EP0946467A1

EP0946467A1 - Method for splitting 1-amino-alkan-2-ol compounds

Info

Publication number: EP0946467A1
Application number: EP97948960A
Authority: EP
Inventors: Gérard Coquerel; Lionel Catroux; Yvette Combret
Original assignee: Universite de Rouen
Current assignee: Universite de Rouen
Priority date: 1996-11-29
Filing date: 1997-11-28
Publication date: 1999-10-06
Also published as: JP2001509789A; FR2756557B1; CA2273012A1; FR2756557A1; WO1998023559A1

Abstract

The invention concerns a method for splitting 1-amino-alkan-2-ol compounds of general formula (I) in which R can represent a large variety of alkyl groupings using as splitting agent one of the enantiomers R or S of N-tosyl-leucine.

Description

PROCESS FOR SPLITTING 1-AMINO-ALCAN-2-O COMPOUNDS.

The present invention relates to a process for splitting 1-amino-alkan-2-ol compounds of general formula:

OH

_R ^ V / ^N 2 (I) in which the radical R can represent a wide variety of linear, branched or cyclic alkyl groups, comprising up to around 20 to 25 carbon atoms and preferably from 1 to 15 carbon atoms. These groups may optionally include one or more double bonds, one or more heteroatoms such as oxygen or sulfur, as long as these are separated from the asymmetric carbon by at least one carbon link and do not remove the radical R son aliphatic character. These groups can also be substituted by one or more halogen atoms such as chlorine or lower alkoxy radicals like methoxy or ethoxy radicals.

From an industrial point of view, the resolution of chiral compounds (±) is in most cases an advantageous alternative to the asymmetric synthesis of one of the enantiomers.

In the case of the compounds of formula (I), the resolution by means of crystallization can be carried out by several methods when R is an aryl group (1, 2). Syntheses of compounds of formulas (I), in which R is an alkyl group, from chiral reagents have also been described (3 to 11). These syntheses do not represent a general method but are defined on a case by case basis, and to date, the resolutions based on a crystallization someric di as t eroi or preferential crystallization did not receive a satisfactory solution (12 to 18).

The present invention aims precisely to provide a process for the resolution of salts by selective crystallization, easy to implement, reproducible and allowing access to the two enantiomers with a high enantiomeric purity possibly greater than 99%.

This object is achieved thanks to the formation of l-amino-alkan-2-ols salts corresponding to the following general formula: ιX -, RCHOH-CH ₂ -NH ₃ ⁺ [with X producing couples of diastereoisomers of different solubility , or with X forming a conglomerate.

More particularly, the invention is based on the use of a simple and very selective chiral agent, which also has the advantage of being easy to prepare and easily recovered at the end of the process. This chiral agent is one of the R enantiomers or

S of N-tosyl-leucine.

Thus, when X, in the above formula, is one of the R or S enantiomers of N-tosyl-leucine, pairs of diastereoisomers of different solubilities are produced.

According to another aspect of the invention, when X, in the above formula, is transcinnamic acid, a conglomerate is produced, in certain cases.

The process of the invention is characterized in that it comprises the following stages: a) dissolving a compound of formula (I) in racemic form and one of the R or S enantiomers of N-tosyl-leucine, hereinafter designated TOSLEU, in pure alcohol, in adequate proportions, then b) isolating by any suitable means the diasteroisomeric salt of the compound of formula (I) in crystallized form.

A suitable means for isolating the diasteroisomeric salt from the compound of formula (I) obtained in step (b) consists of filtration and / or centrifugation. It should be noted that the diasteroisomeric salt of the compound of formula (I) and of the resolving agent which is obtained in step (b) is the least soluble.

Advantageously, in step (a) of the preceding process, approximately 1 molar equivalent of resolving agent is dissolved for one mole of compound of formula (I) to be split.

According to the enantiomer of the 1-amino-alkan-2-ol compound of formula (I) desired, the R or S enantiomer of N-tosyl-leucine is used. In the examples of the invention given below, the S enantiomer of N-tosyl-leucine was chosen arbitrarily.

One of the essential advantages of the invention is the possibility of allowing very easy recovery of the resolving agent in a strong acid medium.

The first enantiomer of the compound of formula

(I) to be split is easily obtained after step (b) by step (c) defined below: c) treatment of the diasteroisomer salt isolated in step (b) to obtain the first enantiomer of the compound of formula (I) to split. The treatment in step (c) consists, for example, in subjecting the diastereoisomer salt obtained in step (b) to stirring in basic medium, then in extracting the first enantiomer of the compound of formula (I) to be split with CH ₂ CI ₂ .

Other treatments can be envisaged, such as in particular the use of other organic extraction solvents in correlation with the more or less marked hydrophilic nature of each amino alcohol. As for example, 1,2 dichloroethane, chloroform, ethyl acetate, or diethyl ether for 1-amino-3-3dimethylbutane-2-ol and 1-amino-2-cyclohexylethan-2-ol, which are the two least hydrophilic amino alcohols tested below. In the case where it is desired to obtain the second enantiomer of the compound of formula (I) to be split, the method of the invention comprises step (c ') defined below: c') treatment of the stock solutions resulting from isolating the diastereoisomeric salt from step (b) to obtain the second enantiomer of the compound of formula (I) to be split.

It should be noted that the enantiomer recovered at the end of step (C) corresponds to the diasteroisomer salt of the compound of formula (I) and of the resolving agent obtained in step (b) which is the most soluble.

The treatment in step (c ¹ ) consists, for example, in subjecting the stock solutions to evaporation, then in treating the residue resulting from the evaporation with a basic solution and in extracting, for example by CH ₂ CI ₂ , the second enantiomer of the compound of formula (I) to be split.

Other treatments can be considered. Among these, a preferred embodiment of the process of the invention suitable for some of the compounds of formula (I) consists in producing the cinnamate of said second enantiomer obtained in step (c ¹ ), by adding approximately 1 equivalent of transcinnamic acid, then advantageously, in carrying out a recrystallization with ethanol.

The conversion to cinnamate is particularly useful for recovering and purifying the second enantiomer at the end of step (c '), but also for purifying, if necessary, the first enantiomer after step (c).

Consequently, the process of the invention can comprise, after step (c '), a step (d) of purification without loss of the enantiomeric excess via the cinnamate of the second enantiomer of the compound of formula to be split.

The inventors have further observed that the addition of transcinnamic acid after step (c ') leads, for certain 1-amino-alkan-2-ol compounds, to the formation of a conglomerate. The formation of such a conglomerate allows:

the recovery of the enantiomeric excess by the recrystallization methods described in the prior art, and also to significantly increase the yields of this recovery and to reach enantiomeric purity levels of the order of 99%; the application of preferential crystallization techniques.

Among the alternate preferred crystallization methods known in the prior art, one can distinguish:

- A conventional method designated SIPC for "Seeded Isothermal Preferential Cristallization" or S3PC which is described in the United Kingdom patent published under No. GB-A-1197809. This continuous method is based on sowing or preferential nucleation (Eliel, Ernest L., Samuel H. Wilen; Lewis N. Mander. A Wiley-Interscience Publication. John Wiley & Sons, Inc.). - An original method designated AS3PC which is described in the PCT patent application published under No. WO 95/08522. This method is based on the controlled growth of one of the optical enantiomers of the compound to be split and does not require either sowing or preferential nucleation.

