WO2003091235A1

WO2003091235A1 - Manufacture of ketopantolactone

Info

Publication number: WO2003091235A1
Application number: PCT/EP2003/003655
Authority: WO
Inventors: Werner Bonrath; Reinhard Karge; Matthias Nuechter; Bernd Ondruschka
Original assignee: Dsm Ip Assets B.V.
Priority date: 2002-04-25
Filing date: 2003-04-09
Publication date: 2003-11-06
Also published as: CN1649860A; KR100969111B1; TW200307676A; AU2003240450A1; CN1332956C; KR20040111543A

Abstract

A process for the oxidation of pantolactone to ketopantolactone comprises carrying out the oxidation with a periodate in the presence of a ruthenium catalyst, in an aqueous solvent system and in a microwave field. Ketopantolactone is a key intermediate in the manufacture of pantothenic acid, the latter being a member of the B complex vitamins and a constituent of coenzyme A. Asymmetric hydrogenation of ketopantolactone yields (D)(-)-pantolactone, from which pantothenic acid can then be manufactured.

Description

Manufacture of Ketopantolactone

The present invention relates to an oxidation process for the manufacture of ketopantolactone. More particularly, the invention relates to a process for the oxidation of pantolactone to ketopantolactone in a microwave field.

Ketopantolactone is a key intermediate in the manufacture of pantothenic acid, the latter being a member of the B complex vitamins and a constituent of coenzyme A. Asymmetric hydrogenation of ketopantolactone yields (D)-(-)-pantolactone, from which pantothenic acid can then be manufactured.

The oxidation of pantolactone, which is the compound of the formula

to ketopantolactone of the formula

has been described in various publications, e.g. in Japanese Kokai 04/095087 A2 (CA 117, 69720m): oxidation using manganese dioxide; Japanese Kokai 04/095086 A2 (CA 117, 69719t) and Japanese Kokai 05/306276 A2 (CA 120, 163965d): oxidation using dimethyl sulphoxide; Japanese Kokai 61/242586 A2 (CA 107, 5783v) and Reel. Trav. Chim. Pays- Bas, 110(5), 155-7 (1991): microbial oxidation; Synth. Commun. 14(7), 697-700 (1984): ruthenium-catalyzed aerobic oxidation; and Angew. Chem. 96(7), 519-520 (1984): ruthenium-catalyzed dehydrogenation with tert. butyl hydroperoxide.

The hitherto available processes are unsatisfactory with respect to yield, selectivity and reaction time for use in the commercial scale production of ketopantolactone.

It has now been found that ketopantolactone can be produced from pantolactone in superior selectivity and conversion and in a shorter reaction time by oxidation with a periodate (IO₄ , also known as "metaperiodate"; further references to "periodate" hereafter are to be considered equally as references to "metaperiodate") in the presence of a ruthenium catalyst, in an aqueous solvent system and in a microwave field. Accordingly, the present invention provides a process for the oxidation of pantolactone to ketopantolactone which comprises carrying out the oxidation with a periodate in the presence of a ruthenium catalyst, in an aqueous solvent system and in a microwave field.

The periodate used in the process of the present invention is suitably an alkali metal periodate such as sodium or potassium periodate [Na⁺IO or K⁺IO ]. The ruthenium catalyst can be any ruthenium catalyst conventionally used in oxidation processes and which is soluble in the aqueous solvent system used in the process of the invention. Examples of such catalysts are ruthenium(III) salts, such as ruthenium(III) halides, particularly ruthenium(III) chloride [RuCl₃] and ruthenium(III) bromide [RuBr₃], and ruthenium oxides, particularly ruthenium(III) oxide [Ru₂O₃] and hydrates thereof, and ruthenium(IV) oxide [RuO₂] and hydrates thereof. The preferred catalyst is ruthenium(III) chloride.

The term "aqueous solvent system" as used herein denotes a solvent system comprising a mixture of water and an organic water-miscible solvent wherein pantolactone and ketopantolactone are soluble. The organic solvent must be at least partially soluble in water; the system, depending upon the organic solvent used, is often a two-phase system. This is the case with for example ethyl acetate as the organic solvent. Examples of suitable organic solvents are aliphatic esters, e.g. ethyl acetate and isopropyl acetate; cyclic esters, e.g. γ-butyrolactone; and carbonates ("carbonate esters"), e.g. ethylene carbonate and propylene carbonate. Preferred are two-phase aqueous solvent systems. The volume ratio of water to the organic solvent in the aqueous solvent system is suitably about 1.5 : 1 to about 10 : 1, preferably about 3 : 1 to about 5 : 1. The amount of water in the solvent system relative to the amount of starting material pantolactone is suitably from about 1 ml to about 5 ml of water per mmol of pantolactone, preferably about 1.5 ml to about 2.5 ml of water per mmol of pantolactone. The preferred organic solvent is ethyl acetate, and the preferred aqueous solvent system containing ethyl acetate as the organic solvent is a mixture of about 2 volumes of water to 1 volume of ethyl acetate.

Regardless of its specific nature, the amount of periodate relative to the amount of starting material, pantolactone, used in the process of the present invention is suitably from about 4 g to about 10 g per 1 g of pantolactone, preferably from about 4.5 g to about 6.5 g per 1 g of pantolactone.

In respect of the relative amount of ruthenium catalyst, there is suitably used from about 0.001 g to about 0.05 g of ruthenium catalyst per 1 g of pantolactone, preferably about 0.01 g to about 0.015 g of said catalyst per 1 g of pantolactone.

