U.S. patent application number 12/737613 was filed with the patent office on 2011-07-28 for process of isolating enantiomer component from enantiomer mixtures by particle-size-controlled crystallization.
Invention is credited to Sabine Gottburg-Reininger, Guntram Koller, David Maillard, Ewgenij Wakaresko.
Application Number | 20110184169 12/737613 |
Document ID | / |
Family ID | 41412444 |
Filed Date | 2011-07-28 |
United States Patent
Application |
20110184169 |
Kind Code |
A1 |
Maillard; David ; et
al. |
July 28, 2011 |
PROCESS OF ISOLATING ENANTIOMER COMPONENT FROM ENANTIOMER MIXTURES
BY PARTICLE-SIZE-CONTROLLED CRYSTALLIZATION
Abstract
The present invention discloses a process for isolating
enantiomer components from a mixture of enantiomers through
particle-size-controlled crystallization, comprising the steps of:
(a) forming a solution of a mixture of enantiomers (R) and (S) in a
solvent in the absence of any further additives or agents; (b)
seeding the solution of step (a) simultaneously or consecutively
with seed crystals of enantiomer (R) and with seed crystals of
enantiomer (S), wherein the seed crystals of enantiomer (R) differ
in size and/or in quantity from the seed crystals of enantiomer (S)
to allow separation of the crystals composed of a mixture enriched
with enantiomer (R) from the crystals composed of a mixture
enriched with enantiomer (S); (c) inducing simultaneous
crystallization of enantiomer (R) and enantiomer (S); and (d)
isolating crystals composed of a mixture enriched with enantiomer
(R) from crystals composed of a mixture enriched with enantiomer
(S) through size separation of the crystals, preferably through
sieving, melting or sedimentation, in particular through
sieving.
Inventors: |
Maillard; David; (Darmstadt,
DE) ; Koller; Guntram; (Klein-umstadt, DE) ;
Wakaresko; Ewgenij; (Aschaffenburg, DE) ;
Gottburg-Reininger; Sabine; (Darmstadt, DE) |
Family ID: |
41412444 |
Appl. No.: |
12/737613 |
Filed: |
July 28, 2009 |
PCT Filed: |
July 28, 2009 |
PCT NO: |
PCT/EP2009/059769 |
371 Date: |
April 15, 2011 |
Current U.S.
Class: |
544/205 ;
568/810; 568/811 |
Current CPC
Class: |
C07C 29/78 20130101;
C07B 57/00 20130101; C07C 29/78 20130101; C07D 251/10 20130101;
C07B 2200/07 20130101; C07C 33/26 20130101; C07D 251/08
20130101 |
Class at
Publication: |
544/205 ;
568/810; 568/811 |
International
Class: |
C07D 251/18 20060101
C07D251/18; C07C 29/78 20060101 C07C029/78; C07C 33/26 20060101
C07C033/26 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 29, 2008 |
EP |
08013586.6 |
Claims
1. A process for isolating enantiomer components from a mixture of
enantiomers through particle-size-controlled crystallization,
comprising the steps of: (a) forming a solution of a mixture of
enantiomers (R) and (S) in a solvent in the absence of any further
additives or agents; (b) seeding the solution of step (a)
simultaneously or consecutively with seed crystals of enantiomer
(R) and with seed crystals of enantiomer (S), wherein the seed
crystals of enantiomer (R) differ in size and/or in quantity from
the seed crystals of enantiomer (S) to allow separation of the
crystals composed of a mixture enriched with enantiomer (R) from
the crystals composed of a mixture enriched with enantiomer (S);
(c) inducing simultaneous crystallization of enantiomer (R) and
enantiomer (S); and (d) isolating crystals composed of a mixture
enriched with enantiomer (R) from crystals composed of a mixture
enriched with enantiomer (S) through size separation of the
crystals, preferably through sieving, melting or sedimentation, in
particular through sieving.
