, and product can be purified by distillation, therefore can carry out large-scale industrial production.
Embodiment:
The following example helps to understand the present invention, but is not limited to content of the present invention.
Embodiment 1
Synthesizing of N-(((dimethylin) methylene amido) methene)-N-alkyl dimethyl ammonium chloride (gold reagent)
Cyanuric chloride (280g) and N, dinethylformamide (720g) adds 1,4 dioxane (1500mL), is heated to 65 ℃, reacts one hour, and reheat reacted two hours to 75-85 ℃.Be cooled to room temperature, filter, with 1,4 dioxane (1000mL) washing leaching cake, oven drying at low temperature under the vacuum obtains the 650g product, productive rate: 81%.
1H?NMR(400MHz，CDCl
3)：δ9.58(s，2H，CH，CH)，3.35(s，6H，C
2H
6)，3.17(s，6H，CH
3，CH
3)
Synthesizing of 1-Methylimidazole-5-ethyl formate
Methylglycine carbethoxy hydrochloride (100g) is added t-butyl methyl ether (2500mL), add 30% alcohol sodium alcohol solution (900mL) of dimethyl oxalate (30g) and prepared fresh again.Feed nitrogen to system, add gold reagent (150g) simultaneously, allow be reflected in the nitrogen gas stream and take place.Be heated to 30 ℃ of reactions 24 hours.Cool to room temperature filters (78-80 ℃/1mmHg) obtain 50g product, productive rate: 52.8% of filtrate evaporate to dryness and underpressure distillation.
1H?NMR(400MHz，CDCl
3)：δ7.65(s，1H，CH)，7.47(s，1H，CH)，4.25(m，2H，CH
2)，3.84(s，3H，CH
3)，1.30(m，3H，CH
3)
Embodiment 2
Synthesizing of ethyl glycine carbethoxy hydrochloride
Ethyl ammonia (45g) is dissolved in ethanol (400mL), adds salt of wormwood (70g).Slow dripping bromine ethyl acetate (83g) under the condition of ice bath dropwises the back and reacted 3 hours under the condition of room temperature (10-15 ℃).Filter, the evaporate to dryness organic solvent, standing demix divides and falls down a layer water.The upper strata organism add 2N hydrogenchloride 1,4-dioxane solution (500mL) is filtered stirring at room half an hour, with 1,4-dioxane (500mL) washs and obtains 60g product, productive rate: 72%.
1H?NMR(400MHz，DMSO-d
6)：δ9.48(s，2H，NH，HCl)，4.20(m，2H，CH
2)，3.90(m，2H，CH
2)，2.93(m，2H，CH
2)，1.19(m，6H，CH
3，CH
3)
Synthesizing of 1-ethyl imidazol(e)-5-ethyl formate
Ethyl glycine carbethoxy hydrochloride (60g) is added t-butyl methyl ether (650mL), add 30% alcohol sodium alcohol solution (250mL) of dimethyl oxalate (10g) and prepared fresh again.Feed nitrogen to system, add gold reagent (92g) simultaneously, allow be reflected in the nitrogen gas stream and take place.Be heated to 30 ℃ of reactions 24 hours.Cool to room temperature filters (105-110 ℃/1mmHg) obtain 30g product, productive rate: 50% of filtrate evaporate to dryness and underpressure distillation.
1H?NMR(400MHz，CDCl
3)：δ7.70(s，1H，CH)，7.57(s，1H，CH)，4.30(m，4H，CH
2，CH
2)，1.41(m，3H，CH
3)，1.33(m，3H，CH
3)
Synthesizing of 1-ethyl imidazol(e)-5-formic acid
Sodium hydroxide (400mL) with 1-ethyl imidazol(e)-5-ethyl formate (50g) adding 2N is heated under 50 ℃ of conditions and stirred 2 hours, and regulating pH with the aqueous hydrochloric acid of 5N behind the cool to room temperature is 5-6.Be concentrated into～200mL, add 1000mL ethanol, reconcentration adds 1000mL ethanol to～200mL, reflux half an hour is cooled to room temperature, filters, and the mother liquor evaporate to dryness gets product 35g, productive rate: 88%.
