WO2008090078A1

WO2008090078A1 - Method for the synthesis of rhein and derivatives thereof

Info

Publication number: WO2008090078A1
Application number: PCT/EP2008/050500
Authority: WO
Inventors: Charles Mioskowski; Vanessa Gonnot; Rachid Baati; Steve Tisserand; Marc Nicolas; Jean Fabre
Original assignee: Pierre Fabre Medicament
Priority date: 2007-01-18
Filing date: 2008-01-17
Publication date: 2008-07-31
Also published as: FR2911602A1; FR2911602B1

Abstract

The invention relates to a method for the synthesis of a compound of the formula (1) in which R1 is a hydroxyl or acetoxy group, characterised it comprises: a metallation step of the aromatic cycle of a compound of the formula (2) in which R2 and R3 independently represent a C1 - C4 alkyl group selectively in the ortho position of the -OR2 substituent; reacting the metalled compound thus obtained with a compound of the formula (3) in which R2 is such as defined above and R4 is an electrophile group selected from the group including the following groups -CHO, -COX with X=Cl, Br, I, -COCN, -CONCH3OCH3, -CON(R)2, -COOR or R is a C1 - C4 alkyl group and is preferably a -CHO or -COCl group; followed by the steps of acid hydrolysis, reduction, cycling and oxidation in order to obtain the compound (1).

Description

Process for the synthesis of Rhein and its derivatives

The present invention relates to a novel process for the preparation of Rhein and its derivatives as well as the corresponding synthetic intermediates.

Rhein, of formula (1)

in which R1 = OH, and Diacerhein, of formula (1) in which R1 = acetoxy have anti-inflammatory and anti-osteoarthritic properties whose activity is related to the inhibition of the production of interleukin 1 (Pelletier (1996) , Arthritis Rheum., 39, 1531). They also have activity in the treatment of nephropathic diabetes (EP 0 990 441 A1), another disease in which overproduction of IL-1 is involved.

They have been used for many years in the treatment of arthritis and osteoarthritis, and a pharmaceutical preparation already exists on the market.

Industrially, the production method is performed by semisynthesis from plant extracts from rhubarb. It comprises fastidious extraction stages producing Aloin, which by oxidation and acetylation reaction produces Diacerhein, as well as very carcinogenic impurities such as Aloe-emodin of general formula (1) in which R 1 = OH and where a -CH ₂ OH group replaces the -COOH group. The Rhein synthesis was carried out for the first time by Hauser et al. (JOC (1982), 47 (2),

383-4) in 1982 from a sulfonated phthalide and a cyclohexenone derivative, but the preparation of the starting materials requires reaction sequences difficult to implement on an industrial scale. In 1987,

Lemli (J. of labeled compounds and pharmaceuticals

(1988), 25, 23-33) discloses a synthesis from 7-methoxyphthalide and 6-bromo-3-methylanisole; but here again the preparation of these intermediates does not make it possible to transpose this synthesis into an industrial environment.

Synthetic routes of anthraquinone by Diels Aider cycloaddition reaction have been described by several teams. Thus, Bloomer et al. (J. O. C, (1993), 58, 7906) describe in 1993 a synthesis of Rhein whose key step is a Diels Aider reaction between chlorojuglone and a cyclic diene. However, four steps are necessary for the preparation of the chlorojuglone with a yield of 31%. Another team describes the synthesis of Rhein via a Diels reaction

Help between 5-Hydro-1,4-naphthoquinone and another cyclic diene (Ayyangarn, Chemistry and Industry,

(1988), 124), but Gallagher et al. fail to reproduce these results and publish a synthesis (Tet Lett (1994), 35, 289) whose key step is the olefination of a naphthaldehyde with a phosphonate of formula (EtO) ₂ P (O ) CH (CO ₂ Et) CH ₂ CO ₂ CMe ₃ , but overall yield very low (6%).

