JPH07278105A - Pyrrole derivative - Google Patents

Abstract

PURPOSE:To obtain a novel pyrrole derivative useful as an intermediate for synthesizing a texaphyrin metal complex useful as an internal diagnostic, and enabling to safely produce the metal complex in a short process. CONSTITUTION:This compound is expressed by formula I (R<1> is H, 1-4C alkyl, 7-10C aralkyl; R<2> is H, 1-4C alkyl), e.g. 5-acetyloxymethyl-4-(3-acetyloxypropyl)-3- methylpyrrole-2-carboxylic acid benzyl ester. The compound is obtained by reacting a 4-(3-acyloxypropyl)-3,5-dimethylpyrrole-2-carboxylic acid ester of formula II with lead tetraacetate in acetic acid solvent or with a halogenating agent in the presence of an acetate salt. The compound of formula I can be reacted with 3,4-diethylpyrrole and, if necessary, subsequently reduced or acylated to give a compound of formula III (R<3> is H, benzyl; R<4> is H, acetyl) which is a synthetic intermediate for the texaphyrin metal complex.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel pyrrole derivative, and more particularly to a pyrrole derivative useful as an intermediate for the synthesis of metal complexes of texaphyrin which can be used as an in-vivo diagnostic agent.

[0002]

2. Description of the Related Art Metal complexes of texaphyrin, such as gadolinium texaphyrin, are known to be useful as in-vivo diagnostic agents (Sessler et al., J. Am. Chem. So.
c. , 1993, page 10368). Conventionally, this compound is the following intermediate (II)

[0003]

[Chemical 2]

It is known that R ³ represents a hydrogen atom or a benzyl group, and R ⁴ represents a hydrogen atom or an acetyl group (Sessler et al.
WO9314093 A1 and Sessler et al.,
Inorg. Chem. , 32, 1993, 317
(See page 5). For example, as shown in Scheme 1 below, 5-acetoxymethyl-3-methyl-4- (2-methoxycarbonylethyl) -2-pyrrolecarboxylic acid
Compound (V) obtained by reacting benzyl ester (III) with 3,4-diethylpyrrole is reduced with diborane to give intermediate (II-a), which is further acetylated. To give the intermediate (II-b). Further, the intermediate (II-b) is reduced in the presence of Pd / C to obtain the intermediate (II-c). Scheme 1

[0005]

[Chemical 3]

In addition, the intermediate (II-a) is hydrogen, Pd / C
The intermediate (II-d) is obtained by reduction in the presence of. Scheme 2

[0007]

[Chemical 4]

However, this method has a long process, and not only the selectivity of reduction of two ester groups existing in the same molecule becomes a problem but also diborane, which is extremely toxic and difficult to handle, must be used. There is. Therefore, this 5-acetoxymethyl-3-methyl-4- (2
There has been a demand for a method capable of synthesizing (II) without passing through -methoxycarbonylethyl) pyrrole-2-carboxylic acid ester (III).

[0009]

Means for Solving the Problems As a result of searching for a compound capable of easily synthesizing compound (II) in order to solve these problems, the present inventors have found a novel and useful pyrrole derivative and completed the present invention. Came to. That is, the gist of the present invention is the following general formula (I)

[0010]

[Chemical 5]

(In the above general formula (I), R ¹ is a hydrogen atom,
It represents a C ₁ -C ₄ alkyl group or a C ₇ -C ₁₀ aralkyl group, and R ² represents a hydrogen atom or a C ₁ -C ₄ alkyl group. ) Exists in the pyrrole derivative represented by. The present invention will be described in detail below. The compound of the present invention has the following general formula (I)

[0012]

[Chemical 6]

[In the above general formula (I), R ¹ is a hydrogen atom,
Alkyl C ₁ -C ₄ (methyl, ethyl, n- propyl, n- butyl group, an isopropyl group, an isobutyl group, t- butyl group:. Of the following groups 1) or C ₇ ~
Represents a C ₁₀ aralkyl group (benzyl group, 2-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group, etc.), R ² represents a hydrogen atom or a C ₁ -C ₄ alkyl group (group 1). Represent ] It is a pyrrole derivative represented by these. Among the compounds of the present invention, preferred compounds include R ¹
Is a benzyl group, and R ² is a methyl group. Next, a method for producing the compound of the present invention represented by the following formula will be described.

