FR2756557A1 - PROCESS FOR SPLITTING 1-AMINO-ALCAN-2-OL COMPOUNDS - Google Patents

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 THE SPLITTING OF 1-AMINO- COMPOUNDS

ALCAN-2-OL.

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

R ,, / NH2 (I)

  in which the radical R can represent a wide variety of linear, branched or cyclic alkyl groups, comprising up to on the order of from 25 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 radicals

or ethoxy.

  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, starting 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 diastereoisomeric crystallization or a preferential crystallization have not received a satisfactory solution.

(12 to 18).

  The present invention aims precisely to offer a method of resolution of salts by selective crystallization, easy to implement, reproducible and allowing access to the two enantiomers with high enantiomeric purity

  possibly greater than 99%.

  This object is achieved thanks to the formation of 1-amino-alkan-2-ols salts corresponding to the following general formula: {X -, RCHOH-CH2-NH3 + t with X producing couples of diastereoisomers of different solubility, or with X

achieving 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.

  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, ci -after designated TOSLEU, in pure alcohol, in adequate proportions, then b) isolating by any suitable means the diastereoisomeric salt of the compound of formula (I) in crystallized form. A suitable means for isolating the diasteroisomer salt of the compound of formula (I) obtained in step (b) consists of filtration and / or centrifugation. It should be noted that the diasteroisomer salt of the compound of formula (I) and of the resolving agent which is obtained in step (b) is the

less 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 compound

  alkan-2-ol of formula (I) desired, the R or S enantiomer of N-tosylleucine is used. In the examples of the invention given below, we have chosen

  arbitrarily the S enantiomer of N-tosyl-leucine.

  One of the essential advantages of the invention is the possibility of allowing recovery very

  easy of the resolving agent in 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

  compound of formula (I) to be 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 CH2C12. Other treatments can be envisaged, such as in particular the use of other organic extraction solvents in correlation with the character

  more or less marked hydrophilic of each amino alcohol.

  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 amino alcohols

  tested below the least hydrophylic.

  In the case where it is desired to obtain the second enantiomer of the compound of formula (I) to be split, the process 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 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 resolution agent obtained in step (b) which is the more soluble. The treatment of step (c ') 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 CH2C12, 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 certain of the compounds of formula (I) consists in producing the cinnamate of said second enantiomer obtained in step (c '), by adding approximately 1 equivalent of transcinnamic acid, then advantageously, to carry 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

composed 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. However, 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 levels of purity enantiomeric of the order of 99%; - the application of

preferential crystallization.

  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 use either a

  seeding 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 crystallization

  preferential, 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 crystallization

preferential.

  There is shown in Figure 1 in the appendix a summary diagram of the process of the invention, in which is indicated the products used in

  each of steps a, b, c, c ', d and e.

  The invention further relates to the use of one of the R or S enantiomers of N-tosyl-leucine as a splitting agent for 1-amino-alkan-2-ol of general formula: OH

R, / NH2 (I)

  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: - purification, without loss of the enantiomeric excess, of said enantiomer in a process for splitting of 1-amino-alkan-2-chiral compounds, - the formation of a conglomerate allowing the recovery of the enantiomeric excess by the recrystallization methods and more particularly according to the alternate crystallization methods

  preferential, advantageously AS3PC.

  The invention relates more particularly to the application of the method described above and its

  variants to the duplication of the compounds of table I below

after.

Table I

  Compounds Formulas Code 1-amino-propan-2- ol OH APR

/H./NH2

  1-amino-butan-2-ol OHABU NH2 l-amino-pentan-2-ol OH APE

J ,, NH2

  l-amino-3-methylbutan-2-ol OH AMB NH2 l-amino-hexan- 2-ol OH AHX

__ _ __ NH2

1-amino-4-methylpentan-2-ol OH AMP

/JV_.../__NH2

  l-amino-3,3-dimethylbutan-2-ol OH ADB w <"'NH2 1- amino-heptan-2-ol OH AHP NH2 l-amino-3- ethylpentan-2-ol OH AEP NH2 1-amino- 2cyclohexyléthan-2-ol CH ACE NH2 In the case of l-amino-propan-2-ol (APR), the application of the process of the invention more particularly comprises the following stages: (a) 1 equivalent of APR and from 0.5 to 1 equivalent of one of the R or S enantiomers of TOSLEU with a concentration of the order of 19% by mass in absolute ethanol or any other organic solvent

suitable without water.

  (b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt (D1), 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 CH2Cl2. The organic phases are combined and dried with Na2SO4, then these are evaporated.

  in order to obtain the first enantiomer of APR.

  (c ′) The mother liquors resulting from the crystallization of step (b) are evaporated and the second 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-isopropyl ether 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 the 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 stage (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 from the

cinnamate from APR.

