Process for the manufacture of alkyl compounds

The present invention relates to a process for the manufacture of long chain alkyl compounds and to reagents for use in such manufacture.

Long-chain alkyl compounds are useful, amongst others in pharmaceutical or in particular cosmetic preparations, where they act as skin penetration enhancers. A particular advantageous compound of this class is 4-decyloxazolidin-2-one which is commercialized by Girindus AG.

WO-A-90/00407 discloses the manufacture of the latter compound by reaction of 2-aminododecan-l-ol with ethylene carbonate. However, the 2-aminododecan-l-ol required is not readily available. According to Ishizuka et al, Chem. Lett. 1992, p.991-994, certain chiral

4-substituted 2-oxazolidinones have been manufactured by a reaction sequence involving addition of certain organometallics, including organocuprates, to 4-methoxy-2-oxazolidinone. However that reference is unrelated to the manufacture of long chain alkyl compounds. Now, applicants have found a process which allows for efficient and selective manufacture of long chain alkyl compounds such as in particular 4-decyloxazolidin-2-one.

The invention concerns in consequence a process for the manufacture of a compound of formula I

wherein Rl is H, acyl, alkyl or carbamoyl, R2 is a linear alkyl or alkenyl group, preferably a linear alkyl group comprising from 6 to 20 carbon atoms and n is 0, 1, 2, or 3, which comprises reacting a compound of formula II

wherein Rl and n are as above and X is a leaving group with a reagent of formula III

M-R2 wherein R2 is as above and M denotes a metal or a metal containing group.

The process according to the invention allows in particular for efficient industrializable production of long chain alkyl substituted compounds. This is unexpected, as reactivity of long-chain organometallics is expected to decrease. Compounds of formula II are readily available for example starting from commercially available oxazolidin-2-one.

An embodiment of the process according to the invention consequently further comprises synthesizing the compound of formula II by electrochemically oxidizing a compound of formula IV

wherein Rl is H, acyl, alkyl or carbamoyl and n is 0, 1, 2, or 3, in the presence of a precursor of leaving group X.

Electrochemical oxidation of oxazolidin-2-one to provide certain

4-substituted oxazolidin-2-ones was described in Tavernier et al. Bull. Soc.

Chim. BeIg. 1988, p.859-865, however this reference falls short of any suggestion that the 4-substituted oxazolidin-2-ones disclosed therein could be reactive in the present invention and be efficiently converted into oxazolidin-2-ones having a long-chain alkyl substituent in 4-position.

In the process according to the invention, the leaving group X is often a substituent which is bonded to the heterocycle through a sulphur or, preferably, an oxygen atom. Examples of O-bonded leaving groups are alkoxy or acyloxy

groups. Alkoxy groups useful as substitutent X generally contain 1 to 4 carbon atoms. Ethoxy and, in particular, methoxy are preferred. Acyloxy groups useful as substitutent X generally contain 2 to 10 carbon atoms. Propionyloxy, and, in particular, acetoxy are preferred. In the process according to the invention, if the substituent Rl is a linear alkyl group it is often a Cl to ClO alkyl group, more specifically a methyl or an ethyl group. If the substituent Rl is an acyl group it is often a Cl to ClO acyl group, more specifically a formyl or, preferably, an acetyl group. In a particularly preferred embodiment, Rl is H. The process according to the invention applies in particular to compounds wherein n is 1 or 2, preferably 1. It is understood that the process according to the invention will equally apply to compounds in which the optional methylene group or groups shown in the formulae bear one or more substituents which are substantially stable under the conditions of the reaction. Such substituents are for example alkyl or aryl substituents. However the process according to the invention applies preferably when all groups are methylene. It applies more particularly to the manufacture of 4-n-decyloxazolidin-2-one.

In the process according to the invention, the substituent R2 is generally a linear C6-C20 alkyl group. R2 is preferably a linear alkyl group comprising 8, 9, 10, 11, 12, 13, 14, 15 or 16 carbon atoms and more preferably 8, 10, 12, 14 or 16 carbon atoms. An n-decyl group is more particularly preferred as R2.

In the process according to the invention M in the reagent M-R2 contains often a metal selected from lithium, magnesium, or transition metals, such as copper, zinc, cadmium, mercury, cerium and zirconium. Often the metal is selected from copper, zinc, cadmium, mercury, cerium and zirconium and is preferably copper.