2. The process as claimed in claim 1, further comprising the steps
of: (e) dissolving the isolated crystals composed of a mixture
enriched with the enantiomer (R) in a solvent in the absence of any
further additives or agents and, separately therefrom, dissolving
the isolated crystals composed of a mixture enriched with the
enantiomer (S) in a solvent in the absence of any further additives
or agents; (f) seeding the solution of enantiomer (R) with seed
crystals of enantiomer (R) and, separately therefrom, seeding the
solution of enantiomer (S) with seed crystals of enantiomer (S);
(g) inducing crystallization of enantiomer (R) and, separately
therefrom, inducing crystallization of enantiomer (S); (h)
isolating the crystals composed of a mixture further enriched with
enantiomer (R) and, separately therefrom, isolating the crystals
composed of a mixture further enriched with enantiomer (S).
3. The process as claimed in claim 1 or 2, wherein the mixture of
enantiomers (R) and (S) is a racemate of enantiomers (R) and (S),
preferably forming a conglomerate.
4. The process as claimed in claim 1, wherein the "mother liquor"
solution remaining after step (d) and/or step (h) is recycled as
solution in step (a) and/or the solution in step (a) is replenished
prior to step (b) and the entire process is repeated.
5. The process as claimed in claim 1, wherein the solvent in step
(a) and/or step (e) is selected from the group consisting of:
water, organic solvents, aliphatic or aromatic hydrocarbons,
alcohols, ethanol, methanol, propanol, isopropanol, n-butanol,
tert-butanol, esters, ketones, acetone or methylethylketon or
mixtures thereof, and preferable is ethanol.
6. The process as claimed in claim 1, wherein the mixture of
enantiomers (R) and (S) is a mixture of
((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylam-
ine (1) and
((S)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylam-
ine (2), preferably a racemate of
((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylam-
ine (1) and
((S)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylam-
ine (2), such that: ##STR00004##
7. The process as claimed in claim 1, wherein the mixture of
enantiomers (R) and (S) is a mixture of
((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylam-
ine and
((S)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dim-
ethylamine, and wherein said enantiomers are present as
hydrochloride salts
8.
((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethy-
lamine hydrochloride obtainable by the process as claimed in claim
1.
9. The process as claimed in claim 1, wherein the mixture of
enantiomers (R) and (S) is a mixture of (R,R)-hydrobenzoin (3) and
(S,S)-hydrobenzoin (4), preferably a racemate of (3) and (4), such
that: ##STR00005##
10. (R,R)-Hydrobenzoin obtainable by the process as claimed in
claim 9.
11. (S,S)-Hydrobenzoin obtainable by the process as claimed in
claim 9.
Description
TECHNICAL FIELD
[0001] The present invention relates to a process for isolating
enantiomer components from a mixture of enantiomers through
particle-size-controlled crystallization.
PRIOR ART
[0002] Isolation of enantiomers from a mixture of enantiomers is
typically difficult because the enantiomers generally have
identical chemical and physical properties, such as melting and
boiling points, or other such properties typically used for
separation. Moreover, they tend to crystallize as racemic crystals
rather than as a conglomerate consisting of a mixture of pure
enantiomer crystals which would be separable by preferential
crystallization (also called resolution by entrainment). Thus, a
common way today to obtain enantiomers is not through isolating
individual enantiomers from a mixture, but rather through
asymmetric synthesis of the enantiomer. The efficiency of such a
synthesis is strongly depending on the chemical structure of the
enantiomer and can suffer from lack of selectivity.
[0003] Techniques for isolating enantiomers in use today include
various embodiments of chromatography, such as simulated moving bed
chromatography (SMB) for example. Chromatography-based methods,
however, to date are not capable of isolating enantiomers and/or
cannot isolate some enantiomers economically in commercial
quantities.
[0004] Various crystallization methods have been proposed for
separating enantiomers from a mixture, including preferential
crystallization, co-crystallization and emulsion-crystallization.
Relevant prior art documents are as follows:
[0005] DE 2135717 describes a process for the purification of a
component of a fluid mixture selected from aromatic hydrocarbons
and impurities by crystallization in a cooling agent as well as a
crystallization apparatus. The process does not involve the
separation of enantiomers and comprises the production of an
emulsion.