1H?NMR(400MHz，DMSO-d
6)：δ7.59(s，1H，CH)，7.19(s，1H，CH)，4.36(m，2H，CH
2)，1.31(m，3H，CH
3)
Embodiment 3
Synthesizing of n-pentyl glycine ethyl ester hydrochloride
Glycine ethyl ester hydrochloride (14g) is dissolved in ethanol (200mL), is cooled to 0 ℃, add salt of wormwood (20g).Drip positive penta bromine (15g), dropwise the back and under the condition of room temperature (0-5 ℃), reacted 3 hours.Filter, the evaporate to dryness organic solvent adds methyl tertbutyl ethereal solution (100mL), and standing demix divides and falls down a layer water.The upper strata organism adds the dioxane solution (30mL) of the hydrogenchloride of 5N, filters stirring at room half an hour, washs with methyl tertiary butyl ether (50mL) and obtains 15g product, productive rate: 71.4%.
1H?NMR(400MHz，DMSO-d
6)：δ9.40(s，2H，NH，HCl)，4.21(m，2H，CH
2)，3.91(m，2H，CH
2)，2.94(m，2H，CH
2)，1.97(m，2H，CH
2)，1.29-1.32(m，7H)，0.92(m，3H，CH
3)
Synthesizing of 1-n-pentyl imidazoles-5-ethyl formate
N-pentyl glycine ethyl ester hydrochloride (10g) is added tetrahydrofuran (THF) (100mL), add dimethyl oxalate (2g) and sodium tert-butoxide (5g) again.Feed nitrogen to system, add gold reagent (15g) simultaneously, allow be reflected in the nitrogen gas stream and take place.Be heated to 40 ℃ of reactions 24 hours.Cool to room temperature filters filtrate evaporate to dryness and underpressure distillation (130-140 ℃/1-2mmHg) obtain the 3g product is colourless liquid, productive rate: 30%.
1HNMR(400MHz，CDCl
3)：δ7.71(s，1H，CH)，7.58(s，1H，CH)，4.30(m，4H，CH
2，CH
2)，1.97(m，2H，CH
2)，1.29-1.32(m，7H)，0.93(m，3H，CH
3)
Synthesizing of 1-n-pentyl imidazoles-5-formic acid
1-n-pentyl imidazoles-5-ethyl formate (3g) is added ethanol (10mL), and the lithium hydroxide of 3N (10mL) is heated under 50 ℃ of conditions and stirred 3 hours, and regulating pH with the aqueous hydrochloric acid of 5N behind the cool to room temperature is 5-6.Be concentrated into～10mL, add 10mL Virahol and 30mL ethyl acetate, leave standstill, separatory, water are used 10mL Virahol and 30mL ethyl acetate extraction once again, merge organic phase, anhydrous Na 2SO4 drying, reconcentration slowly adds the 30mL normal heptane to～10mL, stirs 1h, filter, oven dry gets product 2g (white solid), productive rate: 77%.
1H?NMR(400MHz，DMSO-d
6)：δ12.52(s，1H，COOH)，7.93(s，1H，CH)，7.75(s，1H，CH)，4.32(m，CH
2)，1.98(m，2H，CH
2)，1.29-1.32(m，4H)，0.94(m，3H，CH
3).
Embodiment 4
Synthesizing of N-(((dimethylin) methylene amido) methene)-N-alkyl dimethyl ammonium chloride (gold reagent)
Cyanuric chloride (28g) and N, N-dimethylformamide (72g) adds tetrahydrofuran (THF) (150mL), is heated to 65 ℃, reacts one hour, and reheat reacted two hours to refluxing.Be cooled to room temperature, filter, with tetrahydrofuran (THF) (100mL) washing leaching cake, oven drying at low temperature under the vacuum obtains the 70g product, productive rate: 87%.Analytical data is seen embodiment 1.
