JPH07324072A - Production of 3,4-dialkylpyrrole - Google Patents

Abstract

PURPOSE:To produce a pyrrole which is useful as a synthetic intermediate for porphyrin important in the curative field in a high yield through short-cut steps by reduction of a pyrrole represented by a specific formula, thus in no need of use of some raw materials which are expensive or troublesome in their physical properties. CONSTITUTION:A 3-acyl-4-alkylpyrrole of formula I (R<1> and R<2> are each a 1-5C alkyl) is subjected to Wolff-Kishner reduction or the reduction with lithium borohydride to give a pyrrole compound. In case of the Wolff-Kishner reduction, it is preferable that potassium t-utoxide is used as a salt.

Description

Detailed Description of the Invention

[0001]

The present invention relates to porphyrins (Or compounds), which are important compounds in various fields including the medical field.
g. Syn. , 70 , 68 (1992)) or its analogs (Inorg. Chem., 32 , 3175 (1)
993)), and at the same time, relates to a method for producing 3,4-dialkylpyrroles which are synthetic intermediates useful for their production.

[0002]

2. Description of the Related Art Conventionally, 3,4-dialkylpyrroles have been synthesized by the following limited methods due to their unstable physical properties. (1) A method for decarboxylating 3,4-dialkylpyrroles having a carboxyl group at the 2-position or 5-position, or at both 2-position and 5-position (Chem. Rev., 62 , 51).
1 (1962)). This method is a generally practiced method, but the process is complicated, and there are problems such as using a nitro compound which is a malodorous substance as a raw material and has an explosion risk (Org. Syn., 70 ). , 68 (199
2)) (2) Method for decomposing dihydrothiazine-1-oxide in the presence of chlorine (Bull. Chem. So.
c. Jpn. , 49 , 1157 (1976)). This method is not versatile as a method for producing pyrroles, and is practically used only for the synthesis of 3,4-dimethylpyrrole. (3) Azine (Heteroules, 653 (19
70)) or its N, N-dibenzoyl derivative (J. Chem. Soc., Chem Commu.
n. , 624 (1982)). This method is an excellent method for synthesizing 3,4-dialkylpyrrole from a simple raw material in a short step, but has poor reproducibility and
There are problems such as low yield.

Further, it is known that acylpyrroles are reduced with sodium borohydride to produce alkylpyrroles (J. Org. Chem., 50 , 1).
6, 2961 (1985)). However, this reaction
Acyl-4-alkylpyrroles as raw materials 3,4-
When applied to the production of dialkylpyrroles, there are problems that the reduction reaction stops at the alcohol production stage, and the yield is low as shown in the reference example described later.

[0004]

The present inventors have found that 3,4-
For the purpose of developing a method for producing dialkylpyrroles, as a result of intensive studies to solve the above problems, a method for reducing 3-acyl-4-alkylpyrroles can achieve a high yield, The present invention has been achieved by finding that it is an industrially advantageous manufacturing method.

That is, the gist of the present invention is the following general formula (I)

[0006]

[Chemical 3]

(In the above formula, R ¹ and R ² each independently represents a C ₁ -C ₅ alkyl group), and a 3-acyl-4-alkylpyrrole is represented by Wolff-K.
isher reduction or reduction with lithium borohydride, represented by the following general formula (II)

[0008]

[Chemical 4]

(In the above formula, R ¹ and R ² are as defined above.) In the process for producing the 3,4-dialkylpyrroles. Hereinafter, the present invention will be described in detail. In the present invention, the following general formula (I)

[0010]

[Chemical 5]

(In the above formula, R ¹ and R ² each independently represent a C ₁ -C ₅ alkyl group) and a 3-acyl-4-alkylpyrrole is represented by Wolff-K.
The following general formula (II) can be obtained by reducing with ishner reduction or lithium borohydride.

[0012]

[Chemical 6]

The 3,4-dialkylpyrroles represented by the formula (R ¹ and R ² are as defined above) are prepared. In the general formulas (I) and (II), R ¹ and R ² are each independently a methyl group, an ethyl group, an n-propyl group, a t-propyl group, an n-butyl group, an n-pentyl group or the like. It represents an alkyl group of C ₁ -C _5.