Consequently, in the case where step (d) leads to the formation of a conglomerate, the method of the invention comprises a step (e) of preferential crystallization, advantageously of the AS3PC type.

As it appears in the examples given below, the addition of transcinnamic acid does not lead, for all the compounds of formula (I), to the formation of a conglomerate which can be exploited in normal preferential crystallization and of the AS3PC type. For some of these compounds, such as 1-amino-butan-2-ol, the formation of a metastable racemate is observed, the stability of which is comparable to that of the conglomerate, but which does not allow the use of '' a preferential crystallization.

There is shown in Figure 1 in the appendix a summary diagram of the process of the invention, in which the products used in each of steps a, b, c, c ', d and e are indicated.

The invention further relates to the use of one of the R or S enantiomers of N-tosyl-leucine as a splitting agent for l-amino-alkan-2-ol of general formula: in which R has the same meaning as before

The invention also relates to the use of the transcinnamate of an enantiomer of a chiral 1-amino-alkan-2-ol compound for:

the purification, without loss of the enantiomeric excess, of said enantiomer in a process of resolution of chiral 1-amino-alkan-2-ols compounds,

- The formation of a conglomerate allowing the recovery of 1 enantiomeric excess by the recrystallization methods and more particularly according to the alternate preferential crystallization methods, advantageously AS3PC.

The invention relates more particularly to the application of the method described above and its variants to the resolution of the compounds of Table I below.

Table I

In the case of 1-amino-propan-2-ol (APR), the application of the process of the invention more particularly comprises the following steps:

(a) 1 equivalent of APR and 0.5 to 1 equivalent of one of the R or S enantiomers of TOSLEU are dissolved with a concentration of the order of 19% by mass in absolute ethanol or any other solvent organic suitable without water.

(b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt (Dl), optionally after washing or recrystallization from absolute ethanol.

(c) The salt is treated with a saturated NaOH solution, then the first enantiomer of the APR is extracted with CH ₂ CI ₂ • The organic phases are combined and dried with Na ₂ Sθ ₄ then these are evaporated to obtain the first enantiomer of APR.

(c ¹ ) The mother liquors resulting from the crystallization of step (b) and the second are evaporated enantiomer of APR is obtained as in step (c) but impure.

(d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di-i sopr opy lé ther followed by several recrystallizations from ethanol.

(e) Optionally, part of the crystals from step (d) is selectively dissolved (AS3PC) in a 24.5% by mass solution of racemic mixture in the form of cinnamate, prepared as in step (d), in ethanol to obtain a balance between the saturated solution and cinnamate crystals of the second enantiomer of APR. This suspension is cooled and then filtered in order to obtain a total mass of initial enantiomer greater than the enantiomeric excess with high optical purity. Still at this step (e), it is then possible to add racemic mixture in an amount equal to that of the enantiomer obtained in order to isolate one then the other enantiomer of the cinnamate from the APR.

In the case of 1-amino-butan-2-ol (ABU), the application of the process of the invention more particularly comprises the following steps: (a) dissolving 1 equivalent of ABU and from 0.5 to 1 equivalent of one of the R or S enantiomers of TOSLEU with a concentration of the order of 7% by mass in absolute ethanol or any other suitable organic solvent devoid of water. (b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt (Dl), optionally after washing or recrystallization from absolute ethanol.

(c) The salt is treated with a saturated NaOH solution, then the first enantiomer of ABU is extracted with CH ₂ CI ₂ • The organic phases are combined as dried with Na ₂ Sθ ₄ then these are evaporated in order to obtain the first enantiomer of ABU.

(c ¹ ) The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of ABU is obtained as in step (c) but impure.

(d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di-sopropy lé ther followed by several recrystallizations from ethanol.

In the case of 1-amino-pentan-2-ol (APE), the application of the process of the invention more particularly comprises the following steps: (a) dissolving 1 equivalent of EPA and from 0.5 to 1 equivalent of one of the R or S enantiomers of TOSLEU with a concentration of the order of 15% by mass in absolute ethanol or any other suitable organic solvent devoid of water. (b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomeric salt (Dl), optionally after washing or recrystallization from absolute ethanol.

(c) The salt is treated with a concentrated NaOH solution, then the first enantiomer of the EPA is extracted with CH ₂ CI ₂ . The organic phases are combined and dried with Na ₂ SO 4, then these are evaporated in order to obtain the first enantiomer of the EPA.

(c ¹ ) The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of the EPA is obtained as in step (c) but impure.

(d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di-sopropylated ther followed by several recrystallizations from ethanol. (e) Optionally, part of the crystals from step (d) is selectively dissolved (AS3PC) in a 15.1% by mass solution of racemic mixture in the form of cinnamate, prepared as in step (d), in ethanol to obtain a balance between the saturated solution and cinnamate crystals of the second enantiomer of the EPA. This suspension is cooled and then filtered in order to obtain a total mass of initial enantiomer greater than 1 enantiomeric excess with high optical purity. Still at this step (e), it is then possible to add racemic mixture in an amount equal to that of the enantiomer obtained in order to isolate one then the other enantiomer of the cinnamate of the EPA.

In the case of 1-amino-3-methylbutan-2-ol (AMB), the application of the process of the invention more particularly comprises the following steps:

(a) 1 equivalent of AMB and 0.5 to 1 equivalent of one of the R or S enantiomers of the

TOSLEU with a concentration of the order of 9% by mass in absolute ethanol or any other suitable organic solvent devoid of water.

(b) After 4 hours of stirring, the suspension is filtered in order to recover the diastereoisomeric salt

(Dl) pure, optionally after washing or recrystallization from absolute ethanol.

(c) The salt is treated with a concentrated NaOH solution, then the first enantiomer of 1 AMB is extracted with CH ₂ CI ₂ . The organic phases are combined and dried with Na ₂ S0 _4, then these are evaporated in order to obtain the first enantiomer of AMB.

(c ¹ ) The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of AMB is obtained as in step (c) but impure. (d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di-is opropy ler followed by several recrystallizations from ethanol. (e) Optionally, part of the crystals from step (d) is selectively dissolved (AS3PC) in a 15.0% by mass solution of racemic mixture in the form of cinnamate, prepared as in step (d), in ethanol to obtain a balance between the saturated solution and cinnamate crystals of the second enantiomer of AMB. This suspension is cooled and then filtered in order to obtain a total mass of initial enantiomer greater than the enantiomeric excess with high optical purity. Still at this step (e), it is then possible to add racemic mixture in an amount equal to that of the enantiomer obtained in order to isolate one then the other enantiomer of the cinnamate of AMB.

In the case of 1-amino-hexan-2-ol (AHX),

The application of the process of the invention more particularly comprises the following steps:

(a) 1 equivalent of AHX and 0.5 to 1 equivalent of one of the R or S enantiomers of TOSLEU are dissolved with a concentration of the order of 12% by mass in absolute ethanol or any other solvent organic suitable without water.

(c) The salt is treated with a concentrated NaOH solution, then the first enantiomer of AHX is extracted with CH ₂ CI ₂ . The organic phases are combined and dried with Na ₂ Sθ _4, then these are evaporated in order to obtain the first enantiomer of AHX. (c ¹ ) The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of AHX is obtained as in step (c) but impure. (d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di-i sopr opy lé ther followed by several recrystallizations from ethanol.