Another synthetic route was described in 2003 (J.Org.Chem., (2004), 69 (25), 8982-8983J, but presents steps that can not be transposed to industry, specifically a Fries rearrangement requiring 6 Equivalents of Lewis acid and a bis-carbonylation using 20 mol% of an expensive palladium catalyst.

The inventors of the present invention have surprisingly discovered a process for the preparation of anthraquinones of general formula (1), and in particular Rhein and Diacerhein, with a significantly improved overall yield compared to the state of the art. and using synthesis steps easily transferable on an industrial scale and economically viable.

The key step involves a regioselective ortho-metallization reaction of the dicarboxamide of the general formula (2)

wherein R2 and R3 represent an alkyl group, followed by the reaction between the ortho-metallated intermediate with an electrophile.

Snieckus et al. (J. O.C. (1919), 44 (26), 4802-4808) conducted a thorough study of the metallation reaction and used it for the preparation of other anthraquinones.

However, the unexpected regioselectivity described in the present invention makes it possible to introduce from the starting substrate of general formula (2) the carboxylic acid function of the final Rhein.

Indeed, the amide groups present on the starting material of formula (2) are known to be among the best leader groups during ortho-metallation reactions. The selectivity of the metallation between the methoxy group (R2 = Me) and the amide group is therefore quite surprising, since a cooperation between the two amide groups, more leaders than an amide and a methoxy, should have, unlike what is observed, lead to a metallation between the two amide groups. We have also observed this metallation between the two amides on a substrate of general formula (2) in which R2 = H. In this case, the metallation takes place at fifty percent between the two amides, and fifty percent at the other position because of the steric gene due to the clutter of the amides. This compound was further metallized under different conditions by Hart et al. (Tetrahedron (1996), 52, 3841-3856), the resulting intermediate then reacting by conjugate addition to a naphthoquinone to give a product with a low yield of 25%.

The present invention, using an electrophile, such as for example an aldehyde or an acid chloride, is therefore quite original and allows the realization of a synthesis involving new intermediates leading to Rhein and Diacerhein.

In addition, the condensation with the acid chloride is carried out with a good yield without transmetallation of the intermediate lithian, this method being generally used to limit the competitive carbanion addition reaction on the new arylketone formed.

Thus, the subject of the invention is more specifically a process for the synthesis of a compound of formula (1)

in which R 1 represents a hydroxyl or acetoxy group, characterized in that it comprises: a step of metallation of the aromatic ring of a compound of formula (2)

wherein R2 and R3 independently represent alkyl to C _4, selectively at the ortho position of the substituent -OR2; the reaction of the metallated compound thus obtained with a compound of formula (3)

wherein R2 is as defined above, and R ₄ is an electrophilic group which may be selected from the group consisting of -CHO, -COX groups with X = Cl, Br, I, -COCN, -CONCH ₃ OCH ₃ , -CON (R) ₂ , -COOR wherein R represents a C ₁ -C ₄ alkyl group;

followed by acid hydrolysis, reduction, cyclization and oxidation steps leading to the compound (1). These steps of acid hydrolysis, reduction, cyclization and oxidation can be carried out according to techniques known to those skilled in the art. According to an advantageous embodiment of the invention, the electrophilic group is an aldehyde or an acid chloride.

In formula (2) above, R2 is advantageously a methyl group, and R3 is an ethyl group.

The metallation of the compound (2) may advantageously be carried out with an organolithium which may be selected from the group consisting of n-butyllithium, sec-butyllithium, or tert-butyllithium.

The metallation of the compound (2) can advantageously be carried out in an ethereal solvent chosen from the group comprising diethyl ether and tetrahydrofuran. The metallation of the compound (2) is advantageously carried out at a temperature between -8O ⁰ C - 40 ⁰ C.

When R ₄ represents an aldehyde group, the reaction of said metallated compound with the compound (3) is followed by an acid hydrolysis to obtain a compound of formula (4)

wherein R2 and R3 are as defined above.