[0014]

[Chemical 7]

(Wherein R ¹ and R ² are the same as defined above) The compound (I) of the present invention is represented by the general formula 4-
(3-acyloxypropyl) -3,5-dimethylpyrrole-2-carboxylic acid ester (VI) is reacted with lead tetraacetate in an acetic acid solvent, or is less toxic.
As a method suitable for mass production, it can be synthesized by reacting with a halogenating agent in the presence of acetate. Examples of the acetate include lithium acetate, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, ammonium acetate, etc., which are used in an amount of about 0.5 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound (VI). Use about equivalent amount. Examples of the halogenating agent include sulfuryl chloride, chlorine, bromine, iodine, N-bromosuccinimide, N-chlorosuccinimide and the like, which are 0.5 to 1.5 equivalents relative to compound (VI). Degree, preferably 0.8
Use about 1 to 1.2 equivalents. The reaction solvent is not particularly limited as long as it does not adversely affect the reaction, but acetic acid,
N, N-dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene, chloroform, methylene chloride, tetrahydrofuran, etc. can be used. The reaction temperature is between -20 ° C and the boiling point of the solvent, preferably 0 ° C to 70 ° C. The obtained crude product is recrystallized,
It can be purified by a conventional purification method such as column chromatography. The above compound (V
I) is 4- (2-alkoxycarbonylethyl) -3,
Although it can be obtained by acylating 4- (3-hydroxypropyl) -3,5-dimethylpyrrole-2-carboxylic acid ester obtained by reducing 5-dimethylpyrrole-2-carboxylic acid ester with diborane, (J.Hio
m et al., Can. J. Chem. 61, p. 2220, 1983), 3- (3
-Acyloxypropyl) -2,4-pentanedione and a general method for synthesizing a pyrrole derivative with acetoacetic acid esters (for example, edited by J. ApSimon, The Total).
Synthesis of Natural Prod
cts, Vol. 1, pp. 143-278 (1973)).

The compound of the present invention represented by the above general formula (I) is reacted with 3,4-diethylpyrrole and, if necessary, reduced or acylated to lead to a synthetic intermediate (II) of a metal complex of texaphyrin. be able to.

[0017]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples as long as the gist of the present invention is not exceeded. Reference Example 1 Synthesis of 3- (3-acetyloxypropyl) -2,4-pentanedione 2,4-pentanedione (37.09 g, 0.37 mol) and acetic acid 3-chloropropyl ester (50.6 g,
0.37 mol) of N, N-dimethylformamide (18
5 ml) and add sodium carbonate (39.22
g, 0.37 mol), sodium iodide (11.1 g,
0.074 mol) was added, and the mixture was heated with stirring at 95 to 100 ° C. for 5.5 hours. After cooling the reaction solution, ethyl acetate (600 m
1) and water (500 ml) were added, and 6N hydrochloric acid was added to adjust the pH of the aqueous layer to about 7.0. The layers were separated and the aqueous layer was washed with ethyl acetate (3
25 ml), the organic layers were combined and 5% brine (20
The extract was washed with 0 ml × 5), then saturated saline (200 ml), and dried over anhydrous magnesium sulfate. The organic solvent was distilled off under reduced pressure, and acetic acid (130 ml) and water (3
3 ml) was added and the mixture was stirred at 70 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (300 ml) was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (100 ml × 5) and then saturated brine (50 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the remaining oil was distilled under reduced pressure to obtain the title compound (30.08 g, yield 42%). bp1
31-135 ° C / 3.5mmHg

¹ H NMR (250 MHz, CDC
l ₃ ) δ 1.52-2.45 (m, 13H), 3.6
6 (t, J = 7.3 Hz, 0.76H, peak of keto body), 4.04-4.12 (m, 2H), 16.74
(S, 0.24H, peak of enol form)

Reference Example 2 Synthesis of 4- (3-acetyloxypropyl) -3,5-dimethylpyrrole-2-carboxylic acid benzyl ester Acetoacetic acid benzyl ester (3.84 g, 20 mmol) was dissolved in acetic acid (8 ml). Then, a solution prepared by dissolving sodium nitrite (1.66 g, 24 mmol) in water (3 ml) was added dropwise thereto at 3 to 13 ° C. The brown solution obtained after stirring for 2 hours was treated with 3- (3-acetyloxypropyl) -2,4-pentanedione (4.00 g, 2) obtained in Reference Example 1.
0 mmol), zinc powder (2.62,40 mmol),
Drop into a mixture of acetic acid (8 ml) at 66-73 ° C.
The reaction solution was heated under reflux for 30 minutes, cooled to about 50 ° C., and poured into ice water (50 ml). After stirring for 30 minutes, the precipitated crystal was collected by filtration, washed with water, and recrystallized from water-containing methanol to obtain the title compound (2.96 g, yield 45%) as a pale yellow crystal. mp76-77 ° C