(e) Optionally, part of the crystals from step (d) is selectively dissolved (AS3PC) in a 15.0% by mass solution of racemic mixture in the form of cinnamate, prepared as in step (d), in ethanol to obtain a balance between the saturated solution and cinnamate crystals of the second enantiomer of AHX. This suspension is cooled and then filtered in order to obtain a total mass of initial enantiomer greater than 1 enantiomeric excess with high optical purity. Still at this step (e), it is then possible to add racemic mixture in an amount equal to that of the enantiomer obtained in order to isolate one then the other enantiomer of the cinnamate of AHX.

In the case of 1-amino-4-methylpentan-2-ol (AMP), the application of the process of the invention more particularly comprises the following steps:

(a) 1 equivalent of AMP and 0.5 to 1 equivalent of one of the R or S enantiomers of TOSLEU are dissolved with a concentration of the order of 11% by mass in absolute ethanol or any other solvent organic suitable without water.

(b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt (Dl), optionally after washing or recrystallization from absolute ethanol. (c) The salt is treated with a solution of

NaOH concentrated, then the first enantiomer of AMP is extracted with CH2CI2. The organic phases are combined and dried with Na ₂ S0 _4, then these are evaporated in order to obtain the first enantiomer of AMP.

(c ¹ ) The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of AMP is obtained as in step (c) but impure. (d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di-sopropy lé ther followed by several recrystallizations from ethanol.

(e) Optionally, part of the crystals from step (d) is selectively dissolved (AS3PC) in a 15.1% by mass solution of racemic mixture in the form of cinnamate, prepared as in step (d), in ethanol to obtain a balance between the saturated solution and cinnamate crystals of the second enantiomer of AMP. This suspension is cooled and then filtered in order to obtain a total mass of initial enantiomer greater than 1 enantiomeric excess with high optical purity. Still at this step (e), it is then possible to add racemic mixture in an amount equal to that of the enantiomer obtained in order to isolate one and then the other enantiomer of the cinnamate from AMP.

In the case of 1-amino-3, 3-dimethylbutan-2-ol (ADB), the application of the process of the invention more particularly comprises the following steps:

(a) 1 equivalent of ADB and 0.5 to 1 equivalent of one of the R or S enantiomers of the

TOSLEU with a concentration of the order of 9% by mass in absolute ethanol or any other suitable organic solvent devoid of water. (b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt (Dl), optionally after washing or recrystallization from absolute ethanol. (c) The salt is treated with a solution of

NaOH concentrated, then the first enantiomer of ADB is extracted with CH2CI2. The organic phases are combined and dried with Na ₂ Sθ _4, then these are evaporated in order to obtain the first enantiomer of ADB. (c ¹ ) The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of ADB is obtained as in step (c) but impure, the purification could be done with another TOSLEU enantiomer.

In the case of 1-amino-heptan-2-ol (AHP), the application of the process of the invention more particularly comprises the following steps:

(a) 1 equivalent of AHP and 0.5 to 1 equivalent of one of the R or S enantiomers of the

(Dl) pure, optionally after washing or recrystallization from absolute ethanol.

(c) The salt is treated with a concentrated NaOH solution, then the first enantiomer of AHP is extracted with CH ₂ CI ₂ . The organic phases are combined and dried with Na ₂ S0 _4, then these are evaporated in order to obtain the first enantiomer of AHP.

(c ¹ ) The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of AHP is obtained as in step (c) but impure, purification could be done with the other TOSLEU enantiomer.

In the case of 1-amino-3-ethylpentan-2-ol (AEP), the application of the process of the invention more particularly comprises the following steps:

(a) 1 equivalent of AEP and 0.5 to 1 equivalent of one of the R or S enantiomers of TOSLEU are dissolved with a concentration of the order of 2% by mass in absolute ethanol or any other solvent organic suitable without water.

(b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomeric salt (Dl), optionally after washing or recrystallization from absolute ethanol.

(c) The salt is treated with a concentrated NaOH solution, then the first enantiomer of EPA is extracted with CH2Cl2. The organic phases are combined and dried with Na2SO4, then these are evaporated in order to obtain the first enantiomer of EPA.

(c ') The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of EPA is obtained as in step (c) but impure, the purification could be done with another TOSLEU enantiomer.

In the case of 1-amino-2-cyclohexylethan-2-ol (ACE), the application of the process of the invention more particularly comprises the following steps: (a) dissolving 1 equivalent of ACE and 0.5 to 1 equivalent of one of the R or S enantiomers of TOSLEU with a concentration of the order of 4% by mass in absolute ethanol or any other suitable organic solvent devoid of water. (b) After 4 hours of stirring, the suspension is filtered in order to recover the diastereoisomeric salt (Dl) pure, optionally after washing or recrystallization from absolute ethanol.

(c) The salt is treated with a concentrated NaOH solution, then the first enantiomer of the ACE is extracted with CH ₂ CI2 • The organic phases are combined and dried with Na ₂ Sθ ₄ then these are evaporated in order to obtain the first enantiomer of the ACE.

(c ′) The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of the ACE is obtained as in step (c) but impure.

(d) The said second enantiomer is purified by producing its cinnamate stochiometrically in di-isopropyl ether followed by several recrystallizations from ethanol.

(e) Optionally, part of the crystals from step (d) is selectively dissolved (AS3PC) in an 8.2% by mass solution of racemic mixture in the form of cinnamate, prepared as in step (d), in ethanol to obtain a balance between the saturated solution and cinnamate crystals of the second enantiomer of ACE. This suspension is cooled and then filtered in order to obtain a total mass of initial enantiomer greater than 1 enantiomeric excess with high optical purity. Still at this step (e), it is then possible to add racemic mixture in an amount equal to that of the enantiomer obtained to alternately isolate one then the other enantiomer of the cinnamate of the ACE.

The preferential crystallization (AS3 PC) of steps (e) above could be replaced by a conventional crystallization (SIPC) which is less advantageous.

Other advantages and characteristics of the invention will appear on reading the examples which follow given without limitation and concerning the preparation of l-amino-alkan-2-ols (±) to be split and N-tosyl-leucine, as well as the implementation of the process of one invention with a step AS3PC preferential crystallization.

I - Preparation of l-amino-alkan-2-ols (±).

The amino alcohols in Table I were prepared.

The preparations were carried out thanks to the reaction of Henry (19) in which the yield is between 65 and 85%, followed by a catalytic hydrogenation, with the following conditions: - Pd / C in dry alcohol,

- P (H ₂ ) ≡ 2 atm.

The yields are between 80% and 85%. All amino alcohols (+) and (±) have a melting point between 5 ° C and 30 ° C with the exception of: - ADB (Racemate: Tf = 63, 8 ° C; ΔH =

180 J / g. Enantiomer: Tf = 43.3 ° C; ΔH = 101 J / g).

- ACE (Racemate: Tf = 85.7 ° C; ΔH = 178 J / g. Enantiomer: Tf = 85.0 ° C; ΔH = 174 J / g).

The resolution by means of diastereoisomeric salts of the compounds of Table I was carried out in accordance with the invention with, as the same resolving agent, (S) N-tosyl-leucine, designated below (S) TOSLEU.

II - Summaries of the (S) TOSLEU.

