CN1422846A

CN1422846A - Pyrrole derivative preparation method

Info

Publication number: CN1422846A
Application number: CN 01140235
Authority: CN
Inventors: 栗同林; 隋军龙
Original assignee: Beijing Research Institute of Beijing Yanshan Petrochemical Corp
Current assignee: China Petroleum and Chemical Corp
Priority date: 2001-12-07
Filing date: 2001-12-07
Publication date: 2003-06-11
Anticipated expiration: 2021-12-07
Also published as: CN1176075C

Abstract

The invention refers to a preparing method of pyrrole derivative. It makes a acyl-ester compound R2COCH2COOR react with halogen substituted aldehyde or ketone R5CHXCOR5 in the polar solvent with alkaline to obtain formic acid ester substituted tetraethyldiaminobenzophenone R5COCH(R4)CH(COOR)COR2, then which reacts with ammonia or ammonium salt at 50-100 C degree for 1-10h, R and R2 are both C1-5 alkyls, R4 and R5 are both H1-5 or C1-5 alkyls, and X is Cl, Br or I.

Description

Process for preparing pyrrole derivatives

Technical Field

The invention relates to a preparation method of a pyrrole derivative, in particular to a preparation method of a formate alkyl substituted pyrrole.

Background

Formylalkyl-substituted pyrrole derivatives are important intermediates for the preparation of alkyl-substituted pyrroles, which are important catalytic promoters, such as 2, 5-dimethylpyrrole. Canadian JOURNAL OF CHEMISTRY (CANADIAN JOURNAL OF CHEMISTRY VOL.48P 1689-1697, 1970) discloses a process for the preparation OF formylalkyl-substituted pyrrole derivatives by the addition OF aqueous ammonia to an acyl ester compound R²COCH₂COOR and halogenated compound R⁴In CHXCOH, the reaction is carried out to obtain the formylalkyl-substituted pyrrole derivative. The disadvantage is the low yield of the reaction product.

Disclosure of Invention

The invention aims to provide a preparation method of a pyrrole derivative. The process of the present invention can give a highly pure pyrrole derivative in high yield.

The invention provides a preparation method of pyrrole derivatives with the following general formula,comprising reacting an acyl ester compound R₂COCH₂COOR with halogenated aldehydes or ketones R in polar solvents in the presence of a base₄CHXCOR₅Reaction to give the formate-substituted diketones R₅COCH(R₄)CH(COOR)COR₂Then reacting with ammonia water or ammonium salt capable of releasing ammonia when heating at 50-100 deg.C for 1-10 hr, wherein R, R₂Independently an alkyl group having 1 to 5 carbon atoms, R₄、R₅Independently hydrogen or alkyl having 1-5 carbon atoms, and X is chlorine, bromine or iodine, preferably chlorine or bromine.

The preparation method of the pyrrole derivative comprises β -substitution reaction, cyclization reaction and the like, and the specific process can be expressed as follows:

(1) the acyl ester compound and alkali are subjected to β -substitution reaction to generate acyl ester sodium The dosage is as follows: the molar ratio of the base to the acyl ester compound is 1 to 5, and the number of moles is preferably substantially equal.

(2) Reacting sodium acyl ester with halogenated aldehyde or halogenated ketone to generate formic ester substituted diketoneThe amount of the halogenated aldehyde or the halogenated ketone is as follows: the molar ratio of the halogenated aldehyde or halogenated ketone to the acyl ester compound is 0.1 to 10, preferably approximately equal molar.

(3) The formate substituted diketone directly reacts with ammonia to form a ring to generate the formate alkyl substituted pyrrole

Because ammonia is readily available, cheap and volatile, the formate-substituted diketone reacts directly with ammonia to form a ring, preferably with an excess of more than 2 times, most preferably with an excess of 2 to 10 times.

The sodium acyl ester of the present invention can be produced by the method disclosed in (handbook of organic preparation chemistry) (first edition of 11 months 1977, first edition of petrochemical industry, p.158, compiled by Reunion of Okawa, Korean Candian, etc.) or by the method disclosed in JP 56-169639A.

The formate-substituted diketones of the present invention can be prepared by the method of JP 56-169639A.

The ammonium salt is ammonium carbonate or ammonium bicarbonate.

