Method for separating optically active hydroxy cineole derivatives

Abstract

The present invention relates to a method for separating an optically active hydroxy cineole derivatives by lixiviation and crystallization and enantiomerically pure optically active hydroxy cineole derivatives of purity greater than 99.5% that have been prepared by this process. The present invention further relates to use of the desired enantiomer having enantiomeric excess of at least 99.5% ee as prepared according to the present invention, for the synthesis of enantiomerically pure 7-oxabicyclo[2.2.1]heptane derivatives.

Claims

1. A method for separating an optically active hydroxy cineole derivative of formula (I-R), ##STR00007## or an optically active hydroxy cineole derivative of formula (I-S), ##STR00008## wherein R.sup.1 is methyl and R.sup.2 is isopropyl; from a mixture comprising the enantiomers of formula (I-R) and formula (I-S), the method comprising the steps of: i) Providing a suspension comprising a mixture of the enantiomers of formula (I-R) and formula (I-S), wherein the desired enantiomer is present in the mixture in an amount of 51 to 95 wt.-%, related to the sum of the enantiomers of the mixture, in at least one non-polar solvent; ii) Separating the desired enantiomer by lixiviation consisting of stirring the suspension obtained in step (i) at temperature in the range of 10 C. to reflux temperature of the non-polar solvent such that the desired enantiomer is separated from soluble substances, wherein the desired enantiomer is present as an insoluble material; and iii) Isolating the desired enantiomer obtained in step (ii) by filtration.

2. The method of claim 1, wherein the desired enantiomer is either the optically active hydroxy cineole derivative of formula (I-R) or the optically active hydroxy cineole derivative of formula (I-S).

3. The method of claim 1, wherein in step (ii) the suspension is stirred at temperature in the range of 10 to 120 C.

4. The method of claim 1, wherein in step (iii) the desired enantiomer as isolated has enantiomeric excess of at least 99.5% ee.

5. The method of claim 1, wherein in step (i) the non-polar solvent is a hydrocarbon.

6. The method of claim 5, wherein in step (i) the non-polar solvent is the hydrocarbon having polarity index of 0.0 to 2.5.

7. The method of claim 6, wherein the hydrocarbon is selected from the group consisting of petroleum ether, pentane, cyclopentane, hexane, cyclohexane, heptane, n-octane, iso-octane, cyclooctane, benzene, xylene and toluene.

8. The method of claim 1, wherein the mixture of enantiomers of formula (I-R) and formula (I-S) is prepared by a process comprising the steps of: (iv) epoxidation of a terpinen-4-ol derivative of formula II ##STR00009## wherein R.sup.1 is methyl and R.sup.2 is isopropyl; in the presence of at least one metal to obtain an epoxide of formula (III); ##STR00010## wherein R.sup.1 and R.sup.2 are defined as above, and (v) subjecting the epoxide of formula (III) to at least one acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) For the purposes of promoting an understanding of the principles of the invention, a specific language will be used to describe exemplary embodiments of the present invention. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended. The invention includes any alterations and further modifications in the described methods and described optically active compounds of the principles of the invention which would normally occur to one skilled in the art to which the invention relates.

(2) A racemate is optically inactive, meaning that there is no net rotation of plane-polarized light. Although the two enantiomers rotate plane-polarized light in opposite directions, the rotations cancel because they are present in equal amounts.

(3) In contrast to the two pure enantiomers, which have identical physical properties except for the direction of rotation of plane-polarized light, a racemate sometimes has different properties from either of the pure enantiomers. Different melting points are most common, but different solubilities and boiling points are also possible.

(4) Preparation of enantiopure (ee100%) compounds is one of the most important aims both for industrial practice and research. Actually, the resolution of racemic compounds (1:1 mixture of molecules having mirror-imagine relationship) still remains the most common method for producing pure enantiomers on a large scale. In these cases, the enantiomeric mixtures or a sort of their derivatives are separated directly. This separation is based on the fact that the enantiomeric ratio in the crystallized phase differs from the initial composition. In this way, obtaining pure enantiomers requires one or more crystallizations.

