U.S. patent application number 11/675408 was filed with the patent office on 2007-08-30 for resolution of alpha-(phenoxy) phenylacetic acid derivatives.
This patent application is currently assigned to Metabolex, Inc.. Invention is credited to Edward D. Daugs.
Application Number | 20070203243 11/675408 |
Document ID | / |
Family ID | 40635606 |
Filed Date | 2007-08-30 |
United States Patent
Application |
20070203243 |
Kind Code |
A1 |
Daugs; Edward D. |
August 30, 2007 |
RESOLUTION OF ALPHA-(PHENOXY) PHENYLACETIC ACID DERIVATIVES
Abstract
The present invention provides a method for producing an
enantiomerically enriched .alpha.-(phenoxy)phenylactic acid
compound of the formula: ##STR1## from its enantiomeric mixture,
where R.sup.1 is alkyl or haloalkyl and X is halide.
Inventors: |
Daugs; Edward D.; (Midland,
MI) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
Metabolex, Inc.
Hayward
CA
|
Family ID: |
40635606 |
Appl. No.: |
11/675408 |
Filed: |
February 15, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10656567 |
Sep 4, 2003 |
7199259 |
|
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11675408 |
Feb 15, 2007 |
|
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60608927 |
Jun 20, 2003 |
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Current U.S.
Class: |
514/571 ;
562/401 |
Current CPC
Class: |
C07C 59/68 20130101;
C07C 51/487 20130101; C07C 51/487 20130101 |
Class at
Publication: |
514/571 ;
562/401 |
International
Class: |
A61K 31/192 20060101
A61K031/192 |
Claims
1. A method for resolving an enantiomerically enriched
.alpha.-(phenoxy)phenylactic acid compound of the formula:
##STR12## wherein R.sup.1 is alkyl or haloalkyl, and X is halide;
from an enantiomeric mixture of the .alpha.-(phenoxy)phenylactic
acid compound comprising a first and a second enantiomers, said
method comprising: (a) contacting the enantiomeric mixture of the
.alpha.-(phenoxy)phenylactic acid compound with less than 0.5 molar
equivalents of an enantiomerically enriched chiral amine compound
with respect to the .alpha.-(phenoxy)phenylactic acid compound and
(b) separating the solid acid-base salt of the first enantiomer
from the second enantiomer of the .alpha.-(phenoxy)phenylactic acid
compound.
2. The method of claim 24, wherein said step (i) of producing the
crystallization solution comprising the solid enantiomerically
enriched acid-base salt of the first enantiomer comprises: (i1)
heating the solution mixture to a temperature above the nucleation
temperature of the first enantiomer; and (i2) lowering the solution
mixture temperature to a temperature at or below the nucleation
temperature of the first enantiomer to produce the solid acid-base
salt of the first enantiomer.
3. The method of claim 2, wherein said step (ii) of separating the
solid acid-base salt of the first enantiomer is conducted at a
temperature near or above a saturation temperature of an acid-base
salt of the second enantiomer.
4. The method of claim 1 further comprising recovering the chiral
amine compound by removing the chiral amine compound from the
separated solid acid-base salt of the first enantiomer.
5. The method of claim 4, wherein the enantiomerically enriched
chiral amine compound used in producing the acid-base salt of said
step (a) comprises the recovered chiral amine compound.
6. The method of claim 1 further comprising racemizing at least a
portion of the second enantiomer in the separated solution mixture
by contacting the second enantiomer with a base.
7. The method of claim 6, wherein the enantiomeric mixture of the
.alpha.-(phenoxy)phenylactic acid compound used in said step (a)
comprises a racemized .alpha.-(phenoxy)phenylactic acid
compound.
8. The method of claim 1, wherein the chiral amine compound is of
the formula: ##STR13## wherein each of R.sup.2 and R.sup.3 is
independently hydrogen or alkyl; or R.sup.2 and R.sup.3 together
with atoms to which they are attached to form a heterocyclic ring
moiety; R.sup.4 is hydrogen or alkyl; each of R.sup.5 and R.sup.6
is independently hydrogen or alkyl, or one of R.sup.5 or R.sup.6 is
an amine protecting group; and Ar is aryl.
9. The method of claim 1, wherein the .alpha.-(phenoxy)phenylactic
acid is an enantiomeric mixture of
4-chloro-.alpha.-(3-trifluoromethylphenoxy)phenylactic acid, said
method comprising: (a) producing a crystallization solution mixture
comprising an enantiomerically enriched acid-base salt of
(-)-4-chloro-.alpha.-(3-trifluoromethylphenoxy)phenylactic acid by
contacting the enantiomeric mixture of
4-chloro-.alpha.-(3-trifluoromethylphenoxy)phenylactic acid with
less than 0.5 molar equivalent of an enantiomerically enriched
(1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol in about 4 grams
of an alcoholic solvent per gram of
(-)-4-chloro-.alpha.-(3-trifluoromethylphenoxy)phenylactic acid;
(b) separating the enantiomerically enriched acid-base salt from
the solution mixture which is enriched with
(+)-4-chloro-.alpha.-(3-trifluoromethylphenoxy)phenylactic acid;
and (c) removing (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol
from the acid-base salt to produce enantiomerically enriched
(-)-4-chloro-.alpha.-(3-trifluoromethyl-phenoxy)phenylactic
acid.
10. The method of claim 9, wherein the alcoholic solvent is
isopropanol.
11. The method of claim 10, wherein about 0.47 molar equivalent or
less of (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol is used
to form the acid-base salt.
12. The method of claim 11, wherein said step (a) of producing a
solution comprising an enantiomerically enriched acid-base salt of
(-)-4-chloro-.alpha.-(3-trifluoromethyl-phenoxy)phenylactic acid
comprises heating the solution mixture to a temperature at or above
a nucleation temperature of the (-)-acid-base salt.
13. The method of claim 12, wherein said step (b) of separating the
enantiomerically enriched acid-base salt is performed at a
temperature near or above a saturation temperature of an acid-base
salt of the (+)-enantiomer.
14. The method of claim 10, wherein the enantiomerically enriched
(1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol comprises at
least a portion of
(1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol that is removed
from the acid-base salt of said step (c).
15. The method of claim 10 further comprising racemizing at least a
portion of
(+)-4-chloro-.alpha.-(3-trifluoromethylphenoxy)phenylactic acid
obtained in said step (b).
16. The method of claim 15, wherein the enantiomeric mixture of
4-chloro-.alpha.-(3-trifluoromethylphenoxy)phenylactic acid
comprises at least a portion of
(+)-4-chloro-.alpha.-(3-trifluoromethylphenoxy)phenylactic acid
that is racemized.
17. An acid-base salt derived from the method of claim 1.
18. The acid-base salt of claim 17, wherein the
.alpha.-(phenoxy)phenylactic acid compound and the chiral amine
compound are enantiomerically enriched.
19. The acid-base salt of claim 18, wherein the
.alpha.-(phenoxy)phenylactic acid compound is
(-)-4-chloro-.alpha.-(3-trifluoromethylphenoxy)phenylactic
acid.
20. The acid-base salt of claim 18, wherein the chiral amine
compound is (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol.
21. The acid-base salt of claim 19 having an enantiomeric excess of
at least about 95%.
22. (canceled)
23. (canceled)
24. The method of claim 1, wherein said step (a) comprises: (i)
producing a crystallization solution mixture comprising a solid
enantiomerically enriched acid-base salt of a first enantiomer by
contacting the enantiomeric mixture of the
.alpha.-(phenoxy)phenylactic acid compound with the
enantiomerically enriched chiral amine compound under conditions
sufficient to produce the ratio of the amount of first enantiomer
to the amount of the second enantiomer in the salt is at least
about 3:1, wherein the total amount of enantiomerically enriched
chiral amine compound used is less than 0.5 molar equivalents with
respect to the .alpha.-(phenoxy)phenylactic acid compound and (b)
separating the solid acid-base salt of the first enantiomer from
the solution mixture at a temperature where the concentration of an
acid-base salt of the second enantiomer of the
.alpha.-(phenoxy)phenylactic acid compound is near or below its
saturation point.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to an enantioselective
resolution process for the separation of
.alpha.-(phenoxy)phenylactic acids from its enantiomeric
mixture.
BACKGROUND OF THE INVENTION
[0002] Esters and amides derivatives of
.alpha.-(phenoxy)phenylactic acids, such as halofenate, are chiral
compounds and are useful in ameliorating a variety of physiological
conditions, including conditions associated with blood lipid
deposition, e.g., Type II diabetes and hyperlipidema. See, for
example, U.S. Pat. Nos. 3,517,050 and 6,262,118.
.alpha.-(phenoxy)phenylactic acids contain a single chiral center
at an asymmetrically substituted carbon atom alpha to the carbonyl
carbon atom, and therefore exist in two enantiomeric forms.
[0003] Cytochrome P450 2C9 is an enzyme known to play a significant
role in the metabolism of specific drugs. It is known to one
skilled in the art that changes in drug metabolism mediated by
inhibition of cytochrome P450 enzymes has a high potential to
precipitate significant adverse effects in patients. It is also
known that a racemic .alpha.-(phenoxy)phenylactic acid, e.g.,
halofenic acid, inhibits cytochrome P450 2C9. See, for example,
U.S. Pat. No. 6,262,118. Thus, administration of a racemic
.alpha.-(phenoxy)phenyl-acetic acid, such as halofenic acid or its
derivatives, can lead to a variety of drug interaction problems
with other drugs, including anticoagulants, anti-inflammatory
agents and other drugs that are metabolized by this enzyme. It has
been found that the (-)-enantiomer of halofenic acid is about
twenty-fold less active in its ability to inhibit cytochrome P450
2C9 compared to the (+)-enantiomer. Id. Thus, it is desirable to
administer the (-)-enantiomer of halofenic acid or its derivatives
which is substantially free of the (+)-enantiomer to reduce the
possibility of drug interactions.
[0004] Therefore, there is a need for an efficient process for
producing a product enriched in a desired enantiomer of a
.alpha.-(phenoxy)phenylacidic acid, e.g., (-)-halofenic acid.
SUMMARY OF THE INVENTION
[0005] One aspect of the present invention provides a method for
producing an enantiomerically enriched .alpha.-(phenoxy)phenylactic
acid compound of the formula: ##STR2## wherein [0006] R.sup.1 is
alkyl or haloalkyl, and [0007] X is halide; from an enantiomeric
mixture of the .alpha.-(phenoxy)phenylactic acid compound
comprising a first and a second enantiomers. In one particular
embodiment, the enantiomeric mixture is a racemic mixture.
[0008] Methods of the present invention includes: [0009] (a)
producing a solution comprising a solid enantiomerically enriched
acid-base salt of the first enantiomer by contacting the
enantiomeric mixture of the .alpha.-(phenoxy)phenylactic acid
compound with less than 0.5 molar equivalents of an
enantiomerically enriched chiral amine compound under conditions
sufficient to produce the ratio of the amount of free first
enantiomer to the amount of the free second enantiomer in the
solution is about 1 to 3; and [0010] (b) separating the solid
acid-base salt of the first enantiomer from the solution at a
temperature where the concentration of an acid-base salt of the
second enantiomer of the .alpha.-(phenoxy)phenylactic acid compound
is near or below its saturation point.
