CA2172519C - Method of resolution of two enantiomers by crystallysation - Google Patents

Abstract

A method of optical enantiomer resolution by preferential crystallization involves entering, each time crystallization starts, the two-phase domain containing excess enantiomer and the saturated solution, and cooling according to a well-defined kinetic schedule. A racemic mixture of fine particle size is added to the mother liquors obtained after harvesting the crystals, the mother liquors then being heated to a temperature lower than that of homogenization of the solution so that excess enantiomer is present only in a solid state in equilibrium with the solution. Further cooling produces the other enantiomer and completes the cycle of operations which may then be carried out repetitively.

Description

~ 9510522 ~~~ ~~ '''PC'TIFI2 ~ 4/01107 PROCESS FOR DEDOLISHING OPTICAL ANTIPODES BY CRYSTALLIZATION.
The present invention relates to the field of the separation of two optical antipodes from one species chemical preferential crystallization. This method relies on the alternating crystallization of two chiral compounds called R and S, realizing a conglomerate in a solvent A and for a given range 8T temperature. This sign_Lfie that in this range of temperature, any mixture, in thermodynamic equilibrium of the two antipodes with the solution, consists of two types of crystals each containing only molecules of the same configuration, incorporating or not, solvent molecules (solvates). The existence of such conglomerate, without miscibility in the solid state, will be implicitly accepted in what follows, at least in the temperature range ~, T and for the solvent A.
The crystallization technique preferential is largely implemented in laboratories and in 1 ° industry thanks to the main benefits it brings.
- it avoids the use of a chiral agent intermediate, expensive, whose subsequent recovery involves losses rarely inferior to 10 ô (ne Min, M., Levy, G., and Micheau, JC (1988) J. Chim. Phys.
85, 603-19);
the two antipodes are obtained directly, contrary to: the method classical splitting by formation of salts diastereoisomers;
° the yield is theoretically quantitative as a result of successive recycling;

~ 7 ~ 9510522 ~ ~ ~ ~ ~ ~ I ~ CC'iCl ~ r'l ~~ l ~~~~ 7

2 - the purification of the crystals It is easy to obtain crude enantiomers.
Two classes of factors influence the crystallization of optical antipodes parameters related to ternary heterogeneous equilibria and on the other hand, factors affecting the kinetics of crystallization.
Parameters related to balances heterogeneous ternary include - the positions of the tablecloths crystallisation of solid species that settle each temperature and more particularly the solubility values of the stable and metastable racemic mixture s (~ -) and antipodes s (+) - s (-) s depending on the temperature ~ and the ratio of solubilities ~ 2. = s (- ~) / s (~) - 1 ° extent of stable domains and metastables of solid solutions of racematea racemic solvate of active solvates and varieties polymorphic crystallized solids.
Factors affecting the kinetics of crystallization include:
- factors internal to the crystals relationship with the bonds between the molecules that are not modifiable by the Experimenter ~
- external factors that are modifiable by 1 ° experimenter ~ this is the nature of the solvent of the nature and concentration of impuritya of the supersaturation acquired as a function of time, 1 ° temperature interval ~ Ta of the speed and the mode of agitation ~ of the mass and the granulometry of germs ~ 1 ° effect of walls etc ....
These two classes of factors influence directly the yields the purity of the phases obtained and the progress of the separation operations. The ~ 9 ~ I0 ~ 522. ~~ '~ 4101107

3 feasibility of filtration. will thus be dependent on granulometric spectrum and habitus crystals, the viscosity of the suspension, the tension of solvent vapor, supersaturations acquired by each of the antipodes and the possible presence of a true racemate with a metastable character. These choices also intervene on the kinetics of racemization antipodes or degradation of the molecule.
For each set made up of the couple antipodes (R and S) and solvent (A), the factors intervening on the kinetics are. a case in point.
The present invention aims at improving the Preferred crystallization processes of Art previous from a better knowledge of ternary heterogeneous equilibria made from the solvent A and R and S optical antipodes.
knowledge of heterogeneous equilibria provides data put to use in the process of the invention to achieve more efficient and rational duplication of two optical antipodes by crystallization preferential (or swinging).
More particularly, the method of the invention makes it possible to optimize and generalize a process of the type described in the French patent No. 1,456,627 concerning the resolution of acid glutamic acid and its salts.
The method of the invention is based on a general modification of conventional processes hereinafter referred to as PCIS for °° Seeded isothermal preferential crystallization '° and variants polythermic, thanks to the exploitation of information contained in the representation of balances ternary. antipode R - antipode S - solvent A.
The method of the invention consists.

4 a) to produce a mixture of the mixture racemic crystals in the form of cor-agglomerate, first enantiomer and solvent, whose point figurative E, defined by the concentration and temperature Tg, is in the 1.e biphase domain of the first enantiomer in excess, and in equilibrium with its saturated solution;
(b) to apply a programming law of lowering the temperature to the two-phase mixture prepared in the previous step, such as mother liquors keep a slight oversaturation which favors 1a growth of the enantiomer present in the form of crystals, while prohibiting the spontaneous nucleation of the second enantiomer present in the solution;
(c) to adapt throughout the duration of the crystalline growth, from the step before ~ te a speed slightly increasing stirring time function so that it is at all times, slow enough to encourage growth in first enantiomer by avoiding generating forces of strict; ~ on too important causing nucleation r_on controlled, and suf fi ciently fast to achieve homogeneous suspension and a rapid renewal of the mother liquor around each crystallite of the first enantiomer;
d) to harvest the crystals of the first enantiomer;
e) to add to ~, ~ x mother liquors resulting from the harvest at. the previous step, the racemic mixture of crystals in the form of conglomerate, and to bring the new set to a plateau temperature Tg during the. time required getting the thermodynamic balance so that the figurative point E 'is symmetrical with respect to E
in terms of racemic mixtures of the solvent system, C. '' antipode (-), antipode (+), said point E 'being in the domain biphasic second enantiomer in excess and in equilibrium with its saturated solution and temperature Tg being the temperature of selective dissolution of the enantiomer in default;
(f) to apply the same programming law of the cooling of the temperature as in step (b), in the two-phase mixture prepared in the previous step containing the second enantiomer, so that the mother liquors keep a low supersaturation during crystallization in order to favor the growth of the enantiomer present under crystal form while forbidding nucleation spontaneity of the first enantiomer present in the solution;
(g) to adapt throughout the duration of the crystalline growth of the previous step, a slightly increasing stirring speed depending on the time so that it is, at all times, slow enough to support the growth of the second enantiomer by avoiding generating forces of too much necking causing non-nucleation mastered, and fast enough to get a homogeneous suspension and rapid renewal of mother liquor around each crystallite;
h) to harvest the crystals of the second enantiomer;
~ i) to add to mother liqueurs resulting from the crystalline harvest achieved at the stage previous, the racemic mixture of crystals in form conglomerate, to obtain a set whose composition is identical to that of the set E
initial;
j) repeating steps (a), (b); (c), (d), (e), (f), (g), (h) and (i) to successively obtain one then the other of two enantiomers.
Optimization and reproducibility of the process of the invention are carried out thanks to the I

determination of thermodynamic parameters and kinetics.
Thus, in step (a) of the method of the invention, the choice of the solvent (s) and the range of working temperature are defined in order to have simultaneously .
- Antipodes who realize a conglomerate and whose eventual racemate is metastable in the range working temperature;
liqueurs sufficiently concentrated but low viscosity and low vapor pressure;
- an absence of soil.volysis and racemization;
a stability of the solvates if they are present at equilibrium and if it is enantiomers splittable.
In steps (a) and (e) of the process of the invention, the temperature T $ is higher than the temperature TL, the temperature TL being the homogenization temperature of the racemic mixture alone Without any enantiomeric excess, and in that, from the curve of variation of TxoMO as a function of the enantiomeric excess and for a constant concentration of racemic mixture XL, said temperature TB is defined so that the mass of fine crystals of the first enantiomer of steps (a) and (i) and the second enantiomer of step (e), in equilibrium with their saturated solution, represents at maximum 50 '~ and preferably between about 25 and 40'. ~ of the harvest expected, said temperature THOMOas the lowest temperature homogenization.
In steps (b) and (f) of the method of the invention, the law of programming of cooling temperature Tg to Tg, suitable for mounting experimental, is defined in a way.
- to obtain a low supersaturation during the entire duration of crystallization of the enantiomer ~ VO 95/08522 PCT / fR94101107 present in the form of crystals at the beginning of each cycle, this weak supersaturation causing growth and a mild secondary nucleation;
- to achieve at TF the maximum of supersaturation of the other enantiomer without primary nucleation, the temperature TF
being the final temperature of the doubling process enantiomers by crystallization, to get a crop in crystals to steps (d) and (h) which, after addition of mixture racemic and compensation steps (e) and (i)., allows the cyclicity of operations.
In effect, each experimental setup influences on the supersaturation capacities of the mixtures used and the efficiency of agitation, and, consequently, the temperature cooling programming law is adapted to circumstances in which the process is put into artwork. However, the temperature TB, the solubilities of the racemic mixture as a function of temperature, the TgOMO curve as a function of the enantiomeric excess for a constant concentration of XL racemic mixture, are they completely independent of the assembly experimental.
The law of programming of the cooling of the temperature which is the function connecting temperature to time, is determined for its part of TL to Tg by cooling XL concentration solution from TL + 1 ° C to TF, TF
being less than TL - (THOMO - TL> o in order to obtain a stable saturated solution without primary nucleation while allowing a double harvest of the enantiomeric excess initial, and in that the said programming law of the The cooling of the temperature is determined for its portion of TB to TL
by extrapolation of this same determined law of TL - ~
1 ° C to TF.
The process of the invention has other advantageous characteristics, alone or in combination, as .

WO 95/08522 PCT / FR9 ~ 1I01107 in steps (a) and (i), the mass of ends crystals of the first enantiomer, in equilibrium with its saturated solution represents between, approximately, 25 and 40 the expected harvest, 50% representing a limit maximum;
in step (e), the mass of fine crystals the second enantiomer in equilibrium with its solution saturated represents between about 25 and 40% of the expected harvest, 50 ~ representing a maximum limit;
in steps (b) and (f). the thermicity accompanying the deposition of the first enantiomer and the second enantiomer is incorporated into the law of programming of the cooling of the temperature;
in steps (e) and (i), solvent offsets;
- in steps (a), (e) and (i), the purposes crystals of the racemic mixture conglomerate which are added, have undergone before being introduced a pre-treatment accelerating the dissolution step, such as grinding and sieving, treatment with ultrasonic waves, partial lyophilization; these treatments also intended to provide ends clean crystals to generate a growing surface high crystalline;
steps (a), (e) and (i), having a dissolution, the stirring speed is raised by report to steps (c) and (g).
In addition to the data of heterogeneous equilibria required to implement the process of the invention, the operations also remain subject to adjustable kinetic constraints, in particular lai programming of the cooling of the temperature, which are, for each set of solvents, enantiomers, a case in point.
The process of the invention has several advantages over methods of the prior art ~ 1 ~ 9510522 _ 1 ~ C ° fIF "It9 ~ 101107 at - absence of introduction of germs, - obtaining a better harvest in crystals - obtaining a better purity of crystals - obtaining a better reproducibility operations, - possibility of undertaking duplication without prior recourse, separation and purification of the two enantiomers ~~ s, - saving time during each operation cycle.
The advantages mentioned above allow also to consider greater ease d ° automation of the process of the invention in relation to to the methods of the prior art.