(5) At the same time, there are some enantiomeric mixtures having racemate properties which show conglomerate behaviour during its purification by fractionated precipitation. Always the enantiomeric excess is crystallized independently from the starting isomeric composition. This is explained by the kinetic crystallization of the enantiomeric excess. Consequently, if the enantiomeric purity obtained after recrystallization or by other partial crystallization (as the result of splitting between the two phases) is plotted against the initial enantiomeric composition, either racemate or conglomerate behaviour is expected, or a conglomerate is obtained.

(6) In the entrainment procedure, the conditions described below suffice in practice to achieve some separation of the enantiomers. Firstly, a saturated solution of the desired enantiomer of hydroxy cineol derivatives is provided at a given temperature. Suitable solvents for the procedure include hydrocarbons. Incorporation of a suitable solvent having polarity index of 0.0 to 2.5 is also beneficial and allows more efficient enantiomer crystallization.

(7) The term Lixiviation means the process of separating soluble from insoluble substances by dissolving the former in water or some other solvent.

(8) According to the present invention, there is provided a method for separating an optically active hydroxy cineole derivative of formula (I-R) or formula (I-S), from a mixture comprising the enantiomers of formula (I-R) and (I-S). Typically, the mixture of the enantiomers of formula (I-R) and formula (I-S), wherein the desired enantiomer is present in the mixture in an amount of 51 to 95 wt.-%, related to the sum of the enantiomers of the mixture. The mixture of the enantiomers is suspended in at least one non-polar solvent. The suspension is stirred at a temperature in the range of 10 C. to reflux temperature of the non-polar solvent. The crystals of the desired enantiomer are isolated.

(9) The method further comprising adding seed crystals of the desired enantiomer in either suspension or solution to increase enantiomeric excess of the desired enantiomer.

(10) Typically, the suspension is stirred at a temperature in the range of 10 to 120 C., preferably at 20 to 115 C.

(11) Typically, the isolation of the crystals of the desired enantiomer is carried out at temperature in the range of 10 to 30 C., preferably at 10 to 25 C.

(12) According to the invention, an amount of racemate from the mixture comprising the enantiomer of formula (I-R) and the enantiomer of formula (I-S) is dissolved in the solvent and leaves behind the desired enantiomer which is isolated. The supersaturated suspension can be seeded with crystals of the desired enantiomer to increase the enantiomeric excess.

(13) Accordingly, a supersaturated solution of the hydroxy cineol derivatives may be entrained by seeding with crystals of the single enantiomer to grow larger crystals having an excess of the enantiomer seeded, and leaving the opposite enantiomer or racemate enriched in the mother liquors. In order to make such an entrainment crystallisation procedure useful for the production of single enantiomer hydroxy cineol derivatives it is desirable that the optically-enriched hydroxy cineol derivatives obtained can be raised in enantiomeric purity through recrystallisation. Nonetheless the overall procedure is a resolution leaving an issue of utilisation of the wrong enantiomer. If it could be racemized or the configuration inverted, then all material could in principle be directed to the required isomer.

(14) An amount of the desired enantiomer from the mixture comprising the enantiomers of formula (I-R) and the enantiomer of formula (I-S) is dissolved in the solvent by warming to effect complete dissolution. The solution is then cooled so that the solution becomes supersaturated to crystalize the desired enantiomer which is isolated. The supersaturated solution is seeded with crystals of the desired enantiomer to increase the enantiomeric excess.

(15) The cooling can be carried out either by a rapid chilling with brine or other refrigerant, or it can be carried out by permitting the vessel containing the solvent and ingredients to set at ordinary room temperatures. The latter form of cooling is preferred in certain embodiments of the present invention, both because of economy in not requiring expensive refrigeration and because good crystal growth and separation from the liquid are obtained.

