Method for producing indanone derivatives

Abstract

A method is described for producing a compound having the formula (I) ##STR00001##
or an admixture comprising a compound having the formula (I),
having the following steps: dissolving an indanone having the formula (II) in a solvent or in an admixture which contains a solvent, the solvent being selected from the group of solvents which form an azeotrope with water, converting the indanone having the formula (II) with an aromatic aldehyde having the formula (III) in the presence of at least one organic base, according to the drawing: ##STR00002##
where R.sup.1 and R.sup.2 independently of each other signify hydrogen or a branched or unbranched alkyl group having from 1 to 12 carbon atoms and
where R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 independently of each other signify hydrogen, hydroxy or a branched or unbranched alkyl or alkoxy group having from 1 to 12 carbon atoms and removing water formed from the reaction admixture during the conversion. An admixture comprising a compound of the formula (I) and other components is further described.

Claims

1. Method for the manufacture of a compound of formula (I) having a purity of at least 99.9% comprising: ##STR00011## dissolving an indanone of formula (II) in a solvent or in a mixture containing a solvent that forms an azeotrope with water and has a solubility that is less than 20 g of solvent per liter of water at 20 C., conversion of the indanone of formula (II) with an aromatic aldehyde of formula (III) in the presence of at least one organic base that is an alkali metal or alkaline earth metal alcoholate with a branched alcoholate anion, according to the scheme ##STR00012## wherein R.sup.1 and R.sup.2 represent, independently of each other, hydrogen or a branched or unbranched alkyl group with 1 to 12 carbon atoms, respectively, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 represent, independently of each other, hydrogen, hydroxy or a branched or unbranched alkyl or alkoxy group with 1 to 12 carbon atoms, respectively, and the molar ratio of the used amount of organic base to the used amount of indanone of formula (II) is smaller than 0.05, and removal of the generated water from the reaction mixture during the conversion.

2. Method according to claim 1, wherein R.sup.1 and R.sup.2 represent, independently of each other, methyl, ethyl, n-propyl or iso-propyl, respectively, and R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 represent, independently of each other, hydrogen, methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, propoxy or butoxy, respectively.

3. Method according to claim 1, wherein the molar ratio of the used amount of indanone of formula (II) to the used amount of aldehyde of formula (III) is in the range of 0.6 to 1.4.

4. Method according to claim 1, further comprising: removal of the water that is generated during the conversion from the reaction mixture by means of azeotropic distillation and/or removal of the water that is generated during the conversion from the reaction mixture by means of adsorption to a water adsorber.

5. Method according to claim 1, wherein the solvent that forms an azeotrope with water is selected from the group consisting of benzene, toluene, xylene, n-hexane, n-heptane, cyclohexane, methylcyclohexane and carbon tetrachloride.

6. Method according to claim 1, comprising the following additional steps for treatment of an existing product mixture once conversion has taken place: neutralisation of the product mixture, removal of the solvent by distillation from the neutralised product mixture, and subsequently, recrystallisation of the product.

7. Method according to claim 1 with the following step before the conversion of the indanone of formula (II) with the aromatic aldehyde of formula (III): washing of the solution that is present after dissolving of the indanone of formula (II) with an aqueous, alkaline solution and separation of the aqueous phase after washing.

8. Method according to claim 1 with the following steps: provision or production of an indanone of formula (II) and of an aldehyde of formula (III), dissolving of the indanone in the solvent or in a mixture containing the solvent so as to achieve a solution of the indanone, washing of the solution that is present after dissolving of the indanone of formula (II) with an aqueous, alkaline solution and separation of the aqueous phase after washing, addition of the organic base and of the aldehyde to the solution of the indanone, so that a reaction mixture is formed in which the indanone of formula (II) reacts with the aromatic aldehyde of formula (III), removal of the water that is generated during the conversion from the reaction mixture by means of azeotropic distillation, neutralisation of the product mixture that is present once the conversion has taken place, removal of the solvent by distillation from the neutralised product mixture, and recrystallisation of the product.

9. Method according to claim 1, wherein the process conditions are adjusted such that the molar ratio of the produced amount of the compound of formula (I) to the amount of the compound of formula (IV) that has been produced as side-product, where appropriate, ##STR00013## in which the denotation of the groups R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11 and R.sup.12 is the same as the denotation of the groups termed equally in the compound of formula (I), is larger than 50.