A description of the ternary system A
(solvent), R and S (optical antipodes), at equilibrium is necessary before comparing the classical procedure SIPC, on the one hand with its variants, and on the other hand with the process of the invention, hereinafter referred to as AS3PC
for °° Self-seeded program polythermic preferential crystallization ".
This description will also include non-limiting examples intended to illustrate other characteristics and advantages of the process of the invention.
As examples of implementation of the process of the first invention, will be developed in the following description, the split of the two optical enantiomers. 3-5-dinitrobenzoate-1-penylethanol, sodium and ammonium double tartrate tetrahydrate, glutamic acid hydrochloride, threonine, 5-methyl-5-phenylhydantoin,

5-methyl, 5- (4-methylphenyl) -hydantoin, 5-ethyl-5-phenylhydantoin, 5-methyl, 5- (4-chlorophenyl) -~ ~ ~ 95/0 ~ 52 ~ ~ ~ d ~ ~ ~ s ~ 1 ~ CC ~ ~ ~ / ~ ° ~ ~ 9 ~ s / 0ll ~ 07 hydantoinea of threitol ~ according to an experimental setup particular.
Reference will be made in the following to attached drawings on which.
5 - Figure 1 is a representation in perspective of the solvent ternary system A - antipode R -antipode S ~ depending on the temperature as well as crystallization layers of each constituent and compositions of doubly saturated solutions (curves 10 monovariants) ~ on this figure are also represented isotherms at temperatures TD and TF
and the plane of eutexia ternary at temperature T ~ and containing four phases.
- Figure 2 is a projection on the plan of concentrations ~ equilibria at TD and TEp as well as a representation of the trace of the cut isopleth RY ~ on which point E materializes the composition of the initial mixture slightly enriched in antipode R and having to deposit this same antipode.
- Figure 3 is the vertical section isopleth RY of figure 2 containing the points composition of the antipode in excess and that of the initial solution E, on which is represented the pathways to equilibrium and cooling of the point-solution for a mixture of composition XE (in bold line). For T <The point-solution n ° belongs more to this cut.
- Figure 4 is a projection on the map concentrations of the solution-point bold line) when alternating Isothermal training at TF temperature and sowingD
according to the SIPC method.
- Figure 5 is the vertical section isopleth containing the line RY of FIG.
illustrating the path of the point-solution (in lines a ~
~ 95/0522 ~~ ~~ 'I ° / g'ië94101107 fat) from E to F during isothermal training (at TF) and seeded, according to the SIPC method.
- Figure 6 is a projection on the map concentrations of the solution-point bold line) when doubling by the process of the polythermic invention pro ~ rammed and self-seeded (AS3PC).
- Figure 7 is the vertical section isopleth containing the line RY of FIG.
illustrating the path of the point-solution (in lines fat) from SE to F during the doubling by the method of the polythermic invention programmed and self-seeded (AS3PC).
- Figure 8 is a projection on the map concentrations of the path ~ 4ment of the point-solution (in bold line) at the time of the splitting by the method of the polythermic invention programmed and self-seeded (AS3PC) and checking the relation s (~) <2 - ~ C.
All isothermal and isoplethic sections represented in these figures have variables compositions expressed in mass fractions.
I ° HETEROGENEUS TERNARY EOUILIBERS
ANTIPODES R AND S. AND SOLVENT A.
For example, the publication of JE Ricci (Ed.
Douer Publication Inc. New York (1966) "The Phase Rule and Heterogeneous Equilibrium'e) deals with the general case heterogeneous equilibria in ternary systems.
The description below will be limited to the aspects peculiarities of the ternary system. A (achiral solvent), R and S (non-racemizable enantiomers in the field of temperature operated), necessary for the understanding different crystallization processes preferred.

~~~~ 10 ~ 5 ~~ ~ ~ ~ ~ ~ ~ ~ ~~~ "11 ~~ 9 ~! / O ~ y07 In order to highlight the role particular of the solvents this ternary system will be represented from a right prism to triangle section isosceles rectangle ~ on which the temperature is brought on an axis perpendicular to the plane of the concentrations.
The identity of the thermodynamic variables of the two enantiomers. Tf ~ ~ Hfo solubility in a aohiral solvent ~ etc ... o makes the representation of domains is symmetrical with respect to the vertical plane A-RS-Tg combining optically inactive mixtures of Figure 1. In order to facilitate a first description of this system, the following simplifications have been adopted:
- the only phases that crystallize are pure constituents in a given arrangement (absence of racemate ~ solvate and polymorphism for antipodes) miscibility between constituents independent is zero at 1 ° solid state the solvent has a melting point significantly lower than antipodesv - in the temperature range exploited the solubility of an antipode is not influenced by the presence of the second in the solution (Meyerhoffer's law respected) y which results in a report value ~. = 2).
1 - Representation of ternary equilibria according to the temperature Figure 1 shows the following phase domains.
- the single-phase domain of the diluted solution (~ = 1) - the three layers of crystallization of the constituents delimiting the two-phase domains (~ = 2).

~ 9510522 $ ~ p ~ T ~ ~~ ~ 101107 The solvent deposition surface is confined to the vicinity of A because the melting point of this constituent is significantly lower than that of other constituents, in accordance with the conditions previously given ~
- the three monovariant curves (~ = 3) goose Eutectic valleys from eutectic points binary ~
- 1st invariant ternary eutectic at T ~ (~ = 4), below which the three constituents are crystallized.
Figure 2 is a superimposed representation two isothermal sections at TD and TF of the ternary visualized in Figure 1. At each temperature the cut is composed of four areas as detailed in the table below.
Temp- Nature limit of phases Number of the area where it is 1 'uilibre TD A-SD-ID-SD diluted solution 1 TD R-sD-ID solut ion 2 + R crystals TD S-SD-ID solution 2 + S crystals TD ID-RS solution 3 + R crystals and S

TF A-SF-IF-SF diluted solution 1 TF R-SF-IF Solution + R crystals TF S-SF-IF solution 2 + S crystals TF IF-RS solution 3 + R crystals and S

2 - Isopleth RYT soup.
Figure 3 shows the isopleth R-section YT which is fundamental in understanding the crystallization driving pai- cooling of ternary solutions, in quasi-thermodynamic equilibrium.
This same cut is also needed for tracking W ~ ~ 5/0 ~ 522 ~ ~ ~ ~ ~ 'cCTI ~ E ° ~ / 0 ~~ 07 methods out of balance SIPC ~ variants and AS3P3.
This plane is the locus of the points verifying the relationship .
~ A / ~ S - (1-Y) / l = constant y with XA and XS giving the mass fractions in solvent and in antipodes S.
From Figure 3a we distinguish.
- The single-phase domain of the solution ternary.
- The liquidus of 1 ° antipode R ~ this curve represents the 1st intersection of the plane RY of FIG. 2 with the crystallization layer of this constituent.
This steady equilibrium curve starts at the merging of 1 ° antipode R (not shown) and is found limited to low temperatures by Lo point belonging to the eutectic valley ternary mixtures racemates. This last curve and the trace of the conoid to TL (horizontal segment to TL) delimit the domain two-phase. saturated solution plus crystals of R ~ she gets extends into the underlying three-phase domain by a metastable solubility curve of the same antipode R (in broken lines).
- The three-phase domain. crystals of R and So more saturated solution. This domain is limited at the top by the horizontal trace of Ro's conoid down by the trace of the eutectic invariant plane ternaryp to left by the trace Lm of 1 ° one of the conoids relative to 1 ° antlpOde S.
The KL trace of the crystallization layer of 1 ° antipode S which limits in the upper part the two-phase domain. saturated solution plus crystals of S.
This area is limited in its lower part by the traces of the two conoids of S. gm and Lm. The localization of this second trace Lm of the conoid of S
relative to the metastable susceptibility curve of R

W ~ 9510522, aP ~ 'T / F 4101107 extension of EL will be discussed later about the relative position of F1 and F according to the ratio solubilities a.
- The ternary invariant at temperature T ~
5 below which are the three constituents crystallized A, R and S.
II ° EVOLUTION TO COOLING AND
THERMODYNAMIC THERMODYNAMIC GUASI OF TERNARY SOLUTIONS
10 ~ RESFNTANT N LOW EXCES IN: IOMERIOUE.
It is considered in the following that the point system set (ie the representative point of the overall composition of the mixture) is on the 15 through point E of FIGS. 2 and 3, her precise position is defined by its temperature (or rating) T. Only the interval following temperature is envisaged.

- TD. temperature for lac211e the mixture of departure is a homogeneous solution, and, - TF. end of crystallization temperature and filtration, located in the tripha domain.

This global composition E corresponds to a a racemic solution slightly enriched by a mass M

antipode R and realizing a total mass Mt (the excs Nantiomeric R - S / R + S is generally understood between 4 and 9 ~). The conditions of equilibrium are obtained by a very slow cooling and by a seeding into solid phases) as soon as the figurative E set of the mixture arrives in a domain o this (these) phases are (are) present) the balance.

At the TD start temperature, the solution is homogeneous. When cooling is observed successively.

21 ~ 25 ~~
- crystallization. of the antipode R seu l of TgO ~, qO up to TL ~ simultaneously the solution point moves on the solubility curve of 1 ° antipode R to know from the point E to the dimension Tg ~ 0 ~ 0 ~ at point L to 1 ° inside the isopleth RY cut. At point L ~ the mass M of crystals R in equilibrium with the solution saturated is given by Mt (XE - XL / 1 - XL) - P ~! and corresponds to the enantiomeric excess present in the initial solution (figure 3) ~ the abscissa of the points Lg E and R correspond to compositions XLo ~ E and 1 (Figure 3).
- From TL ~ the solution point evolves from L to Ig on the monovariant curve containing the solutions of racemic composition represented in the 15 Figure 2D thus coming out of the isopleth RY cut of the Figure 3 ~ the crystals of R and S are deposited then simultaneously and in equal quantity.
Duplication can not be achieved under equilibrium conditions for temperatures less than TL.
III - EVOLUTION OF THE SOLUTIQN POINT DURING THE
DEDOUBLENlENT THROUGH CONVENTIONAL CONVENIENCE ~
IN ACCORDANCE WITH THE SIPC PROCESS
1 - Cristallisatipn of the first antipode ~ n excess ~
The previous solution E is homogenized at the temperature TD (figures 4 and 5) e Afir ~ to make it supersaturated it is cooled rapidly to the TF temperature without any crystallization No. appears. This off-balance solutions thermodynamic, is then seeded by germs very pure antipode R of the same chirality as that of 1 ° antipode in excess. Isothermal crystallization of W ~ 9 ~ / 0 ~ 522 ~ a. ~ C ° I '4/01107 the antipode R is established and the representative point of the solution evolves to 1 ° inside the RYT cut from E to the TF rating with which it is first confused, up to F where 1 ° is carried out quickly a filtration. The mass recovered antipode R is 2M or equal to Mt (XE - ~ F / 1 - ~ F).
2 - Crystallization of the second antipode the operation.
The previous fundamental operation has therefore created a solution F enriched with antipode S. By adding a 2M mass of racemic mixture (equal to that of 1 ° antipode recovered) and by heating this mixture to the TD temperature, we obtain a homogeneous solution E °
symmetrical of E with respect to the vertical plane A- (RS) -T.