(16) Once a certain amount of crystallisation has taken place, the crystals are harvested and show a greater weight excess of single desired enantiomer than is represented by the seed crystals. Also, the mother liquors now contain an excess of the enantiomer opposite to that used for the seeding. By recrystallisation of the crystals, a single desired enantiomer hydroxy cineol derivatives (of high optical purity) is obtained in greater amount.

(17) Mother liquors from the procedure containing an excess of one enantiomer can be resubjected to the above procedure but seeding with the opposite enantiomer. By an iterative process of crystallisation (cyclic entrainment), seeding with opposite enantiomers alternately, it is in principle possible to separate an amount of racemic hydroxy cineol derivatives entirely into its enantiomeric components.

(18) Other techniques may be employed to achieve the same separation, such as, for instance, seeding the enantiomeric mixture either in suspension or solution with seeds of both enantiomers but which are of different particle sizes. Then, after crystallisation, the enantiomers may be separated by a size-separation process such as sieving.

(19) In the enrichment procedure of this invention, for crystallisation, a variety of solvents can be chosen and crystallisation can be induced by conventional techniques that obtain a supersaturated solution, such as by cooling of a saturated solution, by solvent evaporation from a saturated solution, or by addition of an additional solvent in which the hydroxy cineol derivatives are less soluble. Suitable solvents for this purpose are, for example, non-polar solvent having polarity index of 0.0 to 2.5. Preferably, a hydrocarbon having polarity index of 0.0 to 2.5. More preferably, the hydrocarbon is selected from the group consisting of petroleum ether, pentane, cyclopentane, hexane, cyclohexane, heptane, n-octane, iso-octane, cyclooctane, benzene, xylene and toluene.

(20) The crystals or precipitate formed can be separated from the mother liquor by conventional techniques, such as filtration, vacuum or pressure filtration, centrifugation, and the like. The remaining mother liquor is enriched in the racemate and accordingly provides a source of this enantiomer mixture.

(21) Preferably, the desired enantiomer is isolated by a method selected from the group consisting of filtration or evaporation.

(22) Essentially the desired enantiomer is either the optically active hydroxy cineole derivative of formula (I-R) or the optically active hydroxy cineole derivative of formula (I-S).

(23) Essentially enantiomerically pure hydroxy cineole derivative of the formulae (I-S) and (I-R) should be understood in the context of the present invention to mean that they are present in an enantiomeric purity of in each case at least 98% ee, preferably at least 99% ee and in particular at least 99.5% ee.

(24) The enantiomeric excess of the hydroxy cineole derivative of formulae (I-S) and (I-R) can be determined by means of common processes, for example by determining the optical rotation or by chromatography on a chiral phase, for example by HPLC or gas chromatography using chiral columns.

(25) The remarks made above regarding suitable and preferred embodiments of the invention and of the process apply here correspondingly.

(26) The process according to the presently claimed invention affords the desired enantiomer of cineole derivative in high yields and with a very high enantiomeric purity.

(27) Use of the desired enantiomer of hydroxy cineol derivative of formula (I-R) or formula (I-S) having enantiomeric excess of at least 99.5% ee as prepared according to the invention, is for the synthesis of enantiomerically pure 7-oxabicyclo[2.2.1]heptane derivatives.

(28) Accordingly, enantiomerically pure 7-oxabicyclo[2.2.1]heptane derivatives are selected from the group consisting of (1S,2R,4R)-4-isopropyl-1-methyl-2-(o-tolylmethoxy)-7-oxabicyclo[2.2.1]heptane and (1R,2S,4S)-4-isopropyl-1-methyl-2-(o-tolylmethoxy)-7-oxabicyclo[2.2.1]heptane.

(29) Essentially the mixture of enantiomers of formula (I-R) and formula (I-S) is prepared by metal catalysed epoxidation of a terpinen-4-ol derivative of formula II to obtain an epoxide of formula (III); and subjecting the epoxide of formula (III) to acid catalysed rearrangement.

