Process for preparing a macrocyclic diketone

Abstract

The present invention relates to a process for preparing a macrocyclic diketone compound of the formula (I), which comprises the oxidation of a bicycloolefine compound of the formula (II) with an oxidizing agent, formulae (I) (II) where in formulae (I) and (II) A is (CH.sub.2).sub.n with n being an integer from 2 to 12, where two hydrogen atoms may be replaced by C.sub.1-C.sub.4-alkyl, in particular methyl, or two hydrogen atoms, which are bound to adjacent carbon atoms may be replaced by a fused 5- or 6-membered saturated carbocycle; B is (CH.sub.2).sub.m with m being 1 or 2, where 1 or 2 hydrogen atoms may be replaced by C.sub.1-C.sub.4-alkyl, in particular methyl. ##STR00001##

Claims

1. A process for preparing a macrocyclic diketone compound of the formula (I), which comprises the oxidation of a bicycloolefine compound of the formula (II) with an oxidizing agent, ##STR00004## where in formulae (I) and (II) A is (CH.sub.2).sub.n with n being an integer from 2 to 12, where two hydrogen atoms are optionally replaced by C.sub.1-C.sub.4-alkyl or two hydrogen atoms, which are bound to adjacent carbon atoms are optionally replaced by a fused 5- or 6-membered saturated carbocycle; B is (CH.sub.2).sub.m with m being 1 or 2, where 1 or 2 hydrogen atoms are optionally replaced by C.sub.1-C.sub.4-alkyl, where the oxidizing agent comprises a catalytic amount of a ruthenium compound and a co-oxidizing agent selected from oxyanions of chlorine.

2. The process of claim 1, where the total amount of the ruthenium compound in the reaction mixture, calculated based on the number of ruthenium atoms, is in the range of from 0.001 to 0.2 mol per 1 mol of compound of formula (II).

3. The process of claim 1, where the ruthenium compound is selected from the group consisting of ruthenium oxides, ruthenates, perruthenates, ruthenium halides, ruthenium nitrates and mixtures thereof.

4. The process of claim 1, where the total amount of the co-oxidizing agent used in the oxidation is in the range of from 2 to 10 mol per 1 mol of compound of formula (II), calculated as oxygen equivalent.

5. The process of claim 1, where the co-oxidizing agent is selected from hypochlorites.

6. The process of claim 1, where the pH of the reaction mixture is maintained in the range of from 7 to 14 during the oxidation of the compound of formula (II).

7. The process of claim 6, where the maintenance of the pH is achieved by adding an aqueous buffer solution, comprising at least one buffering agent, having a pKa-value in the range of from 8 to 12, to the reaction mixture.

8. The process of claim 1, where the co-oxidizing agent is added to the reaction mixture in the form of an alkaline aqueous solution, having a pH of at least pH 10.

9. The process of claim 1, where the co-oxidizing agent is added continuously to the reaction mixture during the oxidation of the compound of formula (II).

10. The process of claim 1, where the molar ratio of the co-oxidizing agent to the ruthenium compound, which are applied to the reaction mixture, is in the range of from 10:1 to 10000:1.

11. The process of claim 1, where the oxidation of the compound of formula (II) is performed in the presence of an organic solvent or an organic solvent mixture.

12. The process of claim 1, where, after completion of the oxidation of the compound of formula (II), the ruthenium compound is recovered from the reaction mixture for further reuse.

13. The process of claim 1, where the compound of formula (I) is 3-methylcyclopentadecane-1,5-dione and the compound of formula (II) is 14-methylbicyclo[10.3.0]pentadecen[1(12)].

14. The process of claim 1, where the compound of formula (I) is cyclopentadecane-1,5-dione and the compound of formula (II) is bicyclo[10.3.0]pentadecen[1(12)].

Description

EXAMPLES

I) Gas Chromatographic Analysis

(1) GC-System and Separation Method:

(2) GC-system: Agilent 5890 Series II;

(3) GC-Column: 5CB-WAX-52CB (50 m (Length), 0.32 mm (ID), 1.2 m (Film));

(4) Temperature program: 40 C. for 6 minutes, 40 C. to until 250 C. in 8 C./min.

II) Production Examples

Example 1: Oxidation of IIa in 1,2-Dichloroethane

(5) 5.0 g (22.7 mmol) of the monoene of formula (IIa) and 0.3 g (1.15 mmol) RuCl.sub.3 in 25 ml 1,2-dichloromethane were placed into a 250 ml reaction flask, equipped with an 100 ml dropping funnel, an intensive condenser and a mechanical stirrer. Under vigorous stirring at 35 C., 75 ml of a 12.5 weight-% NaOCl-solution (126 mmol) in H.sub.2O charged with 1.5 g NaOH, were added. The pH of the reaction mixture was 14.0 at the start of the addition and dropped to pH 7.9 over time.