[0011] At least a portion of the second enantiomer can be converted
to the first enantiomer, e.g., racemized, by contacting the second
enantiomer with a base. The resulting enantiomeric mixture can then
be recycled and subjected to a similar enantiomeric enrichment
process to increase the yield of the first enantiomer acid-base
salt.
[0012] In one particular embodiment, the chiral amine compound is
of the formula: ##STR3## wherein [0013] each of R.sup.2 and R.sup.3
is independently hydrogen or alkyl; or R.sup.2 and R.sup.3 together
with atoms to which they are attached to form a heterocyclic ring
moiety; [0014] R.sup.4 is hydrogen or alkyl; [0015] each of R.sup.5
and R.sup.6 is independently hydrogen or alkyl, or one of R.sup.5
or R.sup.6 is an amine protecting group; and [0016] Ar is aryl.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 is a graph showing the solubility profiles of (-)-
and (+)-CPTA/CAF D-Base salts in 2-propanol.
[0018] FIG. 2 shows results of a process for resolving a racemic
mixture of CPTA using CAF D-Base under a variety of crystallization
conditions.
[0019] FIG. 3 is a graph showing the solubility of (-)- and
(+)-CPTA/CAF D-Base salts in pure isopropanol and a solution
comprising a mixture of isopropanol and CPTA (11%).
[0020] FIG. 4 is a graph showing the composition of a mixture with
a various amount of each components.
[0021] FIG. 5 is a graph showing a (-/+)-salt saturation profile
for crystallization and heating.
[0022] FIG. 6 is a table showing comparison of the model prediction
to experimental results for entry 4 of FIG. 2.
[0023] FIG. 7 is a graph showing the amount of (+)-salt formation
as a function of the amount of CAF D-Base added.
[0024] FIG. 8 is a graphic representation of experimental data for
the resolution shown in entry 11 of FIG. 2.
[0025] FIG. 9 shows the actual and calculated amount of CPTA in
mother liquor and a graphic comparison of a calculated percentage
of (+)-CPTA salt with the experimental data.
[0026] FIG. 10A shows tables showing experimental data and a
solubility model calculation for FIG. 7 (i.e., entry 13 of FIG.
2).
[0027] FIG. 10B is a table showing experimental data and a
solubility model calculation for entry 4 of FIG. 2 at 28.3.degree.
C.
[0028] FIG. 11 is a graph showing solubility of racemic CPTA at
various temperatures in 1,2-dichloroethane.
[0029] FIG. 12 is a graph showing solubility of racemic CPTA at
various temperatures in heptane.
[0030] FIG. 13 is a table of results in Example 24 showing yield of
CPTA resolution using CAF D-Base under variety of crystallization
conditions.
[0031] FIG. 14 shows a cooling profiles for the resolution
crystallization of various entries in FIG. 2.
[0032] FIG. 15 is a table showing the amount of (-)-halofenate
yield from (-)-CPTA salt in Example 26.
[0033] FIG. 16 is a graph showing solubility of racemic CPTA sodium
salt at various temperatures in water.
[0034] FIG. 17 is a graph showing CPTA racemization profile at
various pH during hydrolysis of (-)-halofenate.
[0035] FIG. 18 is a table showing the results of CAF D-Base
recovery at various pH as described in Example 30.
[0036] FIG. 19 is experimental results of solubility determination
of racemic CPTA in 1,2-dichloroethane and heptane as determined in
Example 33.
[0037] FIG. 20 is experimental results of solubility determination
of racemic CPTA sodium salt in water as determined in Example
41.
[0038] FIG. 21 is experimental results of basic hydrolysis of
(+)-halofenate as determined in Example 42.
DETAILED DESCRIPTION
I. Definitions
[0039] "Alkyl" refers to straight or branched aliphatic
hydrocarbons chain groups of one to ten carbon atoms, preferably
one to six carbon atoms, and more preferably one to four carbon
atoms. Exemplary alkyl groups include, but are not limited to,
methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl, and the
like.
[0040] "Aryl" refers to a monovalent monocyclic or bicyclic
aromatic hydrocarbon moiety of 6 to 10 carbon ring atoms. Unless
stated or indicated otherwise, an aryl group can be substituted
with one or more substitutents, preferably one, two, or three
substitutents, and more preferably one or two substitutents
selected from alkyl, haloalkyl, nitro, and halo. More specifically
the term aryl includes, but is not limited to, phenyl, 1-naphthyl,
and 2-naphthyl, and the like, each of which is optionally
substituted with one or more substitutent(s) discussed above.
[0041] "CAF D base" refers to chloramphenicol D base, i.e.,
D-threo-(-)-2-amino-1-(nitrophenyl)-1,3-propanediol.
[0042] "Chiral" or "chiral center" refers to a carbon atom having
four different substitutents. However, the ultimate criterion of
chirality is non-superimposability of mirror images.
[0043] The terms "CPTA" and "halofenic acid" are used
interchangeably herein and refer to
(4-chlorophenyl)(3-trifluoromethylphenoxy)acetic acid.
[0044] "Enantiomeric mixture" means a chiral compound having a
mixture of enantiomers, including a racemic mixture. Preferably,
enantiomeric mixture refers to a chiral compound having a
substantially equal amounts of each enantiomers. More preferably,
enantiomeric mixture refers to a racemic mixture where each
enantiomer is present in an equal amount.
[0045] "Enantiomerically enriched" refers to a composition where
one enantiomer is present in a higher amount than prior to being
subjected to a separation process.
[0046] "Enantiomeric excess" or "% ee" refers to the amount of
difference between the first enantiomer and the second enantiomer.
Enantiomeric excess is defined by the equation: % ee=(% of the
first enantiomer)-(% of the second enantiomer). Thus, if a
composition comprises 98% of the first enantiomer and 2% of the
second enantiomer, the enantiomeric excess of the first enantiomer
is 98%-2% or 96%.
[0047] The terms "halide" and "halo" are used interchangeably
herein and refer to halogen, which includes F, Cl, Br, and I, as
well as pseudohalides, such as --CN and --SCN.
[0048] "Haloalkyl" refers to alkyl group as defined herein in which
one or more hydrogen atoms have been replaced with halogens,
including perhaloalkyls, such as trifluoromethyl.
[0049] "Halofenate" refers to 2-acetamidoethyl
4-chlorophenyl-(3-trifluoromethyl-phenoxy)acetate (i.e.,
4-chloro-.alpha.-(3-(trifluoromethyl)phenoxy)benzeneacetic acid,
2-(acetylamino)ethyl ester or
(4-chlorophenyl)(3-trifluoromethylphenoxy)acetic acid),
2-(acetylamino)ethyl ester).
[0050] "Heteroalkyl" means a branched or unbranched acyclic
saturated alkyl moiety containing one or more heteroatoms or one or
more heteroatom-containing substitutents, where the heteroatom is
O, N, or S. Exemplary heteroatom-containing substitutents include
.dbd.O, --OR.sup.a, --C(.dbd.O)R.sup.a, --NR.sup.aR.sup.b,
--N(R.sup.a)C(.dbd.O)R.sup.b, --C(.dbd.O)NR.sup.aR.sup.b and
--S(O).sub.nR.sup.a (where n is an integer from 0 to 2). Each of
R.sup.a and R.sup.b is independently hydrogen, alkyl, haloalkyl,
aryl, or aralkyl. Representative examples of heteroalkyl include,
for example, N-acetyl 2-aminoethyl (i.e.,
--CH.sub.2CH.sub.2NHC(.dbd.O)CH.sub.3).
[0051] The terms "heterocyclyl" and "heterocyclic ring" are used
interchangeably and refer to a non-aromatic cyclic moiety of 3 to 8
ring atoms in which one, two, or three ring atoms are heteroatoms
selected from N, O, or S(O).sub.n (where n is an integer from 0 to
2), the remaining ring atoms being C, where one or two C atoms may
optionally be replaced by a carbonyl group. Unless stated or
indicated otherwise, the heterocyclyl ring can be optionally
substituted independently with one, two, or three substitutents
selected from halogen, alkyl, aryl, hydroxy, amino, or alkoxy. More
specifically the term heterocyclyl includes, but is not limited to,
1,3-dioxane and its derivatives, and the like.
[0052] "Leaving group" has the meaning conventionally associated
with it in synthetic organic chemistry, i.e., an atom or a group
capable of being displaced by a nucleophile and includes halo (such
as chloro, bromo, and iodo), alkanesulfonyloxy, arenesulfonyloxy,
alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, mesyloxy,
tosyloxy, trifluoromethanesulfonyloxy, aryloxy (e.g.,
2,4-dinitrophenoxy), methoxy, N,O-dimethylhydroxylamino, and the
like.
[0053] The term "metal" includes Group I, II, and transition metals
as well as main group metals, such as B and Si.
[0054] "Optical purity" refers to the amount of a particular
enantiomer present in the composition. For example, if a
composition comprises 98% of the first enantiomer and 2% of the
second enantiomer, the optical purity of the first enantiomer is
98%.
[0055] Unless otherwise stated, the term "phenyl" refers to an
optionally substituted phenyl group. Suitable phenyl substitutents
are same as those described in the definition of "aryl."Similarly,
the term "phenoxy" refers to a moiety of the formula --OAr.sup.a,
wherein Ar.sup.a is phenyl as defined herein. Thus, the term
".alpha.-(phenoxy)phenylactic acid" refers to acetic acid that is
substituted on the 2-position with an optionally substituted phenyl
and optionally substituted phenoxy moieties.
[0056] "Protecting group" refers to a moiety that when attached to
a reactive group in a molecule masks, reduces or prevents that
reactivity. Examples of protecting groups can be found in T. W.
Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis,
3.sup.rd edition, John Wiley & Sons, New York, 1999, and
Harrison and Harrison et al., Compendium of Synthetic Organic
Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996), which are
incorporated herein by reference in their entirety. Representative
hydroxy protecting groups include acyl groups, benzyl and trityl
ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl
ethers. Representative amino protecting groups include, formyl,
acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ),
tert-butoxycarbonyl (Boc), trimethyl silyl (TMS),
2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted
trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl
(FMOC), nitro-veratryloxycarbonyl (NVOC), and the like.
[0057] The term "rate" when referring to a formation of a salt
refers to kinetic and/or thermodynamic rates.
[0058] As used herein, the term "treating", "contacting" or
"reacting" refers to adding or mixing two or more reagents under
appropriate conditions to produce the indicated and/or the desired
product. It should be appreciated that the reaction which produces
the indicated and/or the desired product may not necessarily result
directly from the combination of two reagents which were initially
added, i.e., there may be one or more intermediates which are
produced in the mixture which ultimately leads to the formation of
the indicated and/or the desired product.
[0059] As used herein, the terms "those defined above" and "those
defined herein" when referring to a variable incorporates by
reference the broad definition of the variable as well as
preferred, more preferred and most preferred definitions, if
any.
[0060] Many organic compounds exist in optically active forms,
i.e., they have the ability to rotate the plane of plane-polarized
light. In describing an optically active compound, the prefixes R
and S are used to denote the absolute configuration of the molecule
about its chiral center(s). The prefixes "d" and "1" or (+) and (-)
are employed to designate the sign of rotation of plane-polarized
light by the compound, with (-) or (1) meaning that the compound is
"levorotatory" and with (+) or (d) is meaning that the compound is
"dextrorotatory". There is no correlation between nomenclature for
the absolute stereochemistry and for the rotation of an enantiomer.