Specifically, 3-acyl-4-alkylpyrroles, which are compounds represented by the general formula (I), have the following formula:

[0015]

[Chemical 7]

And the like. Further, as the 3,4-dialkylpyrrole which is a compound represented by the general formula (II),

[0017]

[Chemical 8]

And the like. The 3,4-dialkylpyrroles represented by the general formula (II) can be produced in high yield by the Wolff-Kishner reduction or reduction reaction using lithium borohydride shown below. In an alcohol solvent such as diethylene glycol or triethylene glycol, the 3-acyl-4-alkylpyrrole which is the compound represented by the general formula (I) is preferably added in an amount of 0.1 to 50 molar equivalents relative to the compound. Is 0.5 to 3 molar equivalents of hydrated hydrazine and 0.1 to 20
After reacting in the presence of a molar equivalent of a base such as sodium hydroxide or potassium hydroxide to form a hydrazone of 3-acyl-4-alkylpyrrole which is a compound represented by the general formula (I), Water and residual hydrazine are distilled off, and the temperature is in the range of 150 ° C to 250 ° C, preferably 19 ° C.
Wolff-K that heats in the temperature range of 0 ° C to 200 ° C
The 3,4-dialkylpyrroles, which are compounds represented by the general formula (II), can be produced by ishner reduction.

In the Wolff-Kishner reduction, the 3-acyl-4-alkylpyrrole which is the compound represented by the general formula (I) is treated with a suitable solvent such as methanol, ethanol, i-propanol or the like. 0.1 to 50 molar equivalents, preferably 0.5 to 20
With a molar equivalent of hydrated hydrazine, in the temperature range of 0 ° C to 200 ° C, preferably in the temperature range of 30 ° C to 100 ° C, 30
3-acyl-4, which is a compound represented by the general formula (I) produced by being allowed to act for from minutes to 2 days, preferably from 1 to 5 hours.
After replacing the hydrazone of the alkylpyrrole with toluene, xylene or the like as the reaction system solvent, 0.1 to 20 relative to 3-acyl-4-alkylpyrrole which is the compound represented by the general formula (I). Molar equivalent, preferably 0.5-3
In the presence of a molar equivalent of potassium t-butoxide, 50 ° C to 15 ° C.
By heating in a temperature range of 0 ° C., preferably in a temperature range of 80 ° C. to 120 ° C., 3,4-dialkylpyrrole which is a compound represented by the general formula (II) can be produced. At this time, thermal decomposition of hydrazone to 3,4-dialkylpyrroles, which are compounds represented by the general formula (II), can be continuously performed in the same vessel.

Further, i-propanol, diglyme, D
In a solvent such as MF, the 3-acyl-4-alkylpyrrole which is the compound represented by the general formula (I) is 0.1 to 20 molar equivalents, preferably 0.5 to 6 moles, relative to the compound. Equivalent amount of lithium borohydride and a temperature range of 0 to 150 ° C., preferably room temperature to 100 ° C. for 5 minutes to
After being allowed to act for 10 days, preferably 1 hour to 2 days, 3,4-dialkylpyrroles which are compounds represented by the general formula (II) can be produced.

As the lithium borohydride used, commercially available products can be used, but in order to carry out the reduction reaction more economically, a metal such as sodium borohydride or potassium borohydride is used in the reaction system. It is also possible to prepare by reacting a hydrogen complex compound with a lithium salt such as lithium chloride, lithium bromide, lithium iodide or the like. In this case, the lithium salt is 0.1 to 1 with respect to the metal hydrogen complex compound.
0 molar equivalents, preferably 0.5-2 molar equivalents are used.
When producing lithium borohydride in the reaction system,
A method of reacting a compound represented by the general formula (I) after preliminarily producing lithium borohydride, or a lithium salt is added to a metal hydrogen complex compound in the presence of the compound represented by the general formula (I). It does not matter which method is used. The required amount of lithium borohydride is 0.1 to 20 molar equivalents, preferably about 0.5 to 6 molar equivalents, with respect to the compound represented by the general formula (I). The reaction solvent is not particularly limited as long as it does not adversely affect the reaction, but diethyl ether, tetrahydrofuran, n-hexane, benzene, toluene, ethanol, isopropanol and the like can be used. The reaction temperature is −50 ° C. to 150 ° C., preferably −
20 to 100 ° C.