  In the case of 1-amino-butan-2-ol (ABU), the application of the process of the invention more particularly comprises the following stages: (a) 1 equivalent of ABU and 0.5 to 1 are dissolved 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 organic solvent

suitable without water.

  (b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt (D1), 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 CH2Cl2. The organic phases are combined and dried with Na2SO4, then these are evaporated.

  in order to obtain the first enantiomer of ABU.

  (c ′) The mother liquors resulting from the crystallization of stage (b) are evaporated and the second enantiomer of ABU is obtained as in stage (c) but impure. (d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di-isopropyl ether 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 organic solvent

suitable without water.

  (b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt (D1), 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 CH2Cl2. The organic phases are combined and dried with Na2SO4, then these are evaporated.

  in order to obtain the first enantiomer of the APE.

  (c ′) The mother liquors resulting from the crystallization of stage (b) are evaporated and the second enantiomer of the EPA is obtained as in stage (c) but impure. (d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di-isopropyl ether 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 the enantiomeric excess with high optical purity. Still at this stage (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 from the

cinnamate from 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) dissolving 1 equivalent of AMB and 0.5 to 1 equivalent of one of the R or S enantiomers of TOSLEU with a concentration of the order of 9% by mass in absolute ethanol or any other organic solvent

suitable without water.

  (b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt (D1), optionally after washing or

  recrystallization from absolute ethanol.

  (c) The salt is treated with a concentrated NaOH solution, then the first enantiomer of AMB 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 AMB.

  (c ′) The mother liquors resulting from the crystallization of stage (b) are evaporated and the second enantiomer of AMB is obtained as in stage (c) but impure. (d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di-isopropyl ether 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 stage (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 from the

AMB cinnamate.

  In the case of 1-amino-hexan-2-ol (AHX), the application of the process of the invention more particularly comprises the following stages: (a) 1 equivalent of AHX and 0.5 to 1 are dissolved equivalent of one of the R or S enantiomers of TOSLEU with a concentration of around 12% by mass in absolute ethanol or any other organic solvent

suitable without water.

  (b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt (D1), optionally after washing or

  recrystallization from absolute ethanol.

  (c) The salt is treated with a concentrated NaOH solution, then the first enantiomer of AHX 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 AHX.

  (c ′) 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-isopropyl ether followed by several

recrystallizations from ethanol.

  (e) Optionally, part of the crystals from step (d) is selectively dissolved (AS3PC) in a solution at 15.0% by mass 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 the enantiomeric excess with high optical purity. Still at this stage (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 from the

AHX cinnamate.

  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) dissolving 1 equivalent of AMP and 0.5 to 1 equivalent of one of the R or S enantiomers of TOSLEU with a concentration of the order of 11% by mass in absolute ethanol or any other organic solvent

suitable without water.

  (b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt (D1), optionally after washing or

  recrystallization from absolute ethanol.

  (c) The salt is treated with a concentrated NaOH solution, then the first enantiomer of AMP 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 AMP. (c ′) 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-isopropyl ether 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 the enantiomeric excess with high optical purity. Still at this stage (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 from the

AMP cinnamate.

  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) dissolving 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 around 9% by mass in absolute ethanol or any other organic solvent

suitable without water.

  (b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt (D1), optionally after washing or

  recrystallization from absolute ethanol.

  (c) The salt is treated with a concentrated NaOH solution, then the first enantiomer of ADB 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 ADB.

  (c ') 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 other

TOSLEU enantiomer.

  In the case of 1-amino-heptan-2-ol (AHP), the application of the method of the invention more particularly comprises the following steps: (a) dissolving 1 equivalent of AHP and from 0.5 to 1 equivalent of one of the R or S enantiomers of TOSLEU with a concentration of the order of 9% by mass in absolute ethanol or any other organic solvent

suitable without water.

  (b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt (D1), 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 CH2Cl2. The organic phases are combined and dried with Na2SO4, then these are evaporated.

  in order to obtain the first enantiomer of AHP.

  (c ') 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, the purification could be done with 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) dissolving 1 equivalent of AEP and 0.5 to 1 equivalent of one of the R or S enantiomers of TOSLEU with a concentration of the order of 2% by mass in absolute ethanol or any other organic solvent

suitable without water.

  (b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt (D1), 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 other

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 from 0.5 to 1 equivalent of one of the R or S enantiomers of the TOSLEU with a concentration of around 4% by mass in absolute ethanol or any other organic solvent

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 ACE 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 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

in 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 the enantiomeric excess with high optical purity. Still at this stage (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 from the

ACE cinnamate.

  The preferential crystallization (AS3PC) of steps (e) above could be replaced by a

  less advantageous classical crystallization (SIPC).

  Other advantages and characteristics of the invention will appear on reading the examples which follow, given without limitation and concerning the preparation of 1-amino-alkan-2-ols () to be split and N-tosyl-leucine , as well as the implementation of the process of the invention with a preferential crystallization step AS3PC.