(6) The course of the oxidation reaction was followed by gas chromatographic analysis: After 2 hours, the conversion of the monoene (IIa) was 100% and the formation of the diketone of formula (Ia) 80% (GC area percent). After 3 hours, the formation of the diketone of formula (Ia) reached 94% (GC area percent).

(7) After completion of the reaction, the reaction mixture was allowed to cool down to room temperature and the organic phase was separated from the water phase. The water phase was washed with 1,2-dichloromethane. The ruthenium compound (catalyst) was separated from the organic phase by filtration and washed with 1,2-dichloromethane and water. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. An analysis of the reaction residual revealed 100% conversion of the monoene (IIa) and the formation of the wanted diketone of formula (Ia) of 95% (GC weight percent).

Example 2: Oxidation of IIa in Ethyl Acetate and in the Presence of a Buffer Solution

(8) 5.0 g (22.7 mmol) of the monoene of formula (IIa), 0.3 g (1.15 mmol) RuCl.sub.3 in 25 ml ethyl acetate and 25 ml of a Na.sub.2CO.sub.3/NaHCO.sub.3 buffer solution (pH 9.7) were placed into a 250 ml reaction flask, equipped with an 100 ml dropping funnel, an intensive condenser and a mechanical stirrer. Under vigorous stirring at 35 C., 75 ml of a 12.5 weight-% NaOCl-solution (126 mmol) in H.sub.2O charged with 1.5 g NaOH, were added. The pH of the reaction mixture was 10.8 at the start of the addition and dropped to pH 9.0 over time.

(9) The course of the oxidation reaction was followed by gas chromatographic analysis: After 2 hours, the conversion of the monoene (IIa) was 99.6% and the formation of the diketone of formula (Ia) 77.6% (GC area percent).

(10) After completion of the reaction, the reaction mixture was allowed to cool down to room temperature and the organic phase was separated from the water phase. The water phase was washed with ethyl acetate. The ruthenium compound (catalyst) was separated from the organic phase by filtration and washed with ethyl acetate and water. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. An analysis of the reaction residual revealed 100% conversion of the monoene (IIa) and the formation of the wanted diketone of formula (Ia) of 83.5% (GC weight percent).

Example 3: Oxidation of IIa in Ethyl Acetate Without the Addition of a Buffer Solution

(11) 5.0 g (22.7 mmol) of the monoene of formula (IIa) and 0.3 g (1.15 mmol) RuCl.sub.3 in 25 ml ethyl acetate were placed into a 250 ml reaction flask, equipped with an 100 ml dropping funnel, an intensive condenser and a mechanical stirrer. Under vigorous stirring at 35 C., 75 ml of a 12.5 weight-% NaOCl-solution (126 mmol) in H.sub.2O charged with 1.5 g NaOH, were added. The pH of the reaction mixture was 14.0 at the start of the addition and dropped to pH 7.6 over time.

(12) The course of the oxidation reaction was followed by gas chromatographic analysis: After 2 hours, the conversion of the monoene (IIa) was 100% and the formation of the diketone of formula (Ia) 66.7% (GC area percent).

(13) After completion of the reaction, the reaction mixture was allowed to cool down to room temperature and the organic phase was separated from the water phase. The water phase was washed with ethyl acetate. The ruthenium compound (catalyst) was separated from the organic phase by filtration and washed with ethyl acetate and water. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. An analysis of the reaction residual revealed 100% conversion of the monoene (IIa) and the formation of the wanted diketone of formula (Ia) of 75.8% (GC weight percent).

Example 4: Oxidation of IIa in Methyl Tert.-Butyl Ether (MTBE) and in the Presence of a Buffer Solution

(14) 5.0 g (22.7 mmol) of the monoene of formula (IIa), 0.3 g (1.15 mmol) RuCl.sub.3 in 25 ml MTBE and 25 ml of a Na.sub.2CO.sub.3/NaHCO.sub.3 buffer solution (pH 9.7) were placed into a 250 ml reaction flask, equipped with an 100 ml dropping funnel, an intensive condenser and a mechanical stirrer. Under vigorous stirring at 35 C., 75 ml of a 12.5 weight-% NaOCl-solution (126 mmol) in H.sub.2O charged with 1.5 g NaOH, were added. The pH of the reaction mixture was 12.7 over the course of the reaction. The course of the oxidation reaction was followed by gas chromatographic analysis. The total reaction time was 5 hours.

(15) After completion of the reaction, the reaction mixture was allowed to cool down to room temperature and the organic phase was separated from the water phase. The water phase was washed with MTBE. The ruthenium compound (catalyst) was separated from the organic phase by filtration and washed with MTBE and water. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. An analysis of the reaction residual revealed 100% conversion of the monoene (IIa) and the formation of the wanted diketone of formula (Ia) of 66.3% (GC weight percent).