The general formula (II) obtained by these methods
The 3,4-dialkylpyrrole which is a compound represented by can be purified by a general method such as distillation after the usual treatment. In the present invention, the origin of 3-acyl-4-alkylpyrroles, which are the compounds represented by the general formula (I), is not particularly limited, but for example, the following general formula (III)

[0023]

[Chemical 9]

(Wherein R ¹ and R ² are as defined above) and the following general formula (IV)

[0025]

[Chemical 10]

A method known from the compound represented by (Tet
rhedoron Lett. , 17 , 1473 (1
977)). The compound represented by the general formula (III) is commercially available and can be easily produced from inexpensive raw materials.

[0027]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the following examples unless it exceeds the gist thereof. Example 1 1.31 g of 3-acetyl-4-ethylpyrrole (9.5
6 mmol), 2.23 g of potassium hydroxide (39.68)
mmol), 1.34 g (26.8) of hydrazine monohydrate.
9 mmol) to 15 ml of diethylene glycol,
After heating at 110 ° C. for 4 hours in a nitrogen atmosphere, heating was performed at 200 ° C. for 4 hours. After cooling, add 30 ml of water and add 40 ether.
Extracted twice with ml. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. After filtering the desiccant,
The solvent was concentrated under reduced pressure to give 3,4-diethylpyrrole 1.08.
g (yield 89%) was obtained.

Bp 63.0-70.0 ° C./5 mmHg NMR (CDCl ₃ , 250 MHz) δ 1.20
(T, 6H, J = 7.6 Hz), 2.47 (q, 4H,
J = 7.6 Hz), 6.53 (d, 2H, J = 2.5H
z), 7.80 (brs, 1H) Example 2 0.88 g (6.3) 3-acetyl-4-ethylpyrrole.
Hydrazine monohydrate (3.64 g, 72.87 mmol) was added to an ethanol solution (20 ml) of 7 mmol),
The mixture was heated under reflux in a nitrogen atmosphere for 25 hours. After cooling, the solvent was distilled off under reduced pressure. 20 ml of toluene and 1.63 g (14.56 mmol) of potassium t-butoxide were added to the residue, and the mixture was heated under reflux for 14 hours under a nitrogen atmosphere. After the reaction is complete, cool down,
40 ml of 2N sodium hydroxide aqueous solution was added, and the mixture was extracted twice with 20 ml of ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 720 mg of 3,4-diethylpyrrole (yield 8
1%) was obtained.

Example 3 As in Example 2, 1.10 g (8.93 mmol) of 3-acetyl-4-methylpyrrole was added to Wolff-Kis.
10.74 g (76%) by hner reduction
3-ethyl-4-methylpyrrole was obtained. NMR (CDCl ₃ , 250 MHz) δ 1.18
(T, 3H, J = 7.0 Hz), 2.04 (s, 3
H), 2.45 (q, 2H, J = 7.0 Hz), 6.5
0 (d, 2H, J = 2.5 Hz), 7.60 (brs,
1H) Example 4 In the same manner as in Example 2, 1.05 g (6.35 mmol) of 3-propanoyl-4-propylpyrrole was added to Wolff-K.
0.68 g (71
%) 3,4-dipropylpyrrole was obtained.

Bp 69.0-71.0 ° C./1 mmHg NMR (CDCl ₃ , 250 MHz) δ 0.93 (6
H, t, J = 7.0 Hz), 1.50 (m, 4H),
2.37 (m, 4H), 6.37 (d, 2H, J = 2.
5 Hz), 7.60 (brs, s) Example 5 Lithium borohydride 240 mg (10.93 mmo)
1 ml) in anhydrous THF solution (5 ml) at 0 ° C. under a nitrogen atmosphere, and 300 mg (2.1 of 3-acetyl-4-ethylpyrrole).
5 ml of a THF solution of 6 mmol) was added dropwise, and the mixture was heated under reflux for 4 hours. After cooling, 15 ml of saturated saline was added and then extracted twice with 20 ml of n-hexane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering the desiccant, the solvent was concentrated under reduced pressure to obtain 210 mg of 3,4-diethylpyrrole (yield 79%).