(30) According to a literature-known procedure (see: Synthetic Communications 1996, 26 (14), 2531-2735) a solution of crude hydroxycineol (chemical purity 67.3% GC-area) in toluene with a enantiomeric ratio of R:S=80:20, was obtained by reacting 1848 g (11 mol) terpinen-4-ol (enantiomeric ratio R:S=80:20) to the corresponding terpinen-4-ol epoxide followed by rearrangement in the presence of sulfuric acid.

(31) The present invention is illustrated by the non-restrictive examples which follow.

(32) Chemicals Used:

(33) 1. Terpinen-4-ol (enantiomeric ratio R:S=80:20); 2. Sulfuring acid; 3. Toluene; 4. Petroleum ether; 5. n-pentane; 6. n-hexane; 7. n-heptane; 8. Iso-octane; 9. Cyclohexane; 10. NaOH; 11. Na.sub.2SO.sub.4 12. CsCl; 13. Water; 14. Brine; 15. Ethyl acetate; 16. n-heptane; and 17. o-methyl-benzylbromide.
Analytical Methods Used: A. Optical purity determined by Chiral GC (Standard method using a chiral GC-column like Hydrodex--6 TBDM, Macherey & Nagel, 25 m0.25 mm0.25 m); B. Conversion determined by achiral GC (Standard Method using a GC-column like Chrompack CP Sil-8-CB, Agilent J&W, 30 m0.32 mm1 m); and C. Optical rotation determined by Polarimeter (Jasco P-1010).

EXAMPLES

Reference Example

(34) A solution of crude hydroxy cineol (chemical purity 67.3% GC-area) in toluene with an enantiomeric ratio of R:S=80:20, was obtained by reacting 1848 g (11 mol) terpinen-4-ol (enantiomeric ratio R:S=80:20) to the corresponding terpinen-4-ol epoxide followed by rearrangement in the presence of sulfuric acid (Ref.: Synthetic Communications 1996, 26 (14), 2531-2735). The solution was evaporated under reduced pressure (60 C.; 100 mbar). The remaining slurry was filtered off and washed with 1 L of 8 C. cold n-heptane. The filter cake was dried under reduced pressure at 40 C.; yielding 488.9 g of hydroxycineol. The chemical purity of the isolated material was 99.9% (by GC); the chiral GC gave an optical purity of 98% ee (R:S=99:1) in favor of the R-enantiomer. The mother liquor of crystallization was cooled to 10 C. and the precipitate was filtered off and washed with 1 L of 20 C. cold n-heptane. After drying under reduced pressure 425.5 g of 99.9% chemical pure hydroxycineol was isolated. The enantiomeric ratio of the second precipitate was R:S=49.7:50.3%.

Example 1

(35) Determination of the solubility of racemic and enantio pure hydroxy-cineol in different solvents. The solubility of racemic hydroxy cineol and enantiopure hydroxy cineol was checked at room temperature in solvents namely, petroleum ether, n-pentane, n-hexane, n-heptane, iso-octane, cyclohexane and toluene.

(36) The solubility at room temperature was determined by adding under stirring small portions of the substance to 5 mL of solvent until it reached saturation and formation of a no more soluble sediment was observed.

(37) TABLE-US-00001 TABLE 1 Solubility of racemic hydroxy cineol and enantiopure hydroxy-cineol in different solvents Solubility [g/mL] enantiopure solubility racemate/ solvent Racemate material solubilty enantiomer petroleum ether 0.12 0.02 6 n-pentane 0.15 0.03 5 n-hexane 0.1 0.02 5 n-heptane 0.08 0.01 8 iso-octane 0.075 0.02 3.8 cyclohexane 0.38 0.07 5.4 toluene 0.8 0.26 3

(38) According to the results, in non-polar solvents the racemic compound is much better soluble than optical pure material. Most preferred is n-heptane, where the racemate is 8-fold better soluble than the optical pure hydroxy-cineol.