[0006] GB 796 343 discloses a process of purifying sulphuric acid
by fractional crystallization. The process does not involve the
separation of enantiomers and comprises the production of a
dispersion/emulsion.
[0007] GB 865 311 relates to a process for continued resolution of
racemic amino acids, i.e. D- and L-glutamic acid. First, the one
enantiomer is crystallized and separated from the mother liquor.
Then, the antipode isomer is crystallized and removed from the
solution.
[0008] GB 1 455 710 is directed to the resolution of optically
active isomers by selective seeding and crystallization. Again,
first the one enantiomer is crystallized and separated from the
mother liquor. Then, the antipode isomer is crystallized and
removed from the solution.
[0009] EP 0 548 028 describes the purification of organic compounds
from an aggregate mixture by crystallization by means of a
three-phase system. The process comprises the production of a
dispersion/emulsion.
[0010] EP 0 838 448 discloses a process for the separation of a
mixture of enantiomers by means of at least one resolving agent.
The process requires the presence of at least one resolving
agent.
[0011] WO 96/06080 relates to a process for the separation of the
enantiomers of a bicyclic lactam. First, the one enantiomer is
crystallized and separated from the mother liquor. Then, the
antipode isomer is crystallized and removed from the solution.
[0012] WO 97/32644 is directed to a process of separating a desired
substance from an aggregate mixture, in which process a three-phase
dispersion is formed. The process comprises the production of a
dispersion/emulsion.
[0013] WO 99/12623 describes a separation process for separating a
desired substance from an aggregate mixture in an emulsion. The
emulsion further contains one or more surface active agents, such
as solubilizers, surfactants and/or dispersants. The process
comprises the production of a dispersion/emulsion.
[0014] WO 00/53283 discloses a process for isolating enantiomer
components from a mixture of enantiomers through co-crystallization
by means of specific chiral or achiral co-crystallization agents.
The process requires the presence of co-crystallization agents and
requires that the enantiomers crystallize as a conglomerate.
[0015] WO 00/54865 relates to a process of purifying substances
through emulsion crystallization with recycling (recovery) of
emulsion. The process does not involve the separation of
enantiomers and comprises the production of a
dispersion/emulsion.
[0016] WO 04/089917 is directed to a process for resolving amines
derived from dihydro-1,3,5-triazines from the corresponding racemic
mixture. The process makes use of chiral HPLC in supercritical
phase and chiral reagents, such as chiral acids.
[0017] The citation of any reference in this application is not an
admission that the reference is prior art to this application.
DESCRIPTION OF THE INVENTION
[0018] The present invention has the object to provide a novel
process of isolating enantiomer components from an enantiomer
mixture, preferably a racemate, which does not comprise the
production of a dispersion or emulsion and/or does not require the
presence of a resolving agent, surface active agent (surfactant)
and/or co-crystallization agent.
[0019] The object of the present invention has surprisingly been
solved in one aspect by providing a process for isolating
enantiomer components from a mixture of enantiomers through
particle-size-controlled crystallization, comprising the steps of:
[0020] (a) forming a solution of a mixture of enantiomers (R) and
(S) in a solvent in the absence of any further additives or agents;
[0021] (b) seeding the solution of step (a) simultaneously or
consecutively with seed crystals of enantiomer (R) and with seed
crystals of enantiomer (S), wherein the seed crystals of enantiomer
(R) differ in size and/or in quantity from the seed crystals of
enantiomer (S) to allow separation of the crystals composed of a
mixture enriched with enantiomer (R) from the crystals composed of
a mixture enriched with enantiomer (S); [0022] (c) inducing
simultaneous crystallization of enantiomer (R) and enantiomer (S);
and [0023] (d) isolating crystals composed of a mixture enriched
with enantiomer (R) from crystals composed of a mixture enriched
with enantiomer (S) through size separation of the crystals,
preferably through sieving, melting or sedimentation, in particular
through sieving.