The process of obtaining a 2M mass antipode S will also be represented by a symmetrical progression of the precedent with respect to this median plane. We proceed in sequence to the operations following:
the solution E 'homogeneous at the temperature TD is first cooled to TF, then, - sown with very pure antipode germs S; the growth of this antipode moves the point representative of the solution su: r the horizontal Segment E'F ° (at the TF coordinate);
- when the solution point is confused with F ', the solution is filtered and: provides a mass 2M
antipode S;
- after a new addition of a 2M mass of racemic mixture and a new heater at TD, one again gets a homogeneous solution whose point representative is confused with the initial point E at the TD Rating ~~ 9510 ~ 5 ~~ ~ ~ ~ ~ ~ ~ CC ° f / ~ FE / OYll07 - the rest of the process is simply reproduce this cycle of operations.
3 - Variants of the SIPC Method Literature (Amiardo G. (1956) Bull.
Dog. 447 ~ Colletv Aa Brienne ~ Mr. J <o Jacques ~ J.
(1980) Chemical reviews 80a 3 ~ 215-30 ~ Noguchi Tnstitute (1968) patent GB 1 197 809) is based on the general outline previous major changes appeared in the literature are classified the way sui ~ rante a) spontaneous primary nucleation of 1 ° antipode in excess.
When splitting (~) threonine (Amiarda G. (1956) Bull, Soc.Kind, Fr. 447) 1a primary nucleation of 1 ° antipode in excess intervenes spontaneously within the supersaturated homogeneous solution.
This primary nucleation occurs while the point E appearing the composition of the set lies in the three-phase domain and that solution no is not agitated (Ae Brienne Collets ~ MJ, Jacquesa J. (1980) Chemical revie ~ as 80 ~ 3 ~ 215-30). Irregular results which this method leads will be analyzed in compared with those of the AS3PC process.
b) Set ~ ~~~~~~~~~~~~~~~~~~~~~~~~
This protocol is most frequently encountered in literature (Noguchi Institute (1968) GB Patent 1,197,809) when the process differs from SIPC.
Among the procedures cited differences However, we can identify the major following common lines.

~ l ~ 95I0R522 PC'TIF '4/01107 at - cooling of the homogeneous solution of TD at a temperature below TL but above TF ~
seeding, p, ar germs of the same chirality than that of the ant_ ~ pode in excess, of the homogeneous supersaturated solution located in the domain phase - cooling up to TFe In some This last step is controlled by a precise programming of the temperature (Noguchi Institute (1968) patent GB 1,197,809).
We will regroup these protocols under the same term "S3PC" for "Seeded polythermic programmed preferential crystallization "although the programming temperature is either non-existent or limited to second phase of cooling. The obtained results when splitting the (~) hydrochloride of the acid glutamic by the S3PC method (Noguchi Institute (1968) GB Patent 1,197,809) and AS3PC will be compared.
IV - EVOLUTION OF THE POINT SOLUTION DURING
DIFFUSION BY PROGRAM TRAINING AND SELF-ENSEMENCE ACCORDING TO THE METHOD OF THE INVENTION AS3PC.
In order to better compare the processes classics and the method of the invention AS3PC, point initial E is chosen arbitrarily in FIGS.
7, identical to the previous case; however, as this will appear in the examples that follow, the process of the invention makes it possible to take a point E further apart of the plane A- (RS) -T and therefore with an enantiomeric excess more important and thus to improve the harvest in crystals of each operation.

~ ~ ~ 9510 ~ 52 ~ ~ I ~~ '~' ~ l ~ ~ 9 ~ / 0 ~ ~ Oi 1 - crystallization of the first antipode excess.
At the beginning of the process and contrary to classical protocols the crystal set more 5 solutiono No. is more homogenized but is brought to the temperature Tg. The initial solution is then in equilibrium with the crystals of enantiomers in excess (by example R in Figure 7). The figurative points of the solution (SE) and 1 ° together (E) are therefore not 10 confused from the beginning of the process. This two-phase mixture is subject to a scheduled law of descent into temperature without addition of crystalline seeds. Point representative of the solution describes a SEFa curve contained in the plan RYT ~ dependent on the kinetics I5 cooling (Figure 7). With kinetics correctly adjusted, we obtain at the beginning a growth crystals of enantiomers in excess of crystallization then evolves towards a simultaneous growth regime more secondary nucleation. When the representative point 20 of the solution reaches the point Fa one proceeds to the filtration to recover a 2M mass of crystals d ° antlpOde R.
2 - Crystallization of the antipode melt , the exclusivity of operations.
From point F, which corresponds to the previous mother solution we go to point E ° c symmetrical of E with respect to the vertical plane A- (RS) -T ~
by adding a 2M mass of racemic mixture and heating at the temperature Tg. The enantiomeric excess is used to place itself in the two-phase domain containing the saturated solution and the crystals of 1 ° ~ .ntipode in excess. Prior to the racemic mixture added during the transition from F to E ° (as from F ° to E) will be crushed and sieved to accelerate 1 ° dissolution step ~ C ° T / F '4101107 ~ 95I0 ~ 522 ~ "~ _ ..

of the two antipodes and more particularly of the antipode in default, and thus allow the formation of a significant number of antipode crystals in excess playing the role of seeds introduced during the processes classics.
The saturated solution S'E, symmetrical of SE
compared to the plan A- (RS) -T, is subject to the same law cooling. The crystals present from the beginning of cooling grow and then participate in a double mechanism of growth - ~ - secondary nucleation.
As in the case of the first crystallization, no Seeding is therefore not necessary.
Meanwhile, the representative point of the solution moves on a curve SE ° F 'contained in 12 plane of symmetric isoplètlze cut SY ° -T
ratio to the bisector plane A- (RS) - T.
At the moment the solution acquires the point representative in F ', the filtration is carried out to collect a 2M mass of antipode S crystals.
new addition of a 2M mass of racemic mixture crushed and sieved followed by a rise in temperature to Tg restores the two-phase mixture to the starting equilibrium.
The continuation of the process then comes back to repeat this cycle of operations giving alternately crystals of antipodes R and S.
3 - Requirements for implementation of the AS3PC process.
a) The equimolar mixture of the antipodes made in the solvent used and for the temperature range T ~ 3 - TF, a conglomerate (pure antipodes or solvates); however, the existence of a metastable racemate is not a disability (case of sodium tartarate ammonium tet <3hydraté).

W ~ 9510 ~ 52 ~ ~ ~ 5 ~% F ~ cC ° f / ~ "~ 9 ~ 1 ~~~~ 7 b) The molecules to be split are stable in this solvent and in the temperature range used between Tg and TE.
(c) The following examples show that TL ternary equilibrium temperature determination and Tg ~ p ~ p is necessary. The TL temperature is the dissolution temperature of the racemic mixture in 1 ° absence of any enantiomeric excess in the solution.
TL being determined the temperature Tg ~ C ~ C corresponds to the homogenization temperature of the solution. She depends on the starting enantiomeric excess and the ratio ~. solubilities of the racemic mixture and the antipode to TL. Knowledge of the supersaturation capacities of solutions between TL and TF is also necessary following the kinetics of cooling the mode of agitation ~ the nature of the container and the granulometry crystals of the antipode in excess. First approximations the time of appearance of crystals by primary nucleation in the racemic solution L
homogeneous cooled from a temperature slightly higher than Ti, with the same kinetics ~ gives an indication of tolerated supersaturation capacity by the conglomerate under these experimental conditions.
This way of operating has been taken into account in examples.
d) Knowledge of the kinetics of dissolution of a known mass of racemic mixture (from particle size) dispersed in the solution at the temperature TB. Some tests are enough to know this duration.
4 - Advantages of the process of inventing AS3pC
far in relation to. SIPC S3PC processes or their variants The examples below show that the AS3PC process is well suited to different classes ~ 3 '~ 9510522 ~~~ C ° T / F ° It94101107 Enantiomers that can be split. compounds covalent or ionic, solvated or not.
The results obtained illustrate the advantages of this process over SIPC processes, S3PC and all variants, in particular.
- lifting of the constraint of seeding, - improved yield and purity optical, - better reproducibility of each crystallization, - decrease in the duration of each cycle.
A systematic discussion of these benefits is detailed below.
(a) Removal of the constraint seeding.
- The seeds necessary for each crystallization here consist of the crystals in balance in the two-phase domain. saturated solution crystals of 1 ° antipode in excess. This crystalline phase therefore possesses, a priori, a maximum optical purity.
In the case of a limited solid solution, the achievement of 1 "balance allows to have the maximum optical purity germs in the solution at this temperature.
- The ~~ S3PC process does not require of introduction of germs, less dust or solid impurities are introduced into the medium ( will only be those introduced with the mixture racemic crushed and sieved).
- The crystals formed in situ are immediately well dispersed in the stirred solution.
- During the implementation of the process AS3PC, only a partially enriched mixture is necessary; for example the natural chiral forms (case tartrate) or that obtained by diastereoisomers with w ~~ mo ~ s2a ~ c ~~ r ~ ° ~~ io ~ X07.

a natural resolving agent such as an alkaloid natural. From the second manipulation and for all following9 (1) absence of introduction of germs makes the need to isolate and purify the second antipode.
The principle of 1 ° self-seeding according to the method of the first invention AS3PC can be extended to the separation of diastereoisomeric salts enantiomers 1 ° a of 1 ° other and realizing for 1 ° interval of temperature set the stable pair in the system reciprocal quaternary of the two pairs of salts diastereoisomers in the presence of the solvent.
(b) Improvement of purity and performance.
- The temperature Tgy chosen in ~~~~~
approximation as being equal to the average of the values THOl ~ lO and TL ~ one can (assuming a variation linear solubility in this narrow range of temperature) consider that the mass of germs at 1 ° state initial represents a quarter of the mass of crystals obtained at each harvest. In most cases one can ~ by adjusting Tg closer to TLD to have up to 40 ~
of the mass of the final crop present in the form of fine crystals. This is easy to achieve when the variation of THOMO as a function of 1 ° enantiomeric excess has a sufficient slope and that 1st excess enantiomeric from each filtration. is important (as shown in some of the examples below) after). In any case 50 represents the limit that 1 ° can be reached at 1 ° equilibriumD in this case the temperature Tg would be equal to the temperature TL. This large mass of fine crystals allows, when the temperature decreases, to obtain a large area equivalent of crystals and therefore to favor the VV ~ 95108522 PC'T / ~ 'It9 ~ / 01107 growth process rather than directly inducing a strong supersaturation nucleation as in the SIPC process and to a lesser extent in the processes grouped under the symbol 'S3PC ~'.
5 - The descent programming law temperature makes it possible to control the process of growth on the one hand, and n.ucleation + growth on the other hand, in order to adapt it to each particular case.
Slow kinetics of cooling will allow the 10 representative point of the point-solution to move the as close as possible to the solubility curve at stable and then metastable character of the antipode (Mullin, J. Tnl. (1972) Ed. Butterworth). In case the secondary nucleation of the antipode in excess is 15 difficult (case of doubling of (~ -) hydrochloride glutamic acid) (Noguchi Institute (1968) patent of United Kingdom No. 1,197,809), this advantage is decisive.
- For the same point starting set, the AS3PC process thus allows, at the figurative point of the 20 solution, to stay further away from the so-called labile zone metastability of Ostwald (hatched nucleation zone spontaneous enantiomers and / or. metastable racemate possible, Figures 5 and 7) that the SIPC process and its variants. The AS3PC process will therefore be the best suited 25 in cases difficult to implement where additional constraints appear like.
the supersaturation capabilities of quasi-racemic solutions are weak, . 1st report. is unfavorable, . the existence of a metastable racemate but having a high primary nucleation rate in the temperature range used ..