13.25 g of (S) leucine (0.1 mol; Aldrich 99%), 29.1 g of K ₂ C0 ₃ and 300 cc of H ₂ θ are mixed in a reflux flask. heats to 65 ° C. After dissolution with constant stirring, 21 g of tosyl chloride (0.11 mol recrystallized according to the method of Pelletier (20)). After 2 hours, pour in 300 cc of cold water. When the temperature of 20 ° C is reached, the unreacted tosyl chloride is extracted with 2 × 50 cc of CH2CI2 • The aqueous solution is then cooled to 0 ° C, then acidified with a concentrated solution of HCl in excess with vigorous stirring. Most of (S) OSLEU is recovered by filtration and the remaining part in aqueous solution is extracted with 2 × 50 cc of CH ₂ CI ₂ • The organic phases and the solid are combined and dried with Na ₂ θ ₄ . The solvent is removed by evaporation and the product spontaneously crystallizes at 0 ° C. The particularity of the purification method consists in vigorously agitating the crystals in 100 cc of H ₂ θ for 24 hours (21, 22). The solution is then cooled to 6 ° C. and the purified solid is filtered and gives 20.8 g of (S) TOSLEU, ie a yield of 73%.

III - General procedure for the resolution of 1-amino-alkan-2-ols (±) using the (S) TOSLEU as a resolution agent.

1) Preparation of enantiomer No. 1 from the least soluble diastereoisomer salt with (S) TOSLEU.

An amount of X ₂ mole (column 2 of Table II below) of amino alcohol and an equivalent of

(S) TOSLEU are dissolved by heating in X ₃ cc of ethanol (dry) (column 3 of Table II below). The mixture is left for 4 hours at 25 ° C. with constant stirring. The crystallized phase is filtered and dried to provide X ₄ grams of the crude diastereoisomer salt

(column 4 of table II below) with an optical purity of X ₅ % (column 5 of table II below). Recrystallization from ethanol gives a pure salt whose characteristics are in Table II below, where the yields Xβ are indicated in column 6. The theoretical yield indicated in this column 6 is the optical yield.

The pure salt is stirred for 15 minutes in an aqueous NaOH solution in excess and extracted with CH ₂ CI ₂ • The collected organic fractions are dried using Na2Sθ ₄ and the solvent is removed by evaporation under vacuum to give the enantiomer the characteristics of which are summarized in Table II below, where the yields X ₇ are indicated in column 7.

Table II

In Table II above: - columns 2 and 3 indicate the procedure for resolving 1-amino-alkan-2-ol (±) using the (S) TOSLEU; - columns 4 to 7 indicate the results for the enantiomer 1. columns 8 to 10 indicate the results for the enantiomer 2.

Table III below gives the characteristics of the least soluble salt of (S) TOSLEU with the enantiomer (No. 1) of 1-amino-alkan-2-ol.

Apart from AMB, ADB and AEP, all the other salts exhibit a well-characterized polymorphism phenomenon. In addition, by its temperature (column 3) and its enthalpy (column 4) another phenomenon of polymorphism, just before fusion is detected for APR and ACE.

Table III

2) Recovery of the enantiomer No. 2 corresponding to the most soluble diastereoisomer salt with the (S) TOSLEU.

The mother liquor resulting from the filtration product X ₄ is evaporated and the residue is treated with an excess of aqueous NaOH solution. The amino alcohol is extracted with CH ₂ CI ₂ and then dried. One equivalent of transcinnamic acid is added to the dry solution. The solvent is evaporated and the remaining crystals are washed in 5 cc of diisopropyl ether. Cinnamate with optical purity Xs (column 8 of Table II above) is filtered and recrystallized from ethanol. End cinnamate pure X yields _9% and 1 aminoalcohol X ₁ 0% respectively are given in columns 9 and 10 of Table II above.

3) Adaptation of the process.

The process described above has been adapted for the APR and ABU compounds as follows:

The salt is dissolved and stirred in an aqueous solution of excess NaOH, then the solution is saturated with NaOH. A large amount of CH ₂ CI ₂ is added, with vigorous stirring, to the viscous suspension. The two-phase mixture is stirred for 24 hours and filtered under vacuum. The organic phase is then dried with Na ₂ Sθ ₄ .

IV Resolution by preferential crystallization.

Seven of the ten transcinnamates prepared in the previous examples crystallize in the form of a conglomerate. The physical characteristics of the enantiomer and the racemic mixture are summarized in Table IV below. In Table IV: "*" means that a polymorphism is observed just before fusion, and "**" means that a metastable racemate is observed.

Table IV

As no solid solution was detected between the enantiomers, the purification of the following pairs of enantiomers could be carried out with high enantiomeric purity (PO> 99%): APR, ABU, APE, AMB, AHX, AMP, ACE . The cinnamates are prepared in di isopr opylé ther and the recrystallizations are carried out in an ethanol-ethyl acetate mixture (50/50,% vol).

The preferential crystallizations were carried out using the AS3PC method described in the PCT patent application published under No. WO 95/08522, the teaching of which is incorporated here by reference. This process is particularly advantageous because it does not require seeding, it has good reproducibility of the results, and gives high optical purity. The examples below describe the implementation and the results of the AS3PC method with the compounds mentioned above.

1) Resolution of the APR transeinnamate (±) a) Characteristics of the compound.

Specific optical property (Temperature: 20 ° C; mass of enantiomer: 1 g dissolved in 100 ml of methanol):

b) Resolution by the AS3PC method. - Thermodynamic data:

Solubility of the racemic mixture in ethanol with respect to temperature:

Solubility of the enantiomer at: 15.6 ° C, s = 8.9% (mass); Ratio α = 2.15 to 15.6 ° C.

Coordinates of point L: 24.5% at 22.7 ° C.

TH _O MO as a function of the enantiomeric excess (the ratio (mass of the racemic mixture / mass of the solvent + mass of the racemic mixture) is kept constant).

- Kinetic data:

T _B = 24.4 ° C

T _F = 15.6 ° C

T = f (t): temperature as a function of time.

Duration of the supersaturation of the homogeneous solution L undergoing the cooling law defined above: 90 minutes with a stirring speed of 300 rpm.

Duration of crystallization: 55 minutes.

- Initial conditions: Enantiomeric excess: 6.5%.

Stop time at Tβ = 50 minutes Stirring speed: 200 rpm at the start and 300 rpm at the end of the crystallization. - Results:

Average mass of the pure enantiomer: 3.75 g. e.e. medium: 6.2% corresponding to 1.88 g of antipode.

Average optical purity of the raw crystals: 86% without recrystallization or washing.

2) Resolution of the transeinnamate APE (±). a) Characteristics of the compound.

b) Resolution by the AS3PC method.

- Thermodynamic data: Solubility of the racemic mixture in methanol with respect to temperature:

Solubility of the enantiomer at: 16.1 ° C, s = 9.2% (mass); Ratio α = 1.64 at 16.1 ° C.

Coordinates of point L: 15.1% at 16.1 ° C.

T _HO MO as a function of the enantiomeric excess (the ratio (mass of the racemic mixture / mass of the solvent + mass of the racemic mixture) is kept constant).

- Kinetic data:

T _B = 17.5 ° C

T _F = 10.7 ° C

T = f (t): temperature as a function of time.

Duration of the supersaturation of the homogeneous solution L undergoing the cooling law defined above: 80 minutes with a stirring speed of 150 rpm.

Duration of crystallization: 60 minutes.

- Initial conditions: Enantiomeric excess: 4.3%.