The reagents M-R2 can suitably be obtained either through direct reaction or by transmetallation from the corresponding halides Y-R2 wherein Y is selected from Cl, Br and I. It is preferred to use a bromide Br-R2 as starting material.

In a particular embodiment, which is particularly preferred when the leaving group X is an O-bonded leaving group as described herein before, M contains copper. A particularly preferred reagent has the formula Cu-R2 wherein R2 is as described above. A suitable copper containing reagent can be obtained, for example, by the reaction of a Grignard reagent as described above with a copper precursor.

Suitable copper precursors are selected for example from copper (I) complexes or salts such as CuBr, CuI, CuCN or complexes of these salts with thioethers such as in particular dimethylsulphide.

In the process according to the invention, the reagent can be suitably activated with an activator such as for example a Lewis acid. Boron compounds such as in particular BF ₃ which can be supplied to the reaction as adduct with an ether such as diethylether can be used, in particular when M contains copper. In another aspect the activator is an active silyl compound such as a halotrialkylsilane in particular trimethylchlorosilane. A particularly preferred activated reagent corresponds in consequence to the formula BF3.CU-R2.

The invention also concerns the copper-containing reagents described here before. It has been found that these reagents are particularly efficient to introduce long-chain alkyl residues by nucleophilic substitution notably of O-bonded leaving groups as described herein before. In the process according to the invention, the reaction is generally carried out in an organic solvent. This solvent is generally an inert more specifically an aprotic solvent, what means that the solvent does not interfere with the reaction of the compound of formula II with the reagent. Examples of suitable solvents include alkylethers such as diethylether, methyl-tert.butylether, tetrahydrofurane and 1,4-dioxane. Tetrahydrofurane is preferred as solvent.

The invention also concerns a solution of the copper-containing reagents described here before in the solvents described here before.

The invention concerns also the use of the copper-containing reagent or its solution for the manufacture of an organic compound containing a C6-C20 linear alkyl substitutent. In the use according to the invention, the manufacture of the organic compound is preferably carried out by nucleophilic substitution of an O-bonded leaving group as described herein before. More preferably, the O-bonded leaving group is attached to a carbon atom in α-position to a nitrogen atom. Said nitrogen atom is preferably an optionally alkylated or acylated amine.

Particular examples of compounds containing an O-bonded leaving group is attached to a carbon atom in α-position to a nitrogen atom correspond to the formula IV

wherein Rl is as described above, RO is an O-bonded leaving group as described above, preferably methoxy, R3 and R4 are independently selected from H, and optionally substituted alkyl, aryl or aralkyl groups or preferably R3 and R4 form together a heterocycle which contains the nitrogen atom shown in the formula, which heterocycle is preferably 4- to 7-membered and more preferably 5- or 6-membered and which can optionally contain further heteroatoms in the ring and R5 is a substituent, preferably H.

In the process according to the invention or the use according to the invention the reaction is generally carried out at a temperature from -80 ⁰ C to 50 ⁰ C, preferably from -50 ⁰ C to 30 ⁰ C and more preferably from -40 ⁰ C to 25°C.

In the process according to the invention or the use according to the invention the molar ratio of the reagent M-R2 to the compound of formula II or IV respectively is generally equal to or greater than 1 , preferably equal to or greater than about 1.2. Generally this molar ratio is lower than about 4, often equal to or lower than 3, preferably equal to or lower than 2.

It has been found, surprisingly, that high yield of long chain alkyl compound can be obtained with a moderate quantity of organometallic reagent thus allowing for more economic manufacturing. In the process according to the invention, the reagent M-R2, preferably dissolved in a suitable solvent, in particular as described above, can be added to a reaction medium containing compound of formula (II). Alternatively , in particular when the compound of formula (II) is a solid, said compound can be added, if desired as a solid, to a reaction medium containing the reagent M-R2, preferably dissolved in a suitable solvent, in particular as described above.

