CZ278391B6 - Substituted 5,15-diphenylporphyrins and process for preparing thereof - Google Patents

Abstract

New porphyrin derivatives of formula I, where Ar<l> and Ar<2> are phenyl or substituted phenyl, where the substituents are -NH2, -N(CH3)2, NO2, Cl, 2,6-dichlor, -NHCOCH3, CO2H, SO3H, OCH3, OH, or 2,5-dimethoxy and R<l> to R<4> are acryls with one to four carbon atoms. It concerns substances which are suitable as an initial system for synthesis of models of haemoglobin, a photosynthetic reaction centre and catalysts, modelling the characteristics of cytochrome P-450. The method of preparing these substances is based on the reaction of aromatic aldehydes with dipyryl methane derivates and subsequent oxidation of the primary arising porphyrinogen.<IMAGE>

Description

The invention relates to a process for the preparation of substituted 5,15-diphenylporphyrins.

The compounds of the invention are novel and have not been described. The literature describes the preparation of diarylporphyrins for the first time in 1981 by Australian authors (J. Org. Chem. 46, 4792-4795 (1981)), followed by the American group (J. Am. Chem. Soc. 107, 898-909). (1985)) and Soviet authors (Izv. Vys. Ucheb. Introduced. Chim. Tech. 31, 39 (1988)). .

and

The general procedure for the synthesis of 5,15-disubstituted porphyrins is based on the cyclization reaction of appropriately substituted benzaldehydes and dipyrrylmethane derivatives under acid catalysis and subsequent oxidation of the primarily formed porphyrinogen derivative. We have recently described a series of meso- (ortho- and para- substituted) diarylporphyrins, which are very suitable starting systems for the synthesis of models of hemoglobin, photosynthetic reaction center and catalysts modeling the properties of cytochrome P-450.

Water-soluble porphyrin substituted with sulfone groups is also a part of our novel substances. This type of substance appears to be very promising for the photodynamic treatment of cancer (Photochem. Photobiol. 50, 175-183 (1989)). The most important benefit is the simple synthesis of unsymmetrically substituted 5,15-diarylporphyrins. Our synthetic approach is based on the reaction of an equimolar mixture of two differently substituted benzaldehydes with a dipyrrylmethane derivative to produce an unsymmetrically substituted porphyrinogen, which oxidation yielded the corresponding unsymmetrical porphyrin. These compounds may serve, inter alia, as suitable models of the photosynthetic reaction center, wherein in one mesoposition (5-) quinone (electron acceptor) may be generated from the 2,5-dimethoxyphenyl derivative and in the other meso-position (15-) an electron donor is suitable, e.g. dimethylaminophenyl.

The present invention provides 5,15-diaryl-porphyrins of formula (I)

Kde 9 wherein Ar and Ar are phenyl or substituted phenyl wherein the substituents are - HN ₂ , -N (CH ₃ ) ₂ , NO ₂ , Cl, 2,6-dichloro, -NHCOCH ₃ , CO ₂ H, SO ₃ H, OCH ₃ , OH, 2,5-dimethoxy and R ¹ to R ⁴ are C ¹ -C ⁴ alkyls.

The process for preparing these substances consists in the dipyrryl ^7- methane derivative of the general formula II

wherein R ¹ -R ⁴ are as defined above, with a tonic aldehyde of formula III

Ar ^X CHO,

(//) reacting with an aroma (III) or an equimolar mixture of aldehydes of formula III and formula IV

Ar ² CHO (IV) wherein Ar ¹ and Ar ² are higher in the solvent of the alcohol room, then at 4 ° C to the porphyrinogen type product, in an inert atmosphere of the acid catalysis type at a temperature of 10-30 hrs and the resulting intergeneric of formula V

wherein Ar ¹ and Ar ² and R ¹ to R ⁴ are as defined above, are converted to the final product of formula I by oxidation.

As the compound of Formula II can be preferably used readily available and stable 3,3'-diethyl-4,4'-dimethyl-2,2'-dipyrrylmethan (R ¹ = R ⁴ = CH _3, R ² = R ³ = Et) which also gives the highest yields of porphyrins of formula I. For the macrocyclization reaction, methanol appears to be the most preferred solvent, and p-toluenesulfonic acid is the acid catalyst.