The acid hydrolysis of said metallated compound is advantageously carried out with hydrochloric acid.

The process according to the invention then comprises the following successive stages: the reduction of the compound (4) to the compound of the formula (6)

wherein R2 and R3 are as defined above; cyclization of compound (6) to compound of formula (7)

in which R2 and R3 are as defined above - the oxidation of compound (7) to the compound of formula (8)

wherein R2 and R3 are as defined above; and acid hydrolysis of the compound (8) to form the compound

(1) wherein R1 represents the hydroxyl group.

Advantageously, the reduction of compound (4) to compound (6) is carried out by palladium-carbon catalyzed hydrogenation. The cyclization of compound (6) to compound (7) is advantageously carried out using trifluoroacetic anhydride in a dichloromethane / trifluoroacetic acid mixture.

The oxidation of the compound (7) to the compound (8) is advantageously carried out in a polar solvent chosen from the group comprising methanol and dimethylsulfoxide. The oxidation of compound (7) to compound (8) is advantageously carried out in basic medium and in the presence of oxygen.

The oxidation of compound (7) to compound (8) is advantageously carried out in the presence of sodium hydroxide or potassium tert-butoxylate.

The acid hydrolysis of the compound (8) to the compound (1) is advantageously carried out in concentrated hydrochloric acid under reflux. When R ₄ represents a -COX group with X = Cl, Br, I, -COCN, -CON (R) ₂ , -CONCH ₃ OCH ₃ , -COOR where R represents a C ₁ -C ₄ alkyl group, the reaction of said compound metallated with the compound (3) produces a compound of the formula (5)

wherein R ₂ and R ₃ are as defined above.

The method according to the invention further comprises the following successive steps:

the acid hydrolysis of the compound (5) to the compound of the formula (9)

wherein R ₂ is as defined above; and cyclizing the compound (9) in a molten salt medium to obtain the compound of formula (1) in which R 1 represents the hydroxyl group. The molten salt medium is advantageously a mixture of sodium chloride and aluminum chloride.

The molar fraction of aluminum chloride in the mixture of molten salt medium is advantageously greater than 0.5.

The temperature of the molten salt medium is advantageously between 110 and 180 ^° C.

The acidic hydrolysis of the compound (5) to the compound (9) is advantageously carried out in concentrated hydrochloric acid under reflux.

The process according to the invention also comprises a step of reacting the compound of formula (1), in which R 1 represents the hydroxyl group, with acetic anhydride in basic medium, in order to obtain the compound of formula (1) in which Ri represents the acetoxy group.

The following general synthesis scheme illustrates the invention without limiting it.

i) Dt-BuLi, THF, -78 ^° C. 2) o-anisaldehyde, -78 ^° C. to 3 °) conc. ; ii) H ₂ , Pd / C 10%, AcOH, 90 ^° C; iii) I) TFA, CH ₂ C1 ₂ / TFA, ta 2) air / t-BuOK or O ₂ / NaOH, DMSO; iv) Conc. HCl, reflux; v) 1H-BuLi, THF, -78 ^° C 2) chlorine o-anisoyl, -78 ⁰ C to ta; (vi) Conc. HCl, reflux; vii) AlCl ₃ / NaCl, 155 ^° C. The following examples illustrate the invention without limiting it.