The microwave field can be provided by any conventional microwave emitting equipment. The term "microwave" as used herein refers to the region of the electromagnetic spectrum having frequencies of 300 MHz to 30 GHz, thus corresponding to wavelengths of 1 m to 1 cm. In order not to interfere with wavelengths for radar (1 cm - 25 cm), industrial microwave emitters are required by international regulations to operate at wavelengths of either 12.2 cm (2.45 GHz) or 33.3 cm (900 MHz). See in this connection Chem. Soc. Rev. 20, 1-47 ( 1991). Thus, in a preferred embodiment of the invention, the applied microwave field has a wavelength of about 12.2 cm or about 33.3 cm. The microwave field is generally applied to promote the oxidation for a period of about 1 to about 60 minutes, preferably about 5 to about 40 minutes, and especially preferred about 10 to about 30 minutes.

Microwave reactors suitable for use in the process of the present invention are for example those in the "Ethos" range, e.g. the Ethos 1600 reactor, as supplied, e.g., by the firm MLS GmbH, Auenweg 37, D-88299 Leutkirch im Allgau, Germany (suppliers outside Germany are for example Milestone S.r.l., Via Fatebenefratelli, 1/5, 1-24010 Sorisole (BG), Italy and Milestone Inc., 160 B Shelton Road, Monroe, CT 06468, USA). Conveniently, the irradiation in the process of the invention is carried out applying a power of irradiation of from about 400 W to about 1000 W, more preferably from about 500 W to about 800 W.

The microwave field is preferably so applied in the oxidation process in accordance with the present invention that the oxidation is carried out at the boiling temperature of the aqueous solvent system used. In a preferred embodiment of the process of the present invention the microwave field is applied to a solution of pantolactone and the ruthenium catalyst in the appropriate aqueous solvent system until the temperature of the reaction mixture has reached its boiling point, i.e. reflux temperature, whereupon the periodate oxidizing agent is added. The reaction is suitably monitored, e.g., by gas chromatography, to determine the optimal point of conversion of pantolactone into the desired ketopantolactone. In this way, the formation of undesired products which may take place if the reaction time is unnecessarily prolonged and which would lower the ultimately obtainable yield of ketopantolactone can be avoided. Once optimal conversion of pantolactone into ketopantolactone has been achieved, which is typically the case after a 80% conversion of the starting pantolactone, the reaction solution is cooled and the desired product, ketopantolactone, isolated, suitably by separating the two solvent phases and evaporation of the non-aqueous phase after removal of solid materials by filtration. The aqueous phase normally contains the unreacted materials, and can be recycled if desired to recover inter alia unreacted pantolactone.

The following Example illustrates the invention:

Example

A mixture of 29.5 g of pantolactone, 300 mg of rufheniurn(III) chloride, 400 ml of water and 200 ml of ethyl acetate was heated with stirring to reflux temperature by applying a microwave field generated from a microwave reactor (Ethos 1600, available from MLS GmbH, D-88299 Leutkirch im Allgau, Germany) having a power output of 700 W. 145.5 g of sodium (meta)periodate were added to the boiling mixture within 10 minutes. The reaction mixture was then stirred for a further 20 minutes and thereafter rapidly cooled. The organic phase was separated from the aqueous phase and the sodium iodate precipitate in the former phase filtered off by suction and washed five times with 20 ml quantities of ethyl acetate. The two-phase mixture was separated and the aqueous phase extracted twice with 50 ml of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. Ketopantolactone was thus obtained in a purity of 98% and a yield of 60% based on starting pantolactone. From the aqueous phase an additional 12% of product could be isolated. Unreacted pantolactone was recovered from the aqueous phase.

Following this procedure an 80% conversion of the starting pantolactone into ketopantolactone and a selectivity of 0.95 could be achieved.

Claims

1. A process for the oxidation of pantolactone to ketopantolactone which comprises carrying out the oxidation with a periodate in the presence of a ruthenium catalyst, in an aqueous solvent system and in a microwave field.

2. A process according to in claim 1 wherein the periodate is an alkali metal periodate, preferably sodium or potassium periodate.

3. A process according to claim 1 or claim 2 wherein the ruthenium catalyst is a ruthenium(III) salt which is soluble in the used aqueous solvent system, preferably a ruthenium(III) halide or a ruthenium oxide or a hydrate thereof.

4. A process according to claim 3, wherein the ruthenium(III) salt is ruthenium(III) chloride, ruthenium(III) bromide, ruthenium(III) oxide or a hydrate thereof, or ruthenium(IV) oxide or a hydrate thereof.

5. A process according to any one of claims 1 to 4, wherein the organic solvent of the aqueous solvent system is an aliphatic ester, preferably ethyl acetate or isopropyl acetate; a cyclic ester, preferably γ-butyrolactone; or a carbonate, preferably ethylene carbonate or propylene carbonate.

6. A process according to any one of claims 1 to 5, wherein the volume ratio of water to the organic solvent in the aqueous solvent system is about 1.5 : 1 to about 10 : 1, preferably about 3 : 1 to about 5 : 1.

7. A process as in any one of claims 1 to 6, wherein the aqueous solvent system is a two-phase solvent system comprising ethyl acetate as the organic solvent.

8. A process according to any one of claims 1 to 7, wherein the amount of periodate relative to the amount of starting pantolactone used is from about 4 g to about 10 g per 1 g of pantolactone, preferably from about 4.5 g to about 6.5 g per 1 g of pantolactone.

9. A process according to any one of claims 1 to 8, wherein from about 0.001 g to about 0.05 g of ruthenium catalyst is used per 1 g of pantolactone, preferably about 0.01 g to about 0.015 g of the catalyst per 1 g of pantolactone.

10. A process according to any one of claims 1 to 9, wherein the microwave field has a wavelength of about 12.2 cm or about 33.3 cm.

11. A process according to any one of claims 1 to 10, wherein the microwave field is so applied that the oxidation is carried out at the boiling temperature of the aqueous solvent system used.