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

  The amino alcohols in Table I have been

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 (H2) _ 2 atm.

  The yields are between 80% and%. All amino alcohols (+) and () have a melting point between 5 C and 30 C with the exception of: ADB (Racemate: Tf = 63.8 C; AH =

  J / g. Enantiomer: Tf = 43.3 C; AH = 101 J / g).

  - ACE (Racemate: Tf = 85.7 C; AH = 178

  J / g. Enantiomer: Tf = 85.0 C; AH = 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

  resolution agent, (S) N-tosyl-leucine,

after (S) TOSLEU.

II - Summaries of the (S) TOSLEU.

  13.25 g of (S) leucine (0.1 mol; Aldrich 99%), 29.1 g of K2CO3 and 300 cc of H20 are mixed in a reflux flask, which are heated to 65 C. After dissolution with constant stirring, 21 g of tosyl chloride (0.11 mol recrystallized according to the method of Pelletier (20)) are added. 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 CH2Cl2. The aqueous solution is then cooled to 0 ° C., then acidified with a concentrated solution of excess HCl with vigorous stirring. Most of (S) TOSLEU is recovered by filtration and the remaining part in aqueous solution is extracted with 2 x 50 cc of CH2Cl2. The organic phases and the solid are combined and dried with Na2SO4. 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 O 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, representing a yield of 73%.

  III - General resolution procedure of 1-

  amino-alkan-2-ols () using TOSLEU (S) as

aaent resolution.

  1) Preparation of the n 1 enantiomer from the least soluble diastereoisomer salt with the

(S) TOSLEU.

  An amount of X2 mole (column 2 of Table II below) of amino alcohol and an equivalent of (S) TOSLEU are dissolved by heating in X3 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 X4 grams of the crude diastereoisomer salt (column 4 of Table II below) with purity

  X5% optics (column 5 of Table II below).

  Recrystallization from ethanol gives a pure salt, the characteristics of which are in Table II below, where the yields X6 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 solution of excess NaOH and extracted with CH2Cl2. The collected organic fractions are dried using Na2SO4 and the solvent is removed by evaporation under vacuum to give the enantiomer whose

  characteristics are summarized in table II below

  afterwards, where the yields X7 are indicated in the

column 7.

Table II

1 2 3 4 5 6 7 8 9 10

  ETOH mass code Rendt purity mass. Rendt. O.P. Rendt. Rendt.

  (g) (cc) (g) opti- (%) in (%) in (%) of (%) of (%) in amino salt 1 than pure cinna- cinna-alcohol base salt (%) pure 1 pure i mate mate pure 2

(nb eq (X) 436 Enant. Enant.

  x103) theo. / MeOH 2 2 (exp.) C = 1 C

  APR 0.390 8.3 0.87 64 59.6 26 57 31 20

(5.2) (42) (+44.1)

  ABU 0.305 16.6 0.61 76 72.2 51 67 43 31

(3.4) (63) (+13.3)

  APE 1.040 23.2 1.22> 99 62.5 49 46 38 27

(10.0) l (62) (+11.4)

  AMB 1,124 46.7 1.87 67 59.2 42 53 31 21

(10.9) l (52) (+36.6)

  AHX 1,494 40.4 1.84 86 61.6 48 47 44 37

(12.7) (55) (-6.1)

  AMP 1,024 24.4 1.22 95 65.8 55 51 55 53

(8.7) (55) (-26.0)

  ADB 1,000 34.2 1.14 96 63.4 57 49. __

(8.5) _ (60) (+64.4)

  AHP 1,000 26.3 1.21 89 67.8 54 57. __

(7.6) l (60) (-8.8)

  AEP 1,484 193. 1.71> 99 72.6 70 57. __

(11.3) 6 (72) (+15.1)

  ACE 0.547 45.3 0.57 90 62.5 57 48 54 54

  (3.8) l (57) (+20.8) In table II above: - columns 2 and 3 indicate the procedure for solving l-amino-alkan-2-ol () using (S) TOSLEU; - columns 4 to 7 indicate the results

for the enantiomer 1.

  - columns 8 to 10 indicate the

results for enantiomer 2.

  Table III below gives the characteristics of the least soluble salt of (S) TOSLEU

  with the (nl) enantiomer of 1-amino-alkan-2-ol.

  Apart from AMB, ADB and EPA, 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 the fusion is detected for

APR and ACE.