For a given chemical structure, these compounds, called
"stereoisomers," are identical except that they are mirror images
of one another. A specific stereoisomer can also be referred to as
an "enantiomer," and a mixture of such isomers is often called an
"enantiomeric" or "racemic" mixture. See, e.g., Streitwiesser, A.
& Heathcock, C. H., INTRODUCTION TO ORGANIC CHEMISTRY, 2.sup.nd
Edition, Chapter 7 (MacMillan Publishing Co., U.S.A. 1981).
[0061] The terms "substantially free of its (+)-stereoisomer,"
"substantially free of its (+)-enantiomer," are used
interchangeably herein and mean that the compositions contain a
substantially greater proportion of the (-)-isomer in relation to
the (+)-isomer. In a preferred embodiment, the term "substantially
free of its (+) stereoisomer" means that the composition is at
least 90% by weight of the (-)-isomer and 10% by weight or less of
the (+)-isomer. In a more preferred embodiment, the term
"substantially free of its (+)-stereoisomer" means that the
composition contains at least 99% by weight of the (-)-isomer and
1% by weight or less of the (+)-isomer. In the most preferred
embodiment, the term "substantially free of its (+)-stereoisomer"
means that the composition contains greater than 99% by weight of
the (-)-isomer. These percentages are based upon the total amount
of isomers in the composition.
II. Introduction
[0062] While chiral synthesis has made an extensive progress in
recent years, resolution of racemates still remains the method of
choice in industrial process for preparation of optically active,
i.e., chiral, compounds. Typically, a chiral compound is
synthesized in a racemic form and the final product is resolved to
yield an enantiomerically enriched compound.
[0063] This process of resolving the final product is particularly
useful in a large scale preparation of pharmaceutically active
chiral compounds. Although enantiomers of a chiral compound have
exact same chemical bonds, the spatial orientation of atoms in
enantiomers is different. Thus, one enantiomer of a chiral drug
often exerts desired activity with a significantly less
side-effect(s) than the other enantiomer. While such relationship
between chirality of an optically active drug and its
side-effect(s) has been known for sometime, many chiral drugs are
still administered in a racemic form.
[0064] Diastereomeric crystallization is widely used on industrial
scale. The theoretical once-through yield of a resolution via
diastereomer crystallization is 50 percent. Typically, however,
more than one re-crystallization process is necessary in order to
produce a composition that is of a sufficient optical purity.
[0065] The present invention provides a method for enantiomerically
enriching an enantiomeric mixture, preferably a racemic mixture, of
.alpha.-(phenoxy)phenylactic acid compound, e.g., halofenic acid.
Preferably, methods of the present invention provides a solid
acid-base salt of the (-)-enantiomer of
.alpha.-(phenoxy)phenylactic acid compound. In this manner, the
(-)-enantiomer can be readily separated from the solution.
[0066] The carboxylic acid group of the enantiomerically enriched
.alpha.-(phenoxy)phenylactic acid can then be activated by a
carboxylic acid activation group to produce an activated
.alpha.-(phenoxy)phenylactic acid, which can be reacted with an
alcohol, an amine, a thiol, or other nucleophilic compounds to
produce an enantiomerically enriched .alpha.-(phenoxy)phenylactic
acid esters, amides, thioesters, or other derivatives,
respectively. Thus, enantiomerically enriched
.alpha.-(phenoxy)phenylactic acid compounds produced using methods
of the present invention are useful in producing
.alpha.-(phenoxy)phenylactic acid derivatives such as those
disclosed in U.S. Pat. No. 3,517,050. In particular, methods of the
present invention are useful in producing (-)-halofenate.
III. Enantioselective Crystallization
[0067] As noted above, most enantioselective crystallization
processes require more than one re-crystallization process in order
to produce a composition that is of a sufficient optical purity.
However, present inventors have found that under certain conditions
disclosed herein, .alpha.-(phenoxy)phenylactic acid compound of a
sufficient optical purity can be produced by a single
crystallization process. Thus, in one aspect, methods of the
present invention are based on the surprising and unexpected
discovery by the present inventors that an enantiomeric mixture of
a .alpha.-(phenoxy)phenylactic acid compound can be
enantiomerically enriched using a chiral amine compound. In
particular, methods of the present invention provide a desired
enantiomer of the .alpha.-(phenoxy)phenylactic acid compound in
optical purity of at least about 90%, preferably at least about
95%, more preferably at least about 97%, and most preferably at
least about 98%.
[0068] In one embodiment, methods of the present invention provide
enantiomeric enrichment of an enantiomeric mixture, preferably a
racemic mixture, of a .alpha.-(phenoxy)phenylactic acid compound of
the formula: ##STR4## wherein R.sup.1 is alkyl or haloalkyl, and X
is halide. The process generally involves forming a solid
enantiomerically enriched acid-base salt of the
.alpha.-(phenoxy)phenylactic acid compound using a chiral amine
compound.
[0069] In particular, methods of the present invention are directed
to the resolution of .alpha.-(phenoxy)phenylacetate acid, e.g.,
halofenic acid (where R.sup.1 is CF.sub.3 and X is C1), of the
formula: ##STR5## wherein R.sup.1 is alkyl or haloalkyl, and X is
halide.
[0070] In one particular embodiment, methods of the present
invention are directed to the resolution of
.alpha.-(phenoxy)phenylacetate acid of Formula I or, preferably of
Formula II, where X is chloro.
[0071] Yet in another embodiment, methods of the present invention
are directed to the resolution of .alpha.-(phenoxy)phenylactic acid
of Formula I or, preferably, Formula II, where R.sup.1 is
haloalkyl, preferably trifluoromethyl.
[0072] In one particular embodiment, .alpha.-(phenoxy)phenylactic
acid is crystallized using a chiral base. A wide variety of chiral
bases can be used, including those disclosed in the Examples
section below. Preferably, the chiral base used results in a solid
acid-base salt of the (-)-enantiomer of
.alpha.-(phenoxy)phenylactic acid. In this manner, the
(-)-enantiomer is readily separated from the solution, for example,
by filtration. In one particular embodiment, the chiral base is an
amine compound of the formula: ##STR6## wherein each of R.sup.2 and
R.sup.3 is independently hydrogen, alkyl or a hydroxy protecting
group; or R.sup.2 and R.sup.3 together with atoms to which they are
attached to form a heterocyclic ring moiety; R.sup.4 is hydrogen or
alkyl; each of R.sup.5 and R.sup.6 is independently hydrogen or
alkyl, or one of R.sup.5 or R.sup.6 is an amine protecting group;
and Ar is aryl.
[0073] In one particular embodiment, R.sup.2 and R.sup.3 together
along with oxygen atoms to which they are attached to form
1,3-dioxane, a substituted 1,3-dioxane (e.g., dialkyl substituted
1,3-dioxane, such as 5,5-dimethyl-1,3-dioxane), or a derivative
thereof.
[0074] In another embodiment, R.sup.2 and R.sup.3 are hydrogen.
[0075] Yet in another embodiment, R.sup.4 is hydrogen.
[0076] In still another embodiment, Ar is a substituted aryl. A
particularly preferred Ar moiety is optionally substituted phenyl.
An especially preferred Ar moiety is 4-nitrophenyl.
[0077] Still further, combinations of the preferred groups
described above will form other preferred embodiments. For example,
one particularly preferred chiral base is an amine compound of
Formula III above, wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 are hydrogen; and Ar is 4-nitrophenyl. And a particularly
preferred .alpha.-(phenoxy)phenylactic acid compound is of Formula
II above, wherein R.sup.1 is trifluoromethyl and X is chloro. In
this manner, a wide variety of preferred chiral bases and
.alpha.-(phenoxy)phenylactic acid compounds are embodied within the
present invention.
[0078] The present inventors have found that the amount of chiral
base used in crystallization of the .alpha.-(phenoxy)phenylactic
acid has a significant effect on the optical purity of the
enantiomeric enrichment. For example, when a chiral amine compound
of the formula: ##STR7## (wherein R.sup.2, R.sup.3, R.sup.4 and Ar
are those defined herein) is used in crystallization of the
.alpha.-(phenoxy)phenylactic acid compound, higher % ee obtained by
using the chiral amine compound in an amount less than 0.5 molar
equivalent, preferably about 0.48 molar equivalent or less, more
preferably about 0.47 molar equivalent or less, and most preferably
about 0.45 molar equivalent or less. It should be recognized that
the chiral amine compound itself should be of a sufficient
enantiomeric purity in order to yield a highly enantiomerically
enriched .alpha.-(phenoxy)phenylactic acid derivatives.
[0079] The crystallization is typically conducted in a solvent that
allows a different solubility of salts that are formed between two
enantiomers of the .alpha.-(phenoxy)phenylactic acid and the chiral
amine. In this manner, one of the diastereomeric salt precipitates
out of the solution preferentially. Suitable crystallization
solvents include protic solvents, such as alcohols. A particularly
preferred crystallization solvent is isopropyl alcohol.
[0080] The yield of enantiomerically enriched
.alpha.-(phenoxy)phenylactic acid also depends on, among others,
the amount of crystallization solvent used. For example, if a large
quantity of crystallization solvent is used, the mixture becomes
too dilute and the solid formation is reduced. If the amount of
crystallization solvent used is too small, the solution will be
supersaturated with the undesired diastereomeric salt which may
lead to crystallization of the undesired diastereomeric salt,
thereby reducing the optical purity of a desired enantiomer. Thus,
when isopropanol is used as the crystallization solvent, the amount
of crystallization solvent used is preferably from about 2 grams to
about 6 grams per one gram of the .alpha.-(phenoxy)phenylactic acid
compound, more preferably from about 3 grams to about 5 grams,
still more preferably from about 3.5 grams to about 4.5 grams, and
most preferably about 4 grams.
[0081] In one embodiment, the crystallization process involves
heating the crystallization solution mixture to a temperature above
the nucleation temperature of both enantiomers to dissolve
substantially all of both enantiomers. For example, the
crystallization solution is heated to a temperature in the range of
from about 60.degree. C. to the boiling point of the solution,
preferably from about 70.degree. C. to about 80.degree. C. More
preferably, the crystallization solution is heated to about
75.degree. C. The solution can be heated prior to and/or after the
chiral amine compound is added. Heating is carried out until the
solid materials are substantially completely dissolved, which
typically ranges from about 0.5 to about 16 hours, preferably from
about 1 to about 8 hours.
[0082] The crystallization solution is then cooled until it is at
or below the nucleation temperature of the first diastereomeric
salt, e.g., salt of (-)-enantiomer of the
.alpha.-(phenoxy)-phenylactic acid, but preferably above the
nucleation temperature of the second diastereomeric salt, e.g.,
salt of (+)-enantiomer of the .alpha.-(phenoxy)phenylactic acid.
This allows formation of a solid acid-base salt of the first
enantiomer with the chiral amine compound. Without being bound by
any theory, it is believed that the use of a chiral amine compound
results in formation of an acid-base salt with one of the
enantiomer at a significantly faster rate than formation of an
acid-base salt of the other enantiomer. This rate may be due to
kinetic and/or thermodynamic rate difference between the two
enantiomers. As with a typical compound, the solubility profile of
the .alpha.-(phenoxy)phenylactic acid compound of the present
invention has a higher solubility at a higher temperature.
Therefore, by cooling the crystallization solution to just above
the nucleation temperature of the second diastereomeric salt
affords a higher recovery yield of the solid first diastereomeric
salt.