[0024] The terms "particle-size-controlled crystallization" and
"isolating crystals composed of a mixture enriched with enantiomer
(R) from crystals composed of a mixture enriched with enantiomer
(S) through size separation of the crystals" in the meaning of the
present invention refers to a crystallization-based separation of
enantiomers with concomitant control of the particle size of the
enantiomer crystals to be finally separated. To achieve this goal,
(seed) crystals of enantiomer (R) need to differ sufficiently in
size from (seed) crystals of enantiomer (S) thereby allowing
separation by a simple size separation process, such as sieving
using a sieve with a defined pore size which lets the fine crystals
of the mixture of the enriched one enantiomer pass through and
withholds the larger crystals of the mixture of the enriched other
enantiomer by choice of the particle diameter of the respective
seed crystals the necessary sufficient difference in size between
both enantiomer crystal types can be adjusted.
[0025] The term "solvent" in the meaning of the present invention
refers to pure solvents or solvent mixtures, such as water, organic
solvents, aliphatic or aromatic hydrocarbons, alcohols, ethanol,
methanol, propanol, isopropanol, n-butanol, tert-butanol, esters,
ketones, acetone, or methylethylketon or mixtures thereof.
Preferred solvent is ethanol. The choice of the solvent is
depending on the relative solubilities of the enantiomers to be
separated in this solvent.
[0026] The term "in the absence of any further additives or agents"
in connection with "solvent" in the meaning of the present
invention refers to solvents or solvent mixtures as defined herein,
which do not contain one or more additional substances not being
the enantiomers to be separated. Such not contained additional
substances are, for instance, solvent additives, solubilizers,
surfactants and dispersants as disclosed in WO 99/12623 and WO
97/32644, and resolving agents as disclosed in EP 0 838 448.
[0027] The induction of (simultaneous) crystallization of
enantiomer (R) and enantiomer (S) can be achieved by standard
techniques known in the art, for instance, by supersaturation,
whereby an excess amount of enantiomer (R) and enantiomer (S) is
dissolved by means of ultrasound or employing elevated
temperatures. Or supersaturation is achieved by cooling down the
solution containing both enantiomers. The supersaturated solution
is seeded simultaneously or consecutively with seed crystals of
enantiomer (R) and with seed crystals of enantiomer (S), wherein
the seed crystals of enantiomer (R) differ in size and/or in
quantity from the seed crystals of enantiomer (S). The use of
controlled cooling conditions by the following crystallization step
allows mainly crystal growth of the seed crystals and avoids
spontaneous nucleation. As the end-temperature of the
crystallization process is reached, the suspension is simply
filtered on a filter ("Nutsche" or centrifuge). The isolated
crystals are dried and finally sieved in order to separate the fine
crystals composed of a mixture enriched with the one enantiomer
from the larger crystals composed of a mixture enriched with the
other enantiomer.
[0028] In another aspect, the object of the present invention has
surprisingly been solved by providing above described process
further comprising the steps of: [0029] (e) dissolving the isolated
crystals composed of a mixture enriched with the enantiomer (R) in
a solvent in the absence of any further additives or agents and,
separately therefrom, dissolving the isolated crystals composed of
a mixture enriched with the enantiomer (S) in a solvent in the
absence of any further additives or agents; [0030] (f) seeding the
solution enriched with enantiomer (R) with seed crystals of
enantiomer (R) and, separately therefrom, seeding the solution
enriched with enantiomer (S) with seed crystals of enantiomer (S);
[0031] (g) inducing crystallization of enantiomer (R) and,
separately therefrom, inducing crystallization of enantiomer (S);
[0032] (h) isolating the crystals composed of a mixture further
enriched with enantiomer (R) and, separately therefrom, isolating
the crystals composed of a mixture further enriched with enantiomer
(S).
[0033] In a preferred embodiment, the herein disclosed processes
are provided, wherein the mixture of enantiomers (R) and (S) is a
racemate of enantiomers (R) and (S), preferably forming a
conglomerate.