Table III

2 2 3 4 5 6 7

  Code F.W. T AH T AH (C) 20OC / = 436nmn (amine) (trans) (trans) fusion (fusion) MeOH / c = lg / 100 ml / C J / _ C J / g

APR 75.11 138.8 12 166.6 61 +77.0

ABU 89.14 136.8 8 187.8 87 +66.2

APE 103.16 45.8 8 180.0 92 +57.9

AMB 103.16 - - 205.4 90 +69.8

AHX 117.19 41.0 8 181.4 94 +62.0

AMP 117.19 60.1 11 192.1 79 +51.6

ADB 117.19 - - 198.4 83 +76.8

AHP 131.22 142.5 3 172.5 87 +56.1

AEP 131.22 - - 202.5 91 +64.7

ACE 143.23 60.3 17 211.5 96 +64.3

  2) Recovery of the enantiomer n 2 corresponding to the most soluble diastereoisomer salt

with the (S) TOSLEU.

  The mother liquor resulting from the X4 filtration product is evaporated and the residue is treated with an excess of aqueous NaOH solution. The amino alcohol is extracted with CH2C12 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. The cinnamate with an optical purity XS (column 8 of Table II above) is filtered and recrystallized with ethanol. The final yields of pure cinnamate X9% and of amino alcohol X10% are given respectively to

  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 NaOH in excess, then the solution is saturated with NaOH. A large amount of CH2Cl2 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 Na2SO4.

  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 of 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

  Code Tf (C) AHf Tf AHf (5) 20 (o) Type of mixture Enant. (J / g) (C) (J / g) k = 436; racemic Enant. PO = 0 PO = 0 c = l MeOH APR 129.9 * 150 105.3 * 115 34.8 conglomerate ABU 147.5 * 160 124, 5 * 160 20.1 conglomerate APE 158.6 * 175 137.5 * 160 13.8 conglomerate AMB 155.0 * 121 135.2 * 119 29.8 conglomerate AHX 154.0 * 162 132.7 * 143 12.4 conglomerate AMP 160.8 158 139.8 * 149 16.0 conglomerate (c = 4) ADB. __ AHP racemate - - - - AEP racemate __ _ _ ACE racemate 181.1 * 132 163.8 * 99 23.4 racemic conglomerate As no solid solution was detected between the enantiomers, the purification of the following couples d The enantiomers could be produced with high enantiomeric purity (PO> 99%): APR, ABU, APE, AMB, AHX, AMP, ACE. Cinnamates are prepared in diisopropyl ether and recrystallizations are carried out in a mixture

  ethanol-ethyl acetate (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 following examples describe the implementation and results of the AS3PC method with the

compounds cited above.

  1) Resolution of the APR (+) transcinnamate.

a) Characteristics of the compound.

  Enantiomer Racemic mixture Melting point (C) 129.9 105.3 Enthalpy of fusion (J / g) 150 115 Specific optical property (Temperature: C; mass of enantiomer: 1 g dissolved in 100 ml of methanol): k ( nm) 589 578 546 436 365 (a) 20 (o) - 18.8 21.1 34.8 52.6

  b) Resolution by the AS3PC method.

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

T (OC) 5.6 10.6 15.6 20.5 25.5

  s (Mass%) 14.9 16.6 19.2 22.6 27.6 Solubility of the enantiomer at: 15.6 C, s =

  8.9% (mass); Ratio a = 2.15 to 15.6 OC.

  Coordinates of point L: 24.5% at 22.7 OC.

  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). e.e. (%) 0 2 4 6.5

THOMO (C) 22.7 23.6 24.7 26.0

- Kinetic data:

TB = 24.4 OC

TF = 15.6 OC

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

  T (OC) 24.4 122.5 120.7 118.9 17.1 115.6 115.6

  time (min) 0 10 20 30 40 50 1 55 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%.

  Mass of () (g) Mass of pure () (g) mass of solvent (g

28.37 1.97 87.44

  Stop time at TB = 50 minutes.

  Stirring speed: 200 rpm at the start and

  300 rpm at the end of crystallization.

  - Results: N Mass of Purity Compensation of the pure enantiomer (g) optical (%) solution L (g)

1 3.95 88.3 3.22

2 3.76 84.5 3.05

3 3.74 83.0 3.37

4 4.05 84.8 2.53

3.69 90.7 1.22

6 3.69 86.6 2.89

7 3.51 85.7 2.03

8 3.65 87.2 -

  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 rough crystals

  86% without recrystallization or washing.

  2) Resolution of the transcinnamate APE ().

a) Characteristics of the comDose.

  Enantiomer Racemic mixture Melting point (C) 158.6 137.5 Enthalpy of fusion (J / g) 175 160 Specific optical property (Temperature 20 C; mass of enantiomer: 1 g dissolved in 100 ml of methanol): k ( nm) 589 1,578 1,546 1,436 1,365 (5) 20 (o) 6.8 7.1 8.3 13.8 21.2

  b) Resolution by the AS3PC method.