It still means that for a couple given enantiomers, ie the same capacity of supersaturation and the same solubility ratio Oc, the ~
W ~ 951 ~~ 5 ~ 2 ~ '~ ~ ~ ~ ~ t ~~' f / ~. ~ I ~ g ~~ 7 2c AS3PC process allows to obtain a better yield. The crystallization of each antipode can be continued longer without the point solution reaches the composition defined by the Ostwald limit.
The AS3PC process therefore makes it possible to allocate to mixtures E
F ~ E ° ~ F ° g of beginning and end of crystallizations a greater enantiomeric excess than in the process SIPC or its variants. Slower crystallization also allows to obtain solids with less structural defects and in particular inclusions of mother solutions ~ in the crystals. All examples show an improvement in the optical purity of crystals.
For a report ~ such that S (~) <2- ~
(~ = ratio of the solubilities of the racemic mixture and 1 ° antipode to TF. ~, = S (- ~) / S (R)) where the point F1 can be substitute the point F for the end of filtration. A D °
Generally speaking, for a cut isopleth of Fl and F the point of weakest enantiomeric excess which will practically represent the final composition of mother liquors subjected to filtration (Figure 8).
c) Better reproducibility - The settings . hold time at the temperature TBa value of 1 ° enantiomeric excess ~
granulometry of crystals at Tgy speed and fashion d ° agitation, descent programming law in temperature being defined the AS3PC process shows a good reproducibility; The size of the crystals can be adjusted and 1 ° we can notably modulate the parameters in order to avoid the existence of small crystals (fine) impeding filtration.
- The use of a maximum temperature lower for a limited time Tg <TP9 implies that the AS3PC process avoided better than the SIPC process ~ V ~ 95I0 ~ 522 ~ PC'TlF1t94101107 or its variants, degradation. and the racemization of antipodes in the case of a fragility of molecules to split in the greeting used. This property also relates to the solvent and it can prove important as the stock solutions are recycled permanently.
d) Golden haqtycycle.
- The step of homogenization of the solution mother (at T> Tg0 ~ 0) being non-existent, the AS3PC process directly contributes to energy savings and durations of each cycle shorter because growth is established from a large mass of crystals and this from the beginning of the cooling. This gain is appreciable if the racemic mixture introduced after each filtration is finely ground and sifted (from preferably shortly before addition).
- The dissolution step of the mixture racemic (in fact the antipode in default rather than the antipode in excess in the solution resulting from the filtration), can be further accelerated by heating for a limited time at a temperature T> Tg, followed by a quick return to Tg. The duration is adjusted to that all the excess antipode is dissolved in a time minimum. This duration depends on the kinetics of dissolution with, for parameter; s.
. the mass and the granulometry of the mixture racemic, . the law of temperature programming, . the type and speed of agitation, all other parameters being fixed.
This operation has the effect (as Moreover, the expectation of establishing the equilibrium Tg, but for the latter less pronounced) to dissolve the finest crystals, which presents w ~ ~ sio ~ s ~ ~ ~ ~ ~ ~ ~ J ~ ~ i ~ ~~ ~~ ~~~~~~~ a ~ ° r the disadvantage of reducing the available area for the growth. This effect will be strongly limited by a grinding and sieving the racemic mixture added to each step ~ and a high stirring speed. Yes necessary ~ we use the ultrasound (taking into account of their thermal effect) in order to obtain a spectrum finer granulometry more homogeneous and reproducible. You can also use a mixture racemic obtained by partial lyophilization so to speed up the dissolution step and have a fine particle size spectrum of the starting crystals.
Mastering the parameters improves the reproducibility of the crystallization and thus facilitates a process automation study.
V - EXAMPLES
1 - Experimental device.
Operations are performed alternatively in two tubes of about 12 cm height and 29 mm diameter with ground neck (29/32 n ° 4).
These tubes are provided in their upper part with a side tube to establish a necessary depression when filtration. The crystals are recovered on glass sintered n ° 2 or 3 ~ adaptable on each tube by via a rubber ring. agitation is provided by a magnetic bar. Liquors pass successively from one tube to another. These transfers reduced to a minimum do not prevent losses between each operation. More quantities of used product will be low, the more losses will be proportionately large. We can list them in two categories.
- Pertesa at the sintered glass and in the initial tube of 'pinteur-mère' containing the excess W ~ 95/08522 '~~'1'FR94101107 enantiomeric end of crystallization. The compensation is done by adding racemic crystals and of solvent, so that this addition corresponds to the mixture L, as indicated in result tables at the column level "compensation".
- Solvent losses mainly due to filtration created by depression. The compensation is done by adding to each operation additional solvent.
In some cases, for example when one uses a very vo_Latil solvent, the process of compensation must be more precise. A small quantity of the solution is taken, in order to determine the composition, then allowing compensation rigorous.
In order to have good reproducibility results, the coolant circulating in the double envelope of the crystallization chamber is regulated in temperature with an accuracy of ~ 0.1 ° C.
The apparatus used makes it possible to fix a law of reproducible cooling.
The following examples treated by discontinuous crystallization (or in batch), could to be, on the same principle, continuously or semi keep on going.
2 - Duplication of 3-5-dinitrobenzoate-1 pén ~ léthanol.
This ester, crystallized derivative of 1-phenyethanol (Synthon chiral c: ourant), has been separation by the classical method (Brienne, M.
J., Collet, A. and Jacques, J. (1983) Synthesis 9, 704-5). The splitting of this covalent derivative has been repeated comparing the SIPC and AS3PC methods.

~ '~ 95In ~ 522 T ~ ef ° fl / ~ °° ~ 941 ~~ b ~ 7 a) Product characteristics.
- Melting temperature of 1 ° antipode 123 ° C.
B) Duplication by the Ps ~~~ C method - Cond ~ t ~ on ~ b ées to eq ~ s ~ rreç
. Solubility in toluene mixtures racemic.
T (° C) 20 27 9 Solubility (mass °) ~ 27, 4 u 34, 6 . Solubility of 1 ° pure antipode (-). 13.2 at 20 ° C ~ ratio ~, = 2, 07.
. Coordinates of the point L. Concentration -34 ~ 6 ~ mass temperature = 27.9 ° C.
. Evolution of THO MO with excess enantiomeric. (racemic mixture / (solvent ~ - mixture racemic)) - 34.6 ° = constant.
Anti ode 0 ~, ~ 3 5 ~ 7 9 ~ 'fHOMO (° C) I 27, 9 ~ 30 ~ 31, 2 ~ 32, 3 ~ 33, 6 - Conditions related to the business Temperature Tg. 29.5 ° C.
. TF temperature. 19.5 ° C.
. Cooling law. T = f (t).

~ 9108522 PC'TlFIt9110 ~ 107 T ° 29 5 28_01 25 1 22 1 19 5 t (mn) 0 10 2.0 30 40 . Duration of 1 ° state of supersaturation of the solution L subjected to this cooling law about 60 minutes for a stirring speed of 250 revolutions / min.
. Crystallization time 42 minutes.
- Results.
Thanks to a size 9.mportant crystals, the filtration, performed on sintered No. 2, is easy.
mass ~ Optical purity Compensation antipode pure (g) sol. () 34, 6%

2 2 40 (+) 943 1 01 3 2 36 (-) 944 1 86 4 2 55 (+) 859 1 96 5 2 48 (-) 870 1 26

6 2 38 94 3 1 46

7 2 61 906 1 50

8 2 68 (+) 942 1 09

9 2 36 (-) 886 1 66

10 I 2, 28 I (+) 92.0 I ____ I

~ '~ 95/0 ~ 52 ~ ~ ~ ~ ~ C'E ° / ~ R9 ~ / 0 & E 07 After each training, in addition to compensation in racemic solution, indicated in the table above, it has been added on average, 0.7 g of toluene.
. Average mass of pure antipode critics.
2 ~ 55 g.
. Average enantiomeric excesses. 1.23 g 8 ~ 5 ~ is still 9 ~ without loss of mother solution.
. Average optical purity. 91 c) Duplication by the SIP method - Initial conditions The first training by the SIPC method is performed on a solution presenting an excess enantiomeric value of 8.87%.
. TD temperature. 35 ° C.
. TF temperature. 20 ° C.
. TF time before the introduction of germs. 5 minutes.
. Mass of germs. 20 mg.
. Crystallization time 15 minutes.
- Results.
No. 2 sintered filtration is less easy that by the method of the invention, because of the finesse crystals.
Beyond 10 minutes of crystallization, the whole solution plus crystals, takes on the appearance of gel, the agitation is no longer homogeneous over the entire tube height, despite an increase in speed stirring.

Antipode mass% optical purity! Compensation pure (G) ._. ~ ~ sol. () 34.6 1 1.76 (-) 75.8 2.11 2 1.28 (+) 64.1 1.99 3 1.63 (-) 69.9 2.54 4 1.65 (+) 74.0 ----. Average mass with pure antipode. 1, 58 g.
Average enantiomeric excess. 0.79 g 5.63%.
. Optician purity mean. 70.9 d) Results obtained by Brienne, J. Mr. and al. (Svnthesis 9 (1983) 704-5).
- Initial conditions.
mass mass () (g) mass (-) (g) solvent (a) 125.4 66.2 4.4 Racemic mixture concentration 34.6%.
. Excess enantiomeric initial. 6%.
-. TD tem. 60 ° C.
. Temperature T ~. 20 ° C.
. Mass of germs. 100 ma.
. Crystallization time 60 minutes.
. Speed of action. 1 R0 rpm.
- Results.
. Average mass of pure epode. 8.3 g, bringing to the same mass of racemic solution that the one used for the tests, 1.66g.
2S. Average enantiomeric excess. 4.15 g, that is 5, 89 . Average optical purity. 83%.
îw = ..___ ..;

1 ~ V ~ 9108522 PC ~ 'IFt94101107 The results obtained with the SIPC method are worse than those observed with the same process SIPC by Brienne et al. (Synthe ~: is 9 (1983) 704-5) for the following reasons.
. The method has been implemented with five times lower, which implies a less favorable surface / volume ratio.
. Losses due to filtration remain equivalent in mass whatever the total mass put into play, they are proportionally more in this case.
. The agitation used by Brienne, MJ and al. is a propeller, thus not causing friction on the walls of the glass container. In indeed, the friction induces a strong nucleation, that's why the crystallization time in the case of the present example (15 min), for an initial solution identical, is significantly lower than the 60 min indicated by the authors.
It should be noted that these conditions adverse effects are also present when setting implementation of the AS3PC method. The results clearly best obtained with the method of the invention show that it offers, compared to the results obtained with the SIPC method in more favorable, significant benefits that compensate very largely these handicaps ..
3 - Duplication of double tartrate sodium and ammonium tetrahydrate ~
a) Characteristic of the product.
This is the Pasteur salt whose RS-H20 ternary system equilibrium the existence of a stable racemate of formula W ~ 95108522 ~~ P ~ "T / F '4101107 b) Duplication by the AS3PC method.
- Conditions related to equilibria.
<Solubilities in the water of the mixtures racemic.
T ° C) 12 15 0 16 3 17 3 Solubility (~ massi ue) 42 5 45 0 46 0 46 5 . Solubility of the anode R. 32 at 12 ° C;
C = 1.33 to 12 ° C.
. Coordinates of the point L. Mass 46, temperature 16.3 ° C.