Example 1 Synthesis of Rhein via Phthalide (4)

1.1. Synthesis of 3- (2-methoxyphenyl) -4-methoxy-6- (N, N-diethylaminocarbonyl) phthalide (4)

Bis- (N, N-diethyl) -5-methoxybenzene-1,3-dicarboxamide (103 mg, 0.34 mmol, 1 eq) is placed at -45 ° C in anhydrous tetrahydrofuran (4 mL). Tert-Butyllithium (1.7 M in hexane, 0.22 ml, 0.37 mmol, 1.1 eq) was added and the mixture was stirred for 15 min. The anisaldehyde (46 mg, 0.34 mmol, 1 eq) in solution in 1 ml of tetrahydrofuran is added to the yellow-brown reaction mixture at -45 ° C. Stirring is continued for 15 minutes. The yellow reaction mixture is then treated with 0.1 ml of 37% HCl until the medium is decoloured, then the bath is removed and the mixture is stirred for 15 minutes at room temperature. Water is then added, and the product is extracted with ethyl acetate. The organic phases are washed with brine, dried over Na ₂ SO ₄ and then evaporated. The resulting oil (137 mg) was recrystallized from diethyl ether / cyclohexane to give a white solid (83 mg, 67%).

1.2. Synthesis of 3-methoxy-4- (N, N-diethylaminocarbonyl) -2 [(2-methoxyhenyl) methyl] benzoic acid (6) A solution of 3- (2-methoxyphenyl) -4-methoxy-6-

(N, N-diethylaminocarbonyl) phthalide (4) (300 mg, 0.81 mmol, 1 eq) dissolved in 20 ml of acetic acid in the presence of Pd / C (10%) is stirred for 5 hours at 90 ^° C. C under hydrogen atmosphere (balloon, pressure 1 to 1.5 bar). The reaction medium is then filtered on celite and evaporated to dryness. The corresponding acid is then quantitatively obtained in the form of a white powder (303 mg, 100%).

1.3. Synthesis of (N, N-diethyl) -1,8-dimethoxy-9,10-dihydro-10-oxo-anthracene-3-carboxamide (7)

3-Methoxy-4- (N, N-diethylaminocarbonyl) -2 - [(2-methoxyphenyl) methyl] benzoic acid (6) (500 mg, 1.35 mmol;

1 eq.) Is suspended in dichloromethane (7.5 ml). Trifluoroacetic anhydride (0.29 ml, 2 mmol;

1.5 eq) is added at room temperature followed by trifluoroacetic acid (7.5 ml), the reaction mixture then changes from orange to yellow and is stirred for 10 minutes. Water is added and then a solution of saturated sodium carbonate. The product is extracted with ethyl acetate. The organic phases are dried over Na ₂ SO ₄ and then evaporated. A pale yellow solid (458 mg, 96%) is obtained used in the next reaction without purification.

1.4. Synthesis of (N, N-diethyl) -1,8-dimethoxy-9,10-anthraquinone-3-carboxamide (8)

(N, N-diethyl) -1,8-dimethoxy-9,10-dihydro-10-oxo-anthracene-3-carboxamide (7) (300 mg, 0.85 mmol, 1 eq.) and potassium tert-butoxylate (105 mg, 0.94 mmol, 1.1 eq.) are dissolved in dimethylsulfoxide.

(10 ml). The mixture is stirred in air (open flask) at room temperature for 24 h. Water and brine are added, and the product is extracted with ethyl acetate. The organic phases are dried over Na ₂ SO ₄ and then evaporated. An oil containing traces of DMSO (355 mg, 114%) is obtained.

1.5. Synthesis of 1,8-dihydroxyanthraquinone-3-carboxylic acid (1)

(IV, N-diethyl) -1,8-dimethoxy-9,10-anthraquinone-3-carboxamide (8) (355 mg, 0.97 mmol, 1 eq) is dissolved in acid 37% hydrochloric acid (20 ml). The reaction mixture is stirred at reflux for 5 days. The product precipitates from the reaction medium, and is extracted with ethyl acetate. The organic phases are dried over Na ₂ SO ₄ and then evaporated. The resulting orange product (202 mg, 74%) contains Rhein and traces of mono deprotected product (5-10%).