The reaction is usually carried out by adding a solution of the corresponding aromatic aldehyde to the solution of the dipyrrylmethane derivative in methanol under an inert atmosphere at room temperature, bubbling the reaction mixture through an inert gas (preferably argon, also pure nitrogen). carbon dioxide). Then the acid catalyst is added, the reaction is allowed to proceed for 5-10

-2 hours 278391 B6 hours at room temperature, then at 0-4 ° C for 10-30 hours. The resulting porphyrinogen is aspirated and oxidized with 2,3 dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in tetrahydrofuran at room temperature for 30-160 min.

Pure products were isolated by chromatography on silica gel in methylene chloride with 1-5% methanol, optionally by crystallization from methylene chloride / methanol.

A great advantage of the process of the present invention is that, in a simple experimental setup with readily available raw materials, unwritten 5,15-diarylporphyrins are obtained in very good yields. These compounds are important for use in the photodynamic treatment of cancer and further as building blocks for the synthesis of bridged porphyrins and metalloporphyrins.

The present invention is illustrated by the following non-limiting examples.

Example 1

Preparation of 5,15-diphenyl-2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin

3,3'-Diethyl-4,4'-dimethyl-2,2'-dipyrrylmethane (5 mmol, 1.15 g) and benzaldehyde (5 mmol, 0.503 g) were dissolved in 50 mL of methanol. Argon was bubbled through the solution for 15 min before p-toluenesulfonic acid (1 mmol, 0.190 g) was added. The reaction mixture was stirred for 20 minutes, then standing in the dark at room temperature for 7 hours, then the reaction mixture was cooled to 4 ° C and allowed to stand for 16 hours. The aspirated porphyrinogen (0.65 g) was dissolved in 50 ml of tetrahydrofuran, 0.6 g of o-chloranil was added. The reaction mixture was stirred at room temperature for 30 min. Then the solvent was evaporated, the residue was dissolved in methylene chloride and washed twice with saturated NaHCO ₃ solution and water. After drying over magnesium sulfate, the methylene chloride was evaporated and the pure product was obtained by column chromatography on silica gel in methylene chloride.

Yield 0.560 g (35.50%). For C ₄₄ H, _{4 g} of N ₄ (630.88) calculated: 83.77% C, 7.35% H, 8.88% N;

Found:% C, 83.61;% H, 7.37;% N, 8.82.

Mass spectrum (FAB positive, qlycerol, trifluoroacetic acid) m / z (%): 631 ([M ⁺ , 100), 632 ([MH] ⁺ , 64), 630 (M ⁺ , 28).

¹ H NMR spectrum (500 MHz, CDCl ₃ , δ): -2.42 (s, 2 Η, NH, pyrrole),

1.77 (t, 12H, CH ₃ -CH ₂ ), 2 '. (s, 12 H, _CH3), 4.02 (q, 8H,

CH ₂ -CH ₃ ), 7.74 (t, 4H, phenyl, 3-H), 7.78 (t, 2H, phenyl, 4-H), 8.08 (d, 4H, phenyl, 2-H), 10.23 (s, 2H methine).

UV-VIS spectrum (dichloromethane) _max (δ): 624 (3.16), 576 (6.04), 541 (2.23), 505 (1.73), 438 (34.17), 347 ( 8.06), 306 (7.48), 263 (6.26).

3GB 278391 B6

Example 2

Preparation of 5,15-bis (2,5-dimethoxyphenyl) -2,8,12,18-tetraethyl-3,7, -

13,17-tetramethylporphyrin

2,5-Dimethoxybenzaldehyde (10 mmol, 1.6618 g) and 3,3'-Diethyl-4,4'-dimethyl-2,2'-dipyrrylmethane (10 mmol, 2.30 g) were dissolved in 100 mL of methanol argon was bubbled through the reaction mixture for 10 min, then 0.5 g of p-toluenesulfonic acid was added and stirred at room temperature for 20 min. Standing at 25 ° C for 6 hours, then 20 minutes at 4 ° C. Porphyrinogen aspirate (3.8 g), dissolved in 100 ml tetrahydrofuran, 3.2 g 2,3-dichloro-5,6-dicyano-p-benzoquinone added, the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated, the residue washed 3 times with 5% sodium hydroxide solution and water.