Example 2

Separating Enantioenriched R-Enantiomer of 2-hydroxy-1,4-cineole by Lixiviation

(39) 3.8 g of enantioenriched 2-hydroxy-1,4-cineole (ee: 50%; R:S=75:25) was stirred at room temperature with n-heptane (22 mL) for 8 hrs. Insoluble material was filtrated, washed with cold n-heptane (3 mL) and dried. 1.85 g of 99% ee (R:S=99.5:0.5) 2-hydroxy-1,4-cineole was obtained as a white powder, m.p.: 89 C.

(40) The filtrates were combined and evacuated to dryness. 1.95 g of almost racemic 2-hydroxy-1,4-cineole (ee=4%; R:S=52:48) were obtained as a white powder, m.p.: 56 C.

Example 3

Separating Enantioenriched S-enantiomer of 2-hydroxy-1,4-cineole by Recrystallization

(41) 30.5 g of crude S-2-hydroxy-1,4-cineole (ee: 70%, R:S=15:85) was suspended in n-heptane (125 mL) and heated to reflux. A clear solution was obtained. Upon cooling to room temperature, purified material precipitated as white crystals. The precipitate was filtered of, washed with cold n-heptane (10 mL) and dried, yielding 17.9 g (57%) of pure S-enantiomer (ee: >99%), m.p.: 86 C.

(42) By concentrating the mother liquors, 9 g (30%) of nearly racemic (R:S=45:55) 2-hydroxy-1,4-cineole was obtained as a white solid, m.p.: 55 C.

Example 4

Preparation of Enantiopure Cinmethylin (1R,2S,4S)-Enantiomer

(1R,2S,4S)-4-isopropyl-1-methyl-2-(o-tolylmethoxy)-7-oxabicyclo[2.2.1]heptane

(43) ##STR00005##

(44) 10 g (59 mmol) S-2-hydroxy-1,4-cineole (enantiomeric purity=99.9% ee) according to example 3 was dissolved in toluene (100 mL). Powdered NaOH (3.05 g, 76 mmol) and 0.2 g (1.2 mmol) CsCl was added and the mixture was heated on a Dean-Stark-Trap for 6 hours. Then 10.9 g (60 mmol) of o-methyl-benzylbromide was added dropwise and heating was continued for another 60 hours.

(45) Water (100 mL) was added to the cooled reaction mixture and the phases were separated. The organic layer was extracted twice with brine (20 mL each) and dried over Na.sub.2SO.sub.4. The solvent is removed in vacuum to obtain a yellowish oil. The volatile material from the oil was removed in vacuum (bath: 75 C., pressure: 0.1 mbar). The remainder was subjected to column chromatography (eluent: cyclohexane/ethyl acetate 98:2 v/v) yielding a 99.2% pure cinmethylin which was further purified by bulb-to-bulb distillation (0.1 mbar, 135 C.). Finally, 8.5 g (53%) of 1R,2S,4S-cinmethylin with a chemical purity of 99.9% was obtained as a colorless oil.

(46) Optical rotation: []D: +58.2 (pure, d=0.99 g/cm.sup.3) []D: +67.4 (c=5 in ethanol).

Example 5

Preparation of Enantiopure Cinmethylin (1S,2R,4R)-Enantiomer

(1S,2R,4R)-4-isopropyl-1-methyl-2-(o-tolylmethoxy)-7-oxabicyclo[2.2.1]heptane

(47) ##STR00006##

(48) Following the procedure according to example 4, starting from 10 g (59 mmol) R-2-hydroxy-1,4-cineole (enantiomeric purity=99.9% ee) according to example 2 yielded 7.5 g (46%) of 1S,2R,4R-cinmethylin with a chemical purity of 99.96%.

(49) Optical Rotation:

(50) []D: 57.9 (pure, d=0.99 g/cm.sup.3) []D: 68.5 (c=5 in ethanol).