Example 2 Synthesis of Rhein via Benzophenone (5)

2.1. Synthesis of bis-N, N- (diethyl) -4-2-methoxybenzoyl) -5-methoxybenzene-1,3-dicarboxamide (5)

Bis- (N, N-diethyl) -5-methoxybenzene-1,3-dicarboxamide (5.25 g, 17.2 mmol, 1 eq.) Is placed at -78 ° C in anhydrous tetrahydrofuran (200 ml) . Tert-Butyllithium (1.7 M in hexane, 11.1 ml, 18.9 mmol, 1.1 eq) is added and the mixture is stirred. for 1 hour. The mixture is then cannulated over anisoyl chloride (3.32 m, 22.3 mmol, 1.3 eq) dissolved in 100 ml of tetrahydrofuran at -78 ° C. Stirring is continued for 1 h and then the mixture is allowed to return to room temperature. Water is then added, and the product is extracted with ethyl acetate. The organic phases are dried over Na ₂ SO ₄ and then evaporated. The oil obtained is purified by chromatography on silica (ethyl acetate) to give a pale yellow oil (6.48 g, 86%).

2.2. Synthesis of 4- (2-methoxybenzoyl) -5-methoxybenzene-1,3-dicarboxylic acid (9)

Bis- (N, N-diethyl) -4-2-methoxybenzoyl) -5-methoxybenzene-1,3-dicarboxamide (5) (5.56 g, 12.63 mmol, 1 eq.) Is dissolved in 37% hydrochloric acid (55 ml). The reaction mixture is stirred under reflux for 45 hours. The product precipitates from the reaction medium, and is filtered. The filtrate is extracted with ethyl acetate and the organic phases are dried over Na ₂ SO ₄ and then evaporated. The filtered product obtained is beige (2.191 g). The filtrate is extracted with ethyl acetate, dried over Na ₂ SO ₄ and then evaporated (0.161 g). In total, 3.52 g; 84%.

2.3. Synthesis of 1,8-dihydroxyanthraquinone-3-carboxylic acid (1) (Rhein)

4- (2-Methoxybenzoyl) -5-methoxybenzene-1,3-dicarboxylic acid (9) (54 mg, 0.16 mmol, 1 eq) is added to a mixture of molten salt at 155 ° C (AICI3 2.8g + NaCl 0.6 g). The mixture is stirred for 14 h at 155 ° C and then cooled (caking). The mixture is slowly decomposed with ice and extracted with ethyl acetate in an acidic medium (addition of a few ml of 10% HCl). The organic phases are dried over Na ₂ SO ₄ and then evaporated. The dark orange product obtained (43 mg, 92%) contains 5% of 1,5-dihydroxy-anthraquinone-3-carboxylic acid isomer.

Example 3 Synthesis of Diacerhein or 1,8-bis (acetyloxy) -3-carboxylic acid

The previously obtained Rhein (1) (20 mg, 0.07 mmol, 1 eq) is solubilized in acetic anhydride (1 mL, 0.2 mmol, 30 eq). Triethylamine (0.02 ml, 0.14 mmol, 2 eq.) Is added as well as dimethylaminopyridine (5 mg, 0.03 mmol, 0.5 eq) and the mixture is stirred at room temperature for a period of one hour. hour. Water is then added, and the product is extracted with ethyl acetate in an acidic medium. The organic phases are dried over Na ₂ SO ₄ and then evaporated. The product obtained (40 mg, 149%) contains traces of acetic acid).

Claims

1. Process for synthesizing a compound of formula (1)

wherein R2 and R3 independently represent alkyl to C _4, selectively at the ortho position of the substituent -OR2;

the reaction of the metallated compound thus obtained with a compound of formula (3)

wherein R2 is as defined above, and R ₄ is an electrophilic group which may be selected from the group consisting of -CHO, -COX groups with X = Cl, Br, I, -COCN, -CONCH ₃ OCH ₃ , -CON (R) ₂ , -COOR or R represents a C ₁ -C ₄ alkyl group and is preferably a -CHO or -COCl group;

followed by acid hydrolysis, reduction, cyclization and oxidation steps leading to the compound (1).