Yield of the product 2.75 g (73.24%). Analytical sample obtained after crystallization from methylene chloride-methanol. For ^{C 4} H ₅₄ N ₄ O ₄ (750.99) calculated: 76.77% C, 7.25% H, 7.46% N;

Found:% C, 76.62;% H, 7.21;% N, 7.32.

Mass spectrum m / z (%): 751 ([M] ⁺ , 100), 752 ([MH] ⁺ , 66), 750 (20), 753 (19).

¹ H NMR spectrum (500 MHz, CDCl 3, δ): -2.35 (s, 2 Η, NH, pyrrole),

1.78 (t, 12 H, CH ₃ -CH ₂ ), 2.61 (s, 12 H, CH ₃ ), 3.65 and 3.68 (atropisomeric mixture) (s, 6 H, OCH ₃ , 2 , 25'-OCH ₃ ), 3.85 and 3.87 (a mixture of at. Ropoisomers) (s, 6 H, OCH ₃ , 5.5'-OCH ₃ ), 4.03 (q, 8 H, CH ₂ -CH ₃ ),

7.24 (t, 2H, phenyl), 7.31 (d, 2H, phenyl), 7.37 (t, 2H, phenyl), 10.20 (s, 2H, methine).

UV-VIS spectrum (dichloromethane) _max (e +): ⁵⁷⁴ (5.10), 540 (2.68), 439 (40.74), 408 (56.58), 304 (5.44), 238 ( 18.05).

Example 3

Preparation of 5,15-Bis (2-carboxyphenyl) -2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin

3,3'-Diethyl-4,4'-dimethyl-2,2'-dipyrrylmethane (10 mmol, 2.3 g) and 2-carboxybenzaldehyde (10 mmol, 1.501 g) were dissolved in 100 mL of methanol, bubbled through 10 mL min argon, 0.473 (2.5 mmol) p-toluenesulfonic acid was added. Stir at room temperature for 1 hour, then stand for 7 hours, then react at 4 ° C for 24 hours. The aspirated porphyrinogen (2.95 g) was dissolved in 100 ml of tetrahydrofuran, oxidized with 2.5 g of 2,3-dichloro-5,6-dicyano-p-benzoquinone; the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated, the residue washed with saturated sodium bicarbonate solution (3 x 50 mL), water (2 x 50 mL) and dried.

Yield of the product 2.65 g (73.72%). For C ₄₆ H ₄₆ N ₄ O ₄ (718.90) calculated: C 71.30, H 5.98, N 7.23.

Found: C, 71.16; H, 5.93; N, 7.14.

-4GB 278391 B6

Mass spectrum (FAB positive) m / z (%): 720 ((MH ⁺⁾ , 100), 721 ((MH + 1) ⁺ , 72).

¹ H NMR spectrum (500 MHz, DMSO, δ): -2.43 (s, 2 Η, NH, pyrrole),

1.73 (t, 12H, CH ₃ -CH ₂ ), 2.34 (s, 12H, CH ₃ ), 4.00 (m, 8'H,

CH ₂ -CH ₃ ), 7.98 (m, -6 H, phenyl), 8.33 (d, 2H, arom.), 10.18 (s, -2-H, methine) 12.11 ( bs, 2H (COOH).

Example 4

Preparation of 5,15-Bis (4-carboxyphenyl) -2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin

From 0.300 g (2 mmol) of 4-carboxybenzaldehyde and 0.46 g (2 mmol) of the dipyrrylmethane derivative, 0.395 g of product (54.95%) was obtained by the same procedure as in Example 3. For C ₄₆ H ₄₆ N ₄ O ₄ (718.90) calculated: C 71.30, H 5.98, N 7.23.

Found:% C, 71.11;% H, 5.89;% N, 7.12.

Mass spectrum m / z (%): 719 ([M] ⁺ , 100), 720 ([MH] ⁺ , 66), 718 (15).