10. Method for the manufacture of a compound of formula (I) having a purity of at least 99.9% comprising: ##STR00014## dissolving an indanone of formula (II) in a solvent that forms an azeotrope with water and has a solubility of less than 20 g of solvent per liter of water at 20 C., converting the indanone of formula (II) with an aromatic aldehyde of formula (III) in the presence of at least one organic base selected from the group consisting of potassium tert-butylate, sodium tert-butylate, lithium tert-butylate, barium tert-butylate, magnesium tert-butylate, potassium tert-pentylate, sodium tert-pentylate and lithium tert-pentylate, according to the scheme ##STR00015## wherein R.sup.1and R.sup.2 represent, independently of each other, hydrogen or a branched or unbranched alkyl group with 1 to 12 carbon atoms, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 represent, independently of each other, hydrogen, hydroxy or a branched or unbranched alkyl or alkoxy group with 1 to 12 carbon atoms, and the molar ratio of the used amount of organic base to the used amount of indanone of formula (II) is smaller than 0.05, and removing the water generated during the conversion.

11. Method according to claim 10, wherein R.sup.1and R.sup.2 represent, independently of each other, methyl, ethyl, n-propyl or iso-propyl, and R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 represent, independently of each other, hydrogen, methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, propoxy or butoxy.

12. Method according to claim 10, wherein the molar ratio of the indanone of formula (II) to the aldehyde of formula (III) is in the range of 0.6 to 1.4.

13. Method according to claim 10, wherein the water is removed by azeotropic distillation and/or by adsorption to a water absorber.

14. Method according to claim 10, wherein the solvent that forms an azeotrope with water is selected from the group consisting of benzene, toluene, xylene, n-hexane, n-heptane, cyclohexane, methylcyclohexane and carbon tetrachloride.

15. Method according to claim 10, wherein the solvent that forms an azeotrope with water is toluene and/or xylene.

16. Method for the manufacture of a compound of formula (I) having a purity of at least 99.9% comprising: ##STR00016## dissolving an indanone of formula (II) in a solvent that forms an azeotrope with water and has a solubility less than 20 g of solvent per liter of water at 20 C., wherein the solvent is selected from the group consisting of toluene and/or xylene, converting the indanone of formula (II) with an aromatic aldehyde of formula (III) in the presence of at least one organic base selected from the group consisting of potassium tert-butylate, sodium tert-butylate, lithium tert-butylate, barium tert-butylate, magnesium tert-butylate, according to the scheme ##STR00017## wherein R.sup.1and R.sup.2 represent, independently of each other, hydrogen or a branched or unbranched alkyl group with 1 to 12 carbon atoms, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 represent, independently of each other, hydrogen, hydroxy or a branched or unbranched alkyl or alkoxy group with 1 to 12 carbon atoms, and the molar ratio of the used amount of organic base to the used amount of indanone of formula (II) is smaller than 0.05, and removing the water generated during the conversion.

Description

COMPARISON EXAMPLE 1

(cf. WO2007/128723 A1, example 1); production of 2-benzylidene-3,3-dimethyl-5,6-dimethoxy-1-indanone

COMPARISON EXAMPLE 1a

Recrystallisation from Methanol

(1) 0.17 mol of solid potassium hydroxide were suspended in 100 g of diethylene glycol dimethyl ether and 0.40 mol of 3,3-dimethyl-5,6-dimethoxy-1-indanone were added. The admixture was heated to 80 C. with agitation. Within an hour, 0.61 mol of benzaldehyde were added and the solution was stirred for a further three hours at 80 C. For processing, the solution was cooled to ambient temperature, 400 g of iced water was added and neutralised with 30 g of 10% aqueous hydrochloric acid solution. After extraction with 400 g of methyl-tert-butylether, the product was recrystallised from methanol. 96.2 g was obtained (78% by weight of the theoretical quantity with respect to the 3,3-dimethyl-5,6-dimethoxy-1-indanone) of a yellow solid. According to routine GC examinations, the product had a purity of 99.6% by weight (2-benzylidene-3,3-dimethyl-5,6-dimethoxy-1-indanone) and contained 0.3% by weight of 2-benzyl-3,3-dimethyl-5,6-dimethoxy-1-indanone and 0.1% of additional impurities. An L*a*b colour measurement was carried out on the product produced. The L-value of the product was 88.58.

COMPARISON EXAMPLE 1b

Recrystallisation from Ethanol

(2) With an alternative recrystallisation from ethanol, almost identical results were achieved.