2. Method according to claim 1, characterized in that R2 represents a methyl group and R3 an ethyl group.

3. Method according to any one of the preceding claims, characterized in that the metallation of the compound (2) is carried out with an organolithium may be selected from the group comprising n-butyllithium, sec-butyllithium and tert-butyllithium.

4. Method according to any one of the preceding claims, characterized in that the metallation of the compound (2) is carried out in an ethereal solvent selected from the group comprising diethyl ether and tetrahydrofuran.

5. Method according to any one of the preceding claims, characterized in that the metallation of the compound (2) is carried out at a temperature between -8O ⁰ C and -40 ⁰ C.

6. Process according to any one of the preceding claims, characterized in that when R ₄ represents an aldehyde group, the reaction of said metallated compound with the compound (3) is followed by an acid hydrolysis to obtain a compound of formula (4). )

wherein R2 and R3 are as defined above.

7. Process according to claim 6, characterized in that the acid hydrolysis of said metallated compound is carried out with hydrochloric acid.

8. Method according to any one of claims 6 and 7, characterized in that it comprises the following successive steps:

reducing the compound (4) to a compound of formula (6)

wherein R2 and R3 are as defined above; and

the acid hydrolysis of the compound (8) to form the compound (1) in which R 1 represents the hydroxyl group.

9. Process according to claim 8, characterized in that the reduction of the compound (4) to the compound (6) is carried out by palladium-carbon catalyzed hydrogenation.

10. Process according to any one of claims 8 and 9, characterized in that the cyclization of the compound (6) compound (7) is carried out using trifluoroacetic anhydride in a dichloromethane / trifluoroacetic acid mixture.

11. Method according to any one of claims 8 to 10, characterized in that the oxidation of the compound (7) compound (8) is carried out in a polar solvent selected from the group comprising methanol and dimethylsulfoxide.

12. Method according to any one of claims 8 to 11, characterized in that the oxidation of the compound (7) compound (8) is carried out in basic medium and in the presence of oxygen.

13. Process according to any one of claims 8 to 12, characterized in that the oxidation of compound (7) to compound (8) is carried out in the presence of sodium hydroxide or potassium tert-butoxylate.

14. Process according to any one of Claims 8 to 13, characterized in that the acidic hydrolysis of compound (8) to compound (1) is carried out in concentrated hydrochloric acid under reflux.

15. Method according to any one of claims 1 to 3, characterized in that when R ₄ represents a -COX group with X = Cl, Br, I, -COCN, -CON (R) ₂ , CONCH ₃ OCH ₃ , -COOR where R represents a C ₁ -C ₄ alkyl group, the reaction of said compound metallated with the compound ( 3) produces a compound of formula (5)

wherein R ₂ and R 3 are as defined above.

16. Process according to claim 15, characterized in that it comprises the following successive stages: the acid hydrolysis of the compound (5) to the compound of the formula (9)

wherein R ₂ is as defined above; and cyclizing the compound (9) in a molten salt medium to obtain the compound of formula (1) in which R 1 represents the hydroxyl group.

17. The method of claim 16, characterized in that the molten salt medium is a mixture of sodium chloride and aluminum chloride.

18. The method of claim 17, characterized in that the molar fraction of aluminum chloride in the mixture of molten salt medium is greater than 0.5.

19. Method according to any one of claims 16 to 18, characterized in that the temperature of the molten salt medium is between 110 and 180 ⁰ C.

20. Process according to any one of claims 16 to 19, characterized in that the acid hydrolysis of the compound (5) compound (9) is carried out in concentrated hydrochloric acid under reflux.

21. Process according to any one of the preceding claims, characterized in that it comprises a step of reacting the compound of formula (1), in which R 1 represents the hydroxyl group, with acetic anhydride in a basic medium, to obtain the compound of formula (1) in which R 1 represents the acetoxy group.