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

  T (OC) 10.7 112.8 115.3 116.1 126.4 135.2

  s (Mass%) 13.7 14.0 14.8 15.1 20.0 24.9 Solubility of the enantiomer at: 16.1 OC, s =

  9.2% (mass); Ratio a = 1.64 to 16.1 OC.

  Coordinates of point L: 15.1% to 16.1 OC.

  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). e.e. (%) 0 2.0 4.7

THOMO (C) 16.1 17.3 18.8

- Kinetic data:

TB = 17.5 OC

TF = 10.7 OC

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

T (OC) 17.5 12.9 11.2 11.2 10.7

  time (min) 0 13 20 50 60 Duration of the supersaturation of the homogeneous solution L undergoing the cooling law defined above: 80 minutes with a stirring speed of

rpm.

  Duration of crystallization: 60 minutes.

- Initial conditions:

Enantiomeric excess: 4.3%.

  Mass of () (g) Mass of pure () (g) mass of solvent (g)

4.238 0.190 23.86

  Stop time at TB = 50 minutes.

  Stirring speed: 150 rpm at the start and

  rpm at the end of crystallization.

  - Results: N Mass of Purity Compensation of the pure enantiomer (g) optical (%) solution L (g)

1 0.417 90.5 1.1

2 0.447 90.9 1.3

3 0.468 93.0 0.80

4 0.483 96.7 0.71

0.471 88.3

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

of antipode.

  Average optical purity of the rough crystals:

  91.8% without recrystallization or washing.

  3) Resolution of the transcinnamate AMB (+).

a) Characteristics of the compound.

  Enantiomer Racemic mixture Melting point (C) 155.0 135.2 Enthalpy of fusion (J / g) 121 119 Specific optical property (Temperature: C; mass of enantiomer: 1 g dissolved in 100 ml of methanol): X ( nm) 589 1,578 1,546 1,436 1,365 l

(5) 20 (0) 15.1 16.0 18.0 29.8 44.9

  b) Resolution by the AS3PC method.

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

  T (OC) 5.3 10.3 15.3 19.3 22.8 23.2 27.6

  s (mass%) 20.3 22.1 25.8 ..... _ racemate s (mass%) 7.7 8.8 10.0 11.3 12.7 13.0 15.0 conglomerate __ Solubility of the enantiomer at: 27.6 C, s =

  7.75% (mass); Ratio a = 1.93 to 27.6 OC.

  Coordinates of point L: 15.0% at 27.6 OC.

  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). e.e. (%) o0.0 2.0 4.0 6.0

THOMO (C) 27.6 28.7 29.8 30.9

- Kinetic data:

TB = 28.6 OC

TF = 23.2 C

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

  T (OC) 28.6 127.2 127.2 125.225.2 23.2 23.2

  time (min) 0 6 16 22 41 51 69 Duration of the supersaturation of the homogeneous solution L undergoing the cooling law defined above: 75 minutes with a stirring speed of

rpm.

  Duration of crystallization: 69 minutes.

- Initial conditions:

Enantiomeric excess: 3.52%.

  Mass of () (g) Mass of pure () (g) mass of solvent (g)

7.119 0.260 40.335

  Stop time at TB = 45 minutes.

  Stirring speed: 100 rpm at the start and

  rpm at the end of crystallization.

  - Results N Mass of Purity Compensation of the pure enantiomer (g) optical (%) solution L (g)

1 0.562 83 1.10

2 0.520 85 -

  Average mass of pure enantiomer

0.541 g.

  e.e. medium: 3.65% corresponding to 0.270 g of antipode. Average optical purity of rough crystals

  84% without recrystallization or washing.

  4) Resolution of the transcinnamate AHX (+).

a) Characteristics of the compound.

  Enantiomer Racemic mixture Melting point (C) 154.0 132.7 Enthalpy of fusion (J / g) 143 162 Specific optical property (Temperature C; mass of enantiomer: 1 g dissolved in 100 ml of methanol): | X ( nm) 546 1,436 1,365

()) 20 (0) 7.2 12.4 19.1

  b) Resolution by the AS3PC method.

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

T (C) 13.1 17.2 18.7 21.5

  s (Mass%) 11.8 13.2 13.7 15.0 Solubility of the enantiomer at: 21.5 C, s =

  9.5% (mass); CX 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).

e.e. (%) 0 12.0 14.7

THOMO (OC) 21.5 22.7 24.0

- Kinetic data

TB = 22.7 C

TF = 18.7 C

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

T (OC) 22.7 119.1 118.7 118.7 |

  time (min) 0 7 14 20 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%.

  Mass of () (g) Mass of pure () (g) mass of solvent (g)

4.238 0.110 24.0

  Stop time at TB = 30 minutes.

  Stirring speed: 100 rpm at the start and

  rpm at the end of crystallization.