Duration of the plateau at Tβ = 50 minutes. Stirring speed: 150 rpm at the start and 180 rpm at the end of the crystallization. - Results

Average mass of the pure enantiomer: 0.474 g for experiments 3 to 5. e.e. medium: 5.3% corresponding to 0.237 g of antipode.

Average optical purity of the raw crystals: 91.8% without recrystallization or washing.

3) Resolution of the AMB transcinnamate (±). a) Characteristics of the compound.

b) Resolution by the AS3PC method. - Thermodynamic data:

Solubility of the racemic mixture in methanol with respect to temperature:

Solubility of the enantiomer at: 27.6 ° C, s = 7.75% (mass); Ratio α = 1.93 at 27.6 ° C.

Coordinates of point L: 15.0% at 27.6 ° C.

THOM _O as a function of the enantiomeric excess (the ratio (mass of the racemic mixture / mass of the solvent + mass of the racemic mixture) is kept constant).

- Kinetic data:

T _B = 28.6 ° C

T _F = 23.2 ° C

T = f (t): temperature as a function of time.

Duration of the supersaturation of the homogeneous solution L undergoing the cooling law defined above: 75 minutes with a stirring speed of 180 rpm.

Duration of crystallization: 69 minutes.

- Initial conditions: Enantiomeric excess: 3.52%.

Duration of the landing at T _B = 45 minutes. Stirring speed: 100 rpm at the start and 120 rpm at the end of the crystallization. Results:

Average mass of the pure enantiomer:

0.541 g. e.e. medium: 3.65% corresponding to 0.270 g of antipode -

Average optical purity of the raw crystals 54% without recrystallization or washing.

4) Resolution of the transeinnamate AHX (±). a) Characteristics of the compound.

b) Resolution by the AS3PC method. - Thermodynamic data:

Solubility of the racemic mixture in methanol with respect to temperature:

Solubility of the enantiomer at: 21.5 ° C, s = 9.5% (mass); Ratio = 1.58 to 21.5 ° C.

Coordinates of point L: 15.0% at 21.5 ° C. THOMO as a function of the enantiomeric excess (the ratio (mass of the racemic mixture / mass of the solvent + mass of the racemic mixture) is kept constant).

- Kinetic data:

T _B = 22.7 ° C

T _F = 18.7 ° C

T = f (t): temperature as a function of time.

Duration of the supersaturation of the homogeneous solution L undergoing the cooling law defined above: 40 minutes with a stirring speed of 150 rpm.

Duration of crystallization: 20 minutes.

- Initial conditions: Enantiomeric excess: 2.6%.

Duration of the landing at T _B = 30 minutes. Stirring speed: 100 rpm at the start and 120 rpm at the end of the crystallization. - Results:

Average mass of the pure enantiomer

0.215 g. average: 2.5% corresponding to 0.107 g of antipode.

Average optical purity of the raw crystals: 93.5% without recrystallization or washing.

5) Resolution of the trance innama te AMP (±). a) Characteristics of the compound.

Specific optical property (Temperature: 20 ° C; mass of enantiomer: 4 g dissolved in 100 ml of methanol):

b) Resolution by the AS3PC method. - Thermodynamic data:

Solubility of the racemic mixture in methanol with respect to temperature:

Solubility of the enantiomer at: 13.1 ° C, s = 9.4% (mass); Ratio α = 1.61 at 13.1 ° C.

Coordinates of point L: 15.1% at 13.1 ° C.

TH _O M _O as a function of the enantiomeric excess (the ratio (mass of the racemic mixture / mass of the solvent + mass of the racemic mixture) is kept constant).

- Kinetic data T _B = 14.5 ° C T _F = 6.4 ° C

T = f (t): temperature as a function of time.

Duration of the supersaturation of the homogeneous solution L undergoing the cooling law defined above: 60 minutes with a stirring speed of 120 rpm.

Duration of crystallization: 48 minutes.

- Initial conditions: Enantiomeric excess: 3.9%.

Average mass of the pure enantiomer for experiments 6 to 9: 0.515 average gee: 5.7% corresponding to 0.257 g of antipode. Average optical purity of the raw crystals 94% without recrystallization or washing.

6) Resolution of the ACE innama te trance (±) a) Characteristics of the compound.

b) Resolution by the AS3PC method. - Thermodynamic data:

Solubility of the racemic mixture in ethanol with respect to temperature:

Solubility of the enantiomer at: 22.7 ° C, s = 4.95% (mass); Ratio α = 1.66 at 22.7 ° C.

Coordinates of point L: 8.2% at 22.7 ° C.

- Kinetic data:

T _B = 24.8 ° C

T _F = 15.8 ° C

T = f (t): temperature as a function of time

Duration of the supersaturation of the homogeneous solution L undergoing the cooling law defined above: 80 minutes with a stirring speed of

300 rpm.

Duration of crystallization: 70 minutes - Initial conditions: Enantiomeric excess: 3.45%.

Stop time at T _B = 60 minutes. Stirring speed: 300 rpm at the start and 300 rpm at the end of the crystallization. - Results:

Average mass of the pure enantiomer:

0.312 g. e.e. medium: 5.0% corresponding to 0.156 g of antipode.

Average optical purity of the raw crystals 93% without recrystallization or washing.

V - Control of enantiomeric purity.

Enantiomeric purity was determined by polarimetry and by chiral gas chromatography. This study makes it possible to verify that the diastereoisomeric salts and the cinnamates obtained by recrystallization have indeed a high purity. Example of the MPA:

The analyzes were carried out on a column manufactured in the laboratory with perpentylated β cyclodextrin. The 1-amino-4-methylpentan-2-ol (AMP) was mono-trifluoroacetylated according to the following protocol: With stirring at room temperature, an excess of trifluoroacetic anhydride is added to 1 equivalent of amino alcohol in dichloromethane. After a few minutes, an excess of methanol is added, then the stirring is left for 24 hours. The solution is evaporated and leaves a yellowish oil. This is diluted in methanol to be injected into the column.

The results of the enantiomeric excesses obtained for the MPA are summarized in the table below:

*: (-) 1-amino-4-methylpentan-2-ol under the measurement conditions () 20 ° C / λ = 436 nm (c = 1 / MeOH).

**: (+) 1-amino-4-methylpentan-2-ol derived from cinnamate (-) under the preceding measurement conditions.

VI - Preparation of the least soluble diastereoisomer salt of l-amino-2-propanol.

1) First step

25.64 g (leq.) Of aminopropanol (Acros 95%) previously distilled in the presence of CaH dissolved in 550 ml of ethanol (water content <0.5%) are placed in a 2 liter reactor. The whole is heated to 27 ° C. and 97.4 g of TOSLEU (1 eq.) Are added. The reaction is allowed to continue with good stirring for 4 h. It is filtered on frit n ° 4 and the product is re-packed in (50/50) at 55 ° C. The whole is left to return to 15 ° C. and filtered.

p = 67% PO = 68% 2) Second step: Isolation of

The enantiomer of aminopropanol.

We make a concentrated soda solution

(30g of NaOH in 50cc of water). The 41.73 g of the tosylate are triturated with 50 ml of the sodium hydroxide solution and extracted 3 times with 100 g of CH ₂ C1 ₂ .

The filtrate is recovered and after extraction, the organic phase is set aside. Furthermore, the aqueous phase is retreated 3 other times with 80 ml of

CH ₂ C1 ₂ . The organic phases are combined and dried over Na ₂ S0. The mixture of partially enriched enantiomers is recovered in the form of a yellow oil after evaporation under vacuum at 50 ° C.

p = 83% PO = 68%

3) Third step: Preparation of the cinnamate of the (+) enantiomer of the aminopropanol.