[0034] In another preferred embodiment, the herein disclosed
processes and preferred embodiments are provided, wherein the
"mother liquor" solution remaining after step (d) and/or step (h)
is recycled as solution in step (a) and/or the solution in step (a)
is replenished prior to step (b) and the entire process is
repeated. This recycling results in significant improvements in
yield.
[0035] In a further preferred embodiment, the herein disclosed
processes and preferred embodiments are provided, wherein the
solvent in step (a) and/or step (e) is selected from the group
consisting of: water, organic solvents, aliphatic or aromatic
hydrocarbons, alcohols, ethanol, methanol, propanol, isopropanol,
n-butanol, tert-butanol, esters, ketones, acetone or
methylethylketon or mixtures thereof. Preferred is ethanol.
[0036] In yet another preferred embodiment, the herein disclosed
processes and preferred embodiments are provided, wherein the
mixture of enantiomers (R) and (S) is a mixture of
((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylam-
ine (1) and
((S)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylam-
ine (2), preferably a racemate of
((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylam-
ine (1) and
((S)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylam-
ine (2).
##STR00001##
[0037] In yet another preferred embodiment, the herein disclosed
processes and preferred embodiments are provided, wherein
((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylam-
ine and
((S)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dim-
ethylamine are present as hydrochloride salts.
Above two enantiomers co-exists with their different mesomers as
depicted below. These mesomers are intended to be comprised by the
scope of the present invention.
##STR00002##
[0038] In another aspect, the object of the present invention has
surprisingly been solved by providing
((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylam-
ine hydrochloride obtainable by the herein disclosed processes and
preferred embodiments.
[0039] The triazin derivative compounds were named using AutoNom
2000 software (ISIS.TM./Draw 2.5; MDL).
[0040] In yet another preferred embodiment, the herein disclosed
processes and preferred embodiments are provided, wherein the
mixture of enantiomers (R) and (S) is a mixture of
(1R,2R)-1,2-diphenyl-ethane-1,2-diol usually called
(R,R)-hydrobenzoin (3) and (1S,2S)-1,2-diphenyl-ethane-1,2-diol
usually called (S,S)-hydrobenzoin (4), preferably a racemate of (3)
and (4).
##STR00003##
[0041] In another aspect, the object of the present invention has
surprisingly been solved by providing (R,R)-Hydrobenzoin and/or
(S,S)-Hydrobenzoin separately obtainable by the herein disclosed
processes and preferred embodiments.
[0042] The contents of all cited references are hereby incorporated
by reference in their entirety. The invention is explained in more
detail by means of the following examples without, however, being
restricted thereto.
EXAMPLES
Example 1
Isolation of enantiomers of
(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]-triazin-2-yl)-dimethylamine
hydrochloride
First Step--Particle-Size-Controlled-Crystallization:
[0043] 1.1 kg
((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylam-
ine
hydrochloride/((S)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-
-2-yl)-dimethylamine hydrochloride racemate is dissolved in 5.5 kg
Ethanol and the resulting solution is carefully stirred with a
metallic propeller (angle-45.degree., 150 rpm) and cooled down to
55.degree. C. for seeding. 70 g
((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimet-
hylamine hydrochloride crystals (sieve-size >300 .mu.m) are
added, and it is then isothermally stirred for 30 min before
seeding with 15 g
((S)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]-triazin-2-yl)-dimethyla-
mine hydrochloride crystals (sieve-size <59 .mu.m) and further
30 min stirring at 55.degree. C.
[0044] The mixture is finally carefully cooled down with a slow
programmed ramp:
-0.07K/min until 45.degree. C., fast heating up to 50.degree. C.
and 30 min stirring at 50.degree. C. -0.07K/min until 30.degree.
C., fast heating up to 35.degree. C. and 30 min stirring at
35.degree. C. -0.07K/min until 10.degree. C., fast heating up to
15.degree. C. and 30 min stirring at 15.degree. C. -0.07K/min until
-15.degree. C.