[0083] After the slurry is formed, the crystallization solution can
be further cooled until the temperature of the solution is near or
above the saturation point of the second diastereomeric salt. This
prevents formation of a diastereomeric solid acid-base salt from
the second enantiomer while increasing the formation of the
diastereomeric solid acid-base salt of the first enantiomer.
[0084] The rate of cooling the crystallization solution may affect
the optical purity of the solid acid-base salt that is formed. For
example, if the crystallization solution is cooled too fast, the
undesirable enantiomer may get trapped within the lattice of the
solid acid-base salt of the desired enantiomer. However, a too slow
cooling rate increases the production time and cost. Therefore, the
crystallization solution should be cooled at a rate which minimizes
the loss of optical impurity but at a rate sufficient to be
economical. Typically, the crystallization solution cooling rate is
from about 0.05.degree. C./min to about 1.degree. C./min,
preferably from about 0.1.degree. C./min to about 0.7.degree.
C./min, and more preferably from about 0.25.degree. C./min to about
0.4.degree. C. The crystallization solution is then maintained at
above the saturation point of the solid acid-base salt of the
second, i.e., undesired, enantiomer. Typically, the crystallization
solution is maintained at this temperature for about 1 to about 72
hours, preferably from about 2 to about 48 hours, and more
preferably from about 3 to about 30 hours.
[0085] As expected, using a small amount of chiral amine compound
allows selective formation of the solid acid-base salt of the first
enantiomer. However, the resulting yield will correspondingly be
small. Theoretically, the amount of yield of the desired enantiomer
from a racemic mixture is 50%. Thus, if 0.5 molar equivalent of the
chiral amine compound is used, the theoretical yield is 50% of the
total .alpha.-(phenoxy)phenylactic acid (or 100% of the desired
enantiomer). In order to be economically desirable, methods of the
present invention provide at least about 50% yield of the desired
enantiomer, preferably at least about 60%, more preferably at least
about 70%, and most preferably at least about 75%. Assuming 100%
selectivity, these yields correspond to adding about 0.25, 0.30,
0.35 and 0.375 molar equivalent of the chiral amine compound, which
represent a minimum amount of the chiral amine compound that need
to be added to the crystallization solution.
[0086] It is believed that the tendency for the second enantiomer
to form a solid acid-base salt with the chiral amine compound is
one of the major causes for variability of conventional
crystallization processes. Thus, by determining the supersaturation
point of the second, i.e., undesired, enantiomer, one can minimize
or prevent unpredictability of a solid acid-base formation of the
second enantiomer. Supersaturation points can be readily determined
by one skilled in the art, e.g., by a solubility experiment.
[0087] It should be noted that while methods of the present
invention are discussed in reference to the enrichment of
(-)-enantiomer that is present in the racemic mixtures, methods of
the present invention are also applicable for enriching the
(+)-enantiomer. The method of the present invention essentially
provides a solid precipitate enriched in the (-)-enantiomer and a
liquid filtrate, i.e., mother liquor, enriched in the
(+)-enantiomer. Liberation of the desired (-)-enantiomer and
recovery of the chiral amine compound from the precipitated salt
can be readily accomplished by acidification of the salt with, for
example, a dilute mineral acid or any other inorganic or organic
acid conventionally known to hydrolyze salts of this nature. While
this procedure leaves the filtrate as an undesired by-product, the
filtrate can be further treated with acid or, preferably, base to
convert the (+)-enantiomer enriched filtrate to the racemic
mixture. For example, the (+)-enantiomer can be racemized using
aqueous sodium hydroxide solution. This racemic mixture can then be
reused, i.e., recycled. In addition, the chiral amine compound can
also be recovered from the above described conversion step and
recycled. Thus, the process of the present invention lends itself
readily to a recycling-type of procedure.
IV. Synthesis of Racemic .alpha.-(phenoxy)phenylactic Acid
[0088] One method of producing a racemic mixture of
.alpha.-(phenoxy)phenylactic acid of Formula I is shown in Scheme I
below. ##STR8##
[0089] Thus, conversion of phenylactic acid 1 to an activated
carboxylic acid derivative, e.g, acid chloride, followed by
.alpha.-bromination gave .alpha.-bromophenylacetyl chloride (not
shown). The acid chloride was then converted to ester 2, where R is
typically alkyl. Preferably, alcohol ROH, which is used to convert
the acid chloride to ester 2, is the same alcohol that is used as a
solvent in a subsequent reaction. In this manner, the number of
different solvent types is minimized. In addition, by using the
same ROH as the solvent in the subsequent reaction, the amount of
by-product, e.g., by trans-esterification, formation is minimized.
For example, isopropyl ester 2, i.e., where R is isopropyl, is
particularly advantages as the subsequent reaction is conveniently
carried out in isopropanol solvent. A displacement reaction of
ester 2 with a phenol compound 3 in the presence of a base, such as
a hydroxide (e.g., potassium hydroxide), gave a
.alpha.-(phenoxy)phenylactic acid ester 4. Hydrolysis of
.alpha.-(phenoxy)phenylactic acid ester 4 afforded
.alpha.-(phenoxy)phenylactic acid I.
[0090] In this manner,
(4-chlorophenyl)-(3-trifluoromethylphenoxy)-acetic acid, i.e.,
CPTA, can be prepared in five steps without intermediate isolation
in about 85% yield following crystallization from heptane.
V. Utility of Enantiomerically Enriched
.alpha.-(phenoxy)phenylactic Acid
[0091] Enantiomerically enriched .alpha.-(phenoxy)phenylactic acid
compounds are useful intermediates in preparing a variety of
pharmaceutically active compounds, including
.alpha.-(phenoxy)phenylactic acid compounds disclosed in U.S. Pat.
No. 3,517,050. Thus, anther aspect of the present invention
provides a method for enantioselectively producing a
.alpha.-(phenoxy)phenylacetate compound of the formula: ##STR9##
from a racemic mixture of a .alpha.-(phenoxy)phenylactic acid
compound Formula I, wherein R.sup.1 is alkyl or haloalkyl, X is
halide and R.sup.7 is heteroalkyl, preferably N-acetyl 2-aminoethyl
(i.e., a moiety of the formula
--CH.sub.2CH.sub.2NHC(.dbd.O)CH.sub.3). The method involves
resolving the racemic mixture of the .alpha.-(phenoxy)phenylactic
acid compound of Formula I as described above and producing an
enantiomerically enriched activated .alpha.-(phenoxy)phenylactic
acid by reacting the enantiomerically enriched
.alpha.-(phenoxy)phenylactic acid with a carboxylic acid activating
reagent. Suitable carboxylic acid activating reagents include
thionyl halides (e.g., thionyl chloride), anhydrides, thioester
generating reagents, and other carboxylic acid activating reagents
known to one skilled in the art.
[0092] The activated .alpha.-(phenoxy)phenylactic acid is than
reacted with a compound of the formula (R.sup.7--O).sub.wM, e.g.,
N-acetyl ethanolamine derivative, to produce enantiomerically
enriched .alpha.-(phenoxy)phenylacetate compound of Formula III,
where R.sup.7 is as defined above, M is hydrogen or a metal, e.g.,
Na, K, Li, Ca, Mg, Cs, etc. and the superscript w is the oxidation
state of M. The present inventors have discovered that the reaction
between the activated acid and the compound of formula
(R.sup.7--O).sub.wM can be carried out without any significant
racemization.
[0093] Additional objects, advantages, and novel features of this
invention will become apparent to those skilled in the art upon
examination of the following examples thereof, which are not
intended to be limiting.
EXAMPLES
Reagents and Experimental Setup
[0094] Unless otherwise stated, reagents and solvents were
purchased from Aldrich Chemical or Fisher Scientific.
N-Acetylethanolamine was also obtained from Lancaster Synthesis.
The racemic CPTA, i.e., halofenic acid was prepared according to
the procedures disclosed in U.S. Pat. Nos. 3,517,050 and 6,262,118
all of which are incorporated herein by reference in their
entirety. (1R,2R)-(-)-2-Amino-1-(4-nitrophenyl)-1,3-propandiol
(i.e., CAF D-Base) was obtained from TCI Americas.
[0095] Operations were conducted under a positive nitrogen
atmosphere. A Camile process control computer attached to a
recirculating heating and cooling system was used to regulate
jacket temperatures in the jacketed straight-walled bottom-drain
glass reactors. Unless otherwise indicated, solvents were removed
using a Buchi rotary evaporator at 15 to 25 torr with a bath
temperature of up to 40.degree. C. Solid samples were dried in a
vacuum oven at 40.degree. C., 15 to 25 torr. A Cenco HYVAC vacuum
pump was used to supply vacuum of less than 1 torr for vacuum
distillations. Water levels were determined by Karl Fisher analysis
using a Metrohm 756 KF Coulometer and HYDRANAL Coulomat AG reagent.
Melting points were determined using a Mettler Toledo FP62 melting
point apparatus. pH was measured using a calibrated Orion Model
290A pH meter. Proton and .sup.13C NMR spectra were recorded on a
Bruker Avance 300 MHz spectrometer.
[0096] Chiral HPLC analysis was carried out at .lamda.=240 nm by
injecting 10 .mu.L of sample dissolved in mobile phase onto a
(R,R)WHELK-O 1.5 .mu.m 250.times.4.6 mm column (Regis Technologies)
and eluting with a 1.0 mL/min flow of 95/5/0.4 (v/v/v)
hexanes/2-propanol/acetic acid. For solid samples of the CPTA/CAF
D-Base diastereomeric salt, the solid was added to aqueous
hydrochloric acid and the CPTA was extracted into methylene
chloride; after removing the solvent from the methylene chloride
layer, the residue was dissolved in mobile phase for analysis.
[0097] Achiral HPLC analysis was carried out at .lamda.=220 nm by
injecting 5 .mu.L of sample dissolved in mobile phase onto a
Phenomenex LUNA 5 .mu.m C18(2) 250.times.4.6 mm column at
25.degree. C. A 1.5 mL/min flow of the gradient starting at 66 vol
% water/34 vol % acetonitrile/0.1 vol % trifluoroacetic acid and
increasing linearly to 26 vol % water/74 vol % acetonitrile/0.1 vol
% trifluoroacetic acid at 20 minutes was used.
[0098] For analysis of acidic solutions of esters, such as
halofenate, acetonitrile was used as the injection solvent. When
determined, product concentrations for CPTA and halofenate were
evaluated by HPLC assay using the external standard method and the
achiral analysis procedure at sample concentrations of less than
2.5 mg/mL.
Example 1
[0099] Previous resolution of CPTA has been reported in U.S. Pat.
No. 3,517,050, in which cinchonidine was used as the chiral base,
and the (+)-enantiomer of CPTA precipitated as the diastereomeric
salt. One major drawback to this procedure was that the desired
(-)-enantiomer remained in the mother liquor, making separation of
a pure (-)-enantiomer fraction difficult.
[0100] This example shows the results of resolving a racemic
mixture of CPTA using a variety of different chiral bases to obtain
a solid enantiomerically enriched (-)-isomer. Unlike the previous
method, methods of the present invention allow the solid
enantiomerically enriched (-)-CPTA to be readily isolated from the
solution.