In general, the reaction is carried out in the substantial absence of water. Typical contents of water in the reaction medium are from 1 mg/kg to 1000 mg/kg relative to the total weight of the reaction medium. Preferably the water contents is from 5 mg/kg to 100 mg/kg. The reaction mixture can be worked up by extraction/crystallization. It has been found that notably the isolation of 4-n-decyloxazolidin-2-one can be improved by (a) controlling and optionally reducing the water content of a crude product obtained from extraction and recrystallizing the dry crude product.

It has also been found that work up comprising a crystallization from an aliphatic alcohol, particularly a C1-C4 aliphatic alcohol, preferably methanol or ethanol and more preferably methanol is advantageous, in particular for isolation

of pure 4-decyloxazolidin-2-one. In fact, such crystallization allows for efficient removal of paraffϊnic impurities such as for example, in particular in the case of 4-decyloxazolidin-2-one manufacture, ClO or C20 alkanes.

In a particular embodiment of the process according to the invention, the reagent M-R2 is a Grignard reagent. Preferably, in this embodiment, the reagent consists essentially of Grignard reagent. Typical Grignard reagents correspond to the formula X-MgR2 wherein X is Cl or, preferably, Br and R2 is as defined above. It has been found that use of the Grignard reagents allow for good yield and also allow to avoid very low reaction temperatures. In the particular embodiment of the process according to the invention, the reaction is generally carried out at a temperature from 10 ⁰ C to 120 ⁰ C, preferably from 20 ⁰ C to 100 ⁰ C and more preferably from 30 ⁰ C to 80 ⁰ C. It may be advantageous to initiate the reaction at a lower temperature and to run the reaction to the desired conversion, in particular complete conversion of compound of formula (II), in the temperature range described before.

In the particular embodiment of the process according to the invention, the molar ratio of the reagent M-R2 to the compound of formula II or IV respectively is generally equal to or greater than 1, preferably equal to or greater than about 1.5. Generally this molar ratio is lower than about 2.5, preferably equal to or lower than 2. Working in the preferred range of molar ratio is particularly efficient to obtain an optimum yield while minimizing formation of by-products.

It is understood that the general description of the process according to the invention also applies to the particular embodiment where no more specific information concerning this embodiment is given here before.

When the process according to the invention further comprises synthesizing the compound of formula II by electrochemically oxidizing a compound of formula IV, the precursor of leaving group X is advantageously selected from methanol, acetic anhydride and acetic acid. In a particular preferred embodiment the precursor of leaving group X consists essentially of methanol.

In this embodiment, the electrochemical oxidation can be carried out in a compartmentalized or non-compartmentalized cell.

The electrodes used in the electrochemical oxidation should be resistant with respect to the conditions of the electrochemical reaction. Suitable materials are in particular chosen from metals, metal oxides and graphite. Particularly

suitable metals are chosen from steel, iron and titanium, and in particular from the metals of the group of platinum and their oxides, or electrodes coated with the latter materials. Platinum or rhodium is preferred. An electrode comprising platinum is particularly suitable. The distance between the electrodes is generally at least 0.2 mm. This distance is often at least 0.5 mm. It is preferably at least 1 mm. The distance between the electrodes is generally at most 20 mm. This distance is often at most 10 mm. It is preferably at most 5 mm.

In this embodiment, the electrochemical oxidation is generally carried out at a current density greater than or equal to 0.1 A/dm ² . The current density is often greater than or equal to 1 A/dm ² . It is preferably greater than or equal to 3 A/dm ² . In this embodiment, the electrochemical oxidation is generally carried out at a current density less than or equal to 50 A/dm ² . The current density is often less than or equal to 30 A/dm ² . It is preferably less than or equal to 20 A/dm ² .

In this embodiment, the electrochemical oxidation is generally carried out at a temperature greater than or equal to -50°C. The temperature is often greater than or equal to -20°C. It is preferably greater than or equal to 0°C. In this embodiment, the electrochemical oxidation is generally carried out at a temperature less than or equal to 100°C. The temperature is often less than or equal to 80°C. It is preferably less than or equal to 60°C.

In this embodiment, the electrochemical oxidation is generally carried out in the presence of a conducting salt such as tetraalkyl ammonium tetrafluoroborate in particular tetrabutylammonium tetrafluoroborate, alkali tetrafluoroborate such as potassium tetrafluoroborate or alkali perchlorates, preferably lithium perchlorate. It has been found that alkali perchlorates, in particular lithium perchlorate allow for highly selective manufacture of compound of formula II and allow for efficient isolation of compound of formula II from the reaction medium. The examples below are intended to illustrate the invention without, however, limiting it.