[0045] As soon as the final temperature of -15.degree. C. is
reached, the complete suspension is filtered on a suction filter,
the resulting filter cake is washed with 550 g cold (5-7.degree.
C.) ethanol and finally dried 2 days under vacuum (.about.200 mbar)
at room temperature in a dessicator.
[0046] 1011.6 g dried crystals are isolated corresponding to a
yield of 92% (seed-crystals not considered).
[0047] The dried crystals are subsequently sieved (Table 1):
TABLE-US-00001 TABLE 1 Sieve values m Yield HPLC contents [%]
Fraction [.mu.m] [g] [%] R-enantiomer S-enantiomer 07EW075.1 --
1005.76 100 -- -- 07EW075.2 >900 10.24 1.0 65.1 34.8 07EW075.3
500-900 131.95 13.1 87.1 12.7 07EW075.4 200-500 180.91 18.0 83.4
16.3 07EW075.5 100-200 117.43 11.7 50.7 48.9 07EW075.6 <100
565.23 56.2 34.2 65.5
Second Step--Thermodynamically Controlled Crystallization of
((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylam-
ine hydrochloride-enriched Fraction:
[0048] The fractions 07EW075.3 and 07EW075.4 (Table 1) are mixed
affording 312.4 g crystals with the following composition
(((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]-triazin-2-yl)-dimethyl-
amine hydrochloride 85.2%,
((S)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]-triazin-2-yl)-dimethyla-
mine hydrochloride 14.8%). These crystals are dissolved in 3755 g
ethanol at 55.degree. C. under stirring (200 rpm). The resulting
solution is cooled down to 48.degree. C. and seeded with 13.7 g
((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylam-
ine hydrochloride crystals.
[0049] The mixture is first stirred 1 h at 46.degree. C. and then
cooled down to 0.degree. C. with a controlled ramp of -0.2K/min.
The resulting suspension is directly filtered at 0.degree. C. on a
suction filter, the cake washed with 150 g cold ethanol
(5-7.degree. C.) and finally dried under vacuum in a dessicator at
room temperature.
[0050] This affords 206.4 g
((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylam-
ine hydrochloride crystals with an ee=93.8% (composition:
((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]-triazin-2-yl)-dimethyla-
mine hydrochloride 96.6%,
((S)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylam-
ine hydrochloride 3.1%).
[0051] The yield of the second step is 66.1% (seed-crystals not
considered).
[0052] The same process is carried out with the
((S)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]-triazin-2-yl)-dimethyla-
mine hydrochloride-enriched fraction in a similar fashion in order
to increase the process yield.
Example 2
Isolation of Enantiomers of Hydroxybenzoic
First Step--Particle-Size-Controlled-Crystallization:
[0053] 20 g (R,R)-hydrobenzoin/(S,S)-hydrobenzoin racemate is
dissolved in 80 g Ethanol and the resulting solution is carefully
stirred with a teflon propeller (angle .about.45.degree., 180 rpm)
and cooled down to 34.4.degree. C. for seeding. 1 g
(S,S)-hydrobenzoin crystals (sieve-size >500 .mu.m) are added,
the mixture is then isothermally stirred for 1 h before seeding
with 0.2 g (R,R)-hydrobenzoin crystals (sieve-size <59 .mu.m)
and further 1 h stirring at 34.degree. C.
[0054] The mixture is finally carefully cooled down with a slow
programmed ramp:
-0.05K/min until 25.5.degree. C., fast heating up to 27.4.degree.
C. and 30 min stirring at 27.4.degree. C. -0.05K/min until
15.3.degree. C., fast heating up to 17.7.degree. C. and 30 min
stirring at 17.7.degree. C. -0.05K/min until 5.7.degree. C., fast
heating up to 7.8.degree. C. and 30 min stirring at 7.8.degree. C.
-0.05K/min until -13.6.degree. C.