^{Τ Η} NMR (500 MHz, CF ₃ CO ₂ D 8): 1.59 (t, 12H, CH ₃ -CH ₂₎

2.45 (s, 12 H, _CH3), 3.96 (m, 8 H, CH ₂ CH _3), 4.03 (m, 4 H, NH ₂ ^+, pyrrole), 8.28 (d, 2H, phenyl), 8.32 (d, 2H, phenyl), 8.54 (d, 2H, phenyl);

H, phenyl), 8.81 (d, 2H, phenyl).

Example 5

Preparation of 5,15-Bis (2-methoxycarbonylphenyl) -2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin

The compound was prepared by esterification of 5,15-bis (2-carboxyphenyl) -2,8, -

12,18-tetraethyl-3,7,13,17-tetramethylporphyrin using dimethyl sulfate and potassium carbonate in 70% yield. For ^c 48 ^H 50 ^N 4 ° 4 (746.96) calculated: 77.18% C, 6.75% H, 7.50% N;

Found: C, 77.06

Mass spectrum m / z (%): 747 ([M] ⁺ , 100), 748 ((MH) ⁺ , 69); 740 (21).

Nuclear Magnetic Resonance Spectrum (500 MHz, CDCl ₃ , δ): -2.37 (s, 2H, NH, pyrrole), 1.74 (t, 12H, CH ₃ -CH ₂ ), 2.41 (s, 12H). H, CH ₃ ), 3.55 and 3.60 (s, 6 H, OCH ₃ ), 3.99 (m, 8 H, CH ₂ -CH ₃ ), 7.98 (m, 6 H, phenyl) 8.36 (m, 2H, phenyl), 10.18 (s, 2H, methine).

-5GB 278391 B6

Example 6

Preparation of 5,15-Bis (2-methoxyphenyl) -2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin.

o-Methoxybenzaldehyde (20 mmol, 2.72 g) and 3,3'-diethyl-4,4-dimethyl-2,2'-dipyrrylmethane (20 mmol, 4.40 g) were dissolved in 200 mL of methanol, bubbled through 10 % p-toluenesulfonic acid was added. The reaction mixture was stirred for 20 minutes, then standing at room temperature for 6 hours and then at 4 ° C for 20 hours. The resulting porphyrinogen is aspirated (6 g), dissolved in 200 ml of tetrahydrofuran and oxidized with 5 g of 2,3-dichloro-5,6-dicyano-p-benzoquinone. The reaction was worked up in the usual manner (see Example 2).

Yield: 5.45 g (78.88%). For ^C 46 ^H 45 ^N 4 ^O 4 (690.94) calculated: 79.97% C, 7.29% H, 8.11% N;

Found: C 79.81, H 7.31, N 8.06.

Mass spectrum, m / z (%): 692. ((MH ⁺⁾ , 100), 693 ([MH + 1] ⁺ , 68), 662 (95), 663 (75).

¹ H NMR spectrum (500 MHz, CDCl ₃ , δ): -2.34 (s, 2H, NH, pyrrole),

1.77 (t, 12H, CH ₃ -CH ₂ ), 2.54 (s, 12H, CH ₃ ), 3.72 and 3.76 (s,

H, OCH ₃ ) (cis- and trans-pair of atropisomers), 4.01 (m, 8 H,

CH ₂ -CH ₃ ), 7.34 (m, 4H, phenyl), 7.67 (d, 1H, phenyl), 7.76 (m,

H, phenyl), 10.17 (s, 2H, methine).

Example 7

Preparation of 5,15-Bis (2-hydroxyphenyl) -2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin

The compound was prepared by cleavage of methyl groups from the appropriate bismethoxy derivative (Example 6). boron tribromide, Bismethoxy derivative (1 mmol, 0.691 g) was dissolved in 50 mL of absolute dichloromethane, 6 mL of 1 mmol of boron tribromide was added, stirred at room temperature for 3 days, after working up by shaking with saturated sodium bicarbonate solution 0.583 g (87.95%) was obtained by chromatography on silica gel, eluting with dichloromethane-methanol 20: 1. For C ₄ H ₄₆ N ₄ O ₂ (662.88) calculated: 79.73% C, 6.99% H, 8.45% N; Found: C 79.59, H 6.93, N 8.39.

Mass spectrum, m / z (%): 663 ((M] ⁺ , 100), 664 ([MH] ⁺ , 62).

