JPS63238078A - Production of porphyrin having perfluoroalkyl group - Google Patents

Abstract

PURPOSE:To readily obtain the titled substance useful as a ligand of metal complex which is a oxidation-reduction reaction catalyst inn good yield, by subjecting hydroxymethylpyrrol to cyclotetramerization in the presence of an acid catalyst or in the absence of catalyst. CONSTITUTION:A compound expressed by formula I (R is -4C perfluoroalkyl; R' is H, alkyl, aryl or alkenyl) (novel substance) is subjected to cyclotetramerization in the presence of an acid catalyst (e.g. hydrobromic acid) or in the absence of catalyst to provide the compound expressed by formula II. Improvement of catalytic function as well as effect for prolonging catalyst life is expected by introducing a perfluoroalkyl group having large electron- attracting properties into a porphyrin ring.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] 7 The present invention relates to a method for producing a fluorine-containing porphyrin useful as a ligand for a gold J# complex, which is a catalyst for redox reactions.

Porphyrin compounds, especially iron-porphyrin complexes, play important roles in living organisms, such as oxygen transport, oxidation reactions, and electron transfer.

Porphyrins have attracted attention from the viewpoint of mild and selective catalyst searches, and porphyrins with central metals such as Fe, Go, Mn, and Rh have been used for epoxidation of 2N1f bonds, hydroxylation of aromatic and aliphatic compounds, and oxidation of ketones. It has been found to be an effective catalyst for reduction.

By introducing a highly electron-withdrawing perfluoroalkyl group into the porphyrin ring, it is expected that the catalytic activity will be improved due to changes in electron distribution and interaction with the central metal.

Furthermore, the introduction of a perfluoroalkyl group that is resistant to oxidation is expected to have the effect of extending the catalyst life.

On the other hand, the specific accumulation of porphyrins in tumor areas has been utilized to diagnose and treat cancer.
If fluorine-containing porphyrins are modified in some way, they can be incorporated into affected areas in living organisms, and are expected to be used as chemical probes that utilize the magnetic properties of F nuclei.

[Conventional technology and problems]

The present inventors derived a tetrasubstituted virole having a trifluoromethyl group at the β-position and a carboxyl group and a carbinol group at the α-position from trifluoroacetoacetic ester through several steps, and conducted a template reaction using copper. Copper porphyrin is obtained and then metal removed to obtain tetrakis(trifluoromethyl) (Tetrahedron Lett., 24. 43
43 (1983)).

However, this manufacturing method is complicated and requires multiple steps.
Template reactions using copper also resulted in low yields.

[Means to solve the problem]

After studying an advantageous method that does not have the above-mentioned problems, the present inventors found that
A pyrrole compound having a perfluoroalkyl group at the β-position and hydrogen at the α-position, which is easily obtained from a perfluoroalkyl-substituted olefin compound and tosylmethylisocyanide, is formylated at the α-position, and then this formyl group is reduced. and a novel hydroxymethylpyrrole (general formula (■
)) was obtained.

(In the formula, R represents a perfluoroalkyl group having up to 4 carbon atoms, or R represents a hydrogen, alkyl, aryl, or alkenyl group.) By cyclizing and tetramerizing this new compound with an acid catalyst or without a catalyst, We succeeded in obtaining porphyrin in good yield.

That is, the present invention provides a porphyrin having a perfluorofurkyl group represented by the general formula CI A method for producing a porphyrin having a perfluoroalkyl group, which comprises tetramerizing hydroxymethylvirol represented by the general formula (n) (wherein R and R' have the above-mentioned meanings). be.

The novel compound (n) used in the present invention can be produced by formylating pyrrole of the general formula (I[[) (R, R' have the above-mentioned meanings) and then reducing it.

Various reaction reagents can be used in the formylation step, but Vils using DMF in the presence of phosphoryl chloride
The meier reaction proceeds with good yield. It is also characteristic that the formyl group is introduced selectively into the virol ring from the 2-position to the 4-position perfluoroalkyl group.

Reduction of the formyl group is easily carried out by hydrogen reduction in the presence of a catalyst such as Pd or pt, or by using a metal hydride such as lithium aluminum hydride or sodium borohydride. The step of producing porphyrin by converting the hydroxymethylvirol obtained in this way into 4u does not require the use of a template reaction using copper or the like, and the compound undergoes condensation and ring formation due to its own high reactivity. However, in order for the reaction to proceed smoothly, pyrrole must be dissolved in an alcohol or halogen-containing medium, and organic acids such as formic acid or acetic acid, or mineral acids such as hydrochloric acid, hydrobromic acid, or hydroiodic acid, must be added. It is preferable to use the method of

Hereinafter, the present invention will be explained in more detail with reference to Examples.

Reference example-1 a, 1.1.1-trifluoro-2-pentene-4
- Production of acetylmethylenetriphenylphosphorane 6.36g
(20 mmol) was suspended in 50 ml of ether complex,
Trifluoroacetaldehyde ethyl hemiacetal 1
0g (69mmol) and 50ml of concentrated sulfuric acid to 70~8
Fluoral, which was generated dropwise at 0°C, was passed through. After removing solids from the reaction mixture, distillation is performed to reduce the boiling point to 85-8.
1.1.1-trifluoro-2-pentene-4- at 7°C
2.08 g (yield: 75.2%) of ion was obtained.