[0101] Racemic CPTA was prepared by the potassium hydroxide
hydrolysis of racemic halofenate. For chiral base screening, equal
molar mixtures of CPTA and the chiral base were mixed in ethanol,
methanol and acetone in glass vials, and the solutions were allowed
to stand undisturbed. After holding overnight at ambient
temperature, the samples that remained in solution were placed in a
refrigerator at 5.degree. C. After holding overnight in the
refrigerator, a small amount of water was added to the samples that
remained a solution in ethanol. After four days at ambient
temperature, the aqueous ethanol solutions were placed back in the
refrigerator. All of the samples remained in the refrigerator, and
were periodically checked for precipitate formation over the course
of a month. A list of the bases and solvent conditions examined,
and temperatures at which crystalline salts were found is shown in
Table 1. TABLE-US-00001 TABLE 1 Bases Examined for CPTA Resolution.
Solvent System Base EtOH EtOH (aq) Acetone MeOH
S-(-)-Methylbenzylamine E E E E Quinine C (22 .degree. C.) C
(22.degree. C.) C (22 .degree. C.) Quinidine E E L-Tyrosine
Hydrazide C (22 .degree. C.) L-Leucine Methyl Ester Hydrochloride*
E E 1-2-Amino-1-butanol E E E E Brucine E E E E
(S)-(+)-2-Pyrrolidine-methanol E E E E
(S)-(+)-2-Amino-3-methyl-1-butanol E (S)-(+)-2-Amino-1-propanol E
(S)-(-)-2-Amino-3-phenyl-1-propanol E (1S,25)-(+)-Pseudoephedrine E
E E E (1S,2S)-(+)-2-Amino-1-phenyl-1,3-propanediol E E E E
(1S,2S)-(+)-2-Amino-1-(4-nitrophenyl)-1,3-propandiol C (5 .degree.
C.) (1R,2S)-(-)-Norephedrine E E E E (1R,2S)-(-)-Ephedrine E
(1R,2R)-(-)-2-Amino-1-(4-nitrophenyl)-1,3-propandiol C (22 .degree.
C.) (+)-Cinchonone E E E E (-)-Cinchonidine C (22 .degree. C.)
(-)-Strychnine E E E E E - Evaluated C - Crystallized at
(Temperature) *-With 1 mol/mol of Aqueous Sodium Hydroxide
[0102] Four chiral bases, quinine, L-tyrosine hydrazide,
(-)-cinchonidine, and both enantiomers of
2-amino-1-(4-nitrophenyl)-1,3-propandiol, were found to give
crystalline salts from racemic CPTA. For samples that crystallized,
the solid was isolated by filtration, and both the solid phase and
mother liquor were analyzed by chiral HPLC to determine the
enantiomeric composition of both streams. The results from the
screen are shown in Table 2. Three of the bases shown in Table 2
gave the (+)-enantiomer enrichment in the solid phase.
TABLE-US-00002 TABLE 2 Results from Chiral Base Screen. Mother
Solid Liquor % Yield Base Solvent Temp .degree. C. % (+) % (-) %
(+) % (-) Calculated L-Tyrosine Hydrazide Acetone 22 86.6 13.4 40.7
59.3 20.3 (-)-Cinchonidine Ethanol 22 66.8 33.2 12.0 88.0 69.3
(1S,2S)-(+)-2-Amino-1-(4- Ethanol 22 93.2 6.8 28.5 71.5 33.2
nitrophenyl)-1,3-propandiol Quinine Ethanol 22 39.9 60.1 60.1 39.9
50.1 Acetone 22 28.2 71.8 58.9 41.1 28.9 Acetone* 5 23.0 77.0 83.5
16.5 55.4 Methanol 22 25.8 74.2 53.0 47.0 10.9 2-Propanol 30 43.2
56.8 64.3 35.7 67.6 2-Propanol** 30 40.4 59.6 78.8 21.1 75.0
2-Propanol* 21 42.3 57.7 59.1 40.9 53.9 *More Dilute **Slower
Cooling Profile
[0103] Included in Table 2 is the percent yield of solid calculated
from the isomeric ratio in the solid and mother liquor streams. The
equation used is shown below. The maximum theoretical yield with
100% isomeric purity is 50%. Yields over 50% indicate inclusion of
the other isomer.
Equation to calculate yield from isomer ratios.
[0104] Set: a=area % Component 1 in starting material; b=area %
Component 2 in starting material; x=area % Component 1 in isolated;
y=area % Component 2 in isolated; w=area % Component 1 in mother
liquor; z=area % Component 2 in mother liquor; E=g material
isolated; F=g material in mother liquor.
And: a+b=100%; E+F=1
Then: xE+wF=a; yE+zF=b
Solving: xE+w(1-E)=a; yE+Z(1-E)=b
E=isolated yield=(a-w)/(x-w)=(b-z)/(y-z)
Example 2
[0105] This example shows the results of resolving CPTA with CAF D
base in ethanol and 2-propanol.
[0106] The results for ethanol and 2-propanol are summarized in
Table 3 below. For this evaluation, the slurries were sampled at
various points in the cooling profile, and the enantiomeric
composition of both the solid and solution phases determined. From
this information, the % ee of the solid phase and expected weight
percent yield (maximum 50% yield with 100% ee), calculated from the
isomer ratio, were determined. Included in Table 3 is the yield of
(-)-CPTA, which is derived from the weight percent yield and the
(-)-CPTA content of the solid phase (maximum 100% yield with 100%
ee).
[0107] In this particular study, the best results in ethanol used 1
mole of CAF D Base per mole of CPTA. Approximately 72% yield of the
(-)-CPTA CAF D Base salt was calculated from the chiral composition
of both phases, with an 87.6% ee of the (-)-CPTA salt in the solid
phase. Use of one molar equivalent of CAF D Base in 2-propanol at a
similar concentration gave a lower resolution. Higher enantiomeric
enrichment was achieved when 0.55 mole of CAF D Base per mole of
CPTA was used. Under these conditions, approximately 76-79% yield
of the (-)-CPTA CAF D Base salt was calculated from the phase
compositions, with an 87-90% ee of (-)-CPTA in the solid phase.
Calculated weight percent yields, which do not take into account
physical losses, were 41 to 42%; actual weighed isolated yields
were 37 to 39%. TABLE-US-00003 TABLE 3 Resolution of CPTA with CAF
D Base. wt % mole/mole Solid M.L. % Yield % Yield CPTA base T
.degree. C. % (+) % (-) % (+) % (-) % ee 50% Max (-)-CPTA Ethanol
13.68 1.02 11 10.2 89.8 75.8 24.2 79.7 39.4 68.9 0 8.9 91.1 76.4
23.6 82.3 39.1 69.9 -9 6.2 93.8 78.0 22.0 87.6 39.0 72.4 14.09 0.50
18 6.6 93.4 55.5 44.5 86.7 11.2 20.7 -5 10.3 89.7 59.7 40.3 79.3
19.7 35.0 2-Propanol 15.72 1.01 12 45.9 54.1 66.9 33.1 8.2 80.4
85.8 -8 46.6 53.4 68.0 32.0 6.7 84.2 87.1 16.6 0.50 36 8.3 91.7
69.6 30.4 83.5 32.0 58.6 22 10.2 89.8 73.9 26.1 79.6 37.5 62.3 2
8.0 92.0 74.9 25.1 84.0 37.2 68.5 16.7 0.55 49 26.3 73.7 64.5 35.5
47.4 38.0 56.1 50 7.5 92.5 63.3 36.7 85.0 23.8 44.0 20 6.7 93.3
79.7 20.3 86.6 40.7 75.6 16.7 0.55 50 8.8 91.2 64.2 35.8 82.3 25.6
46.6 35 9.1 90.9 69.0 31.0 81.7 31.7 57.6 6 5.2 94.8 75.0 25.0 89.6
35.8 67.9 5 5.7 94.3 81.9 18.1 88.6 41.8 78.9 1 5.3 94.7 82.2 17.8
89.5 41.9 78.8 18.34 0.54 6 6.3 93.7 82.1 17.9 87.3 42.4 79.2
[0108] Recrystallization of the CPTA CAF D Base salt from
2-propanol increased the optical purity from approximately 87% ee
to 98% ee with 87% mass recovery, or 93% recovery based on the
(-)-CPTA content of the feed (Table 4). TABLE-US-00004 TABLE 4
Recrystallization of (-)-CPTA CAF D Base from 2-Propanol. % ee M.L.
wt % % Yield % ee Feed wt % Salt Isolated % (+) % (-) Yield
(-)-CPTA 86.6 13.0 97.7 48.8 51.2 87.8 93.3 87.3 12.9 98.0 45.0
55.0 87.8 92.8
[0109] Overall, an approximately 35% yield out of a maximum 50% of
the (-)-CPTA CAF D Base salt, with an optical purity of
approximately 98% ee, was obtained from racemic CPTA.
[0110] Crystallization of optically enriched enantiomers often
increases the chiral purity. Following removal of the resolving
agent, crystallization of (-)-CPTA from methylcyclohexanone will
also increase the optical purity to some degree. In one experiment,
crystallization of (+)-CPTA increased the optical purity from 99.1
to 100% ee; the mother liquor was 95% ee.
Example 3
[0111] This example illustrates the solubility profiles of CAF D
Base salt of (+)- and (-)-isomers of CPTA in 2-propanol.
[0112] To aid in optimization of the CPTA resolution using CAF D
Base, the solubility profiles of both of the diastereomeric salts
in 2-propanol were determined. The results are shown in FIG. 1. The
(+)-CPTA CAF D Base salt was prepared using cinchonidine-resolved
(+)-CPTA. As FIG. 1 shows, the desired (-)-CPTA diastereomer is
approximately three times less soluble than the (+)-CPTA form.
Equations describing the solubilities included in the figure were
calculated by least squares analysis (R.sup.2>0.99). The data
point for the (-)-CPTA salt at 82.degree. C. was not included in
determining the equation, but closely fits the calculated
solubility.
[0113] Racemization of the undesired CPTA enantiomer could be
recycled back into the process. Thus, it was found that heating an
enantiomerically enriched undesired isomer of CPTA in 1 N aqueous
sodium hydroxide at reflux resulted in racemization in less than
one hour. No other by-products were detected by HPLC analysis of
the isolated CPTA.
Example 4
[0114] This example illustrates a method for obtaining
(+)-CPTA.
[0115] A 2-L round-bottom flask with an overhead stirrer was
charged with 33.0 g of crude (+)-CPTA--chinconidine salt, 610 mL of
ethanol, and 125 mL of methanol. The slurry was heated to reflux to
give a solution, then cooled. A very thick slurry formed at
42.degree. C. The slurry was heated to 68.degree. C. to give a
light slurry, then allowed to cool to ambient temperature. The
mixture was filtered at 26.degree. C. and rinsed with 150 mL of
ethanol to give, after drying under vacuum at 40.degree. C., 23.48
g of (+)-CPTA--chinconidine salt. The recrystallization procedure
was repeated with 600 mL of ethanol and 120 mL methanol to give
18.23 g of (+)-CPTA--chinconidine salt (55% recovery from two
crystallizations). No (-)-CPTA was detected by chiral
chromatography, although the degree of separation did not allow for
an assessment of low levels (the halofenate chiral analysis
conditions were also used at that time for the CPTA analysis).
[0116] A 3.61 g sample of the purified salt was mixed with 50 mL of
water and 50 mL of toluene, and 2.9 g of sulfuric acid was added.