Bp 63.0-70.0 ° C./5 mmHg NMR (CDCl ₃ , 250 MHz) δ 1.20
(T, 6H, J = 7.6 Hz), 2.47 (1q, 4
H, J = 7.6 Hz), 6.53 (d, 2H, J = 2.
5 Hz), 7.80 (brs, 1H) Example 6 350 mg of potassium borohydride in 3 ml of anhydrous THF.
(6.57 mmol) and 280 mg of lithium chloride (6.
57 mmol) was added, and the mixture was stirred at room temperature for 4 hours under a nitrogen atmosphere. To this solution, 3 ml of a THF solution of 200 mg (1.49 mmol) of 3-acetyl-4-ethylpyrrole was added dropwise, and then the mixture was heated under reflux for 3 hours. After cooling, 15 ml of saturated saline was added and then extracted twice with 20 ml of n-hexane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering the drying agent, the solvent was concentrated under reduced pressure to obtain 175 mg of 3,4-diethylpyrrole (yield 97
%) Was obtained.

Example 7 3-acetyl-4-methylpyrrole 6 was prepared in the same manner as in Example 6.
50 mg (5.28 mol) was reduced with potassium borohydride and lithium chloride to obtain 440 mg (yield 76%) of 3-ethyl-4-methylpyrrole. NMR (CDCl ₃ , 250 MHz) δppm 1.1
8 (t, 3H, J = 7.0 Hz), 2.04 (s, 3
H), 2.45 (q, 2H, J = 7.0 Hz), 6.5
0 (d, 2H, J = 2.5 Hz), 7.60 (brs,
1H) Example 8 In the same manner as in Example 6, 480 mg (2.90 mmol) of 3-propanoyl-4-propylpyrrole was reduced with potassium borohydride and lithium chloride to give 360 mg of 3,4-dipropylpyrrole ( Yield 81
%) Was obtained.

Bp 69.0-71.0 ° C./1 mmHg NMR (CDCl ₃ , 250 MHz) δ 0.93 (6
H, t, J = 7.0 Hz), 1.50 (m, 4H),
2.37 (m, 4H), 6.37 (d, 2H, J = 2.
5 Hz), 7.60 (brs, s) Comparative Example 1 3-acetyl-4-ethylpyrrole 500 mg (3.6
4 mmol), sodium borohydride 280 mg
(7.29 mmol) was added to 20 ml of isopropanol, and the mixture was refluxed for 33 hours under a nitrogen atmosphere. After the reaction was completed, 20 ml of saturated aqueous sodium hydrogen carbonate solution was added at 0 ° C., and the mixture was extracted twice with 20 ml of ether. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. After filtering the drying agent, the solvent was concentrated under reduced pressure to obtain 290 mg (yield 55%) of 3,4-diethylpyrrole.

Comparative Example 2 Sodium borohydride 550 mg (14.57 mmo
l) in anhydrous THF (15 ml) under nitrogen atmosphere,
1.86 g of boron trifluoride diethyl ether at 0 ° C
(13.10 ml) was added, and the mixture was stirred at 0 ° C for 30 minutes. 400 mg of 3-acetyl-4 ethylpyrrole in this solution
THF solution (10 ml) of (2.91 mmol) at 0 ° C
After dripping, the mixture was stirred at 0 ° C for 1 hour and then warmed to room temperature,
It was stirred for another 2 hours. After completion of the reaction, 20 ml of saturated aqueous sodium hydrogen carbonate solution was added at 0 ° C., and the mixture was extracted twice with 20 ml of dichloromethane. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. After filtering the desiccant and concentrating the solvent under reduced pressure, 3,4-dierutipyrrole 28
0 mg (45% yield) was obtained.

[0035]

EFFECTS OF THE INVENTION According to the method of the present invention, a synthetic intermediate of porphyrins, which is an important compound in the medical field and the like, is used without using an expensive raw material having a physical property problem unlike the conventional method. The 3,4-dialkylpyrroles useful as the above can be produced in a short process in a high yield.

Claims (2)

[Claims] 1. The following general formula (I): (In the above formula, R ¹ and R ² are each independently C ₁
It represents an alkyl group having -C _5. ) 3-acyl-
4-Alkylpyrroles as Wolff-Kishner
The following general formula (II) is characterized by being reduced or reduced with lithium borohydride. (In the above formula, R ¹ and R ² are as defined above.) A method for producing 3,4-dialkylpyrroles. 2. The method according to claim 1, wherein potassium t-butoxy is used as a salt in the Wolff-Kishner reduction.