Process for the industrial synthesis of sordidin

Abstract

The present invention relates to a process for preparing sordidin, comprising a step of preparing 4-(2-ethyl-1,3-dioxolan-2-yl)pentan-2-one by means of a reaction in which 2-ethyl-2-(pent-4-en-2-yl)-1,3-dioxolane is oxidized in the presence of a catalyst chosen from the group comprising organometallic complexes of transition metals.

Claims

1. A process for preparing sordidin comprising a step for preparing 4-(2-ethyl-1,3-dioxolan-2-yl)pentan-2-one (compound 4) ##STR00011## by means of a reaction in which 2-ethyl-2-(pent-4-en-2-yl)-1,3-dioxolane (compound 3) ##STR00012## is oxidised in the presence of a catalyst comprising an organometallic complex of a transition metal.

2. The process according to claim 1, wherein the oxidation reaction is carried out in the presence of an oxidising agent chosen from air, oxygen-enriched air, oxygen O.sub.2 and hydroperoxides with the formula ROOH wherein R can be a hydrogen atom, a linear or branched C.sub.1-C.sub.6 alkyl group.

3. The process according to claim 1, wherein the catalyst comprises a Ni, Rh, Ir, Pd, Co or Pt base.

4. The process according to claim 1, wherein the catalyst is chosen from Palladium (II) compounds from Nickel (II) compounds from the Cobalt compounds, or from Rhodium (III) compounds.

5. The process according to claim 1, wherein the catalyst is complexed by a ligand chosen from amines, phosphines and phtalocyanines.

6. The process according to claim 1, wherein a catalyst regenerator is added.

7. The process according to claim 6, wherein the catalyst regenerator is chosen from copper and iron-based regenerators.

8. The process according to claim 1, wherein the catalyst is Pd(Acetate).sub.2.

9. The process according to claim 1, wherein the oxidation reaction of compound 3 into compound 4 is carried out in the presence of at least one solvent chosen from water, alcoholic solvents, acidic solvents, ketone solvents, ether solvents, nitrogen solvents, as well as liquid polymer solvents.

10. The process according to claim 1, wherein the oxidation reaction of compound 3 into compound 4 is carried out in the presence of at least one solvent chosen from water, DMF, DMA, acetone, heptane, tertBuOH and mixtures thereof.

11. The process according to claim 1, wherein the oxidation reaction is carried out under a pressure between atmospheric pressure and 30 bars.

12. The process according to claim 1, wherein the oxidation reaction is carried out at a temperature between 25 C. and 100 C.

13. A process for synthesising sordidin wherein it comprises a process according to claim 1, followed by the modification of the 4-(2-ethyl-1,3-dioxolan-2-yl)pentan-2-one (compound 4) ##STR00013## by magnesium coupling with alkyl magnesium halide, oxidation, opening of the epoxide, and conversion into sordidin by cyclisation.

14. The process according to claim 2, wherein R is a terbutyl group or a cumyl aromatic group.

15. The process according to claim 4, wherein the Palladium (II) compound is selected from the group consisting of PdCl.sub.2, Pd(Acetate).sub.2, Pd(Acetate)(triflate), Pd(OH).sub.2 and PdBr.sub.2, the Nickel (II) compound is selected from the group consisting of Ni(Acetate).sub.2, NiCl.sub.2 and NiBr.sub.2, the Cobalt compound is selected from the group consisting of Co(No.sub.3).sub.2, CoCl.sub.2, CoBr.sub.2 and Co(Acetate).sub.2, or the Rhodium (III) compound is selected from the group consisting of Rh(Cl) and Rh(ClO.sub.4).sub.3.

16. The process according to claim 7, wherein the copper or iron-based regenerator is selected from the group consisting of CuCl, CuCl.sub.2, CuBr, CuBr.sub.2, CuAcetate, FeCl.sub.2, and FeCl.sub.3.

17. The process according to claim 11, wherein the oxidation reaction is carried out under a pressure between atmospheric pressure and 5 bars.

18. The process according to claim 12, wherein the oxidation reaction is carried out at a temperature between 40 C. and 80 C.

Description

EXAMPLES

(1) The starting product, compound 3: 2-ethyl-2-(pent-4-en-2-yl)-1,3-dioxolane can be obtained according to the Ducrot procedure, using 3-pentanone after two first steps described in: P. H. Ducrot, Synth. Comm., 26 (21) 3923-3928, 1996.

(2) ##STR00009##

(3) The other reagents are purchased from conventional chemical suppliers.

(4) Analysis in Gas Phase Chromatography

(5) The reaction follow-up of the various steps of the synthesis of sordidin is carried out by Gas Phase Chromatography (CPG). The results are expressed as a relative percentage. The relative quantities of compounds are evaluated via measuring the area under the curve. The analyses were carried out in the following conditions: CPG device of the Hewlett Packard brand (5890 Series II), provided with an FID detector (Flame Ionisation Detector) and with a HP5 column (Agilent J&W) 30 m0.52 mm Film 0.88 m, with a helium pressure from 3 to 10 psi, an injector temperature of 250 C., a detector temperature of 280 C. The following were also used: an initial oven temperature of 50 C., an initial time of 3 min a ramp 1 of 10 C./min, a final temperature 1 of 260 C. and a dwell time 1 of 5 min.

(6) The samples to be analysed were prepared by diluting 100 mg of synthetic intermediate or of the product to analysed in acetonitrile (QSP 20 ml). The volume of sample injected into the CPG is 1 l.