^{Χ Η} NMR (500 MHz, CDC1 _3, 5): 1.78 (t, 12 H, _{CH3 -CH2),} 2.62 and 2.63 (s, 12 H, _CH3), 4.04 (m, 8 H, CH ₂ ' ^CH 3), 5.25 and 5.29 (s,

H, OH) (cis- and trans-atropisomer, 1: 1.36 ratio), 7.38 (m, 4H, phenyl), 7.74 (m, 4H, phenyl), 10.23 and 10, 27 (s, 2H, methine) (2 atropisomers).

-6GB 278391 B6

Example 8

Preparation of 5,15-Bis (2,6-dichlorophenyl) -2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin

Under the conditions of Example 2, from 2,6-dichlorobenzaldehyde (2 mmol, 0.35 g) and 3,3'-diethyl-4,4'-dimethyl-2,2'-dipyrrylmethane (2 mmol, 0.46 g). ) was obtained after separation by column chromatography (silica gel, methylene chloride) 0.10 g (13.02%) of the product. For

C44H42N4Cl4 (768.66) calculated: 68.75% C, 5.51% H, 7.29% N, 18.45% Cl; Found: C 68.61, H 5.53, N 7.11, Cl 18.22.

Mass spectrum, m / z (%): 769 ([M] ⁺ , 100), 768 (72), 770 ([MH] ⁺ , 58), 771 (22), 623 (24).

¹ H NMR spectrum (500 MHz, CDCl ₃ , δ): -2.34 (s, 2 Η, NH, pyrrole),

1.79 (t, 12 H, CH ₃ -CH ₂ ) 2.58 (s, 12 H, CH ₃ ), 4.03 (m, 8 H, CH ₂ -CH ₃ ), 7.71 (d, 2H, phenyl, 4-H), 7.79 (d, 4H, phenyl, 3-H, 5-H), 10.22 (s, 2H, methine).

Example 9

Preparation of 5,15-bis (2-sulfophenyl) -2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin disodium salt

Sodium salts of 2-formylbenzenesulfonic acid (2 mmol, 0.4884 g) (or 0.6105 and 75% technical grade) were dissolved in 50 mL of methanol and 0.46 g (2 mmol) of 3,3'-diethyl- 4,4'-dimethyl-2,2'-dipyrrylmethane, the reaction mixture is purged with nitrogen for 15 minutes, then 0.1 g of p-toluenesulfonic acid is added, stirred for 30 minutes, then standing at room temperature for 26 hours, then the methanol is evaporated, ml of methylene chloride, porphyrinogen oxidized with 0.5 g of 2,3-dichloro-5,6-dicyano-p-benzoquinone at room temperature, reaction time 3 hours. The product was aspirated, washed 5 times with 20 ml of methylene chloride and dried. Yield 0.31 g (37.12%). An analytical sample was obtained by reverse phase HPLC separation, mobile phase methanol-buffer (triethylammonium hydrogen carbonate). For C ₄₄ H ₄₄ N ₄ S ₂ O ₆ Na ₂ (835.23) calculated: 63.28% C, 5.31% H, 6.74% N, 7.68% S; Found:% C, 63.11;% H, 5.36;% N, 6.61.

Example 10

Preparation of 5,15-Bis (4-acetamidophenyl) -2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin

From 4-acetamidobenzaldehyde (2 mmol, 0.326 g) and 3,3'-diethyl-4,4'-dimethyl-2,2'-dipyrrylmethane (2 mmol, 0.46 g) was obtained analogously to Example 2 after purification by column chromatography 0.21 g (28.11%) of the product. For ^C 48 ^H 54 ^N 6 ° 2 ^(747/0)

-7C 278391 B6 calculated: 77.18% C, 7.29% H, 11.25% N;

Found:% C, 77.02;% H, 7.19;% N, 11.12.

Mass spectrum, m / z (%): 746 ([M ⁺ ], 100), 747 (M ⁺ , 65), 745 (22).