The alkali can be alkali metal M or an alkali metal compound represented by a general formula MY, and Y is a hydrogen atom or alkoxy. Wherein the alkali metal M is sodium or potassium; the alkali metal hydride is an alkali metal hydride such as lithium hydride, sodium hydride, potassium hydride, etc.; the alkali metal alkoxide is alkali metal alkoxide such as sodium methoxide, sodium ethoxide, sodium propoxide, lithium ethoxide, potassium isopropoxide, potassium butoxide and the like; hydrides and alkoxides are preferred. From the viewpoint of easy industrial availability and price, sodium hydride, sodium methoxide or sodium ethoxide is preferable.

The polar solvent for dissolving the raw material and the alkali according to the present invention may be, for example, alcohols such as water and methanol, ethanol, and isopropyl alcohol; polar aprotic solvents such as dimethylformamide, dimethylsulfoxide and hexamethylphosphoramide; esters of dioxane, tetrahydrofuran, and the like. When the base used is an alkali metal hydride or an alkali metal alkoxide in the case of using water as a solvent, such a base reacts with water to form a hydroxide, and as a result, the hydroxide reacts as a base, resulting in a decrease in the yield of the reaction. Therefore, the solvent is preferably a polar nonaqueous solvent. The solvent of the present invention is preferably at least one non-aqueous solvent selected from the group consisting of methanol, ethanol, dimethylformamide, dimethyl sulfoxide and hexamethylphosphoramide. The amount is not critical and is preferably sufficient to dissolve the raw materials and to stir them sufficiently.

R, R of the invention₂Independently an alkyl group having 1 to 3 carbon atoms, more preferably methyl or ethyl, R₄、R₅Independently hydrogen or alkyl with 1-3 carbon atoms, more preferably hydrogen, methyl and ethyl. Most preferably R is methyl or ethyl, R₂Methyl, R₄Is hydrogen, R₅Is methyl or hydrogen.

The acyl ester compound R of the invention₂COCH₂COOR with halogenated aldehyde or halogenated ketone R₄CHXCOR₅The reaction temperature of (A) is-10 to 100 ℃ and preferably-10 to 25 ℃.

The method for preparing the formate alkyl substituted pyrrole has the characteristics of easy operation, high product yield and high purity.

Detailed Description

The following examples will help illustrate the invention without limiting its scope.

Example 1

1. Preparation of acetonylacetoacetate Ethyl ester

Putting a 1000ml round-bottom flask with a stirring device in a water bath, adding 420ml of anhydrous N, N-dimethylformamide and 102g (1.5mol) of sodium ethoxide, slowly adding 195g (1.5mol) of ethyl acetoacetate at room temperature (20 ℃) in a stirring state, wherein the feeding rate is limited by that the material temperature does not exceed 25 ℃, and after the dropwise addition is finished, dropwise adding 140g (1.5mol) of chloropropanone, wherein the feeding rate is still limited by that the material temperature does not exceed 25 ℃. Then, the reaction was continued for 12 hours to obtain a turbid brown reaction solution (1).

And (3) filtering the reaction solution (1) to remove NaCl solids to obtain 650ml (2) of purple red liquid, and performing qualitative analysis and quantitative analysis on the purple red liquid by using a chromatography-mass spectrometer, wherein the content of the acetonyl ethyl acetoacetate is 33%. The magenta liquid (2) was subjected to fractional distillation under reduced pressure to remove the reaction solvent and unreacted components, and a fraction (3) having a temperature of 80 c (3.3kpa) was collected, and its mass was 220 g, which was quantitatively analyzed by chromatography, and its acetonylacetoacetate content was 96 wt.% (211 g, 1.13mol), and its yield was 75% based on chloroacetone. 2. Preparation of ethyl 2, 5-dimethylpyrrole-3-carboxylate

And (3) placing the solution (3) in a 1000ml three-necked bottle in a water bath, maintaining the temperature at 60 ℃, stirring, slowly adding 400ml of 28% ammonia water, dropwise adding for 2 hours, continuing to react for 1 hour at 60 ℃, naturally cooling to room temperature, and standing overnight. A mixed solution (4) having a golden yellow precipitate was obtained. The reaction solution (4) was filtered to give a golden yellow crystal (5) which was characterized by mass spectrometry (5) as 2, 5-dimethyl-3-carboxyethyl pyrrole (161 g, 0.96mol) with a yield of 85% (based on acetonylacetoacetate ethyl ester).

Example 2

The sodium ethoxide in example 1 was replaced by sodium metal, the other conditions were the same as in example 1, and the test results are shown in table 1.

Example 3

The dimethylformamide in example 1 was replaced with ethanol under the same conditions as in example 1, and the test results are shown in Table 1.