  - Results: N Mass of Purity Compensation of the pure enantiomer (g) optical (%) solution L (g)

1 0.218 95 0.65

2 0.212 92 -

  Average mass of pure enantiomer

0.215 g.

  e.e. medium: 2.5% corresponding to 0.107 g of antipode. Average optical purity of the rough crystals:

  93.5% without recrystallization or washing.

  ) Resolution of transcinnamate AMP ().

a) Characteristics of the compound.

  Enantiomer Racemic mixture Melting point (C) 160.8 139.8 Enthalpy of fusion (J / q) 158 149 Specific optical property (Temperature: 20 OC; mass of enantiomer: 4 g dissolved in 100 ml of methanol): ( nm) 436 1365 (a) 20 (o) 16.0 26.9

  b) Resolution by the AS3PC method.

  - Thermodynamic data: Solubility of the racemic mixture in methanol with respect to temperature: T (C) -15 lo, s 16.4 113, 1 120.2 s (Mass%) 10.5 11.5 12.9 15 , 1 18.3 Solubility of the enantiomer at: 13.1 C, s =

  9.4% (mass); Ratio a = 1.61 to 13.1 C.

  Coordinates of point L: 15.1% at 13.1 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 maintained

constant).

e.e. (%) 0 12.0 14.0 l

THOMO (C) 13.1 14.4 15.4

- Kinetic data:

TB = 14.5 C

TF = 6.4 OC

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

T (OC) 14.5 19.5 16.4 16.4

  time (min) 0 20 30 48 Duration of the supersaturation of the homogeneous solution L undergoing the cooling law defined above: 60 minutes with a stirring speed of

rpm.

  Duration of crystallization: 48 minutes.

- Initial conditions:

Enantiomeric excess: 3.9%.

  Mass of (+) (g) Mass of pure () (g) mass of solvent (g)

4.238 0.174 23.89

  Stop time at TB = 30 minutes.

  Stirring speed: 100 rpm at the start and

  rpm at the end of crystallization.

  - Results: N Mass of Purity Compensation of the pure enantiomer (g) optical (%) solution L (g)

1 0.380 95 0.43

2 0.463 96 1.20

3 0.483 95 0.65

4 0.493 94 1.00

0.473 96 0.47

6 0.504 95 0.99

7 0.517 96 0.65

8 0.520 91 0.82

9 0.520 95 0.56

  Average mass of the pure enantiomer for

experiments 6 to 9: 0.515 g.

  e.e. average: 5.7% corresponding to 0.257 g

of antipode.

  Average optical purity of the rough crystals:

  94% without recrystallization or washing.

  6) Resolution of the transcinnamate ACE ().

  a) Characteristics of the compound. Enantiomer Racemic mixture Melting point (C) 181.1 163.8 Enthalpy of fusion (J / g) 132 99 Specific optical property (Temperature: C; mass of enantiomer: 1 g dissolved in 100 ml of methanol): (nm ) 578 546 436 365 (a) 20 (o) 12.7 14.4 23.4 34.8

  b) Resolution by the AS3PC method.

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

IT (OC) 15.8 118.5 122.7 V28.5 I

  s (Mass%) 7.4 7.5 8.2 19.6 Solubility of the enantiomer at: 22.7 OC, s =

  4.95% (mass); Ratio a = 1.66 to 22.7 OC.

  Coordinates of point L: 8.2% at 22.7 OC.

  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). e.e. (%) 0 13.5 14.8

THOMO (C) 22.7 24.9 25.7

- Kinetic data:

TB = 24.8 OC

TF = 15.8 OC

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

  T (OC) 24.8 23.3 21.8 20.3 18.8 17.3 15.8 15.8

  time (min) 0 10 20 30 40 50 60 70 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%.

  Mass of () (g) Mass of pure () (g) mass of solvent (g)

2.964 0.106 33.307

  Stop time at TB = 60 minutes.

  Stirring speed: 300 rpm at the start and

  300 rpm at the end of crystallization.

  - Results: N Mass of Purity Compensation of the pure enantiomer (g) optical (%) solution L (g)

1 0.324 93 1.50

2 0.299 93

  Average mass of pure enantiomer

0.312 g.

  e.e. medium: 5.0% corresponding to 0.156 g of antipode. Average optical purity of the rough crystals:

  93% without recrystallization or washing.

  V - Control of enantiomeric purity.

  The 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 a high purity.

  Example of MPA: The analyzes were carried out on a column manufactured in the laboratory with P

  perpentylated cyclodextrin. 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 enantiomeric excesses

  obtained for the MPA are summarized in the table below

  below: e.e; (%) from salt e.e; (%) derived from less soluble cinnamate with the most soluble base with

(S) TOSLEU * (S) TOSLEU **

AMP 99.3 0.3 99.7 0.3

  *: (-) 1-amino-4-methylpentan-2-ol in the

  measurement conditions (c) 20 C / k = 436 nm (c = l / MeOH).