. Evolution of TH OMO with excess enantiomeric. (racemic mixture / (solvent + mixture Racemic)) - 46 ~ = constant.
% anti ode 0 3 5 I THOMO (° C) 0 16 ~ 3 17 4 18 3 Conditions related to kinetics.
Temperature Tg. 1'7 ~ 3 ° C.
25. TE temperature. 12 ° C.
. Cooling law. T = f (t) 2 ~ f ~~~

T ° C 17 3 17 0 16 5 ~ 15 4 14 0 13 0 ~ 12 1 12 0 12 0 time 0 3 5 8 12a5 16 20 25 30 1 ~ id mn The duration of the 1st state of supersaturation of the homogeneous solution L subjected to this kinetics is greater than 40 minutes for a stirring speed of 150 rpm.
. Duration of crystallization. 20 minutes ~ except in the case of operations 14 to 16 for which the duration is 21 ~ 5 min.
- Conditions ~ n ~ t ~ a ~ es . Initial enantiomeric excess. 4,5 ô.
mass solvent () mass (- ~) () mass (+) () 5, 67 ~ 4, 83 ~ oo 23 . Duration of the plateau at temperature Tg.
40 minutes for a racemic mixture milled on sieve of 250 ~
minutes before its introduction into the tube of crystallization.
. Stirring speed. 150 rpm.

W ~ 9 ~ / 0 ~ 522 P ~ T'lFI ~ 94I01107 - Results.
mass ~ Optical purity Compensation antipode ur (q) sol. () 46%

1 0 47 (+) 947 0 50 2 0 52 (-) 944 0 85 3 0 53 +) 961 0 70 4 0 56 (-) 925 0 88 0 55 +) 955 0 64 6 0 56 (-) 911 0 66 (i) 7 0 59 (+) 972 0 62 8 0 59 (-) 975 0 79 9 0 52 (+) 971 0 50 0 53 (-) 960 0 72

11 0 56 + 961 0 64

12 0 53 (-) 944 0 58

13 0 52 (+) 960 0 70 (i)

14 0 61 (-) 970 0 64 0 62 (+) 967 0 56 16 0 61 (-) 95.4 ~ ----The crystals obtained at each end of 5 processes are easily filterable on sintered No. 2;
they retain very little of the parent solution, such as show the optical purities, despite the concentration high liqueurs.
In addition to the usual losses, we observe, 10 for this compound ammonia losses also due to filtration by depression. The compensation is performed by adding approximately 40 mg of a solution concentrated ammonia which leads to a slight excess in ammonium cation; it is noted (i) in the column

Compensation of the table above. This excess ammonia improves slightly. the purity of the crystals recovered. In case of defect of ammonia, a disorder W ~ 95/0522 ~ ~ ~ ~ ~ ~ ~ ~~ '~ ~ / E ~ ~ 9 ~ 110 ~~ 07 very fino persistent even at 20 ° C, mar ~~~ este in the liqueurs.
. Average mass of pure antipode crystals (manipulations 2 to 13). 0a55 g.
. Average enantiomeric excess. 0a 27 g is 5g 3 . Average optical purity. 95a5ô.
Despite 1 ° existence of a metastable racemate and the low amounts of racemic solution put in play (1005 g) to the AS3PC method therefore gives good results with this hydrate.
b) Duplication by PCIS method - Initial conditions Concentration of the racemic solution 4 6 ° -o.
. Initial enantiomeric excess. 405s . TD temperature. 18 ~ 6 ° C.
. TF temperature. 12 ° C.
. Time to, TF before the introduction of germs. 10 to 12 minutes.
. Mass of germs. 5 mg.
. Crystallization time 10 minutes.

W ~ 95/0522 p ~~ P ~ i '! F'It9 ~ 101107 - Results.
Sintered filtration n ° 2.
N mass antipode optical puret Compensation pure soil. () 4 6 1 0 38 (+) 92 0 51 2 0 42 () 88 0 55 3 0 39 + 92 0 57 . Average mass of an.tipode pure. 0.40 g.
Average enantiomeric excess. 0, 20 g is 4 °
o.
. Average optical purity. 91.5 ~.
The AS3PC method provides better results in particular for the masses in crystals pure antipode.
4 - Duplication ~ of the hydrochloride of the acid excel.
British Patent No. 1,197,780 in the name of Noguchi Institute describes the duplication of this salt of glutamic acid using a polythermic process with seeding of the homogeneous solution (S3PC).
a) Characteristic, due to the product.
1 (mm) 365,589 ~~~ 20 (°) H2C 74 7 20 6 [~~ 20 (°) HC1, 1N 94 26 3 b) Duplication..by the AS3PC method.
- Conditions related to balances.
. Solubility of: racemic mixture in the water .

W ~ 9510 ~ 5 ~~ ~ ~ ~ .. ~~ ~ ~ ~ ~ ~ ~ ~ ~ ~
TemT ~ errature ° C 30 42 8 i Solubility (0 mass) 37 5 49 Coordinates of the point L. 49 ° mass temperature . 4208 ° C.
. Evolution of T ~ ypy ~ p with lgexcés 5 enantiomeric. (racemic mixture / (solvent mixture racemic)) - 49 ~ = constant.
anti ode (+) 0 k 3 4 5 6 9 ~ THO ~ O (° C) 42p 8 ~ 45, 0 46D 8 48 ~ 1 51p 1 - Conditions related to kinetics 10. Temperature Tg. 44x4 ° C.
. TF temperature. 30 ° C.
. Kinetics of cooling. T = f (t) t mn 0 15 45 ~ 55 T (° C) ~ 44 p 4 ~ 37 p 0 ~ 32 ~ 0 ~ 30, 0 15. Duration of 1 ° state of supersaturation of the solution L subjected to this kinetics. 120 minutes for a stirring speed of 150 rpm.
. Crystallization time 55 minutes.
. Duration of bearing at TB. 30 minutes.
25. Stirring speed. 150 rpm crystallization starts, then 250 rpm at the end.

W ~ 95108522 '~~ PC'TIF'R94I01107 4: L
- Results.
Filtration on frit # 3.
antipode mass ~ purity compensation ur o tiqtae sol. (-) 49 1 3 88 +) 93 6 2 26 2 3 97 -) 95 6 2 85 3 4 40 (+) 94 8 2 O1 4 4 27 (- 94 9 1 36 4 43 + 94 9 1 77 6 4 52 (-) 94 5 1 34 7 4 73 (+) 96 0 1 60 8 4 53 (-) 91 8 1 30 9 4 43 (+) 97 1 1 35 4 7 2 (-) 9 6 2 ----5. Average mass of pure antipode. 4.50 g to from the manipulation N ° 3.
Average enantiomeric excess. 2.25 g 10.34.
. Average optical purity. 95o.
c) Results obtained by the S3PC method described in the previous patent 1 197 809, far the S3PC method.
- Initial conditions.
51.7 ~ mass.
. Excess initial enantiomeric value. 9.8 ~.
. TD temperature. 56 ° C (solution homogeneous).

~ 95/0 ~ 52 ~ ~ ~ ~ ~ - ~ ~ ~ ~ <C ° ~ '// ~ "~ ilO ~ tll ~ 7 . TF temperature. 32 ° C.
. Mass of introduced germs. 1 g.
. chilling rate 5 to 8 ° C / hour.
. Crystallization time 150 minutes.
- Results.
. Pure antipode mass. 5, 73 minus 1.00 g of germs equal 4v73 g, that is, by reducing to the same mass of racemic solution than that used for tests. 3.70 g.
. Excess enantiomeric. 2.37 g is 8.6 ~.
Optical purity. 7286 O
The antipode mass obtained and the purity optics are superior by the AS3PC method.
5 - Duplication of threonine This example compares the results obtained by the AS3PC method with the results of the works by Amiard, G. (Bull Soc.Chien (1956) 447) carried out by preferential crystallization with spontaneous nucleation.
(a) the characteristics of the product . Specific rotatory power at 20 ° C, c = 1 g / 100 ml, water.
~, (nm) 365 ~ 589 [~~ 20 (°) - 81, 0 ~ - 28 0 1 b) pedaling by the AS3Pf method - Conditions related to ~ qu ~ l . Solubilities in 1 ° water mixtures racemic.

~ '~ 95I0 ~ 522 PC "f 4101107 T ° C 30, 0 54 5 solubility ~ mass) 14.5 ~ 23.1 I
. Solubility of the year.tipode. 9.1 ~ at 30 ° C, ratio ~ c = 1, 5 9.
. Coordinates of the point L. 23,08 ô mass, TL temperature: 54.5 ° C.
Evolutiton of Tglp ~ p with excess enant ~ omeric (racemic mixture / (solvent + mixture racemic)) - 23.08 ~ - constant.
anti ode (-) 0 _2 4 6 8 THOMO (° C) 54 5 56 u 61, 65,568, 5 - Conditions related to cinema.
. Temperature Tg. 58 ° C.
. Temperature Tp. 31 ° C.
. Kinetics of cooling. T = f (t).

T ° C) 58 55 51 47 43 39 34 31 t mn) 0 12 22 30 38 46 54 60 . Duration of the state of supersaturation of the solution L subjected to this kinetics. 80 minutes.
. Crystallization time 60 minutes.
- In ü ~ ial conditions.
. Excess enantiomériq ~ ue initial. 5 ~.
solvent mass () mass (~) (a) mass (+) () ~ '~ 9 ~ 10 ~ 522 ~ ~ ~ ~ ~ Pc ~ "~ Y ~" ~ 410 ~ 107 - Results.
No i masseantipode ~ puret Soil compensation.

ur o ti ue () 23 1 1 1 02 + 97 5 1 432 2 1 20 ~ 94 0 1 769 3 1 46 +) 93 0 1 663 4 ~ 1 65 (- 97 5 1 443 1 60 + 98 3 552 6 1 64 (-) 98 5 ~ 1,687 7 1 72 (+) 99 1 1,650 8 1 70 (-) 92 4 1 800 9 1 66 (+) 91 8 1 842 ~ 1 p69 ~ (-) 97.8 ~ __-_ d . Average mass of pure epoxy crystals 5 (from handling No. 4). 18665 g.
. Average enantiomeric excess Oo833 8p either 8 ~ 47 . Average optical purity. 9685 C) Results obtained by Amiard - Initial conditions mass solvent () mass (~) (q) mass (+) () 150 ~ 45 5 . Concentration of the racemic mixture 23 ~ 08 ~.
. Excess enantiomérictue. 10 ô
. TD temperature. 80 ° C.
. TF temperature. 20 ° C.
. Mass of germs. spontaneous nucleation at 30 ° C without agitationD after a period not specified by 1 author.

P'C'fffR94I01107 W ~ 9510522 Crystallization time ~ 0 mn (in waving occasionally).
- Results.
5. Average mass of pure antipode. 7.80 g either, by bringing back to the mass of racemic solution used in the tests. 1.55 g.
. Average enantiomeric excess. 3.9 g o.
8 ~
10. Average optical purity. 84.2%.
Using the AS3PC method allowed 1 ° obtaining a crop of superior antipode with much more regularity and especially with purity significantly improved optics.
6 - Duplication of 5-meth-l-5-henyl-hvdantoïne.
a) Product characteristics.
Melting temperature of the antipode 242 ° C.
Melting temperature of the racemic mixture.
19 6 ° C.
b) pedigree by the AS3PC method.
- conditions related to x equilibrium.