Example 5: Oxidation of IIa in Methyl Tert.-Butyl Ether (MTBE) Without the Addition of a Buffer Solution

(16) 5.0 g (22.7 mmol) of the monoene of formula (IIa) and 0.3 g (1.15 mmol) RuCl.sub.3 in 25 ml MTBE were placed into a 250 ml reaction flask, equipped with an 100 ml dropping funnel, an intensive condenser and a mechanical stirrer. Under vigorous stirring at 35 C., 75 ml of a 12.5 weight-% NaOCl-solution (126 mmol) in H.sub.2O charged with 1.5 g NaOH, were added. The pH of the reaction mixture was 9.4 over the course of the reaction. The course of the oxidation reaction was followed by gas chromatographic analysis. The total reaction time was 5 hours.

(17) After completion of the reaction, the reaction mixture was allowed to cool down to room temperature and the organic phase was separated from the water phase. The water phase was washed with MTBE. The ruthenium compound (catalyst) was separated from the organic phase by filtration and washed with MTBE and water. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. An analysis of the reaction residual revealed 100% conversion of the monoene (IIa) and the formation of the wanted diketone of formula (Ia) of 93.6% (GC weight percent).

Example 6: Large Batch Oxidation of IIa in Methyl Tert.-Butyl Ether (MTBE)

(18) 89.5 g (0.40 mol) of the monoene of formula (IIa) and 5.8 g (23 mmol) RuCl.sub.3 in 500 ml MTBE were placed into a 2.5 l H=D reactor equipped with an 1 l dropping funnel, an intensive condenser and a 3-fold cross-arm stirrer (400 rpm). Under vigorous stirring at 35 C., 1.0 l of a 13.4 weight-% NaOCl-solution in H.sub.2O (1.80 mol), charged with 26.5 g NaOH (0.66 mol), were added. Following this, the reaction was run at 35 C. for additional 10 hours.

(19) The course of the oxidation reaction was followed by gas chromatographic analysis: After 5 hours, the conversion of the monoene (IIa) was 83% and the formation of the diketone of formula (Ia) 72% (GC area percent). After 10 hours, the conversion of the monoene (IIa) was 100% and the formation of the diketone of formula (Ia) 91% (GC area percent).

(20) After completion of the reaction, the reaction mixture was allowed to cool down to room temperature and the organic phase was separated from the water phase. The water phase was washed with MTBE. The organic phase was first washed with 250 ml of a 20 weight-% solution of NaOH in water followed by 250 ml of water. The ruthenium compound (catalyst) was separated from the organic phase by filtration and washed with MTBE and water. After this washing step, the ruthenium compound (catalyst) was dried at 50 C. for 2 hours and directly applied to the next oxidation reaction (vide example 7).

(21) The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. 120.8 g of residual were obtained. An analysis of the residual revealed complete conversion of the monoene (IIa) and 76.7% of the wanted diketone (92.6 g, 0.367 mol, 91.7% yield).

Example 7: Large Batch Oxidation of IIa in Methyl Tert.-Butyl Ether (MTBE) Using the Recovered Ruthenium Compound (Catalyst) of Example 6

(22) 89.5 g (0.40 mol) of the monoene of formula (IIa) and 5.9 g of recovered ruthenium compound (catalyst) from example 6 in 500 ml MTBE were placed into a 2.5 l H=Dreactor equipped with an 1 l dropping funnel, an intensive condenser and a 3-fold cross-arm stirrer (400 rpm). Under vigorous stirring at 35 C., 1.0 l of a 13.4 weight-% NaOCl-solution in H.sub.2O (1.80 mol), charged with 26.5 g NaOH (0.66 mol), were added. Following this, the reaction was run at 35 C. for additional 10 hours.

(23) The course of the oxidation reaction was followed by gas chromatographic analysis: After 5 hours, the conversion of the monoene (IIa) was 85% and the formation of the diketone of formula (Ia) 74% (GC area percent). After 10 hours, the conversion of the monoene (IIa) was 100% and the formation of the diketone of formula (Ia) 89% (GC area percent).

(24) After completion of the reaction, the reaction mixture was allowed to cool down to room temperature and the organic phase was separated from the water phase. The water phase was washed with MTBE. The organic phase was first washed with 250 ml of a 20 weight-% solution of NaOH in water followed by 250 ml of water. The ruthenium compound (catalyst) was separated from the organic phase by filtration and washed with MTBE and water. After this washing step, the ruthenium compound (catalyst) was dried at 50 C. for 2 hours.

(25) The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. 102.3 g of residual were obtained. An analysis of the residual revealed complete conversion of the monoene (IIa) and 89% of the wanted diketone (91.0 g, 0.361 mol, 90.3% yield).