The organic phase washed with 30 mL of water, then evaporated to a
residue. The residue was crystallized from 20 mL of cyclohexane to
give 1.22 g of (+)-CPTA. Alternatively, 6.3 g of the
(+)-CPTA--chinconidine salt (10.2 mmol) was mixed with 56 g of
diethyl ether and 29 g of water, and acidified to a pH of 1.9 with
drops of sulfuric acid. The organic phase washed with 25 mL of
water, dried (magnesium sulfate), filtered, and evaporated to a
residue. The residue was stirred with 22 mL of methylcyclohexane at
ambient temperature to form a slurry. The slurry was warmed to
40.degree. C., then cooled in an ice bath and the solid isolated by
filtration to give, after drying at 40.degree. C. under vacuum,
2.62 g (7.92 mmol, 78% yield) of (+)-CPTA.
Example 5
[0117] This example illustrates a method for synthesizing
(+)-halofenate from (+)-CPTA.
[0118] A 25-mL round-bottom flask was charged with 0.91 g of
(+)-CPTA and 2.6 g of thionyl chloride, and the mixture heated to
reflux to give a solution. Conversion to acid chloride was
monitored by quenching a sample with methanol and analyzing the
product with HPLC. To the acid chloride solution was added 4.8 g of
diethyl ether, and this solution was added to 2.0 g of
N-acetylethanolamine in 12 mL of N,N-dimethylformamide (DMF) with
0.37 g of pyridine chilled in an ice bath. The resulting solution
was added to 25 mL of water and 30 mL of diethyl ether. The organic
phase was separated, washed with 25 ml of water, dried
(MgSO.sub.4), and filtered to give, after removal of the solvent,
0.92 g of an oil. HPLC analysis showed 45 area % of halofenate and
50 area % of CPTA. Chiral HPLC analysis indicated that the
halofenate was 99.78% ee of the (+)-enantiomer.
Example 6
[0119] This example illustrates a method for preparing racemic
CPTA.
[0120] A 2-L round-bottom flask with an overhead stirrer was
charged with 102.7 g of halofenate, 500 mL of water, and 16.3 g of
2-propanol. The slurry was stirred, and 32.3 g of aqueous 45%
potassium hydroxide was added. After heating to reflux for 1 hour,
the solution was cooled to ambient temperature and charged with 380
mL of hexanes. The pH was adjusted from 12.5 to 2 with 24.57 g of
37% hydrochloric acid. The three phase mixture was heated to
60.degree. C. to give two phases. The lower aqueous phase was
removed and extracted with 50 mL of hexanes. The combined organic
layers were heated to distill at atmospheric pressure to remove 100
mL of cloudy distillate. The solution was cooled to 30.degree. C.
and seeded with CPTA. A slurry formed. The slurry was cooled in an
ice bath and the solid isolated by filtration to afford 64.0 g
(78.4% yield) of racemic CPTA, i.e.,
(4-chlorophenyl)(3-trifluoro-methylphenoxy)acetic acid.
Example 7
[0121] This example shows representative results of chiral
resolution screening in ethanol using a variety of chiral
bases.
[0122] A sample of 1.16 g (3.51 mmol) of CPTA was dissolved in 6.98
g of ethanol to give a solution (0.431 mmol/g). Glass vials were
individually charged with the amounts of each base listed in Table
5, and the amount of the ethanolic CPTA solution calculated to give
a 1 to 1 molar ratio of acid to base was added. In some cases, a
small amount of ethanol was added to wet the base prior to addition
of the CPTA solution. The vials were allowed to stand overnight at
ambient temperature. Vials 7G and 71 gave precipitates. A sample of
each supernate was removed and analyzed by chiral HPLC analysis.
The solids were isolated by filtration, and also analyzed. Some of
the results are shown in Table 2 (see Example 1 above). The
remaining vials were placed in a refrigerator at 5.degree. C. After
one day, 7E give a precipitate. The sample was analyzed as
previously described. The remaining vials were charged with 50
.mu.L of water, and held at ambient temperature for three days
before placing in the refrigerator. No additional precipitates were
noted after one month. TABLE-US-00005 TABLE 5 Base Screening in
Ethanol. wt CPTA Wt Solution Base EtOH Water Base (g) (g) Added
Added 7A S-(-)-Methylbenzylamine 0.8836 0.4620 0 g .sup. .sup. 0.05
g 7B 1-2-Amino-1-butanol 0.8198 0.0314 0 0.05 7C
(1R,2S)-(-)-Norephedrine 0.5273 0.0342 0.2007 0.05 7D
(1S,2S)-(+)-Pseudoephedrine 0.7295 0.0515 0.1459 0.05 7E
(1S,2S)-(+)-2-Amino-1-(4- 0.5580 0.0510 0.1228 0
nitrophenyl)-1,3-propanediol 7F (1,2S)-(+)-2-Amino-1-phenyl- 0.5640
0.0405 0.1287 0.05 1,3-propanediol 7G (-)-Cinchonidine 0.3484
0.4390 0.3637 0 7H (+)-Cinchonine 0.6409 0.0796 0.2103 0.05 7I
Quinine 0.5391 0.0750 0.1735 0 7J (-)-Strychnine 0.5812 0.0828
0.2295 0.05 7K Brucine 0.7566 0.1287 0 0.05 7L
(S)-(+)-2-pyrrolidine- 0.8681 0.0383 0 0.05 methanol
Example 8
[0123] This example shows representative results of chiral
resolution screening in acetone using a variety of chiral
bases.
[0124] A sample of 1.67 g of CPTA was dissolved in 7.57 g of HPLC
grade acetone to give a solution. Glass vials were individually
charged with the amounts of each base listed in Table 6, and the
amount of the CPTA solution calculated to give a 1 to 1 molar ratio
of acid to base was added. In some cases, a small amount of acetone
was added and the mixture was warmed to about 40.degree. C. to give
a solution. Additionally, 0.300 mL of 1 N sodium hydroxide was
added to vial 16M. The vials were allowed to stand overnight at
ambient temperature. Vial 16D formed a precipitate, and was
analyzed as described above. Some of the results are summarized in
Table 2 (see Example 1). The remaining vials were placed in the
refrigerator. Vial 16 N formed a precipitate, and was analyzed.
Vial 16G formed a very light precipitate. After one week, vial 16L
was found to contain a precipitate. The sample was analyzed as
previously indicated. No additional precipitates were noted.
TABLE-US-00006 TABLE 6 Base Screening in Acetone. wt CPTA Wt
Acetone Base Solution (g) Base (g) Added (g) 16A
(1R,2S)-(-)-Norephedrine 0.8568 0.0704 16B
(1S,2S)-(+)-2-Amino-1-phenyl-1,3-propanediol 0.1824 0.0168 16C
S-(-)-Methylbenzylamine 0.8948 0.0592 16D Quinine 0.1968 0.0347
0.85 16E (S)-(+)-2-pyrrolidine-methanol 0.8181 0.0452 16F Brucine
0.2163 0.0463 16G (+)-Cinchonine 0.3987 0.0630 16H
(1S,2S)-(+)-Pseudoephedrine 1.0835 0.0974 16I (-)-Strychnine 0.1462
0.0265 0.25 16J Quinidine 0.3753 0.0663 16K 1-2-Amino-1-butanol
0.7248 0.0353 16L L-Tyrosine Hydrazide 0.4508 0.0472 0.39 16M
L-Leucine Methyl Ester Hydrochloride 0.5585 0.0544 16N Quinine
0.4712 0.0829 2.00 16O (+)-Cinchonine 0.3363 0.0539 0.30
Example 9
[0125] This example shows representative results of chiral
resolution screening in methanol using a variety of chiral
bases.
[0126] A sample of 2.00 g of CPTA was dissolved in 8.03 g of HPLC
grade methanol to give a solution. Glass vials were individually
charged with the amounts of each base listed in Table 7, and the
amount of the CPTA solution calculated to give a 1 to 1 molar ratio
of acid to base was added. Additionally, 0.300 mL of 1 N sodium
hydroxide was added to vial 27J. The vials were allowed to stand
overnight at ambient temperature. Vial 27B solidified, and an
additional 300 .mu.L of methanol was added before the sample was
analyzed as described above. The remaining vials were placed in the
refrigerator. No additional precipitates were noted after one
month. TABLE-US-00007 TABLE 7 Base Screening in Methanol. wt CPTA
wt solution Base (g) base (g) 27A (1R,2S)-(-)-Ephedrine .sup.
0.4896 g .sup. 0.0478 g 27B Quinine 0.1420 0.0282 27C
(+)-Cinchonine 0.1822 0.0324 27D 1-2-Amino-1-butanol 1.0012 0.0539
27E S-(-)-Methylbenzylamine 0.7892 0.0576 27F
(1S,2S)-(+)-Pseudoephedrine 0.7600 0.0749 27G Brucine 0.1891 0.0436
27H Quinidine 0.5845 0.1144 27I (1S,2S)-(+)-2-Amino-1-phenyl-1,3-
0.3032 0.0299 propandiol 27J L-Leucine Methyl Ester Hydrochloride
0.5033 0.0545 27K (S)-(+)-2-Pyrrolidine-methanol 0.7133 0.0434 27L
(1R,2S)-(-)-Norephedrine 1.1788 0.1070 27M (-)-Strychnine 0.4525
0.0905 27N (S)-(+)-2-Amino-3-methyl-1-butanol 0.1478 0.0092 27O
(S)-(+)-2-Amino-1-propanol 0.9268 0.0417 27P
(S)-(-)-2-mino-3-phenyl-1-propanol 0.3406 0.0307
Example 10
[0127] This example shows the result of resolving CPTA with
quinine.
[0128] A 150-mL jacketed bottom-drain flask was charged with 2.70 g
(8.17 mmol) of CPTA, 2.65 g (8.17 mmol) of quinine, and 50 mL of
2-propanol. The mixture was heated to 70.degree. C. to give a
solution, then cooled to 30.degree. C. at a rate of 0.2.degree.
C./min and held for 2 hours to give a slurry. Chiral HPLC analysis
of a sample showed 42.88 and 56.47 area % of (+) and (-)-CPTA,
respectively, in the solid phase, and 61.54 and 34.19 area % of (+)
and (-)-CPTA, respectively, in the solution. The slurry was heated
to 60.degree. C., then cooled to 30.degree. C. at a rate of
0.04.degree. C./min and held overnight to give a slurry. Chiral
HPLC analysis showed 29.94 and 44.19 area % of (+) and (-)-CPTA,
respectively, in the solid phase, and 77.54 and 20.88 area % of (+)
and (-)-CPTA, respectively, in the solution. The slurry was diluted
with 50 mL of 2-propanol and heated to 57.degree. C. to give a
solution, then cooled to 30.degree. C. at a rate of 0.2.degree.
C./min. A slurry started to form after 1 hour at 30.degree. C. The
mixture was stirred for 2 days at ambient temperature, then the
solid was isolated by filtration and rinsed with 2-propanol to
give, after drying under vacuum, 2.89 g (54% yield by mass) of the
quinine salt of CPTA. Chiral HPLC analysis found 42.25 and 57.75
area % of (+) and (-)-CPTA, respectively, in the solid phase and
56.56 and 39.20 area % of (+) and (-)-CPTA, respectively, in the
mother liquor. The results are also included in Table 2 (see
Example 1).
Example 11
[0129] This example shows the result of resolving CPTA with CAF D
base.