'HNMR (CDCI): δ 2.36 (S
, 3H), 6.58 (IH), 6.65 (18) IR (KBr): W 1711.169
5 (CO), 130B, 1275.1188. 1140 (CF3) -1 Mass (m/e): 138 (M+)b
, 1.1.1-Trifluoro-2-penten-4-one 5
50■ (4.0 mmol) and p-Tolue'Jsu) Lt
Honylmethylisocyanide 780■ (42 mmol)
was dissolved in 13 ml of ether and 6.5 mA of DMSO, and 400 mg of 50% sodium hydride (8,
3 mmol) in 4 ml of ether over 1 hour.

After the dropwise addition, the mixture was stirred for an additional 30 minutes, and then 80 ml of water was added to perform ether extraction. Recrystallization from chlorophorf-n-pentane gave 310 ml of white 3-acetyl-4-)lifluoromethylpyrrole (yield: 43.8%).

The melting point was 175-177°C.

18NMR (CDCI3”): δ 2.47 (S
, 3H), 7.22 (m, IH), 7.46 (n+, IH), 9.14 (S, IH, NH) "PNMR (CD30D): -58,4ppm
(S) (CFCI3 standard) IR (KBr): v 3140 (NH
), 1650 (CO), 123B, 1175
．． 1125. 1097 (CF3) aa-' Mass (m/e): 177 (M”)c
, Production of 3-ethyl-4-trifluoromethylvirol 3~Acetyl-4-trifluoromethylvirol 2.0
g (11.3 mmol) was dissolved in 44 ml of THP, the atmosphere was replaced with nitrogen, and the mixture was cooled on ice. Add 2.06 g (54.5 mmol) of sodium borohydride, then 10.54 g (3.5 mmol) of boron trifluoride/ether complex.
mmol) was added dropwise. After stirring at room temperature for 1 hour, 20 ml of water was added under cooling for decomposition, followed by ether extraction. 1.8 g (yield 98%) of liquid 3-ethyl-4-trifluoromethylvirol was obtained.

l) I-NMR (CDCI3): δ 1.13 (
t, 3u), 2.52 (q, 2H), 6.46 (m, IH), 6.92 (m, IH), 8.95 (S, IH) Reference example-2 a, 1-phenyl- Production of 4,4,4-)rifluoro-2-buten-1-one In the same manner as in Reference Example 1, benzoylmethylenetriphenylphosphorane was reacted with fluoral to produce a product with a boiling point of 200
1-phenyl-4,4,4-trifluoro-2-buten-1-one at ~201°C was obtained with a yield of 81.1%.

'H-NMR (CDC13): 66.86 (II
I), 6.96 (1B), 7.56 (m, 3H), 7.88 (m, 2H) IR (KBr): V 1692 (CO
), 1311 1280°1190.1140 (C
F3) all-1Mass (m/e): 2
00 (M b) Production of 3-benzoyl-4-trifluoromethylvirol from 1-phenyl-4,4,4-trifluoro-2-buten-1-one and tosylmethylisocyanide Reference Example-1
3-benzoyl-4-trifluoromethylvirol, which is a white crystal with a melting point of 182-183°C, was synthesized in the same manner as above. The yield was 49.2%.

11I-NMR (CDCl2): δ 6.93 (
a+, 1B), 7.38 (m, 111), 7.49 (m, 3H), 7.71 (m, 2H), 9.01 (S, 11()"F-NMR (CD30D): - 57.8pp
m (S) (CFC13 standard) IR (KBr): v 3220 (Nl
l>, 1612 (Co) 1239.1190. ．．
1141. 1110 (CF) cm"-'Mass (m
/e): 239 (M”)C0 Production of 3-benzyl-4-trifluoromethylvirol 3-benzoyl-4-trifluoromethylvirol is reduced with diborane to produce liquid 3-benzyl-4-trifluoromethyl Got Virol.

The yield was 93%.

1H-NMR (CDCl2): δ 3.88 (S
, 2) 1), 6.28 (m, It(), 7.00 (m, IH), 7.27 (S, 511), 8.33 (S, IH) Reference example-3 a, 2- Production of formyl-3-ethyl-4-trifluoromethylvirol A Vilsmeier reagent was prepared from 1.2 g of DMF and 2.6 g of phosphorus oxychloride, and 5.2 g of 1,2-dichloroethane was prepared.
mj! The mixture was diluted with water and cooled to 5°C. Next, 3-ethyl-4-trifluoromethylvirol 1 synthesized in Reference Example 1
．． A solution of 8 g (llmmol) in 3.8 ml dichloroethane was added dropwise and stirred.

After the dropwise addition, the mixture was heated under reflux for 15 minutes, a 15 mA aqueous solution of 7 g of anhydrous sodium acetate was added, and the mixture was further refluxed for 15 minutes. After cooling, the mixture was extracted with chloroform and purified by alumina column chromatography (chloroform elution) to obtain 1.82 g (yield: 86.4%) of 2-formyl-3-ethyl-4-trifluoromethylvirol as white crystals. Ta.