7.2 g of the mixture of enantiomers partially enriched in 100 ml of diisopropyl ether are introduced into a 250 ml flask. The whole is cooled to 0 ° C., and the trans-cinnamic acid is added in small portions. The reaction is allowed to continue for 24 hours with good magnetic stirring. The solid is filtered on frit No. 4; the mass recovered is 14.8 g (r = 69%) purity, optical (OP) 82%. The overall yield of the resolution reaction calculated as a pure enantiomer is therefore 32%

REFERENCES

(1) Read, J. and I. G. M. Campbell, 1930, J. Chem. Soc., 2682.

(2) Green, A. L., R. Fielden, D. C. Bartlett, M. J. Cozens, R. J. Eden, D. W. Hills, 1967, J. Med. Chem., 10, 1006.

(3) K. Rossen, P. M. Simpson, K. M. Wells, Synthetic Co m. , 23 (8), 1071-1074 (1993): Synthesis of (R) -l-aminopropan-2-ol by means of decarboxylation of L-threonine.

(4) S. Wallbaum, T. Mehler and J. Martens, Synthetic Comm., 24 (10), 1381-1387, (1994): Synthesis of (R) -l- aminopropan-2-ol by means of decarboxylation of L-threonine.

(5) B. Koppenhoef fer, U. Trettin, A. Wàchtler, Synthesis, 11, 1141-1142, (1994): Synthesis of (S) and (R) -l- amino-3 -methylbutan-2-ol from D and L Valine.

(6) T. Ziegler, B. Hôrsch and F. Effenberger, Synthesis, 575-578, (1990): Synthesis of 1- aminopentan-2-ol and l-amino-3, 3-dimethylbutan-2-ol from chiral cyanohydrin via enzymatic catalysis.

(7) R. Chinchilla, C. Najera and P. Sanchez- Agullo, Tetrahedron Asymmetry, 5, n ° 7, 1393-1402, 1994: Enantioselective synthesis of l-amino-4-methylpentan-2- ol via chiral nitroalcohol and by using chiral guanidine as catalyst. (8) H. M Wenghoefer, KT Lee, RM Srivastava, G Srimannarayana and L. B Clapp, J. Heterocycl. Chem., 7, 6, 1407-1411, (1970): S (+) - 1-aminobutan-2-ol from S (-) 1, 2-epoxy-butan.

(9) D. E Wolf, W. H Jones, J. Valiant, K. Folkers, J ^" . Am. Chem. Soc, 72, 2820, 1950: from Lactic acid.

(10) S. Yamazaki, S. Nagaya, K. Saito, and

T. Tanimura, J ^" . Of Chromatography A, 662, 219-225, (1994): from amino acid 1-aminopentan-2-ol and 1-amino-hexan-2-ol.

(11) V. Gotor, R. Breva, F. Rebolledo, J.

Chem. Soc. Chem. Comm., 957-958 (1988): En zymatic enantioselective acylation of l-aminopropan-2-ol.

(12) R. L Clark, W. H Jones, WJ Raich and K. Folkers, J ^" . Am. Chem. Soc., 76, 3995, (1954).

(13) R. H Sullivan and N. J. Woodbary US Patent n ° 3,116,332 (1963) and modifications of the method proposed in the experimental section of the publication of: G. Nieuwpoort and J. Reedijk, Rec. Trav. Chim. from the Netherlands, J. Of the Royal Netherlands Chemical Society, 100, 378, -382 (1981) (resolution of 1- aminopropan-2-ol by means of fractionnai crystallization of diastereoisomeric salts).

(14) D. A Milkovic, N. Sharaf El-Din, KM Gasi, J. Chem. Soc, 50 (6), 227-282, (1985): resolution of l-aminopropan-2 -ol by means of fractionnai crystallization of diastereoisomeric salts. (15) N. Sharaf El-Din, Egypt. J. Chem. , n ° 3, 363-366, (1985): resolution of l-aminopropan-2-ol by means of fractionnai crystallization of diastereoisomeric salts.

(16) T. Shiraiwa, M. Nakamura, H. Nakagawa, N. Seike, S. Taniguchi, H. Kurokawa, J. Chem. Soc. of Japan, 8, 1549-1555 (1985): resolution of 1- aminopropan-2-ol by means of isothermal and seeded preferential crystallization.

(17) A. Kjaer, B. W Christensen, S. E. Hansen, Acfca Chem. Scandinavia a, 13, 144-150, (1959): resolution of l-aminobutan-2-ol via fractionation crystallization of l-amino-3-buten-2-ol.

(18) L. Gajewczyk and A. Zejc, Polish J. of Chemistry, 64, 567-571, (1990): resolution 1-amino-butan-2-ol by means of derivatization and fractionnai crystallization of diastereoisomeric salts.

(19) C. A Sprang and E. F Degering, J. Am. Chem. Soc, 64, 1063, (1963).

(20) S. W. Pelletier, Chem. Ind. , 1034,

(1953).

(21) EW Me Chesney and WM Swann, J ^" . Am. Chem. Soc, 59, 1116-1118, (1937).

(22) D. Theodoropoulos and L. C. Craig, J. Org. Chem., 21, 1376-1378, (1956).

Claims

1) Process for the resolution of 1- amino-alkan-2-ol compounds of general formula: OH

, ^ * s »NH R * ^{v 2 (J} > in which the radical R can represent a wide variety of linear, branched or cyclic alkyl groups, comprising up to about 20 to 25 carbon atoms and preferably from 1 to 15 carbon atoms and optionally comprising one or more double bonds, one or more heteroatoms such as oxygen or sulfur, provided that these are separated from the asymmetric carbon by at least one carbon chain and do not remove not the radical R its aliphatic nature, said groups possibly also being substituted by one or more halogen atoms such as chlorine or lower alkoxy radicals such as methoxy or ethoxy radicals, characterized in that it consists: (a) in dissolving a compound of formula (I) in racemic form and one of the R or S enantiomers of N-tosyl-Leucine, in pure alcohol, in adequate proportions, then

(b) isolating by any suitable means the least soluble diasteroisomeric salt of the compound of formula (I) in crystallized form.

2) Method according to claim 1, characterized in that the diasteroisomeric salt of the compound of formula (I) obtained in step (b) is isolated by filtration or centrifugation.

3) Method according to any one of claims 1 and 2, characterized in that after step (b), a step is carried out: (c) consisting in treating the diasteroisomer salt isolated in step (b) to obtain the first enantiomer of the compound of formula (I) to be split.

4) Method according to claim 3, characterized in that the treatment of step (c) consists in subjecting the diastereoisomer salt obtained in step (b) to stirring in basic medium, then in extracting the first enantiomer of the compound of formula (I) to be split with a suitable organic solvent.

5) Method according to any one of the preceding claims, characterized in that in step (a) approximately 0.5 to 1 molar equivalent of one of the R or S enantiomers of N-tosyl- is dissolved. leucine for one mole of compound of formula (I) to be split.

6) Method according to any one of the preceding claims, characterized in that it comprises the step:

(c ') consisting in treating the stock solutions resulting from the isolation of the diastereoisomeric salt of step (b) to obtain the second enantiomer of the compound of formula (I) to be split.