. Solubility of racemic mixtures in the 2-methoxyethanol.

~ 9 ~ / 0 ~ 5 ~~ i ~ cC'ü "/ ~ '4/0 ~~ 07 Coordinates of the point L. 21x48 ° massic ~
TL temperature. 37 ° C0 . Evolution of Tg O ~ qO with l9excés enantiomeric (racemic mixture / (solvent + mixture racemic)) - 21 ~ 48% = constant.
enantiomer 0 2 4 6 THOMO (° C) p 37 ~ 0 ~ 39g 8 ~ 42, 7 ~ 450 5 - Conditions related to kinetics . Temperature Tg. 40 ° C.
. TF temperature. 20 ° C.
. Kinetics of cooling. T = f (t) T ° C 40 35 30 I 25 20 20 t (mn) 0 12 22 30 38 ~ 46 . Duration of the state of supersaturation of the solution L subjected to this kinetics. better than 90 minutes for a stirring speed of 150 rpm.
. Crystallization time 60 minutes.
- Condi ~ or ~~ ini ~ a1 PS
. Initial enantiomeric excess. 5 mass solvent (a) mass (- ~) () mass (+) () 15y704 ~ 4,296 ~ Oo229 Duration of the landing at Tg. 3C minutes 5 ~ '~ 9510522 PC'l'l ~' ~% t01107 . Stirring speed ~ _on. 100 rpm start of the crystallization, then 150 rounds at the end.
° Results.
ground antipode puret Ground compensation.

ur o ti ue 23 1 1 0 560 + 94 2 224 3 0 529 (+) 92 1 174 4 0 561 (-) 92 1 095 5 0 599 (+) 91 0 967 7 0 510 (+) 91 0 942 8 0 521 (-) 8 1 181 9 ~ 0, 568 ~ (+) 89 . Average mass of pure antipode crystals.
0.569 g.
. Average enantiomeric excess 0.285 g, 6, 2 Average optical purity. 91 o.
7 - Duplication of 5-methyl, 5- (4-methyl) phenyl) -h ~ dantoin.
a) Characteristic of the product.
- Melting temperature of the antipode.
250 ° C.
- Melting temperature of the racemic mixture . 205 ° C.
- Specific rotatoiz-e power at 20 ° C, c = 1 g / 100 ml, ethanol.

W ~ 95/0522 ~ ~ ~ ~ ~~ Tl ~~~~ 101 ~ 07 ~, (nm) 589 578 545 ~~ 436 365 [~~ 20 (°) 105 110 127 234 418 b) Dedupe ~ a_r the me.bode AP
- çond ~ t; one l; é ~ ~ ec ~ m; 1; ò7YP5 . Solubility of racemic mixtures in the 2-methoxyethanol.
T (° C) 15 25 39 45 50 Solubility (mass) 12 9 14 4 17 0 19 5 I 20 1 . Solubility of 1 ° antipode R. 705 ~ at 25 ° C, ratio ~ = 92 at 25 ° C.
. Coordinates of the point L. 17 ~ mass, TL temperature. 39 ° C.
Evolution of TH OMO with 1 ° exceeded enantiomeric (racemic mixture / (solvent + mixture racemic)) - 17 ~ = constant.
- C ~ nd'ons 1i 's at the in'ic ~ u . Temperature TB. 41 ° C.
. TF temperature. 14 ° C.
. Kinetics of cooling. T = f (t).
T (° C) ~ 41 31 ~ 31 21 ~ _21 14 t (mn) 0 15 30 45 50 60 . Duration of 1 ° state of supersaturation of the solution L subjected to this kinetics. 70 minutes for a stirring speed of 150 rpm.
. Crystallization time 60 minutes.

~ 95/0522 ~ P ~ 'T! ~ "I894 / 01107 - Conditions iz ~ itial ~
. Excess enantiomeric initial. 7.4 ~.
mass solvent (q) mass (- ~) () mass (+) () 27 68 5 667 0 0.458 . Duration of the landing at Tg. 30 minutes Stirring speed. 150 rpm start of crystallization, then 200 rounds at the end.
mass antipode m ~ puret Compensation ground.

ur (o tick () 23 1 ) 1 0 882 (+) 93 085 3 0 860 (+) 93 1 224 4 0 887 (-) 95 1 263 5 0 905 (+) 96 1 100 6 0 929 (-) 95 1,200 7 0 882 (+) 93 1 888 9,064 (+) 93 1,387 10 1 164 (-) 94 1 598 11 1 165 (+) 90 2 356 12 1 071 (-) 82 O 0, 538 Average mass of pure antipode crystals.
0, 977 g.
Enantiomeric excess ~ average 0.489 g, ie 7, 9 . Average optical purity. 93 °.

W ~ 9510 ~ 52 ~ ~ ~ ~ C ~ T ~ ïC'R '/ ~~. ~ / 0 ~~ 07 8 - Duplication of 5-eth ~ l-5-phenyl hvdantoïne.
This compound was split by Cave et al.
(U.S. Patent No. 2,942,004) g using the conventional method SIPC in another solvent less only 2-methoxyethanol.
a) ~ product characteristics>
10 - Melting temperature of the antitipode.
240 ° C.
- Melting temperature of the racemic mixture . 197 ° C.
- Specific rotatory power at 20 ° C
C = 1 g / 100 ml ethanol.
~, (nm) ~ 589 578 ~ 546 436 365 ~~~ 20 (°) 117 122 141 ~ 261 462 b) Doubling the method A ~ r 20 - ~ onditioras related to equ; ~; rrP ~
. Solubility of racemic mixtures in the 2-methoxyethanol.
T (° C) 20 _30, 41 X 50 60 Solubility (mass) 13 6 15 6 17 0 19 23 0 25. Solubility of 1 ° antipode R. 905 ~ at 41 ° Ca report ~. = 1 ~ 8 at 41 ° C.
. Coordinates of the point L. 17 ~ mass, TL temperature. 41 ° C.
. Evolution of TH OMO with 1st excess Enantiomeric (racemic mixture / (solvent ~ - mixture racemic)) - 17 ° - constant.

~ 95/08522 p ~~ / ~ 4101107 0 enantiomer 0 2 4 6 8 THOMO (° C) ~ 41 (43, 6 ~ 46, 3 ~ 48, 7 I 51, 5 - COn, ~ OnS 1 ~ _PS to, ~ a 1 Ytét; af., L72.
. Temperature Tg. 44.5 ° C.
. TE temperature. 23 ° C.
. Kinetics of cooling. T = f (t).
. Duration of the state of supersaturation of the solution L subjected to this kinetics. 70 minutes for a stirring speed of 275 cc> urs / min.
. Crystallization time 56 minutes.
- Initial conditions ~ s.
. Initial enantiomeric excess. 6.4 ~.
mass solvent mass ~ t mass +
27, 666 m 5, 666 0 3877 . Duration of the stage at $ T $. 30 minutes Stirring speed. 200 rpm crystallization starts, then 275 laps at the end.

~~ 9 ~ 1 ~~ 52 ~ ~ ~ ~ ~ ~ ~ ~ ~~ C'flF ~! ~~~~ 7 - Results.
antipode mass ~~ puret Compensation n / a ur o ti ue (~ -) 23 ~

1 0 717 (+ 91 not 2 0 838 -) 80 1,765 3 1 002 +) 92 0 894 4 1 016 (-) 88 1 116 1 088 + 92 0 806 6 1 161 (-) 90 0 654 7 1 137 (+) 86 1 446 8 1 135 (-) 85 2 440 9 ~ lg 179 d (+) 87 . Average mass of pure antipode crystals 5 10030 g.
Excess enantiomeric average Ov515 ga be 8a 5 Average optical purity. 88 ~.
9 - Duplication of 5-th ~ l 5-! 4-chlorophen l ~ ydantoin.
a) product characteristics.
- Melting temperature of the antitipode.
305 ° C.
- Melting temperature of the racemic mixture 263 ° C.

W ~ 95108522 PC'T / F'It94 / 01107 b) Duplication ~ aar: the AS3PC method.
- Conditions linked to a ~ ax equilibrium.
. Solubility of racemic mixtures in the 2-methoxyethanol.
T ° C 20 40 50 60 Solubility (mass) 3 ~ 5 4 7 5 6 6 5 Solubility of the antipode R. 1.72 ~ to 20 ° C, ratio ~ = 2.03 at 20 ° C.
. Coordinates of the point L. 6.05 δ mass, TL temperature. 55 ° C.
Evolution of TH OMO with excess enantiomeric (racemic mixture / (solvent + mixture racemic)) - 6.05 ~ = constant.
enantiomer 0 4 8 THOMO (° C) ~ 55 ~ 60 ~ 65 . Duration of the state of supersaturation of the solution L subjected to this kinetics. 120 minutes to an agitatian speed of 150 rpm.
. Crystallization time 115 minutes.

W ~ 9510 & 522 ~ 5 ~ ~~~~~ ~ l / IF ~ 9 ~ / ~ ~ ~ ~

. Duration of bearing at TB. 60 minutes . Speed of agitation. 200 rpm.
- results.
antipode mass ~ puret Soil compensation.

ur (o ti ue (- ~) 23 1 ) 1 0 889 (+) 90 7 2 010 2 0 931 (- 91 8 1 826 3 0 661 (+) 91 1 1 992 4 1 083 (-) 89 0 2 258 r 5 1 381 (~) 92 9 5 559 6 1 330 (-) 92 4 2 535 7 1 397 (- ~) 91 9 2 195 8 ~ l, 410 ~ (-) 93, 9 Average mass of pure antipode crystals 1913 g.
. Excess enantiomeric average Op568 g ~ either 8 ~ 6 °.
. Average optical purity. 917 °.
10 - - doubling the hr'i o ~
a) Characteristics nhy ~~ aue ~ dl ~ brode.
. Antipode melting temperature 92 ° C.
. Melting temperature of the mixture racemic. 70 ° C.

~ 95108522 '. p ~ ° ~~~ 9qI01107 Solubility of the antipode R. 4.4 ~ to 27 ° C, ratio ~, = 2.8 at 27 ° C.
. Coordinates of the point L. 12.5 ~ mass, TL temperature. 27 ° C.
15. Evolution of THOMO with 1st excess enantiomeric (racemic mixture / (solvent ~ - mixture racemic)) - 12.5 δ = constant.
enantiomer 0 2 4 12 5 85 7 90 ITHOI ~ IO (° C) '27, 0 I 27. 8 28 6 29 3 29 8 . Duration of the state of supersaturation of the solution L subjected to this kinetics <60 minutes for a stirring speed of 100 rpm.

W ~ 9510522 ~ ~ 519 . Crystallization time 60 minutes.
- Initial conditions.
. Initial enantiomeric excess. 6 °.
mass solvent mass ~ mass (+
~ ..
87.50 ~ 12.50 I 0.800 . Duration of the landing at Tg. 20 minutes . Stirring speed. 100 rpm crystallization begins, then 120 rpm at the end.
- Results.
Filtration is performed on a glass sintered IM ° 2 ~ the crystals are washed with diisopropyl ether.
antipode mass ~ puret Soil compensation.

ur (optiaue () 23 1 ) 1 1 637 (+) 89 2 107 2 1 740 (-) 96 2 2 260 3 1 916 + 96 7 2 364 5 1 703 (+) 93 3 2 353 6 1 856 (-) 96 2 2,387 7 1 932 (- ~) 96 2 403 8 1 649 (-) 93 3 ~ 2 39 B
9 1 615 + 93 2 2 17 Average mass of pure antipode crystals 18780 g.
