PROCESS FOR THE MANUFACTURE OF HYDROXY-SUBSTITUTED AROMATIC COMPOUNDS

Abstract

The present invention relates to a process for the manufacture of hydroxy-substituted aromatic styryl or stilbene compounds.

Claims

1. A process for the manufacture of a hydroxy-substituted aromatic compound of the formula (I):
Z(CHCHAr).sub.a (I) wherein Z is a divalent substituted aromatic group or a divalent group of the formula: ##STR00027## wherein denotes a single bond, Ar independently is selected from a substituted aromatic group, and a is 2, or a salt thereof, which comprises reacting a compound of the formula (II):
Z(X).sub.a (II) wherein X is a leaving group and Z and a are as defined above, with a compound of formula (III):
CH.sub.2CHAr (III) wherein Ar is as defined above, in the presence of a transition metal catalyst, with the proviso that the group Z and the group Ar each are substituted by at least one hydroxy group.

2. The process according to claim 1, wherein Z is a divalent substituted aromatic group.

3. The process according to claim 1, wherein the compound of formula (III) is formed in situ from a compound of formula (IV)
HOOCCHCHAr (IV), wherein Ar is as defined above.

4. The process according to claim 1, wherein the transition metal catalyst is a bimetallic catalyst comprising palladium and at least one further transition metal.

5. The process according to claim 1, wherein the leaving group X is a halogenide.

6. The process according to claim 1, wherein Z is derived from a substituted six-membered aromatic group.

7. The process according to claim 1, wherein Z is derived from a hydroxy-substituted benzene group and/or Ar is derived from a hydroxyl-substituted benzene group.

8. The process according to claim 1, wherein each group Ar is derived from a hydroxy-substituted benzene group.

9. The process according to claim 1, wherein the compound of formula (I) is selected from the group consisting of: ##STR00028## ##STR00029## ##STR00030## ##STR00031##

10. The process according to claim 1 for the manufacture of a compound of the formula: ##STR00032##

11. The process according to claim 1, which is carried out in at least one solvent, and in the presence of at least one base.

12. The process according to claim 1 comprising adding water to the process.

13. The process according to claim 1, which is carried out in the presence of at least one phase transfer catalyst compound.

14. The process according to claim 13, which is carried out in the absence of triphenylphosphane.

15. The process according to claim 1, which further comprises at least one subsequent derivatization reaction of the compound of formula (I).

16. The process according to claim 1, which further comprises the admixture of a compound of formula (1) with at least one pharmaceutical or cosmetic excipient.

17. The process according to claim 4, wherein the at least one further transition metal comprises copper or silver.

18. The process according to claim 5, wherein the halogenide is chlorine or bromine.

19. The process according to claim 6, wherein the substituted six-membered aromatic group is benzene, pyridine, or pyrimidine.

Description

EXAMPLES

Example 1

Synthesis of (E,E)-3,5-bis(4-hydroxystyryl)phenol (or 3,5-bis[(E)-2-(4-hydroxyphenyl)vinyl]phenol)

[0151] Literature:

[0152] A) Green Chem, 2014, 16, 3089: Preparation of Functional Styrenes from Biosourced Carboxylic acids by Copper Catalyzed decarboxylation in PEG

[0153] B) J. Am. 2002, 124, 11250-51: Development of a decarboxylative Palladation Reaction and Its Use in a Heck-type olefination of arenes carboxylate

[0154] Reactants:

[0155] 1) 39.2 g (0.24 mol) of p-coumaric acid

[0156] 2) 1.04 g Cu(OH).sub.2

[0157] 3) 1.2 g of 1,10-phenanthroline

[0158] 4) 25.7 g (0.1 mol) of 3,5-dibromophenol (Fa. TCl)

[0159] 5) 0.034 g of Pd(OAc).sub.2 (Palladium(II)-actetate)

[0160] 6) 6.0 g Triphenylphosphan

[0161] 7) 16.4 g of sodium acetate (0.2 mol)

[0162] 8) 30 g water, demineralized

[0163] 9) 30 g of acetonitrile

[0164] 10) 20 g of N-methylpyrrolidone

[0165] Procedure

[0166] In a 500 ml three-necked flask, the components are successively weighed and the greenish suspension is gassed with nitrogen with stirring for 0.5 hours at room temperature to prevent the oxidation of triphenylphosphine by the dissolved air oxygen. Then the mixture is slowly heated with stirring with a Dean Stark water separator. Initially the acetonitrile and then slowly the water is distilled off. The mixture turns yellow in 2 hours and reaches about 100 C., and then slowly begins to foam (decarboxylation). Up to 120 C., which is reached after a further hour, the reaction mixture becomes red-brown. It is held for another 3 hours at 140 C. until the evolution of gas subsides.