7) Method according to claim 6, characterized in that the treatment of step (c ¹ ) consists in subjecting the stock solutions to an evaporation, then in treating the residue resulting from

1 evaporation with a basic solution and to extract by CH ₂ CI ₂ the second enantiomer of the compound of formula

(I) to split. 8) Method according to any one of claims 6 or 7, characterized in that a step is carried out:

(d) consisting in producing the cinnamate of the second enantiomer by adding said second enantiomer obtained in step (c ') of approximately 1 equivalent of transcinnamic acid, then advantageously, in that a recrystallization is carried out with 1 ethanol.

9) Method according to claim 8, characterized in that in the case where the addition of transcinnamic acid in step (d) leads to the formation of a conglomerate, this is followed by a step:

(e) preferential crystallization, advantageously of the AS3PC type.

10) Application of the method according to claims 1 to 9 to the resolution of 1-amino-propan-2-ol according to the following procedure: (a) 1 equivalent of 1-amino-propan-2-ol and of 0 is dissolved, 5 to 1 equivalent of one of the R or S enantiomers of N-tosyl-leucine with a concentration of the order of 19% by mass in absolute ethanol or any other suitable organic solvent devoid of water.

(b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt, optionally after washing or recrystallization from absolute ethanol. (c) The salt is treated with a solution of

Saturated NaOH, then the first enantiomer of amino-1-propanol-2 is extracted with CH ₂ CI ₂ • The organic phases are combined and dried with Na ₂ S0 ₄ then these are evaporated in order to obtain the first enantiomer of 1-amino-propan-2-ol. (c ¹ ) The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of l-amino-propan-2-ol is obtained as in step (c) but impure. (d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di-is opr opy lé ther followed by several recrystallizations from ethanol.

(e) Optionally, part of the crystals from step (d) is selectively dissolved in a 24.5% by mass solution of racemic mixture in the form of cinnamate, prepared as in step (d), in 1 ' ethanol to obtain a balance between the saturated solution and cinnamate crystals of the second enantiomer of 1-amino-propan-2-ol. This suspension is cooled and then filtered in order to obtain a total mass of initial enantiomer greater than the enantiomeric excess with high optical purity and one can then add racemic mixture in an amount equal to that of the enantiomer obtained for alternatively isolating one and then the other enantiomer of the cinnamate of 1-amino-propan-2-ol.

11) Application of the method according to claims 1 to 8 to the splitting of l-amino-butan-2-ol according to the following procedure:

(a) 1 equivalent of 1-amino-butan-2-ol and 0.5 to 1 equivalent of one of the R or S enantiomers of N-tosyl-leucine are dissolved with a concentration of the order of 7% by mass in absolute ethanol or any other suitable organic solvent devoid of water.

(b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt, optionally after washing or recrystallization from absolute ethanol. (c) The salt is treated with a saturated NaOH solution, then the first enantiomer of 1-amino-butan-2-ol is extracted with CH ₂ CI ₂ . The organic phases are combined and dried with a ₂ Sθ _4, then these are evaporated in order to obtain the first enantiomer of l-amino-butan-2-ol.

(c ¹ ) The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of l-amino-butan-2-ol is obtained as in step (c) but impure.

12) Application of the method according to claims 1 to 9 to the resolution of 1-amino-pentan-2-ol according to the following procedure:

(a) 1 equivalent of 1-amino-pentan-2-ol and 0.5 to 1 equivalent of one of the R or S enantiomers of N-tosyl-leucine are dissolved with a concentration of about 15 % by mass in absolute ethanol or any other suitable organic solvent devoid of water. (b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt, optionally after washing or recrystallization from absolute ethanol.

(c) The salt is treated with a concentrated NaOH solution, then the first enantiomer of 1-amino-pentan-2-ol is extracted with CH2CI2 • The organic phases are combined and dried with Na ₂ Sθ ₄ then those -these are evaporated in order to obtain the first enantiomer of 1-amino-pentan-2-ol. (c ¹ ) The mother liquors resulting from the crystallization of step (b) and the second are evaporated enantiomer of 1-amino-pentan-2-ol is obtained as in step (c) but impure.

(e) Optionally, part of the crystals from step (d) is selectively dissolved in a 15.1% by mass solution of racemic mixture in the form of cinnamate, prepared as in step (d), in the ethanol to obtain a balance between the saturated solution and cinnamate crystals of the second enantiomer of 1-amino-pentan-2-ol. This suspension is cooled and then filtered in order to obtain a total mass of initial enantiomer greater than the enantiomeric excess with high optical purity and it is then possible to add racemic mixture in an amount equal to that of the enantiomer obtained for alternately isolating one and then the other enantiomer of the cinnamate of 1-amino-pentan-2-ol.

13) Application of the method according to claims 1 to 9 for the resolution of l-amino-3-methylbutan-2-ol according to the following procedure: (a) 1 equivalent of l-amino-3-methylbutan-2- is dissolved ol and from 0.5 to 1 equivalent of one of the R or S enantiomers of N-tosyl-leucine with a concentration of the order of 9% by mass in absolute ethanol or any other suitable organic solvent devoid of water.

Concentrated NaOH, then the first enantiomer of 1-amino- 3-methylbutan-2-ol is extracted with CH ₂ CI ₂ . The organic phases are combined and dried with Na ₂ S0 _4, then these are evaporated in order to obtain the first enantiomer of 1-amino-3-methylbutan-2-ol. (c ′) The mother liquors resulting from the crystallization of stage (b) are evaporated and the second enantiomer of 1-amino-3-methylbutan-2-ol is obtained as in stage (c) but impure.

(e) Optionally, part of the crystals from step (d) is selectively dissolved in a 15.0% by mass solution of racemic mixture in the form of cinnamate, prepared as in step (d), in 1 ' ethanol to obtain a balance between the saturated solution and cinnamate crystals of the second enantiomer of 1-amino-3-methylbutan-2-ol. This suspension is cooled and then filtered in order to obtain a total mass of initial enantiomer greater than the enantiomeric excess with high optical purity and one can then add racemic mixture in an amount equal to that of the enantiomer obtained for alternatively isolating one and then the other enantiomer of the cinnamate of 1-amino-3-methylbutan-2-ol.

14) Application of the method according to claims 1 to 9 to the resolution of l-amino-hexan-2- ol according to the following procedure:

(a) 1 equivalent of 1-amino-hexan is dissolved

2-ol and from 0.5 to 1 equivalent of one of the R or S enantiomers of N-tosyl-leucine with a concentration of the order of 12% by mass in absolute ethanol or any other suitable organic solvent devoid of of water. (b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt, optionally after washing or recrystallization from absolute ethanol. (c) The salt is treated with a solution of

Concentrated NaOH, then the first enantiomer of 1-amino-hexan-2-ol is extracted with CH ₂ CI ₂ • The organic phases are combined and dried with Na ₂ ≤θ ₄ then these are evaporated in order to obtain the first enantiomer of 1-amino-hexan-2-ol.

(c ¹ ) The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of l-amino-hexan-2-ol is obtained as in step (c) but impure. (d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di-sopropy lé ther followed by several recrystallizations from ethanol.