  **: (+) 1-amino-4-methylpentan-2-ol from

  cinnamate (-) under the previous measurement conditions.

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Claims (16)

  1) Process for the resolution of compounds 1-   amino-alkan-2-ol of general formula: OH R /, NH2 (I) R   in which the radical R can represent a wide variety of linear, branched or cyclic alkyl groups, comprising up to about 25 carbon atoms and preferably 1 to 15 carbon atoms and optionally comprising one or more doubles 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 from its aliphatic character, the 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 R or S enantiomers of N-tosyl-Leucine, in pure alcohol, in adequate proportions, then (b) to isolate the least soluble diasteroisomer salt by any suitable means of the compound of formula (I) in crystallized form.   2) Process according to claim 1, characterized in that the diasteroisomer 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.   ) Method according to any one of   previous claims, characterized in that   step (a) dissolves approximately from 0.5 to 1 equivalent   molar of one of the R or S enantiomers of N-tosyl-   leucine for one mole of compound of formula (I) to be split. 6) Method according to any one of   previous claims, characterized in that   comprises the step: (c ') of 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 ') consists in subjecting the stock solutions to an evaporation, then in treating the residue resulting from the evaporation with a basic solution and in extracting by CH2C12 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 one   performs a step: (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 one   performs recrystallization from 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.   ) Application of the process according to   Claims 1 to 9 to the splitting of 1-amino-propan   2-ol according to the following procedure:   (a) dissolving 1 equivalent of 1-amino-   propan-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 19% by mass in absolute ethanol or any other organic solvent appropriate 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-l-   propanol-2 is extracted with CH2C12. The organic phases are combined and dried with Na2SO4, then these are evaporated in order to obtain the first enantiomer of the 1-amino-propan-2-ol.   (c ') The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of 1-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-isopropyl ether 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 the 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 it is then possible to add racemic mixture in an amount equal to that of the enantiomer obtained for alternatively isolate one then the other enantiomer of the 1-amino-propan-2-ol cinnamate.   11) Application of the process according to the   Claims 1 to 8 to the splitting of 1-amino-butan-2-   ol according to the following procedure:   (a) 1 equivalent of 1-amino-butan is dissolved   2-ol and from 0.5 to 1 equivalent of one of the R or S enantiomers of Ntosyl-leucine with a concentration of the order of 7% by mass in absolute ethanol or all   other suitable organic solvent without 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 1-amino-   butan-2-ol is extracted with CH2C12. The organic phases are combined and dried with Na2SO4, then these are evaporated in order to obtain the first enantiomer of 1-amino-butan-2-ol. (c ′) 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.   (d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di-isopropyl ether followed by several recrystallizations from ethanol.   12) Application of the process according to   Claims 1 to 9 to the splitting of 1-amino-pentan   2-ol according to the following procedure:   (a) 1 equivalent of 1-amino is dissolved   pentan-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 15% by mass in absolute ethanol or any other organic solvent appropriate 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   Concentrated NaOH, then the first enantiomer of 1-amino-   pentan-2-ol 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 1-amino-pentan-2-ol.   (c ') The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of 1-amino-pentan-2-ol is obtained as in step (c) but impure.   (d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di-isopropyl ether 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 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 alternatively isolate one then the other enantiomer of the 1-amino-pentan-2-ol cinnamate.   13) Application of the process according to the   Claims 1 to 9 to the splitting of 1-amino-3-   methylbutan-2-ol according to the following procedure:   (a) 1 equivalent of 1-amino-3- is dissolved   methylbutan-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 9% by mass in absolute ethanol or any other organic solvent appropriate 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   Concentrated NaOH, then the first enantiomer of 1-amino-   3-methylbutan-2-ol is extracted with CH2C12. The organic phases are combined and dried with Na2SO4, 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 step (b) are evaporated and the second enantiomer of 1-amino-3-methylbutan-2-ol is obtained as in step (c) but unclean.   (d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di-isopropyl ether 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 the 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 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   1-amino-3-methylbutan-2-ol cinnamate.   14) Application of the process according to the   Claims 1 to 9 for the splitting of 1-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 Ntosyl-leucine with a concentration of the order of 12% by mass in absolute ethanol or all   other suitable organic solvent without 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 CH2Cl2. The organic phases are combined and dried with Na2SO4, then these are evaporated in order to obtain the first enantiomer of the 1-amino-hexan-2-ol.   (c ′) 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-isopropyl ether 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 d-cinnamate, prepared as in step (d), in l 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 it is then possible to add racemic mixture in an amount equal to that of the enantiomer obtained for alternatively isolate one then the other enantiomer of the 1-amino-hexan-2-ol cinnamate.   ) Application of the process according to   Claims 1 to 9 to the splitting of 1-amino-4-   methylpentan-2-ol according to the following procedure:   (a) 1 equivalent of 1-amino-4- is dissolved   methylpentan-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 11% by mass in absolute ethanol or any other organic solvent appropriate 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   Concentrated NaOH, then the first enantiomer of 1-amino-   4-methylpentan-2-ol 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 1-amino-4-methylpentan-2-ol.   (c ') The mother liquors resulting from the crystallization of step (b) are evaporated and the second enantiomer of 1-amino-4-methylpentan-2-ol is obtained as in step (c) but unclean.   (d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di-isopropyl ether 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 the 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 alternatively isolate one then the other enantiomer of the   1-amino-4-methylpentan-2-ol cinnamate.   16) Application of the process according to   Claims 1 to 7 to the splitting of l-amino-3,3-   dimethylbutan-2-ol according to the following procedure:   (a) 1 equivalent of 1-amino-3,3- is dissolved   dimethylbutan-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 9% by mass in absolute ethanol or any other organic solvent appropriate 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   Concentrated NaOH, then the first enantiomer of 1-amino-   3,3-dimethylbutan-2-ol is extracted with CH2C12. The organic phases are combined and dried with Na2SO4, then these are evaporated in order to obtain the first   enantiomer of 1-amino-3,3-dimethylbutan-2-ol.   (c ') 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 unclean, and purification can   be made with the other enantiomer of N-tosyl-   leucine than that used in step (a).   17) Application of the process according to   Claims 1 to 7 to the splitting of 1-amino-   heptan-2-ol according to the following procedure:   (a) 1 equivalent of 1-amino- is dissolved   heptan-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 9% by mass in absolute ethanol or any other organic solvent appropriate 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   Concentrated NaOH, then the first enantiomer of 1-amino-   heptan-2-ol is extracted with CH2C12. The organic phases are combined and dried with Na2SO4, then these are evaporated in order to obtain the first   enantiomer of 1-amino-heptan-2-ol.   (c ′) The mother liquors resulting from the crystallization of stage (b) are evaporated and the second enantiomer of 1-amino-heptan-2-ol is obtained as in stage (c) but impure, and the purification can be done with the other enantiomer of N-tosyl-leucine that the one used in step (a).   18) Application of the process according to   Claims 1 to 7 to the splitting of 1-amino-3-   ethylpentan-2-ol according to the following procedure:   (a) 1 equivalent of 1-amino-3- is dissolved   ethylpentan-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 2% by mass in absolute ethanol or any other organic solvent appropriate devoid of water.   (b) After 4 hours of stirring, the suspension is filtered in order to recover the pure diastereoisomer salt (D1), 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-   3-ethylpentan-2-ol is extracted with CH2C12. The organic phases are combined and dried with Na2SO4, then these are evaporated in order to obtain the first   enantiomer of 1-amino-3-ethylpentan-2-ol.   (c ′) The mother liquors resulting from the crystallization of stage (b) are evaporated and the second enantiomer of 1-amino-3-ethylpentan-2-ol is obtained as in stage (c) but impure, and the purification can   be made with the other enantiomer of N-tosyl-   leucine than that used in step (a).   19) Application of the process according to   claim 1 to 9 for the splitting of 1-amino-2-   cyclohexylethan-2-ol according to the following procedure:   (a) 1 equivalent of 1-amino-2- is dissolved   cyclohexylethan-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 4% by mass in absolute ethanol or any other organic solvent appropriate 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   Concentrated NaOH, then the first enantiomer of 1-amino-   2-cyclohexylethan-2-ol is extracted with CH2C12. The organic phases are combined and dried with Na2SO4, then these are evaporated in order to obtain the first   enantiomer of 1-amino-2-cyclohexylethan-2-ol.   (c ') 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 unclean.   (d) The said second enantiomer is purified by producing its cinnamate stoichiometrically in di-isopropyl ether followed by several recrystallizations from ethanol.   (e) Optionally, part of the crystals from step (d ') is selectively dissolved in an 8.2% 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-2-cyclohexylethan-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 alternatively isolate one then the other enantiomer of the   1-amino-2-cyclohexylethan-2-ol cinnamate.   ) Method according to any one of   previous claims, characterized in that   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 1-amino-alkan-2-ol of general formula: OH R "NH2 (I)   in which the radical R has the same   meaning as in claim 1.   22) Use of the transcinnamate of an enantiomer of a chiral 1-aminoalkan-2-ol compound for the purification, without loss of the enantiomeric excess, of said enantiomer in a process of resolution of   1-amino-alkan-2-chiral compounds.   23) Use of the transcinnamate of an enantiomer of a chiral 1-aminoalkan-2-ol compound for the formation of a conglomerate allowing the recovery of the enantiomeric excess by the methods of recrystallization and more particularly according to the alternate methods of crystallization preferential, advantageously of the AS3PC type.