Example 4

Bromoacetone was used instead of chloroacetone in example 1, the conditions were otherwise the same as in example 1, and the test results are shown in Table 1.

Example 5

The ammonia solution of example 1 was replaced with 500 ml of 50 wt.% aqueous ammonium carbonate solution, the cyclization reaction temperature was 90 ℃, the other conditions were the same as in example 1, and the test results are shown in table 1. Example 6

The same procedure as in example 1 was repeated except that bromoacetaldehyde was used in place of the chloroacetone in example 1 to obtain 2-methyl-3-carboxyethyl pyrrole (Table 1).

Example 7

The procedure of example 1 was repeated except that methyl acetoacetate was used in place of ethyl acetoacetatein example 1 to give 2, 5-dimethyl-3-carboxylmethylpyrrole, and the test results are shown in Table 1. Comparative example 1

A1000 ml round-bottomed flask with stirring device was placed in a water bath, and 65g (0.5mol) of ethyl acetoacetate, 46g (0.5mol) of chloroacetone, 250ml of 28% ammonia and 250ml of distilled water were added at room temperature. The reaction was carried out for 2 hours while maintaining the temperature at 60 ℃ in a water bath, and then the reaction mixture was naturally cooled to room temperature and left overnight. To obtain a mixed reaction solution of golden yellow precipitates. The reaction solution was filtered to obtain 36 g of 2, 5-dimethylpyrrole-3-carboxylic acid ethyl ester as a golden yellow crystal, the yield of which was 43% (based on chloroacetone).

TABLE 1

Examples	Formate substituted bis Yield of ketone (%)	Alkyl substituted by formylates Yield of pyrrole (%)	Total yield (%)
Examples	Formate substituted bis Yield of ketone (%)	Alkyl substituted by formylates Yield of pyrrole (%)	Total yield (%)	1	75	85	64
2	73	85	62	1	75	85	64
2	73	85	62	3	70	82	57
4	76	84	64	3	70	82	57
4	76	84	64	5	76	87	66
6	80	83	66	5	76	87	66
6	80	83	66	7	69	80	55
Comparative example 1			43	7	69	80	55

Total yield is the product of yield (%) of formate substituted diketones and yield of formate alkyl substituted pyrroles.

Claims

1. A process for the preparation of pyrrole derivatives of the general formula,

comprising reacting an acyl ester compound R₂COCH₂COOR with halogenated aldehydes or ketones R in polar solvents in the presence of a base₄CHXCOR₅Reaction to give the formate-substituted diketones R₅COCH(R₄)CH(COOR)COR₂Then reacting with ammonia water or ammonium salt capable of releasing ammonia when heating at 50-100 deg.C for 1-10 hr, wherein R, R₂Independently an alkyl group having 1 to 5 carbon atoms, R₄、R₅Independently hydrogen or alkyl with 1-5 carbon atoms, and X is chlorine, bromine or iodine.

2. The process for producing an azole derivative according to claim 1, wherein the ammonium salt is ammonium carbonate or ammonium hydrogencarbonate.

3. The process for producing a pyrrole derivative according to claim 1 or 2, wherein the base is an alkali metal M or an alkali metal compound represented by the general formula MY wherein Y is a hydrogen atom or an alkoxy group.

4. The process for the preparation of pyrrole derivatives according to claim 3 characterized in that the alkali metal M is potassium or sodium; the alkali metal hydride is lithium hydride, sodium hydride or potassium hydride; the alkali metal alkoxide is sodium methoxide, sodium ethoxide, sodium propoxide, lithium ethoxide, potassium isopropoxide and potassium butoxide.

5. The process for producing an azole derivative according to any of claims 1 to 4, wherein the polar solvent is at least one non-aqueous solvent selected from the group consisting of methanol, ethanol, dimethylformamide, dimethylsulfoxide and hexamethylphosphoramide.

6. Process for the preparation of pyrrole derivatives according to any one of claims 1 to 5 wherein R is methyl or ethyl and R is₂Is methyl, R₄Is hydrogen, R₅Is methyl or hydrogen.

7. Process for the preparation of pyrrole derivatives according to any one of claims 1 to 6 wherein X is chloro or bromo.

8. Process for the preparation of pyrrole derivatives according to any one of claims 1 to 8, characterized in that the acyl ester compound R₂COCH₂COOR with halogenated aldehyde or halogenated ketone R₄CHXCOR₅The reaction temperature of (A) is-10-25 ℃.