[0055] As soon as the final temperature of -13.6.degree. C. is
reached, the complete suspension is filtered on a suction filter,
the resulting filter cake is washed with 5 g cold (-12.degree. C.)
ethanol and finally dried 24 h under vacuum (-200 mbar) at room
temperature in a dessicator.
[0056] 16.9 g dried crystals are isolated corresponding to a yield
of 84.5% (seed-crystals not considered).
[0057] The dried crystals are subsequently sieved (Table 2):
TABLE-US-00002 TABLE 2 Sieve values m Yield HPLC contents [%]
Fraction [.mu.m] [g] [%] R-enantiomer S-enantiomer -- 16.62 100 --
-- 09EW047.1 >500 6.90 41.5 91.15 8.85 09EW047.2 300-500 3.68
22.1 53.30 46.70 09EW047.3 200-300 3.67 22.1 22.41 77.59 09EW047.4
100-200 1.89 11.4 12.63 87.37 09EW047.5 <100 0.48 2.9 6.43
93.57
Second Step--Thermodynamically Controlled Crystallization of
(S,S)-hydrobenzoin Enriched Fraction:
[0058] The fraction 09EW047.1 (Table 2) composed of 6.6 g crystals
with the following composition ((S,S)-hydrobenzoin 91.2%,
(R,R)-hydrobenzoin 8.8%), is dissolved in 26.4 g ethanol at
63.degree. C. under stirring (220 rpm). The resulting solution is
cooled down to 52.degree. C. and seeded with 0.05 g
(S,S)-hydrobenzoin crystals. The mixture is first stirred 1 h at
52.degree. C. and then cooled down to 0.degree. C. with a
controlled ramp of -0.2K/min. The resulting suspension is directly
filtered at 0.degree. C. on a suction filter, the cake washed with
5 g cold ethanol (0.degree. C.) and finally dried under vacuum in a
dessicator at room temperature for 20 h. This affords 4.7 g
(S,S)-hydrobenzoin crystals with an ee=99.8% (composition:
(S,S)-hydrobenzoin 99.9%, (R,R)-hydrobenzoin 0.1%) corresponding to
an overall yield of 47% for (S,S)-hydrobenzoin over the two-steps
process (seed-crystals not considered). With consideration of
seed-crystals, the process offers an overall yield of 42.5% for
(S,S)-hydrobenzoin (ee=99.8%).
Third Step--Thermodynamically Controlled Crystallization of
(R,R)-Hydrobenzoin-Enriched Fraction:
[0059] The fractions 09EW047.3, 09EW047.4 and 09EW047.5 (Table 2)
are mixed affording 4.65 g crystals with the following composition
((S,S)-hydrobenzoin 18.4%, (R,R)-hydrobenzoin 81.6%). These
crystals are dissolved in 18.6 g ethanol at 64.degree. C. under
stirring (220 rpm). The resulting solution is cooled down to
54.5.degree. C. and seeded with 0.05 g (R,R)-hydrobenzoin crystals.
The mixture is first stirred 1 h at 54.degree. C. and then cooled
down to -1.degree. C. with a controlled ramp of -0.2K/min. The
resulting suspension is directly filtered at -1.degree. C. on a
suction filter, the cake washed with 5 g cold ethanol (0.degree.
C.) and finally dried under vacuum in a dessicator at room
temperature for 20 h.
[0060] This affords 3.0 g (R,R)-hydrobenzoin crystals with an
ee=97.4% (composition: (S,S)-hydrobenzoin 1.3%, (R,R)-hydrobenzoin
98.7%) corresponding to an overall yield of 30% for
(R,R)-hydrobenzoin over the two-steps process (seed-crystals not
considered). With consideration of seed-crystals, the process
offers an overall yield of 29.3% for (R,R)-hydrobenzoin
(ee=97.4%).
[0061] Remark: The mother liquors of all three steps and the almost
racemic sieve-fraction 09EW047.2 of the first step could be
recycled and reused together with fresh racemate in a new
particle-size-controlled-crystallisation cycle in order to reduce
losses and consequently increase the process yield.
* * * * *