The melting point was 90-92°C.

1H-NMR (CDCl2): δ t, 30 (t, 3
+1), 2.91 (q, 211), 7.39 (S, 1B), 9.70 (S, 18), 10.89 (S, 111) 1'F-NMR (CDCl2): -56, 03
1) I)m (CFCI3 standard) IR (KBr): V 3250 (NH
), 1655 (Co) 1288.1288.12
19.1126.1090 (CF3) cm −1 Mass (m/e): 191 (M”)b
, Production of 2-hydroxymethyl-3-ethyl-4-trifluoromethylvirol 200 mg (1,05 mmol) of 2-formyl-3-ethyl-4-trifluoromethylvirol was dissolved in THF.
Dissolve in 40ml of sodium borohydride (800ml)
21.1 mmol) was added thereto, and the mixture was stirred at room temperature for 5 hours.

After neutralization by adding 0.5% diluted hydrochloric acid, extraction with ether and purification by alumina column chromatography (chloroform elution) produced 2-hydroxymethyl-3-, which is a colorless liquid.
Ethyl-4-trifluoromethylvirol 164■
(yield 81.2%).

111-NMR (CDCl2): δ 1.10 (t,
3H), 2.37 (q, 2H), 4.47 (5,211), 6.85 (IH), 8.87 (S, III) Example 1 1.3.5.7 Tetrakis (trifluoro methyl)-2
, 2-hydroxymethyl-3-ethyl- synthesized in Reference Example 3-b
4-trifluoromethylpyrrole 145rrg (0,
75 mmol), 5 ml of chloroform and 20 ml of ethanol! When the solution was dissolved in water, 4 to 5 drops of hydrobromic acid were added thereto, and the mixture was stirred at room temperature F for 2 days, crystals precipitated.

The crystals are filtered, washed with ethanol and dried, 1.3.
5.7-Tetrakis(trifluoromethyl)-2゜4.
3.5 purple crystals of 6.8-tetraethylporphyrin
■(27%) obtained.

"H-NMR (CDCI3): 6-3.58 (S
, 2H, Nl(), 1.94 (t, 12+1), 4.29 (q, 8H), 10.42 (S, 411) "F-NMR (CDC13): -49,47ppm
(CFCI, standard) IR (KBr): v 3310 (NH
), 1120.1050 (CF) am-
1 Reference Example 4 a, Production of 2-formyl-3-benzyl-4-trifluoromethylpyrrole 3-benzyl-4-trifluoromethylpyrrole synthesized in Reference Example 2-C was treated with Vilsmeier reagent in the same manner as in Reference Example 3. formylation with 2-formyl-3-benzyl-4-
Crystals of trifluoromethylpyrrole were obtained. Yield is 76
．． At 6%, the melting point was 92-93°C.

1H-NMR (CDCI3): δ 4.22 (S
, 211), 7.18.7.28 (t, 5H) 7.33 (S, IH), 9.50 (S, IH), 10.98 (S, III) 19F-NMR (CDCI3): - 55,77pp
m (S) (CFC13 standard) IR (KBr): v 3270 (NH)
, 1659 (CO) 1289.1230.1138. 1111 (CF) cm-' Mass (m/e): 253 (M”)b
, Production of 2-hydroxymethyl-3-benzyl-4-trifluoromethylpyrrole The formyl compound was reduced with sodium borohydride to produce 2-hydroxymethyl-3-benzyl-4-trifluoromethylpyrrole.
Hydroxymethyl-3-benzyl-4-trifluoromethylpyrrole was obtained as a liquid.

The yield was 84.3%.

"H-NMR (CDCI, ): 63.91 (S, 2
H), 4.36 (S, 2H), 6.93 (S, 111), 7.12.7.20 (m, 5H) 8.82 (S, IH) Example 2 1.3, 5. 7-tetrakis(trifluoromethyl)-
Production of 2,4,6,8-tetrabenzylporphyrin 85 µm of 2-hydroxymethyl-3-benzyl-4-trifluoromethylvirol synthesized in Reference Example 4-b was treated in the same manner as in Example 1. , purple crystal 1,3.5.7-
Tetrakis(trifluoromethyl)-2,4,6,8-
19 ml of tetrabenzylporphyrin (yield 24%) was obtained.

11I-NMR (CDCI3): δ -3,38 (S
, 2H, NH), 5.62 (S, 8) 1), 7.28.7.59 (m, 2011) 10.48
(S, 4) 191'-NMR (CDC13): -48,72
ppm (S) (CFCI3 internal standard)

Claims (1)

[Claims] General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R is a perfluoroalkyl group having up to 4 carbon atoms, and R^1 is hydrogen, alkyl, aryl, When producing a porphyrin having a perfluoroalkyl group represented by the formula (representing an alkenyl group), general formula (II) ▲ mathematical formula, chemical formula,
There are tables etc. ▼(II) A method for producing a porphyrin having a perfluoroalkyl group, which is characterized by tetramerizing hydroxymethylpyrrole represented by the following (in the formula, R and R^1 have the above-mentioned meanings).