COMPARISON EXAMPLE 2

Production of 2-benzylidene-3,3-dimethyl-5,6-dimethoxy-1-indanone

COMPARISON EXAMPLE 2a

Recrystallisation from Methanol

(3) The procedure in comparison example 2a corresponds to the procedure according to comparison example 1a, but 100 g of diethylene glycol diethyl ether were used as the solvent instead of 100 g of diethylene glycol dimethyl ether.

(4) 90.0 g (73% by weight of the theoretical quantity with respect to 3,3-dimethyl-5,6-dimethoxy-1-indanone) of a yellow solid material were obtained. The product had according to GC examinations a purity of 99.6% by weight (2-benzylidene-3,3-dimethyl-5,6-dimethoxy-1-indanone) and contained 0.3% by weight of 2-benzyl-3,3-dimethyl-5,6-dimethoxy-1-indanone and 0.1% by weight of other impurities.

COMPARISON EXAMPLE 2b

Recrystallisation from Ethanol

(5) With an alternative recrystallisation from ethanol, almost identical results were achieved.

COMPARISON EXAMPLE 3

Production of 2-benzylidene-3,3-dimethyl-5,6-dimethoxy-1-indanone

COMPARISON EXAMPLE 3a

Recrystallisation from Methanol

(6) The procedure in comparison example 3a corresponds to the procedure according to comparison example 2a, but 10 mmol of potassium hydroxide were used. Only 2 g of a 10% aqueous hydrochloric acid solution were used in order to neutralise the solution. 123 g of a yellow educt product admixture were obtained. Using GC measurements, it was possible to establish that the yellow educt product admixture contained 19.7 g (16% by weight of the theoretical quantity with respect to the 3,3-dimethyl-5,6-dimethoxy-1-indanone) of the product.

COMPARISON EXAMPLE 3b

Recrystallisation from Ethanol

(7) With an alternative recrystallisation from ethanol, almost identical results were achieved.

COMPARISON EXAMPLE 4

Production of 2-benzylidene-3,3-dimethyl-5,6-dimethoxy-1-indanone

COMPARISON EXAMPLE 4a

Recrystallisation from Methanol

(8) The procedure in comparison example 4a corresponds to the procedure according to comparison example 2a, but 0.7 g (12 mmol) of potassium hydroxide were used. 100 g of toluol were used as a solvent in place of 100 g of diethylene glycol diethyl ether. Only 2 g of a 10% aqueous hydrochloric acid solution were used in order to neutralise the solution. 21.0 g (17% by weight of the theoretical quantity with respect to the 3,3-dimethyl-5,6-dimethoxy-1-indanone) of a yellow solid product were obtained.

COMPARISON EXAMPLE 4b

Recrystallisation from Ethanol

(9) With an alternative recrystallisation from ethanol, almost identical results were achieved.

EXAMPLE 1

Production of 2-benzylidene-3,3-dimethyl-5,6-dimethoxy-1-indanone

EXAMPLE 1a

Recrystallisation from Methanol

(10) 89 g (0.40 mol) of 3,3-dimethyl-5,6-dimethoxy-1-indanone which was produced in conventional manner were dissolved in 180 g of toluol. This solution was washed with 60 mL of a 5% aqueous solution of potassium hydroxide and then twice, each time with 50 mL of a 10% aqueous cooking salt solution. Subsequently, the organic solution was cleaned of residual water in an azeotropic manner in a water separator. Approximately 80 g of toluol (upper phase) and approximately 2 g of water (lower phase) accumulated in the water separator.

(11) 1.1 g (10 mmol) of potassium-tert-butanolate were added to the dry solution of the 3,3-dimethyl-5,6-dimethoxy-1-indanone in toluol; the resulting admixture was stirred under reflux (approximately 110 C.). Within 1 hour, 65 g (0.61 mol) of benzaldehyde were added and the solution was stirred for a further 3 hours at said temperature. During the entire reaction time, the resultant reaction water produced was distilled in an azeotropic manner by means of a water separator. For processing, the solution was cooled to ambient temperature, 400 g of iced water was added and the solution was neutralised with 3 g of a 10% aqueous hydrochloric acid solution. The remaining organic phase was washed with 100 g of a 10% aqueous cooking salt solution, the remaining solution was distilled. Subsequently, the raw product was distilled by means of a short path distillation installation at a pressure of approximately 1 mbar and a temperature of approximately 170 C. After crystallisation of the distillate from methanol, 82 g (66% of the theoretical quantity with respect to the 3,3-dimethyl-5,6-dimethoxy-1-indanone) of the 2-benzylidene-3,3-dimethyl-5,6-dimethoxy-1-indanone were obtained as a bright yellow solid. The purity of the product was >99.9% by weight. The by-product 2-benzyl-3,3-dimethyl-5,6-dimethoxy-1-indanone observed in the comparison examples could not be detected by means of routine GC examinations. An L*a*b colour measurement was carried out on the product produced. The L-value of the product was 94.09.