. Average enantiomeric excess 0.890 g, 6 ~ 7 Average optical purity. 94D2 11- Duplication of sodium and ammonium double tartrate tetrahydrate.
in step (a), the initial mixture is next .
. solvent. 5.67 g of water, . racemic mixture .4.83 g, . antipode (+). 0.23 g, and, TL = 16.3 ° C, TB = 17.3 ° C, . duration of the plateau at Tg = 40 mn in step (b), the programming law of cooling from Tg to Tg is given by the values temperatures depending on the time below.

t mn 0 3 5 8 12 5 16 20 25 30 in step (c), in the assembly experimental used, the agitation is 150 rpm beginning and 170 rpm at the end of the crystallization;
in step (d), the crystal harvest is performed on sintered glass n ° 2;
in step (e), mixing is added racemic crushed and sieved at 250 ~ 1, and in addition to ~ compensation in solvent, we add a solution of ammonia to maintain a slight excess in this constituent, and.
TL = 16.3 ° C, TB = 17.3 ° C, . duration of the plateau at Tg = 40 mn - in step (f), the programming law of cooling from Tg to TF is given by the values Temperatures as a function of time below.

t mn 0 3 5 8 12 -5 16 20 25 30 in step (g), in the assembly experimental used. the agitation is 150 rpm beginning and 170 rpm at the end of the crystallization;
in step (h), the crystal harvest is performed on sintered glass n ° 2:
in step (i), mixing is added racemic crushed and sieved at 250 ~, the solvent offsets and add ammonia to maintain a slight excess in this component.
12-Duplication of 5-methyl-5-phenyl hydantoin.
in step (a), the initial mixture is the next .
. solvent. 15.704 g of 2-methoxyethanol, . racemic mixture. 9.296 g, . antipode (+). 0.229 g, and, TL = 37 ° C, ,. TB = 40 ° C, . duration of the plateau at Tg = 30 minutes;
- in step (b), the programming law of cooling from Tg to TF is given by the values Temperatures as a function of time below.

t mn) 0 12 22 30 38 46 in step (c), in the assembly experimental used, agitation is 100 rpm start and 150 rpm at the end of the crystallization;
~ - in step (d), the crystal harvest is performed on sintered glass n ° 3;
in step (e), mixing is added racemic, we carry out compensation in solvent, and.
. TL = 37 ° C, TB = 40 ° C, . duration of the plateau at Tg = 30 mn W09S / 0 $ S22 CA 02172519 2005-04-20 pCT / F ~ 41 $ 1 ~ 07 - in step (f), the programming law of cooling from Tg to Tg is given by the values Temperatures as a function of time below.

t mn 0 12 22 30 38 46 in step (g), in the assembly experimental used, agitation is 100 rpm start and 150 rpm at the end of the crystallization;
in step (h). the harvest of the crystals is 10 carried out on sintered glass n ° 3;
in step (i), mixing is added racemic et.an performs the compensations in solvent.
-15 13- Duplication of 5-meth ~ l-4 - (4-methyl ~ hen ~ l) -h ~ dantoï, ne.
in step (a), the initial mixing is the next .
20. solvent. 27.68 g of 2-methoxyethanol, . racemic mixture. 5.667 g, antipode (+). 0, 458 g, and, TL = 39 ° C, 25. TB = 41 ° C, . duration of the plateau at TH = 30 minutes;
- in step (b), the programming law of cooling from Tg to TF is given by the values Temperatures as a function of time below.

t mn 0 15 30 45 50 60 WO 95108522 CA 02172519 2005-04-20 PCT ~ FR94 ~ 01107 in step (c), in the assembly experimental used, the agitation is 150 rpm start and 200 rpm at the end of the crystallization;
in step (d), the crystal harvest is carried out on sintered glass n ° 3 ~
in step te), mixture is added racemic, solvent compensation is carried out.
and.
next .
TL = 39 ° C, . T8 = 41 ° C, . duration of the plateau at Tg = 30 mn - in step (f), the programming law of cooling from Tg to Tg is given by the values Temperatures as a function of time below.

t mn 0 15 30 45 50 60 in step (g), in the assembly experimental used, the agitation is 150 rpm start and 200 rpm at the end of the crystallization;
2p - in step (h), the crystal harvest is carried out on sintered glass n ° 3:
in step (i), mixing is added racemic and solvent compensation is carried out.
14-Duplication of 5-ethyl-5-phenyl hydantoin.
in step (a), the initial mixture is the . solvent. 27.666 g of 2-methoxyethanol, racemic mixture. 5, 666, ~ g, . antipode (+). 0.3877 g, and, TL = 41 ° C, W09S / OgSZ ~ 2. CA 02172519 2005-04-20 p [Z '/ ~ 94 / Q]] 07 TB ~ 94, 5 ° C.
. duration of the plateau at Tg = 30 minutes;
- in step (b), the programming law of cooling from Tg to Tg is given by the values Temperatures as a function of time below.

t mn 0 10 15 20 25 30 35 91 96 51 56 in step (c), in the assembly experimentally used, agitation is 200 rpm beginning and 275 rpm at the end of the crystallization;
in step (d), the crystal harvest is carried out on sintered glass n ° 3:
in step (e), mixing is added racemic, solvent compensation is carried out and.
TL = 91 ° C, TB = 49.5 ° C, . duration of the plateau at Tg = 30 mn - in step (f), the programming law of cooling from Tg to Tg is given by the values Temperatures as a function of time below.
T (C 94 5 91 39 37 35 33 31 29 27 25 23 t mn 0 10 15 20 25 30 35 41 46 51 56 in step (g), in the assembly experimentally used, agitation is 200 rpm beginning and 275 rpm at the end of the crystallization;
in step (h), the crystal harvest is effectuated on sintered glass n ° 3;
in step (i), mixing is added racemic and one performs. the compensation in solvent.

wo 95 ~ U85Z2 CA 02172519 2005-04-20 PCT / FR94 / 01107 15-Duplication of 5-methyl-5- (4-chlorophenyl) hydantoin.
in step (a), the initial mixture is the next .
. solvent. 95.7 g of 2-methoxyethanol, . racemic mixture. 6.166 g, . antipode (+). 0.430 g, and, . TL = 55 ° C, . TB = 57 ° C, . duration of the plateau at Tg = 60 minutes;
- in step (b), the programming law of ~ cooling of TB to Tg is given by the values temperatures as a function of time below.

t mn 0 32 S2 115 in step (c), in the assembly experimental used, the agitation is 150 rpm start and 200 rpm at the end of the crystallization;
in step (d), the crystal harvest is performed on sintered glass n ° 3;
in step (e), mixing is added racemic, solvent compensation is effected.
and TL = 55 ° C, . TB = 57 ° C, . duration of the plateau at Tg = 60 mn - in step (f), the programming law of cooling from Tg to Tg is given by the values Temperatures as a function of time below.
~ T (° C) 5 ~ 35 27 27 wo 9sasszZ 'CA 02172519 2005-04-20 pcrr ~ aroi ~ o ~

t (mn) 0 32, 52 '115 in step (g), in the assembly experimentally used, agitation is 200 rounds per minute at beginning and 275 rpm at the end of crystallization;
in step (h), the crystal harvest is performed on sintered glass n ° 3;
in step (i), mixing is added racemic and solvent compensation is carried out.

16-Duplication of threitol.
in step ~ (a), the initial mixture is the next .
. solvent. 87.5 g of ethanol blend 95 $ /
water 5%, . racemic mixture. 12.50 g, . antipode (+). 0.800 g, and, TL = 27 ° C, . TB = 27.5 ° C, . duration of the plateau at Tg = 20 minutes;
- in step (b), the programming law of cooling from Tg to Tg is given by the values Temperatures as a function of time below.

TC 27 5 26 8 26 8 23 23 19 19.
- _. . _. 3 3 9 ~
- _ _ _ ty) ~ ~ 1 ~ 5 ~ 11 ~ 15 22 ~~~
5 ~ ~

in step (c), in the assembly experimental used, agitation is 100 rpm beginning and 120 rpm at the end of the crystallization;
3d - in step (d), the crystal harvest is carried out on sintered glass n ° 2 followed by a washing with diisopropyl ether:

v ~ vy ~~ ua ~~~ CA 02172519 2005-04-20 PCflI ~ 1t941U11U7 in step (e), mixing is added racemic, we carry out compensation in solvent, and.
TL s 27 oCr - 5. TB = 27.5 ° C, . duration of the plateau at Tg = 20 mn in step (f), the programming law of the cooling from Tg to Tg is given by the values Temperatures as a function of time below.

t mn 0 1 5 5 11 15 22 60 in step (g), in the assembly experimental used, agitation is 100 rpm start and 120 rpm at the end of the crystallization;
in step (h), the crystal harvest is carried out on sintered glass n ° 2 followed by a washing with diisopropyl ether;
in step (i), mixing is added racemic and the compensation is carried out as a solvent.