Example 11

5,15-Bis (2-nitrophenyl)-2,8,12,18-tetrabutyl-3,7,13,17-tetramethylporphyrin

Analogously to Example 2, the product was obtained in 22% yield from the starting 2-nitrobenzaldehyde (1 mmol) and 3,3'-dibutyl-1,4'-dimethyl-2,2'-dipyrrylmethane. For ^C 52 ^H 60 ^N 6 ° 4 (333.096) calculated: 74.97% C, 7.26% H, 10.09% N; Found:% C, 74.79;% H, 7.23;% N, 10.01.

Example 12

Preparation of 5- (4-Dimethylaminophenyl) -15- (2,5-dimethoxyphenyl) -2,8, -

12,18-tetraethyl-3,7,13,17-tetramethylporphyrin

To a mixture of 2,5-dimethoxybenzaldehyde (1 mmol, 0.1662 g) and 4-dimethylaminobenzaldehyde (1 mmol, 0.149 g) in 50 mL of methanol was added 2 mmol of 3,3'-diethyl-4,4'-dimethyl- 2,2'-dipyrrylmethane (0.46 g). The reaction mixture was 10 min. argon was bubbled through, then p-toluenesulfonic acid (0.1 g) was added. Proceed as in Example 2.

Yield of the product 0.125 G (34.06%). For C ₄₈ H ₅₅ N ₅ O ₂ (734.01) calculated: 78.55% C, 7.55% H, 9.54% N;

Found: C 78.39, H 7.47, N 9.51.

Mass spectrum, m / z (%): 735 ([MH] ⁺ , 100), 736 ([MH + 1] ⁺ , 72), 737 (12).

¹ H NMR spectrum (500 MHz, CDCl ₃ , δ): -2.36 (bs, 2H, NH, pyrrole),

1.76 (t, 12H, CH ₃ -CH ₂ ), 2.58 and 2.60 (s, 12H, CH ₃ ), 3.23 (s, 6H, N (CH ₃ ) ₂ , 3 67 (s, 3H, 0CH _3), 3.86 (s, 3H, _OCH3), 4.02 (m, 8 H, CH ₂ CH ₃₎ ^{7 "09 (t" 2H} "phenyl ^{3 7} ) ²⁴ (t, ^1H phenyl), 7.34 (t,

2H, phenyl), 7.86 (m, 2H, phenyl), 10.19 (s, 2H, methine).

Example 13

Preparation of 5- (4-Acetamidophenyl) -15- (2,5-dimethoxyphenyl) -2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin

To a solution of 2,5-dimethoxybenzaldehyde (1 mmol, 0.166 g) and acetemidobenzaldehyde (1 mmol, 0.163 g) in 50 mL of methanol was added

3,3'-diethyl-4,4'-dimethyl-2,2-dipyrrylmethane (2 mmol, 0.46 g).

-8GB 278391 B6

Reaction under similar conditions to Example 2. 0.1 g (26> 74%) of the product was obtained. For C ₄₈ H ₅₃ N ₅ 0 ₃ (747.989) calculated: 77.08% C, 7.14% H, 9 .36% N;

Found: C 77.00%, H 7.16%, N 9.22%.

Mass spectrum, m / z (%): 748 ([M] ⁺ , 100), 749 ([MH] ⁺ , 35), 747 ([M-1], 33).

Claims (2)

PATENT CLAIMS A compound of formula I wherein Ar ¹ and Ar ² are phenyl or substituted phenyl, wherein the substituents are -NH ₂ , -N (CH ₃ ) ₂ , NO ₂ , Cl, 2,6-dichloro, -NHCOCH ₃ , CO ₂ H, SO ₃ H, OCH ₃ , OH, or 2,5-dimethoxy a R ¹ to R ⁴ are alkyl of one to four carbon atoms. 2. A process for preparing 5,15-diarylporfvrinů formula I wherein dipyrrylmethanový derivative of the formula II wherein R ¹ to R ⁴ has the abovementioned meaning, is reacted with an aromatic aldehyde of formula III aAho (III) Or an equimolar mixture of aldehydes of formula III and formula IV / Ar ² CHO (IV) wherein Ar ¹ and Ar ² are as defined herein, in an alcohol-type solvent under acidic quenching in an inert atmosphere at room temperature, then at 4 ° C for 10 to 30 hours and the resulting intermediate of formula V wherein Ar ¹ and Ar ² and R ¹ to R ⁴ are as defined above are converted to the final product of formula I by oxidation. End of document