[0130] A 150-mL bottom-drain flask was charged with 19.54 g of
CPTA, 6.82 g of CAF D Base (i.e.,
D-threo-(-)-2-amino-1-(nitrophenyl)-1,3-propandiol), and 80.2 g of
2-propanol. The mixture was warmed to 70.degree. C. to give a
solution, then cooled to a jacket temperature of 5.degree. C. at a
rate of 0.1.degree. C./min. The mixture was hazy at 62.degree. C.
After holding at 6.degree. C. for 9 hours, the solid was isolated
by filtration, rinsed with 5 mL of 2-propanol, and dried at
40.degree. C. under vacuum to give 12.03 g (37.4 wt % yield) of
(-)-CPTA CAF D Base salt. Chiral HPLC analysis of the solid found
6.34 area % of (+)-CPTA and 93.46 area % of (-)-CPTA; the mother
liquor contained 81.41 area % of (+)-CPTA and 17.76 area % of
(-)-CPTA.
Example 12
[0131] This example shows the result of recrystallizing (-)-CPTA
CAF D Base salt.
[0132] A 150-mL bottom-drain flask was charged with 8.00 g of the
(-)-CPTA CAF D Base salt (from Example 11 above) and 54.2 g of
2-propanol. The mixture was heated to reflux to give a solution,
then cool to a jacket temperature of 20.degree. C. at a rate of
0.1.degree. C./min and held at an internal temperature of
22.degree. C. for 6 hours. The solid was isolated by filtration,
rinsed with 2-propanol, and dried at 40.degree. C. under vacuum to
give 6.93 g (86.6 wt % recovery) of (-)-CPTA CAF D Base salt (m.p.
184-185.degree. C.). The solid contained 0.995 area % of (+)-CPTA
and 99.01 area % of (-)-CPTA; the mother liquor contained 44.53
area % of (+)-CPTA and 54.47 area % of (-)-CPTA. The reactor was
cleaned out with acetone. The acetone was evaporated to a residue
of 0.27 g (3.4 wt %).
Example 13
[0133] This example illustrates a method for preparing (+)-CPTA CAF
D Base salt.
[0134] A 1-L flask was charged with 10.94 g (17.5 mmol) of the
(+)-CPTA cinchonidine salt, 200 mL of water, and 100 mL of
methylene chloride. The pH was adjusted to 1.9 by the addition of
1.8 g of sulfuric acid. The organic layer washed three times with
100-mL portions of dilute aqueous sulfuric acid, dried (magnesium
sulfate), filtered, and evaporated to a residue of 5.79 g. The
residue was dissolved in 22.2 g of 2-propanol, and 3.5 g of CAF D
Base was added. The resulting slurry was heated to reflux to give a
solution, then cooled to ambient temperature and the slurry stirred
for three hours. After cooling in an ice bath, the solid was
isolated by vacuum filtration, rinsed with 5 mL of 2-propanol, and
dried under vacuum at 40.degree. C. to give 7.39 g (80% yield) of
(+)-CPTA CAF D Base salt (m.p. 172-173.degree. C.).
Example 14
[0135] This example shows solubility of diastereomeric CPTA-CAF D
base salts in 2-propanol.
[0136] Samples of (-)-CPTA CAF D Base and (+)-CPTA CAF D Base
(>98% ee) were added to 2-propanol in the amounts shown in Table
8, and mixed using an ultrasonic bath. All samples remained
slurries. The slurries were held overnight at the temperature
listed, then samples of the supernates were removed and analyzed by
quantitative HPLC analysis to determine the CPTA concentration. The
results are shown in the table, and in FIG. 1. Additionally, 8.00 g
of (-)-CPTA CAF D Base salt required 54.2 g of 2-propanol for
solution at 82.degree. C. (14.7 wt %). This data point was included
in FIG. 1, but not included in the solubility equation.
TABLE-US-00008 TABLE 8 Solubility in 2-Propanol. Wt Salt (g) Wt
2-propanol (g) T .degree. C. Wt % in solution (-)-CPTA CAF D Base
Salt 0.31 1.17 45.3 2.35 0.23 2.48 7.8 0.376 0.21 1.31 19.4 0.688
(+)-CPTA CAF D Base Salt 0.25 1.84 20.0 1.85 0.27 1.83 45.8 6.03
0.17 2.09 8.5 1.32
Example 15
[0137] This example illustrates a method for racemizing
enantiomerically enriched CPTA.
[0138] A 50-mL round bottom flask was charged with 0.31 g of
(-)-CPTA (68.7% ee) and 9.4 g of 1N sodium hydroxide. The solution
was heated to reflux for one hour, then cool to ambient temperature
and acidified with 1 g of 37% hydrochloric acid. The CPTA was
extracted into methylene chloride, and the solvent was evaporated
to an oil of 0.46 g. HPLC analysis found 99.4 area % of CPTA, and
chiral HPLC analysis found a 50/50 mixture of the CPTA
enantiomers.
Example 16
[0139] This example illustrates a process for resolving a racemic
mixture of CPTA using CAF D-Base under a variety of crystallization
conditions.
[0140] The general crystallization procedure was to charge CPTA,
CAF D-Base, and 2-propanol at room temperature and heat to a
solution at about 75.degree. C. The solution was cooled to about
60.degree. C. and held until nucleation occurred. Several batches
were seeded with (-)-Salt (i.e., salt of (-)-CPTA and CAF D-Base)
to induce nucleation. After the slurry had developed over about an
hour, the vessel was cooled to the isolation temperature. The first
5 entries in FIG. 2 used a slow cooling rate of about
0.05-0.10.degree. C./minute to reach the isolation temperature. The
other experiments used a faster cooling rate of 0.25-0.40.degree.
C./minute. A fiber optic probe is inserted directly into the
crystallizer to determine the slurry density.
[0141] The amount of CAF D-Base added and the solute concentration
are some of the important variables which give rise to the final
batch composition. The tendency for the (+)-Salt (i.e., salt of
(+)-CPTA and CAF D-Base) to remain supersaturated for varying
amounts of time is believed to be a major cause for variability in
some experiments. This is demonstrated in entry 5 in FIG. 2,
whereby the slurry was held for 8 hours at 13.degree. C. and
produced high purity crystal (99.7% (-)-Salt). Three hours later,
an increase in the signal of the fiber optic probe indicated the
likely nucleation of the (+)-Salt. After another 27 hours, the
slurry was isolated and the crystal product contained a (-/+)-CPTA
ratio of 83.3/16.7%. Analysis of the crystal product by HPLC gives
the ratio of (-)-CPTA and (+)-CPTA. Since the free CPTA in solution
is undersaturated the crystal analysis therefore gives the
diasteriomeric salt ratio. Mother liquors contain both dissolved
salt and free CPTA. Analysis by HPLC reports the combined amount of
each enantiomer as CPTA. Similarly, entry 6 of FIG. 2 shows that
the slurry was held for 20 hours at 1.degree. C. and produced high
purity salt (>98% (-)-CPTA). After heating to 17.degree. C., the
(+)-Salt nucleated and gave poorer quality product
[(-/+)-CPTA=81.2/18.8%].
[0142] In other trials, nucleation of the (+)-Salt occurred more
quickly, as in entries 2, 8, and 10 of FIG. 2. A crystallization is
desirable for which isolation could be done near, preferably just
above, the saturation temperature of the (+)-Salt.
[0143] At a loading of 3.9 g of 2-propanol per gram of CPTA and
with 0.45 equivalent of CAF D-Base, an isolation at room
temperature appears to be very near the saturation level (or within
the metastable zone) of the (+)-Salt. Entry 12 in FIG. 2 started
with 0.43 equivalents of base, and the crystal product at
21.degree. C. remained pure (>99% (-)-Salt), even after seeding
with (+)-Salt. After adding more CAF D-Base to give 0.45
equivalents, the slurry was held for 14 hours, and then for 6 more
hours after seeding with (+)-Salt. The crystal product analyzed at
98.7% (-)-CPTA ratio. Increasing the total base to 0.47 equivalent
gave crystal product which slowly increased in (+)-Salt composition
to (-/+)-CPTA=92.3/7.7%.
[0144] Entry 11 of FIG. 2 (3.9 g of 2-propanol per gram of CPTA,
0.45 eq. base) maintained high purity of the (-)-Salt (99.1%) after
14 hours, but upon addition of more base to 0.48 eq., the resulting
ratio of the product was (-/+)-Salt=89.2/10.8%. Entry 9 of FIG. 2
(at 0.45 eq. base) maintained 99.5% (-)-Salt purity after 16 hours
at 22.degree. C. Calculated yields of (-)-CPTA from the three
batches under these conditions were 70.7-71.6%. Calculated yields
are derived from a forced mass balance from the racemic CPTA feed,
by knowing the crystal and mother liquor composition of (-)-CPTA
and (+)-CPTA.
[0145] These loadings of about 0.45 equivalent of CAF D-Base and
about 4 g of 2-propanol per gram of CPTA provide a high purity
(-)-Salt (>98.5%) product, which can be used without a further
recrystallization.
Example 17
[0146] This example provides a model to describe the
resolution/crystallization of CPTA salt.
[0147] The concentration of free CPTA depends on the amount of base
charged and the solvent loading. For example, a resolution of CPTA
by charging 4.0 grams of 2-propanol and 0.50 equivalent of CAF
D-Base, results in formation of the salt in 2-propanol which
contains 11% free CPTA. This solvent possesses greater solubility
for both the (-)-Salt and the (+)-Salt, and was determined as shown
in FIG. 3. FIG. 3 also includes the solubility data in pure
2-propanol, expressed in gram of component per gram of 2-propanol.
As FIG. 3 shows the curves for the respective salts are of similar
shape.
[0148] By other combinations of the loading of CPTA, CAF D-Base,
and 2-propanol, a system resulting in 11.0% free CPTA in 2-propanol
can also be attained, as shown in FIG. 4. As FIG. 4 shows, the
loading for various experiments in FIG. 2 did not usually fall
exactly on this line. However, the (-)-Salt and the (+)-Salt
solubility can be estimated as follows: a loading which gives a
point above the "11.0% free CPTA" line is more dilute (i.e.,
<11.0% free CPTA in 2-propanol), and exhibits a lower solubility
than the "11.0%" line. Conversely, points below the "11.0%" line
result in solvent containing >11.0% free CPTA, and the salt
solubility is greater than determined in FIG. 3. To estimate
component solubility, a constant multiplier factor, k, was used.
The modified solubility equations for the (-)-Salt and the (+)-Salt
are therefore S.sub.(-)=0.01421ke.sup.0.02613T and
S.sub.(+)=0.02868ke.sup.0.02771T.
[0149] Even with a good estimation of the (-)-Salt and the (+)-Salt
solubility by adjusting k, one can still not describe the
crystallization, for the other unknown is the ratio of (-)-Salt and
(+)-Salt which is formed upon addition of the resolving agent base.
One of the more detailed experiments is shown in FIG. 5 (see also
FIG. 2). This experiment used 0.75 equivalent of base and when
sampled at 21.5.degree. C., gave the product with (-/+)-Salt ratio
of 66.4/33.6%. By heating the slurry and continuing to take
samples, the saturation line for both (-)-Salt and the (+)-Salt in
the solvent can be followed.