Synthesizing of 1-benzyl imidazole-5-ethyl formate
N-benzylglycine ethyl ester hydrochloride (10g) is added tetrahydrofuran (THF) (100mL), add 30% alcohol sodium alcohol solution (40mL) of dimethyl oxalate (2g) and prepared fresh again.Feed nitrogen to system, add gold reagent (15g) simultaneously, allow be reflected in the nitrogen gas stream and take place.Be heated to 30 ℃ of reactions 24 hours.Cool to room temperature, (135-145 ℃/1～2mmHg) obtains the 3.1g product, productive rate: 31% to filter filtrate evaporate to dryness and underpressure distillation.
1H?NMR(400MHz，CDCl
3)：δ7.71(s，1H，CH)，7.58(s，1H，CH)，7.25～7.33(m，5H)，5.60(s，2H，CH
2)，4.31(m，2H，CH
2)，1.41(m，3H，CH
3)。
Claims (6)
1, a kind of industrialized process for preparing of N-alkyl substituted-imidazole-5-carboxylic-acid/ester compound, it is characterized in that cyanuric chloride is a raw material, with N, the dinethylformamide effect generates N-(((dimethylin) methylene amido) methene)-N-alkyl dimethyl ammonium chloride, obtain N-alkyl substituted-imidazole-5-carboxylic-acid ester with the alkyl substituted glycine ester at alkaline condition ShiShimonoseki ring again, hydrolysis can obtain the N-alkyl substituted-imidazole-5-carboxylic-acid.
2, the industrialized process for preparing of N-alkyl substituted-imidazole-5-carboxylic-acid/ester compound according to claim 1, it is characterized in that, in described N-(((dimethylin) methylene amido) methene)-N-alkyl dimethyl ammonium chloride preparation, reaction solvent is to be selected from a kind of in methyl tertiary butyl ether, tetrahydrofuran (THF) or the dioxane, and temperature of reaction is 0 ℃-100 ℃.
3, the industrialized process for preparing of N-alkyl substituted-imidazole-5-carboxylic-acid/ester compound according to claim 1, it is characterized in that, described ring closure reaction need add the catalyzer dimethyl oxalate, the ring closure reaction reaction solvent is selected from a kind of in methyl tertiary butyl ether, tetrahydrofuran (THF) or the dioxane, and alkali is selected from a kind of in sodium methylate, sodium ethylate, sodium tert-butoxide or the potassium tert.-butoxide.
4, according to the industrialized process for preparing of claim 1 or 3 described N-alkyl substituted-imidazole-5-carboxylic-acid/ester compounds, it is characterized in that: in described ring closure reaction, need carry out the molecular distillation aftertreatment for the ring closure reaction product.
5, the industrialized process for preparing of N-alkyl substituted-imidazole-5-carboxylic-acid/ester compound according to claim 1, it is characterized in that, in described hydrolysis reaction, used alkali is selected from a kind of in sodium hydroxide, potassium hydroxide or the lithium hydroxide, reaction solvent is selected from a kind of in water, methyl alcohol, ethanol or the tetrahydrofuran (THF), and temperature of reaction is a room temperature to 78 ℃.
6, the industrialized process for preparing of N-alkyl substituted-imidazole-5-carboxylic-acid/ester compound according to claim 1 is characterized in that, alkyl substituent is the C1-C10 alkyl in the alkyl substituted glycine ester.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109863134A (en) * | 2016-10-19 | 2019-06-07 | Ａｇｃ株式会社 | The manufacturing method of nitrogenous compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109863134A (en) * | 2016-10-19 | 2019-06-07 | Ａｇｃ株式会社 | The manufacturing method of nitrogenous compound |
| CN109863134B (en) * | 2016-10-19 | 2022-09-09 | Ａｇｃ株式会社 | Process for producing nitrogen-containing compound |
| CN115322152A (en) * | 2016-10-19 | 2022-11-11 | Ａｇｃ株式会社 | Process for producing nitrogen-containing compound |
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Open date: 20091007 |