¹ H NMR (250 MHz, CDC
l ₃ ) δ 1.70-1.80 (m, 2H), 2.06
(S, 3H), 2.18 (s, 3H), 2.27 (s,
3H), 2.44 (t, J = 7.2Hz, 2H), 4.
02 (t, J = 6.6 Hz, 2H), 5.29 (s, 2
H), 7.32-7.44 (m, 5H), 8.65 (b
rs, 1H).

Example 1 Synthesis of 5-acetyloxymethyl-4- (3-acetyloxypropyl) -3-methylpyrrole-2-carboxylic acid benzyl ester 4- (3-acetyloxypropyl) -3,5-dimethyl Pyrrole-2-carboxylic acid benzyl ester (11.
53 g, 35 mmol) and anhydrous sodium acetate (11.
48 g, 140 mmol) was dissolved in acetic acid (140 ml), and sulfuryl chloride (2.97 ml, 36.7 mmol) was added dropwise thereto at 16 to 19 ° C. over 20 minutes. After stirring at room temperature for 1 hour, water (280 ml) was added and the mixture was stirred, and the precipitated solid was collected by filtration and washed with water. This was recrystallized from water-containing methanol to give the title compound (8.27 g, yield 61
%) Was obtained. mp103-104 ° C

¹ H NMR (250 MHz, CDC
l ₃ ) δ 1.73-1.82 (m, 2H), 2.06
(S, 6H), 2.28 (s, 3H), 2.54 (t,
J = 7.2 Hz, 2H), 4.02 (t, J = 6.4H
z, 2H), 4.99 (s, 2H), 5.31 (s, 2)
H), 7.32-7.45 (m, 5H), 9.02 (b
rs, 1H).

Reference Example 3 2,5-bis [(3- (3-acetoxypropyl) -5]
Synthesis of-((benzyloxy) -carbonyl) -4-methylpyrrol-2-yl) methyl] -3,4-diethylpyrrole 5-Acetyloxymethyl-4- (3- obtained in Example 1
Acetyloxypropyl) -3-methylpyrrole-2-
Carboxylic acid benzyl ester (5.20 g, 13.4 mmol) was dissolved in acetic acid (100 ml) with slight heating,
After degassing under reduced pressure, the atmosphere was replaced with nitrogen. 3,4-Diethylpyrrole (0.827 g, 6.71 mmol) and then p-toluenesulfonic acid monohydrate (35 mg) were added thereto, and the mixture was stirred at 56 to 61 ° C for 3 hours. After cooling to room temperature, anhydrous sodium acetate (100 mg) and then water (200 m
1) was added and the mixture was extracted with methylene chloride (100 ml, 50 ml). The extracts were combined, washed with saturated aqueous sodium hydrogen carbonate (50 ml × 3) and water (50 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol (100 ml) to obtain the title compound (3.88 g, yield 74%).

Mp 125-126 ° C. ¹ H NMR (250 MHz, CDCl ₃ ) δ 1.1
2 (t, J = 7.5 Hz, 6H), 1.64-1.72
(M, 4H), 2.03 (s, 6H), 2.22 (s,
6H), 2.38 (t, J = 7.7Hz, 4H), 2.
47 (q, J = 7.5 Hz, 4H), 3.59 (s, 4
H), 3.98 (t, J = 6.3 Hz, 4H), 4.5
5 (br s, 4H), 7.05 to 7.34 (m, 10
H).

[0025]

INDUSTRIAL APPLICABILITY The pyrrole compound of the present invention is useful as a synthetic intermediate for a metal complex of texaphyrin, and by using the compound of the present invention, the metal complex of texaphyrin can be safely produced in a short process.

Claims (1)

[Claims] 1. The following general formula (I): (In the general formula (I), R ¹ represents a hydrogen atom, a C _{1 to} C ₄ alkyl group or a C _{7 to} C ₁₀ aralkyl group, and R 1
² represents a hydrogen atom or a C ₁ -C ₄ alkyl group. )
The pyrrole derivative represented by.