(e) Optionally, part of the crystals from step (d) is selectively dissolved in a 15.0% by mass solution of racemic mixture in the form of cinnamate, prepared as in step (d), in 1 ' ethanol to obtain a balance between the saturated solution and cinnamate crystals of the second enantiomer of 1-amino-hexan-2-ol. This suspension is cooled and then filtered in order to obtain a total mass of initial enantiomer greater than the enantiomeric excess with high optical purity and one can then add racemic mixture in an amount equal to that of the enantiomer obtained for alternatively isolating one and then the other enantiomer of the cinnamate of 1-amino-hexan-2-ol.

15) Application of the method according to claims 1 to 9 to the resolution of 1-amino-4-methylpentan-2-ol according to the following procedure: (a) 1 equivalent of 1-amino-4-methylpentan-2-ol and 0.5 to 1 equivalent of one of the R or S enantiomers of N-tosyl-leucine are dissolved with a concentration of the order of 11% by mass in absolute ethanol or any other suitable organic solvent devoid of water.

(b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt, optionally after washing or recrystallization from absolute ethanol.

(c) The salt is treated with a concentrated NaOH solution, then the first enantiomer of 1-amino-4-methylpentan-2-ol is extracted with CH2Cl2. The organic phases are combined and dried with Na2Sθ4, then these are evaporated in order to obtain the first enantiomer of l-amino-4-methylpentan-2-ol.

(c ′) The mother liquors resulting from the crystallization of stage (b) are evaporated and the second enantiomer of l-amino-4-methylpentan-2-ol is obtained as in stage (c) but impure.

(d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di-i sopr opy lé ther followed by several recrystallizations from ethanol. (e) Optionally, part of the crystals from step (d) is selectively dissolved in a 15.1% by mass solution of racemic mixture in the form of cinnamate, prepared as in step (d), in 1 ' ethanol to obtain a balance between the saturated solution and cinnamate crystals of the second enantiomer of 1-amino-4-methylpentan-2-ol. This suspension is cooled and then filtered in order to obtain a total mass of initial enantiomer greater than the enantiomeric excess with high optical purity and it is then possible to add racemic mixture in an amount equal to that of the enantiomer obtained for alternately isolate one then the other enantiomer of the cinnamate of 1-amino-4-methylpentan-2-ol.

16) Application of the method according to claims 1 to 7 for the resolution of 1-amino-3, 3-dimethylbutan-2-ol according to the following procedure:

(a) 1 equivalent of 1-amino-3,3-dimethylbutan-2-ol and 0.5 to 1 equivalent of one of the R or S enantiomers of N-tosyl-leucine are dissolved with a concentration of 1 'order of 9% by mass in absolute ethanol or any other suitable organic solvent devoid of water.

(c) The salt is treated with a concentrated NaOH solution, then the first enantiomer of 1-amino-3, 3-dimethylbutan-2-ol is extracted with CH2Cl2. The organic phases are combined and dried with a2≤θ4, then these are evaporated in order to obtain the first enantiomer of 1-amino-3,3-dimethylbutan-2-ol.

(c ¹ ) The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of 1-amino-3, 3-dimethylbutan-2-ol is obtained as in step (c) but impure, and purification can be done with the other enantiomer of N-tosyl-leucine than that used in step (a).

17) Application of the method according to claims 1 to 7 for the resolution of 1-amino-heptan-2-ol according to the following procedure:

(a) 1 equivalent of 1-aminoheptan-2-ol and 0.5 to 1 equivalent of one of the R or S enantiomers of N-tosyl-leucine are dissolved with a concentration of the order of 9% by mass in ethanol absolute or any other suitable organic solvent free from water.

(c) The salt is treated with a concentrated NaOH solution, then the first enantiomer of 1-amino-heptan-2-ol is extracted with CH2Cl2. The organic phases are combined and dried with Na2Sθ4, then these are evaporated in order to obtain the first enantiomer of l-amino-heptan-2-ol.

(c ') The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of l-amino-heptan-2-ol is obtained as in step (c) but impure, and the purification can be done with the other enantiomer of N-tosyl-leucine than that used in step (a).

18) Application of the method according to claims 1 to 7 for the resolution of l-amino-3-ethylpentan-2-ol according to the following procedure:

(a) 1 equivalent of 1-amino-3-ethylpentan-2-ol and 0.5 to 1 equivalent of one of the R or S enantiomers of N-tosyl-leucine are dissolved with a concentration of order of 2% by mass in absolute ethanol or any other suitable organic solvent devoid of water.

(Dl) pure, optionally after washing or recrystallization from absolute ethanol.

(c) The salt is treated with a concentrated NaOH solution, then the first enantiomer of 1-amino-3-ethylpentan-2-ol is extracted with CH2Cl2. The organic phases are combined and dried with Na2Sθ4 then these are evaporated in order to obtain the first enantiomer of 1-amino-3-ethylpentan-2-ol.

(c ¹ ) The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of 1-amino-3-ethylpentan-2-ol is obtained as in step (c) but impure, and the purification can be carried out with the other enantiomer of N-tosyl-leucine than that used in step (a).

19) Application of the method according to claim 1 to 9 for the resolution of l-amino-2-cyclohexylated than-2 -ol according to the following procedure:

(a) 1 equivalent of 1-amino-2-cyclohexylethan-2-ol and 0.5 to 1 equivalent of one of the R or S enantiomers of N-tosyl-leucine are dissolved with a concentration of order of 4% by mass in absolute ethanol or any other suitable organic solvent devoid of water. (b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt, optionally after washing or recrystallization from absolute ethanol.

(c) The salt is treated with a concentrated NaOH solution, then the first enantiomer of 1-amino-

2-cyclohexylethan-2-ol is extracted with CH ₂ CI ₂ . The organic phases are combined and dried with Na ₂ S0 _4, then these are evaporated in order to obtain the first enantiomer of 1-amino-2-cyclohexylethan-2-ol. (c ¹ ) The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of 1-amino-2-cyclohexylethan-2-ol is obtained as in step (c) but impure.

(d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di - is opr opy lé ther followed by several recrystallizations from ethanol.

(e) Optionally, part of the crystals from step (d ¹ ) is selectively dissolved in an 8.2% by mass solution of racemic mixture in the form of cinnamate, prepared as in step (d), in 1 ethanol to obtain a balance between the saturated solution and cinnamate crystals of the second enantiomer of 1-amino-2-cyclohexylethan-2-ol. This suspension is cooled and then filtered in order to obtain a total mass of initial enantiomer greater than 1 enantiomeric excess with high optical purity and it is then possible to add racemic mixture in an amount equal to that of the enantiomer obtained for alternately isolating one then the other enantiomer of the cinnamate of 1-amino-2-cyclohexylethan-2-ol.

20) Method according to any one of the preceding claims, characterized in that it comprises, after step (b), a strong acidification step making it possible to recover the R or S enantiomer of N-tosyl-leucine.

21) Use of one of the R or S enantiomers of N-tosyl-leucine as a splitting agent for l-amino-alkan-2-ol of general formula:

in which the radi c al R has the same meaning as in claim 1.

22) Use of the transc innamate of an enantiomer of a chiral l-amino-alkan-2 -ol compound for purification, without loss of enantiomeric excess, of the enantiomer in a process of splitting of l compounds -amino-alkan-2 -chiral olols. 23) Use of the transcinnamate of an enantiomer of a chiral 1-amino-alkan-2-ol compound for the formation of a conglomerate allowing the recovery of 1 enantiomeric excess by the methods of recrystallization and more particularly according to the alternate methods of preferential crystallization, advantageously of the AS3PC type.