EXAMPLE 1b

Recrystallisation from Ethanol

(12) With an alternative recrystallisation from ethanol, almost identical results were achieved.

EXAMPLE 2

Production of 2-benzylidene-3,3-dimethyl-5,6-dimethoxy-1-indanone

EXAMPLE 2a

Recrystallisation from Methanol

(13) The procedure in example 2a corresponds to the procedure according to example 1a, but a distillation of the raw product was dispensed with. After crystallisation of the raw product from methanol, 86 g (69% of the theoretical quantity with respect to the 3,3-dimethyl-5,6-dimethoxy-1-indanone) of the 2-benzylidene-3,3-dimethyl-5,6-dimethoxy-1-indanone were obtained as a bright yellow solid. The purity of the product was >99.9% by weight. The by-product 2-benzyl-3,3-dimethyl-5,6-dimethoxy-1-indanone observed in the comparison examples (compound having the formula (V)) could not be detected by means of routine GC examinations. An L*a*b colour measurement was carried out on the product produced. The L-value of the product was 90.15.

EXAMPLE 2b

Recrystallisation from Ethanol

(14) With an alternative recrystallisation from ethanol, almost identical results were achieved.

EXAMPLE 3

Examination of the Crystallisation in Emulsion

(15) According to the indications in the following Table 1, two cosmetic formulations were produced as emulsions [E(I) and E (II)]. The product from example 1a contained pure 2-benzylidene-3,3-dimethyl-5,6-dimethoxy-1-indanone and was used in the emulsion E(I). For the emulsion E(II), 2-benzylidene-3,3-dimethyl-5,6-dimethoxy-1-indanone from example 1a was used, but it was contaminated with benzyl-3,3-dimethyl-5,6-dimethoxy-1-indanone in such a manner that a 5% by weight contamination was present, with respect to the total mass of the contaminated product.

(16) The emulsions were covered and left to stand at ambient temperature for 3 days. Subsequently, the emulsions were examined under a microscope. Emulsion E(I) had no crystals. In emulsion E(II), crystal seeds having a size of from 4 to 7 m were able to be observed.

(17) This means that a proportion of from 250 ppm (0.025% by weight) of the by-product (benzyl-3,3-dimethyl-5,6-dimethoxy-1-indanone) already initiates the formation of crystallisation seeds in the cosmetic formulation, whilst a formulation free from by-products has no crystallisation.

(18) TABLE-US-00001 TABLE 1 Recipe of the cosmetic formulation used for the crystallisation tests: E(I) E(II) Phase Raw material INCI % by wt. % by wt. A Water dem Aqua 84.15 84.15 Symdiol 68 1,2-hexanediol, Gaprylyl 0.60 0.60 Glycol SymMoillent W/S Trideceth-9, PEG-5 0.50 0.50 Isononanoate, Aqua Glycerin 85% Glycerin 1.00 1.00 Hydrolite 5 1,2-pentylene glycol 1.00 1.00 B PCL Liquid 100 Cetearyl Octanoate 3.00 3.00 Lanette O Cetearyl Alcohol 2.00 2.00 Product from example Benzylidene 0.50 1a Dimethoxydimethylindanone Product from example Benzylidene 0.50 1a replaced with 5% by Dimethoxydimethylindanone; weight benzyl-3,3- dimethyl-5,6- dimethoxy-1-indanone Pemulen TR1 Acylates/C10-30Alkyl Acrylate 0.20 0.20 Crosspolymer Carbopol Ultrez-21 Acylates/C10-30Alkyl Acrylate 0.05 0.05 Crosspolymer Paraffin oil 5 Mineral Oil 3.00 3.00 Dragoxat 89 Ethylhexyl Isononanoate 3.00 3.00 Abil 350 Dimethicone 0.50 0.50 C NaOH, 10% aq. Sodium Hydroxide 0.50 0.50 Total 100.00 100.00