Example 1

A solution of the Grignard reagent (1.3 equivalents) obtained by reaction of n-decylbromide with magnesium was added to a stirred suspension of CuBrMe ₂ S (1.5 equivalents) in dry THF, at - 45°C. Subsequently, BF ₃ -Et ₂ O (1.5 equivalents) was added at - 50 ⁰ C and then a solution of 4-methoxy- oxazolidin-2-one (1 equivalent) in THF was added. The mixture was stirred and allowed to reach room temperature. After 4 h the conversion was 100 %, the reaction was quenched with a mixture of an aqueous saturated NH ₄ Cl solution and diluted NH4OH 28 %. The product 4-n-decyloxazolidin-2-one was isolated by extraction. The crude product was dried by azeotropic distillation of water with ethyl acetate. This allowed for improved solidification/crystallization.

Yield 68 % purity GC > 99 %. Example 2

To a THF (50cm ³ ) solution of cuprous cyanide (1.99g, 22 mmol) and anhydrous lithium chloride (1.87 g, 44 mmol), n-decylmagnesium bromide

(20 cm ³ , 1 M in THF) was dropwise added at - 30 ⁰ C under nitrogen atmosphere. 4-methoxy-2-oxazolidin-2-one (0.85 g, 5 mmol) and BF ₃ -Et ₂ O (1.27 cm , 10 mmol) were added successively and the reaction mixture was kept at - 30 ⁰ C overnight. The reaction was quenched by addition of saturated NH ₄ CI solution (5 cm ³ ) and extracted twice with Et ₂ O (100 cm ³ ). Organic phases were concentrated in vacuo and the residue was precipated at low temperature to give an isolated yield of 4-n-decyloxazolidin-2-one of 0.54 g, (48 %). Example 3

Oxazolidin-2-one was dissolved in acetic acid, and added to dry methanol containing tetrabutylammoniumtetrafluoroborate, in an undivided dry cell equipped with a platinum anode at 10 ⁰ C and an electric current of 7A for 9 hours.

After partial evaporation of the solvents, crystallization of the residue at 0 ⁰ C yielded 4-methoxy-oxazolidin-2-one. Yield 61 % purity GC 99 %.

Example 4

Oxazolidin-2-on (355.5 g, 4 moles) dissolved in methanol (1100 cm ³ ) containing lithium perchlorate (7.74 g, 72 mmoles), was subjected to methoxylation in an undivided dry cell equipped with a platinum anode at 18°C and an electric current of 7 A for 41.4 hours. Consumption of oxazolidin-2-on was monitored by GC. After evaporation of the solvents, crystallization of the

residue in isopropyl acetate and tert-butlymethyl ether yielded 4-methoxy- oxazolidin-2-on Yield 74 % purity GC 98 %. Example 5

To a THF (90 cm ³ ) solution of 4-methoxy-oxazolidin-2-one (4.78g, 40 mmol), n-decylmagnesium bromide (80 cm , 1 M in Et ₂ O) was dropwise added at - 5°C under nitrogen atmosphere. The mixture was stirred for 15 min and allowed to reach 80 ⁰ C over a period of 30 min. After 2 h at 80 ⁰ C, reaction was completed and then quenched with a mixture of an aqueous saturated NH ₄ Cl solution for stirring for 1 h. The mixture was twice extracted with toluene (200 cm ³ ) and organic phases were pooled and then evaporated under reduced pressure. The resulting oil was diluted with methanol (25 cm ) and was stored for 1 hour at 0 ⁰ C. Solid impurities were filtered off and mother liquors were evaporated to dryness to afford a yellow oil. The crude product was dried by azeotropic distillation of water with ethyl acetate. The resulting oil was diluted with n-heptane. 4-n-decyloxazolidin-2-one precipitated during storage at -10 ⁰ C. The suspension was filtered at 0 ⁰ C and washed with cold n-heptane. 4-n- decyloxazolidin-2-one was dried under nitrogen atmosphere and isolated as a white solid.

Yield 50 % purity RMN 98 %, GC > 99 %.