Claims (8)

1. Process for the resolution of two optical enantiomers by preferential crystallization, characterized in that it includes the following steps:
a) a set composed of the racemic mixture of crystals in the form of a conglomerate, from the first enantiomer and solvent, including the figurative point E, defined by the variables concentration and temperature T5, is located in the two-phase domain of the first excess enantiomer, and is in equilibrium with its saturated solution, said temperature TB being the enantiomer-selective dissolution temperature in default;

b) a programming law of the two-phase mixing temperature cooling prepared in step (a), said programming law being such that the mother liquors retain a low supersaturation which favors the growth of the enantiomer present in the form of crystals, while prohibiting the spontaneous nucleation of the second enantiomer present in solution;

c) we adapt throughout the growth period crystal from step (b) a stirring speed slightly increasing with time so as to that it is at all times sufficiently slow to promote growth of the first enantiomer avoiding generating too much stricture forces important causing uncontrolled nucleation, and fast enough to achieve a suspension homogeneous and rapid renewal of the liqueur-mother around each crystallite of the first enantiomer;

d) the crystals of the first enantiomer are collected;

e) adding to the mother liquors resulting from the harvest carried out in step (d), the racemic mixture of crystals in the form of a conglomerate, and the new assembly at a temperature level TB during the time needed to reach equilibrium thermodynamics so that the figurative point E' be symmetric of E with respect to the plane of mixtures racemates of the system solvent, antipode (-), antipode (+), said point E' being located in the two-phase range of the second enantiomer in excess and in equilibrium with its saturated solution;
f) the same programming law of the cooling than in step (b), to the two-phase mixture prepared in step (e) containing the second enantiomer, so that the mother liquors keep a low supersaturation during crystallization in order to favor the growth of the enantiomer present in the form of crystals while prohibiting the spontaneous nucleation of the first enantiomer present in solution;
g) we adapt throughout the growth period crystal from step (f) a stirring speed slightly increasing with time so as to that it is, at all times, sufficiently slow to promote growth of the second enantiomer while avoiding generating forces of excessive necking causing nucleation uncontrolled, and fast enough to obtain a homogeneous suspension and rapid renewal of the mother liquor around each crystallite of the second enantiomer;
h) the crystals of the second enantiomer are collected;
i) adding to the mother liquors resulting from the crystalline harvest produced in step (h), the mixture racemate of crystals in the form of a conglomerate, for obtain a set whose composition is identical to that of the initial set E;
j) repeating steps (a), (b), (c), (d), (e), (f), (g), (h), and (i) to successively obtain the first then the second of the two enantiomers;
characterized in that in steps (b) and (f), the law of programming of cooling from temperature TB to TF adapted to the experimental setup, is defined as way:
- to obtain a low supersaturation during the entire duration of the crystallization of the enantiomer present in the form of crystals at the beginning of each cycle, this weak supersaturation causing growth and soft secondary nucleation;
- to reach at TF the maximum supersaturation of the other enantiomer without primary nucleation;
- to obtain a harvest in crystals at the stages (d) and (h) which, after addition of mixture racemate and compensation in steps (e) and (i), allows cyclicality of operations, TF
being the final temperature of the process of resolution of two enantiomers by crystallization;
characterized in that the programming law of the cooling is determined for its part from TL to TF
by cooling the XL concentration solution of TL + 1°C at TF, TF being lower than TL - (T HOMO - TL), in order to to obtain a stable saturated solution without nucleation primary while allowing for a double harvest of excess initial enantiomeric, and in that said law of cooling schedule is determined for its part of TB to TL by extrapolation of this same law determined from TL + 1°C to TF, TL being the temperature homogenization of the racemic mixture alone without any enantiomeric excess, XL being the concentration in racemic mixture and T HOMO being the lowest temperature bass homogenization;
and characterized in that in steps (b) and (f), the thermality accompanying a deposition of the first enantiomer and the second enantiomer is integrated into the programming law of the temperature cooling. 2. Method according to claim 1, characterized in that at step (a) the choice of solvent(s) and the range of working temperature are defined so as to have simultaneously:
- antipodes which form a conglomerate and whose the eventual racemate is metastable in the range of working temperature;
liquors that are sufficiently concentrated but of low viscosity and low vapor pressure;
absence of solvolysis and racemization;
- stability of the solvates if they are present at equilibrium and if they are enantiomers divisible. 3. Method according to any one of claims 1 and 2, characterized in that in steps (a) and (e), the temperature TB is higher than the homogenization temperature TL of the quantity of racemic mixture contained in the initial suspension, in that, from the curve of variation of T HOMO as a function of enantiomeric excess and for a constant concentration of racemic mixture XL, said temperature TB is defined so that the mass fine crystals of the first enantiomer of steps (a) and (i) and the second enantiomer of step (e), in equilibrium with their saturated solution, represents a maximum of 50% of the expected harvest. 4. Method according to claim 3, characterized in that the mass of fine crystals of the first enantiomer of steps (a) and (i) and the second enantiomer of step (e), in equilibrium with their saturated solution, represents between about 25 and 40% of the expected harvest. 5. Method according to any one of claims 1 to 4, characterized in that in steps (e) and (i), one carries out solvent compensations. 6. Method according to any one of claims 1 to 5, characterized in that in steps (a), (e) and (i), the ends crystals of the racemic mixture in the form of a conglomerate which are added, have undergone before being introduced, a pre-treatment accelerating the dissolution step. 7. Method according to claim 6, characterized in that the preliminary treatment is crushing and sieving, treatment with ultrasound waves, or a partial freeze-drying. 8. Method according to any one of claims 1 to 7, characterized in that in steps (a), (e) and (i), raising the speed of agitation relative to steps (c) and (g).

g) Process, according to claim 5, for duplication of the two optical enantiomers of a double sodium tartrate and ammonium tetrahydrate, characterized in that:

in step (a), the initial mixture is the next.

. solvent: 5.67g of water, . racemic mixture: 4.83g, . antipodal (+):0.23g, and, . TL = 16.3°C, . TB = 17.3°C, . Dwell time at Tg =40 min - in step (b), the programming law of the cooling from TB to TF is given by the values temperatures versus time below:

- at step (c), in the assembly used, the agitation is 150 revolutions/min at start and 170 rpm at the end of crystallization;
- in step (d), the harvesting of the crystals is carried out on fritted glass n°2;
- in step (e), mix is added racemate crushed and sieved to 250 .MU., and in addition to compensations in solvent, a solution is added of ammonia to maintain a slight excess in this constituent, and .
. TL = 16.3°C, . TB = 17.3°C, . Dwell time at TB = 40 min - in step (f), the programming law of the cooling from TB to TF is given by the values temperatures as a function of time below.

- in step (g), in assembly used, the agitation is 150 revolutions/min at start and 170 rpm at the end of crystallization;
- in step (h), the harvesting of the crystals is carried out on fritted glass n°2;
- in step (i), mixture is added racemate ground and sieved at 250μ, the solvent compensations and adding ammonia to maintain a slight excess in this component.
10) Process, according to claim 5, for duplication of the two optical enantiomers of a 5-methyl-5-phenyl-hydantoin, characterized in that:
- in step (a), the initial mixture is the next:
. solvent: 15.704 g of 2-methoxy-ethanol, . racemic mixture: 4.296 g, . antipodal (+): 0.229 g, and, . TL = 37°C, . TB = 40°C, . duration of the plateau at TB = 30 min;
- in step (b), the programming law of the cooling from TB to TF is given by the values temperatures as a function of time below:
T (°C) 40 35 30 25 20 20 t (min) 0 12 22 30 38 46 - at step (c), in the assembly used, the agitation is 100 revolutions/min at start and 150 rpm at the end of crystallization;
- in step (d), the harvesting of the crystals is carried out on sintered glass no3:
- in step (e), mix is added racemic, solvent compensations are carried out and . TL = 37°C, . TB = 40°C, . Dwell time at TB = 30 min - in step (f), the programming law of the cooling from TB to TF is given by the values temperatures versus time below:

T (°C) 40 35 30 25 20 20 t (min)~ 0 12 22 30 38 46 - at step (g), in assembly used, the agitation is 100 revolutions/min at start and 150 rpm at the end of crystallization;
- in step (h), the harvesting of the crystals is performed on #3 sintered glass;
- in step (i), mixture is added racemate and solvent compensations are carried out 11) Process, according to claim 5, for duplication of the two optical enantiomers of a 5-methyl-5-(4-methylphenyl)-hydantoin, characterized in that:
- in step (a), the initial mixture is the next:
. solvent: 27.68 g of 2-methoxy-ethanol, . racemic mixture: 5.667 g, . antipodal (+): 0.458 g, and, . TL = 39°C, . TB=41°C, . duration of the plateau at TB = 30 min;
- in step (b), the programming law of the cooling from TB to TF is given by the values temperatures versus time below:

Temperature (°C) 41 31 31 21 21 14 t (min)~ 0 15 30 45 50 60 - at step (c), in the assembly used, the agitation is 150 revolutions/min at start and 200 rpm at the end of crystallization;
- in step (d), the harvesting of the crystals is carried out on sintered glass no3:
- in step (e), add mixture racemic, solvent compensations are carried out, and:
. TL = 39°C, . TB = 41°C, . Dwell time at TB = 30 min - in step (f), the programming law of the cooling from TB to TF is given by the values temperatures versus time below:

Temperature (°C) 41 31 31 21 21 14 t (min)~ 0 15 30 45 50 60 - at step (g), in assembly used, the agitation is 150 revolutions/min, at start and 200 rpm at the end of crystallization;
- in step (h), the harvesting of the crystals is performed on #3 sintered glass;
- in step (i), mixture is added racemate and solvent compensations are carried out 12) Processes according to claim 5, for duplication of the two optical enantiomers of a 5-ethyl-5-phenyl-hydantoin, characterized in that:
- in step (a), the initial mixture is the next:
. solvent: 27.666 g of 2-methoxy-ethanol, . racemic mixture: 5.666 g, . antipodal (+): 0.3877 g, and, TL = 41°C, . TB = 44.5°C, . duration of the plateau at TB = 30 min;
- in step (b), the programming law of the cooling from TB to TF is given by the values temperatures versus time below:
Temperature (°C) 44.5 41 39 37 35 33 31 29 27 25 23 rpm 0 10 15 20 25 30 35 41 46 51 56 - at step (c), in the assembly used, the agitation is 200 revolutions/min at start and 275 rpm at the end of crystallization;
- in step (d), the harvesting of the crystals is performed on #3 sintered glass;
- in step (e), mix is added racemic, solvent compensation is carried out, and:
. TL = 41°C, . TB = 44.5°C, . Dwell time at TB = 30 min - in step (f), the programming law of the cooling from TB to TF is given by the values temperatures versus time below:

Temperature (°C) 44.5 41 39 37 35 33 31 29 27 25 23 rpm 0 10 15 20 25 30 35 41 46 51 56 - at step (g), in assembly used, the agitation is 200 revolutions/min at start and 275 rpm at the end of crystallization;
- in step (h), the harvesting of the crystals is performed on #3 sintered glass;
- in step (i), mixture is added racemate and the solvent compensations are carried out.

13) Process, according to claim 5, for duplication of the two optical enantiomers of a 5-methyl-5-(4-chlorophenyl)-hydantoin, characterized in that:
- in step (a), the initial mixture is the next :
. solvent: 95.7 g of 2-methoxy-ethanol, . racemic mixture: 6, 1-66 g, . antipodal (+): 0.430 g, and, . TL = 55°C, . TB = 57°C, . Dwell time at TB = 60 min:
- in step (b), the programming law of the cooling from TB to Tp is given by the values temperatures-versus-weather below:

- at step (c), in the 1st assembly used, the agitation is 150 revolutions/min at start and 200 rpm at the end of crystallization;
- in step (d), the harvesting of the crystals is performed on sintered glass n°3;
- in step (e), we add the mixture racemic, solvent compensation is carried out and :
. TL = 55°C, . TB = 57°C, . Dwell time at TB = 60 min - in step (f), the programming law of the cooling from Tg to Tg is given by the values temperatures as a function of time below:
t (min) 0 32 52 115 - at step (g), in assembly used, the agitation is 200 revolutions/min at start and 275 rpm at the end of crystallization;
- in step (h), the harvesting of the crystals is performed on #3 sintered glass;
- in step (i), mixture is added racemate and the solvent compensations are carried out.
14) Process, according to claim 5, for duplication of the two optical enantiomers of a threitol, characterized in that:
- in step (a), the initial mixture is the next:
. solvent: 87.5 g of 95% ethanol /
water 5%, . racemic mixture: 12.50 g, . antipodal (+): 0.800 g, and, . TL = 27°C, . TB = 27.5°C, . duration of the plateau at TB = 20 min;
- in step (b), the programming law of the cooling from TB to TF is given by the values temperatures versus time below:
T (°C) 27.5 26.8 26.8 2.3 23.3 19.4 19.4 rpm 0 1.5 5 11 15 22 60 - at step (c), in the assembly used, the agitation is 100 revolutions/min at start and 120 rpm at the end of crystallization;
- in step (d), the harvesting of the crystals is carried out on fritted glass no2 followed by washing with diisopropyl ether;

- in step (e), mix is added racemic, solvent compensation is carried out and:
. TL = 27°C, . TB = 27.5°C, . Dwell time at TB = 20 min - in step (f), the programming law of the cooling from TB to TF is given by the values temperatures versus time below:
Temperature (°C) 27.5 26.8 26.8 23.3 23.3 19.4 19.4 rpm (min) 0 1.5 5 11 15 22 60 - at step (g), in assembly used, the agitation is 100 revolutions/min at start and 120 rpm at the end of crystallization;
- in step (h), the harvesting of the crystals is carried out on fritted glass no2 followed by washing with diisopropyl ether;
- in step (i), mixture is added racemate and solvent compensations are carried out