Example 1

Oxidation Reaction Under Air Pressure in the Conditions: Air Pressure (6 Bars), Catalyst PdCl2 Plus CuCl in a Water-DMF Mixture

(7) Into a 250 ml tricol flask provided with a stirring platform and with a two-blade stirrer are introduced successively 93.5 ml of DMF, 19.5 ml of water, 43 mg of palladium chloride, 295 mg of cuprous chloride and finally 8.5 g of compound 3.

(8) The reaction medium is heated to 80 C. and compressed air is injected resulting in an increase in the pressure of the reactor to 5 bars with a slight renewal of air. After 8 h 30 of stirring, 13% conversion is observed by CPG and the relative purity of the compound 4 formed is 11%. The conversion rate obtained led the inventors to optimise the reaction conditions of which details are provided in the following examples.

Example 2

Oxidation Reaction Under Air Pressure in the Conditions: Air Pressure (6 Bars), Catalyst PdCl2 Plus CuCl in a Water-DMA Mixture

(9) In a 70 L reactor, are loaded under stirring, successively 44 kg dimethylacetamide (DMA), 2.6 kg of the compound 3, 6.6 kg of water, 13.8 g of palladium chloride, and 93 g of cuprous chloride. The reaction medium is heated to 80 C. and compressed air is injected resulting in an increase in the pressure of the reactor to 6 bars with a slight renewal of air. The forming of the compound 4 is followed by gas phase chromatography in the conditions described hereinabove. After 12 h of stirring, it is observed that the starting product has disappeared. The reaction medium is cooled to ambient temperature then water is added (26 kg). Exothermicity is observed. The compound 4 is then recovered by decanting followed by four extracting with methyl-tert-butyl ether MTBE (5V) and completed by two washings with water of the organic phases (1V). After evaporation, the fractions are gathered together and distilled to 72 C. at 4 mbar. The fractions are redistilled, until the obtaining of a pale yellow colour liquid (2.2 kg of compound 4, output 80%, purity CPG=94%).

Example 3

(10) Oxidation reaction under atmospheric air pressure, in the conditions: 60 C., catalyst palladium acetate in acetone, t-butylhydroperoxide oxidant

(11) Into a 250 ml tricol flask provided with a stirring platform and with a two-blade stirrer are introduced 100 ml of acetone, 65.6 ml of t-butyl hydroperoxide (tBuOOH) then under stirring 1.76 g of catalyst: palladium acetate and finally 27.93 g of compound 3.

(12) The reaction medium is heated to 60 C. under atmospheric pressure. The forming of the compound 4 is followed by gas phase chromatography.

(13) After 14 h of stirring (the conversion rate is 97.9%), the reaction medium is cooled to ambient temperature.

(14) 100 ml of a solution containing 50 g sodium thiosulfate and 100 ml of MTBE is then added. The reaction medium is filtered and after decanting the upper organic phase is recovered. After evaporation of the solvents at 60 C., followed by distilling in a vacuum at a pressure of 2 mbar, the compound 4, 11.1 g (36.3% of yield) is obtained in the form of a pale yellow limpid liquid with a relative purity of 90.7% by CPG.

Examples 4 to 8

(15) Examples 4 to 8 make it possible to show the various operating conditions considered concerning the step of transforming the compound 3 into compound 4 in the framework of this invention.

(16) The various processes tested are distributed into two major types, pressurised tests which follow the experimental protocol described in example 2, the atmospheric pressure tests which follow the protocol described in example 3.

(17) TABLE-US-00001 Ex 1 Ex 2 Ex 3 Ex 4 Ex 5 Ex 6 Ex 7 Ex 8 Type of Ex 2 Ex 2 Ex 3 Ex 2 Ex 3 Ex 3 Ex 3 Ex 3 condition Oxidant air air tBuOOH Air tBuOOH H.sub.2O.sub.2 tBuOOH tBuOOH enriched Catalyser PdCl.sub.2 + PdCl.sub.2 + ePdO PdCl.sub.2 + Pd PdOAC.sub.2 PdOAC.sub.2 Pd (OAc).sub.2 + (and Cucl Cucl (Acetate).sub.2 Cucl (Acetate) ligand possible (Triflate) NaOAC regenerator) Solvent DMF + DMA + Acetone Acetone Acetone Tert- Acetone Heptane water water BuOH Temperature 80 80 60 80 50 50 60 98 ( C.) Pressure 5 6 1 5 1 1 1 1 (atm) Conversion 13% 91% 97% 91% 67% 80% 98% >95% rate of the compound 3 into 4

Example 9

(18) Using compound 4, the compound 5 is obtained by reaction with magnesium allyl chloride, then the compound 6 by controlled oxidation and this latter compound is then obtained by acid hydrolysis. The sordidin obtained is characterised by gas phase chromatography. The distribution of the 4 diastereoisomers a, b, c and d of sordidin is measured such as indicated in diagram 1. The elute times correspond to the four diastereoisomers such as was shown by Beauhaire (Tetrahedron Letters, 36 (7) 1043-1046, 1995).

(19) ##STR00010##
Diagram 1: Chemical Formula of Isomers a, b, c, d of Sordidin

(20) The analysis of the quantity, by calculating the area under the curve, of the 4 diastereoisomers of sordidin contained in the sordidin mixture obtained gives the following distribution: a: 34%; b: 19%; c: 16.9%; d: 30.1%.