JPH07316131A - Production of pyrrole derivative - Google Patents

Abstract

PURPOSE:To easily obtain in high purity a pyrrole derivatlve at a low cost useful as an intermediate for synthesizing texaphyrins useful in the medicinal area, by reducing a diethylpyrrole derivative with lithium borohydride. CONSTITUTION:A compound of formula I (R is a 1-4C alkyl; ph is phenyl) is reduced with lithium borohydride in a solvent (e.g. THF) at -50 to 150 deg.C (pref. -20 to 100 deg.C) to obtain the objective compound of formula II. The amount of the lithium borohydride to be used is 0.1-20 (pref. 0.5-5)mol per mol of the compound of formula I. By this method, the objective pyrrole derivative can be produced without the need for using diborane, a highly toxic reducing agent. The texaphyrins derived from this pyrrole derivative, e.g. gadolinium texaphyrin, are useful as in vivo diagnostics.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a process for producing a pyrrole derivative which is a synthetic intermediate useful for producing texaphyrins which are compounds useful in the medical field, and more specifically to 2,5-bis [(pyrrole-2 -Yl) methyl] pyrrole derivatives.

[0002]

BACKGROUND OF THE INVENTION Metal complexes of texaphyrin, such as gadolinium texaphyrin, are useful as in-vivo diagnostic agents (Sessler,
etc. J. Am. Chem. Soc. , 115 , 1
0368 (1993), Sessler. etc. , A
cc. Chem. Res. , 27 , 43 (199
4)). It is known that this compound can be synthesized by a route using a compound represented by the following general formula (II) as an intermediate (Sessler, Inorg. Chem., 3
2 , 3175 (1993)), and the compound of the following general formula (II) is synthesized from the compound of the following general formula (I). At this time, it is necessary to selectively reduce two kinds of ester groups of the compound of the following general formula (I), and diborane is used as a reducing agent. However, since diborane is a highly toxic reducing agent, there has been a strong demand for reducing agents other than diborane that selectively reduce ester groups.

[0003]

[Means for Solving the Problems] As a result of intensive studies aimed at developing a reducing agent having low toxicity, the present inventors have found that the use of lithium borohydride selectively reduces an ester group in the same manner as diborane. The inventors have found what can be done and have reached the present invention. That is, the gist of the present invention is the general formula (I)

[0004]

[Chemical 3]

(In the above formula, R represents a C ₁ -C ₄ alkyl group and ph represents a phenyl group.) A compound represented by the following general formula characterized by reducing with lithium borohydride Formula (II)

[0006]

[Chemical 4]

The method is for producing a pyrrole derivative represented by Hereinafter, the present invention will be described in detail. Examples of R in the general formula (I) include C _{1 to} C ₄ alkyl groups such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n-butyl group. As the lithium borohydride used in the present invention, commercially available products can be used, but in order to carry out the reaction more economically, sodium borohydride or potassium borohydride is added to lithium chloride or lithium bromide in the reaction system. It is also possible to prepare lithium borohydride by reacting a lithium salt such as lithium iodide. The lithium salt is used in an amount of 0.1 to 10 molar equivalents, preferably 0.5 to 2 molar equivalents, based on the metal hydrogen complex compound such as sodium borohydride. When lithium borohydride is produced in the reaction system, a method of reacting the compound of the above general formula (I) after previously producing lithium borohydride, or the presence of the compound of the above general formula (I) It does not matter whether the metal complex compound is reacted with a lithium salt. The required amount of lithium borohydride is 0.1 to 20 molar equivalents, preferably about 0.5 to 5 molar equivalents, with respect to the compound of the general formula (I).

The reaction solvent is not particularly limited as long as it does not adversely affect the reaction, and diethyl ether, tetrahydrofuran, n-hexane, benzene, toluene, ethanol, isopropanol and the like can be used. The reaction temperature is in the range of -50 to 150 ° C, preferably -20 to 100.
It is in the range of ° C. The crude composition thus obtained is recrystallized,
It can be purified by column chromatography or the like.

[0009]

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 Lithium borohydride (22.7 mg, 1.0 mmo
1) tetrahydrofuran (THF) suspension (2 ml)
2,5-bis [(5-benzyloxycarbonyl-
3-methoxycarbonylethyl-4-methylpyrrole-
2-yl) methyl] -3,4-diethylpyrrole (compound of general formula (I), R = Me) (141 mg, 0.19
mmol) was added and the mixture was heated with stirring at 40 ° C. for 4 hours. The reaction solution was cooled, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over potassium carbonate, filtered, and the solvent was evaporated to remove 2,5-bis [(5-benzyloxycarbonyl-3- (3-hydroxypropyl) -4-methylpyrrol-2-yl) methyl. ] -3,4-diethylpyrrole (compound of general formula (II)) (118 mg, yield 8)
4%).

[0010]¹H-NMR 1.11 (6H, t, J = 7.5Hz, CH₂CH₃)
1.57-1.61 (m, 4H, CH₂CH₂CH₂O
H) 2.24 (6H, S, Pyrr-CH₃)  2.41-2.48 (8H, m, CH₂CH₃ and
CH₂CH₂CH₂OH)  3. 51 (4H, t, J = 6.0 Hz) 3.75
(4H, S, Pyrr) ₂-CH₂) 4.99 (4H,
S, C₆H_Five-CH₂) 7.17-7.40 (10H,
m) 8.52 (S, 1H, NH) 9.44 (S, 2)
H, NH)

Example 2 Potassium borohydride (54.6 mg, under a nitrogen atmosphere)
1.0 mmol) and lithium chloride (43.4 mg, 1.
A THF suspension (2 ml) of 0 mmol) was stirred at room temperature for 4 hours to generate lithium borohydride in the reaction solution, and then the compound of general formula (I) (R = Me) (149.8).
(mg, 0.2 mmol) was added and the mixture was heated under reflux for 1.5 hours. By performing the post-treatment in the same manner as in the method of Example 1,
Compound of general formula (II) (137.5 mg, yield 99%)
Got

Example 3 Potassium borohydride (52.1 mg,
1.0 mmol), lithium chloride (42.5 mg, 1.
0 mmol) in THF (2 ml), and a compound of general formula (I) (R = Me) (140.7 mg, 0.1
(9 mmol) was mixed, and the mixture was heated with stirring at 40 ° C. for 6 hours.
Post-treatment was carried out in the same manner as in the method of Example 1 to obtain a compound of the general formula (II) (122.2 mg, yield 93%).

[0013]

Industrial Applicability According to the method of the present invention, a pyrrole derivative useful as a synthetic intermediate for texaphyrins, which is a compound useful in the medical field and the like, can be easily and inexpensively produced without using highly toxic diborane. It can be produced in high purity by the method.

Claims (1)

[Claims] 1. The following general formula (I): (In the above formula, R represents a C ₁ -C ₄ alkyl group, and ph
Represents a phenyl group. ) A compound represented by the following general formula (II), which is characterized by reducing with lithium borohydride. The manufacturing method of the pyrrole derivative represented by.