[0167] Further processing:

[0168] After cooling the reaction mixture is neutralized with 200 ml of 10% hydrochloric acid and with is extracted three times with 100 ml of MTBE (methyl tert-butyl ether). Initially the water phase is bluish later brown. Usually a sugary sticky greenish-yellow precipitate is formed which can be removed with ethyl acetate again. Presumably it is triphenylphosphane oxide (TPPO).

[0169] The combined now yellow-brown organic phases are dried over sodium sulfate, filtered and concentrated on a rotary evaporator.

[0170] This gives about 55 g of crude product, which contains traces of acetic acid, MTBE and TPPO.

[0171] When drying in a drying oven (50 mbar, 50 C.) and then over phosphorus pentoxide in a desiccator under an oil pump vacuum (0.5 mbar) about 49 g of a dark yellow solid foam are obtained that contains the product in about 90% purity (estimated with NMR).

[0172] During evaporation of a solution with ethyl acetate yellow crystals are sometimes formed. Or a crystallization can be induced by using such crystals in a highly viscous crude product.

[0173] In the purification by flash chromatography with a cyclohexane / ethyl acetate gradient further purification to purities of above 95% can be achieved.

[0174] Further examples 2 to 8 are carried out as in example 1 with the amounts of reactants shown in the following table.

[0175] Therein the mol-% values for Cu(OH).sub.2 and 1,10-phenanthroline are based on the molar amounts of p-coumaric acid.

[0176] The mol % values for palladium(II)acetate, triphenylphosphine (triphenylphosphane), tetra-n-butylammonium bromide, sodium acetate, potassium carbonate and 2,6-di-tert-butyl-4-methylphenol BHT are based on the molar amount of the 3,5-dibromophenol used.

TABLE-US-00001 Example 2 3 4 5 6 7 8 Reactant p-coumaric acid 28 mmol 28 mmol 28 mmol 28 mmol 28 mmol 28 mmol 28 mmol copper(II) hydroxide 1.78 mol % 1.78 mol % 1.78 mol % 1.78 mol % 1.78 mol % 1.78 1.78 1,10-phenanthroline 1.78 mol % 1.78 mol % 1.78 mol % 1.78 mol % 1.78 mol % 1.78 1.78 3,5-dibromophenol 10 mmol 10 mmol 10 mmol 10 mmol 10 mmol 10 mmol 10 mmol palladium(II)acetate 0.6 mol % 0.6 mol % 0.6 mol % 0.6 mol % 0.6 mol % 0.6 mol % 0.6 mol % triphenylphosphine 38 mol % (triphenylphosphane) tetra-n-butylammonium bromide 30 mol % 30 mol % 30 mol % 24 mol % 24 mol % sodium acetate 240 mol % potassium carbonate 200 mol % 200 mol % 200 mol % 200 mol % 200 mol % 200 mol % water 3 g 3 g 3 g 3 g 3 g 2,6-di-tert-butyl-4-methylphenol 5 mol % 5 mol % 0.5 mol % 5 mol % 5 mol % 5 mol % BHT acetonitrile 9 g N,N-dimethylformamide 9 g 9 g 9 g 9 g 9 g 9 g Yield 94.84% 59.69% 44.84% 97.57% 41.21% 73% 67.27%

[0177] The examples 2 and 5-8 show that the process according to the invention leads to higher yields if water is added to the process.

[0178] While with triphenylphosphine high yields were obtained, separating the resulting triphenyl phosphine oxide from the product can be difficult. However, working in the presence of a phase transfer catalyst compound such as tetra-n-butylammonium bromide can almost compensate the absence of the triphenyl phosphine and avoids the formation of triphenyl phosphine oxide and its undesirable separation from the product.