[0150] To match the solubility model to the actual data, a
regression technique was used, whereby the solubility factor k and
the feed ratio of (-)-Salt and (+)-Salt were manipulated to give an
answer (i.e., crystal composition, mother liquor composition, and
crystal yield) which was consistent with the observed data. By
selecting k=0.68 and a feed ratio for 0.75 equivalent of salt at
58.1% (-)-Salt/41.9% (+)-Salt (i.e., 0.436 eq. of (-)-Salt and
0.314 eq. of (+)-Salt were formed upon addition of CAF D-Base), a
good agreement was obtained. FIG. 6 shows the comparison. The
solubility model allows calculation of the complete mass balance
for the isolation: the amount of (-)-Salt and (+)-Salt in the
crystal, the amount of (-)-Salt and (+)-Salt in the mother liquor,
and also the amount of (-)-free CPTA and (+)-free CPTA in the
mother liquor. One procedure for quantifying (-/+)-Salt and
(-/+)-free CPTA in mother liquor by an extractive work-up, using
solubility differences, is provide in Example 19 below.
[0151] The regression technique with the solubility model was
applied to other experiments which fed differing amounts of
resolving agent. Using a combination of the solubility factor k and
the composition of the salt as feed (i.e., the ratio of (-)-Salt
and (+)-Salt which was formed upon the addition of base), the model
tended to a unique solution which fit the experimental results.
From these, the graph in FIG. 7 was constructed. This result shows
that as more resolving agent is added (above the extrapolated
minimum point of 0.34 eq.), an increasing amount of (+)-Salt is
formed. Without being bound by any theory, in some embodiments, it
is believed that if less than 0.34 equivalent is added, the CAF
D-Base will coordinate substantially only with (-)-CPTA, forming
almost exclusively (-)-Salt. Additionally, by aid of the curve in
FIG. 7, the amount of (-)-CPTA and (+)-CPTA (free acid) can be
calculated. Between 0.35-0.75 equivalent of base charged, the %
ratio of {(-)-CPTA/total CPTA free acid} is around 25%
(23.3-27.1%). The "selectivity" for the ratio of (-/+)-Salt that is
formed thus is dependent on the amount of free (-)-CPTA that
remains (in solution), which comes to an endpoint of about
(-)-CPTA/(+)-CPTA=1/3. It is believed that once the (-)-CPTA
concentration is depleted by addition of about 0.34 eq. of base to
a (-/+)-CPTA ratio of 1/3, continued addition of base forms the
(-/+)-Salt at a ratio of 1/3 (to keep free (-/+)-CPTA at a constant
1/3 ratio in solution).
Example 18
[0152] This example illustrates resolution of a racemic mixture of
CPTA.
[0153] A 200-mL vessel was charged with 17.0 g of CPTA (51.4 mmol),
4.91 g of CAF D-Base (23.1 mmol, 0.450 eq.), and 85 mL of
2-propanol. The mixture was heated to a solution at 78.degree. C.,
and then cooled at 0.5.degree. C./min to 54.degree. C. About 12
hour later, the solution was seeded with (-)-Salt to induce
nucleation. After holding at 54.degree. C. for about 11/2 hours,
the slurry was cooled to 22.degree. C. at 0.25.degree. C./minute.
After holding for 14 hours at 22.degree. C., a small sample
(.about.5 mL) was taken and separated on a 15-mL, medium-fritted
funnel. The mother liquor was weighted and saved, and the solid
washed with 2 mL of 2-propanol. The wash was weighed and saved, and
suction was continued to dry the crystal. Analysis by the
standardized HPLC system allowed calculation of weight % (-)-CPTA
and (+)-CPTA in each stream. A mass balance around this sample
(total accountability of CPTA in the crystal, mother liquor, and
wash was 0.85 g) gave a 31.9% isolated yield of crystal product
from the total CPTA. Crystal purity was 99.1/0.9%=(-/+)-CPTA ratio
by weight. FIG. 8 shows the analytical and mass balance results in
the rectangular boxes. The calculated yield (from CPTA) based on
feed/mother liquor/crystal composition is given inside the circles.
Abbreviations in FIG. 8 are as follows: R.A.=resolving agent, x or
xtal=crystal, ML=mother liquor, Yld=yield.
[0154] The vessel was seeded several times with crystal containing
(+)-Salt, and about 2 hours later, 0.31 g of CAF D-Base (1.46 mmol,
.about.0.03 eq.) was added. The vessel was sampled two times (see
FIG. 8) before the final isolation on a 60-mL medium-fritted
funnel. The mother liquor was clear, pale yellow-gold, 59.1 g. The
solid washed with 19.2 g of 2-propanol, with recovery of 18.8 g of
wash solution. The washed solid (10.07 g) was further dried by
suction on the funnel for an hour to 8.36 g (15.4 mmol salt).
Analysis of all streams from the final isolation accounted for
13.45 g (40.67 mmol) of CPTA. The final crystal product ratio was
(-/+)-CPTA=89.2/10.8%, for an isolated yield of
(-)-CPTA=33.8.degree./a (from CPTA). The calculated yield of
(-)-CPTA, based upon the feed, mother liquor, and crystal
composition, was 35.0%.
Example 19
[0155] This example illustrates an extractive work-up process to
quantify (-/+)-Salt and (-/+)-CPTA in Mother Liquor.
[0156] A mixture of the (-/+)-Salt, 80/20, was only sparingly
soluble in methylene chloride at about 0.016%, while racemic CPTA
was considerably more soluble at a little less than 3.4%. The final
mother liquor from separation of entry 4 of FIG. 2 at 55.3.degree.
C. (see FIGS. 2 and 5) was analyzed by evaporating 0.1286 g to a
glassy residue of 0.0242 g. The residue was dissolved in 5 mL of
methylene chloride, seeded with (-/+)-Salt=80/20, and allowed to
stand overnight. The bulk of the supernatant liquid was removed, 3
mL of methylene chloride were added, and the bulk of the liquid was
removed and combined with the first extract. The methylene chloride
extract was evaporated to give a glassy solid, 0.0074 g, and then
analyzed by HPLC. The remaining thick slurry was evaporated to
0.0162 g and analyzed by HPLC. Results from the extractive work-up
procedure are generally similar to the composition predicted by the
solubility model, as shown in FIG. 9.
Example 20
[0157] This example shows solubility of (-)- and (+)-CPTA-CAF
D-Base salts in alcohols containing CPTA.
[0158] "Solvent" was prepared by dissolving 2.40 g of racemic CPTA
in 19.42 g of 2-propanol (Fisher HPLC Grade) or 4.90 g of racemic
CPTA in 31.4 g of ethanol. The respective concentrations of CPTA in
solution were 11.0% and 13.5%. Solubility of the (-)-CPTA.cndot.CAF
D-Base Salt (i.e., (-)-Salt) or (+)-CPTA.cndot.CAF D-Base Salt
(i.e., (+)-Salt) was determined by a gravimetric method. At a given
temperature, a portion of the supernatant liquid from a saturated
solution was remove to a vial of known weight. The solution weight
was determined, and the volatile solvent was evaporated with a
purge of nitrogen. The solid was further dried to constant weight
in a vacuum oven at about 50.degree. C./1 mm Hg. The vial was
re-weighed to determine the loss of volatile solvent and weight of
solid remaining. From this, the amount of dissolved CPTA from the
"solvent" could be calculated. Subtracting the weight of total
solid from the CPTA gave the weight of soluble salt in the solvent.
Data are shown in FIGS. 10A and 10B.
Example 21
[0159] This example illustrates a method for preparing
enantiomerically enriched (-)-halofenate.
[0160] CPTA was prepared in five steps, as discussed above, without
intermediate isolation in about 85% yield following crystallization
from heptane. Resolution gave an average of 32% yield (max 50%) of
>98% optically pure (-)-CPTA diastereomeric salt. After removing
the resolving agent, the (-)-CPTA was esterified to give
(-)-halofenate in about 55% yield using thionyl chloride and
N-acetylethanolamine. By hydrolyzing the mother liquor residue with
aqueous sodium hydroxide, (-)-CPTA can be recovered from the final
product mother liquor and cycled back through the process. The
resolving agent was isolated from water in about 90% recovery by a
pH adjustment. Recovery and racemization of the (+)-CPTA using
aqueous sodium hydroxide gave about 90% recovery. Overall, the
first pass yield from 4-chlorophenylactic acid was 15-17%. The
entire eight-step process used three organic solvents, and three
solid isolation steps.
Example 22
[0161] This example illustrates a method for preparing CPTA.
##STR10##
[0162] The synthetic route to CPTA is outlined above. Following
bromination of the acid chloride 1 in 1,2-dichloroethane to give
2,2-propanol was added to give the isopropyl ester 3. The
displacement reaction with
.alpha.,.alpha.,.alpha.-trifluoro-m-cresol was accomplished using
potassium hydroxide in 2-propanol. Following a water quench and
wash and removal of the 1,2-dichloroethane, the liquid 3 was added
to a solution of .alpha.,.alpha.,.alpha.-trifluoro-m-cresol and
potassium hydroxide in 2-propanol to give 4. The 2-propanol solvent
was removed, and the hydrolysis to CPTA was completed by heating
with aqueous sodium hydroxide.
[0163] The sodium salt of CPTA can be isolated as a solid by simply
cooling the reaction mixture. Better isolated yields were obtained,
however, by isolation of the carboxylic acid. For isolation, the
basic aqueous CPTA reaction mixture was acidified with hydrochloric
acid, and the CPTA was extracted into 1,2-dichloroethane. Solvent
exchange of the separated organic phase from 1,2-dichloroethane to
heptane afforded CPTA as a white solid in approximately 85% yield
from 4-chlorophenylactic acid.
Example 23
[0164] This example shows solubility of CPTA in 1,2-dichloroethane
and heptane.
[0165] The solubility of racemic CPTA in 1,2-dichloroethane and
heptane are shown in FIGS. 11 and 12, respectively. Included in the
Figures are the equations for the least-squares fit of the
data.
[0166] Based on the solubility profile of FIG. 11, a concentration
of approximately 25 wt % CPTA in 1,2-dichloroethane at a
temperature of approximately 35.degree. C. was chosen for the CPTA
extraction conditions.
[0167] CPTA crystallization from heptane was exothermic. Seeding of
a solution of approximately 170 g of CPTA in 500 mL of heptane at
46.degree. C. resulted in a temperature increase to 54.degree. C.
as the crystallization progressed. Crystallization increased the
CPTA purity as determined by HPLC analysis from 93-95 to >99
area %. HPLC assay of a crystallization mother liquor, which
contained 15 area % of CPTA, found less than 3% yield loss to the
mother liquor. As the purity was improved by crystallization,
isolated yields were high, and the loss to the mother liquor was
minor.
Example 24
[0168] This example shows yield of CPTA resolution under variety of
crystallization conditions.
[0169] Results of CPTA resolution using CAF D-Base under various
crystallization conditions are shown in FIG. 13. Final chiral
purity for each preparation, obtained after zero, one, or two
recrystallizations, is in bold type. The molar ratio of the CAF
D-Base was varied from 0.5 to 0.56. The amount of 2-propanol
solvent listed for the crystallizations and recrystallizations are
both based on the initial charge of racemic CPTA. Chiral HPLC
results for both the isolated solids and mother liquors are
normalized to 100%. The calculated yield and overall yield are
calculated from the ratio of the (+)-enantiomer and (-)-enantiomer
forms in the isolated solids and mother liquors. The actual percent
yield in the last column is of weighed, dried material, and is
based on a maximum yield of 50%.
[0170] Overall yields of the diastereomeric salt at >98% optical
purity ranged from 28 to 35%, and averaged 32%. In one case, using
the lowest ratio of resolving agent, this was obtained without
recrystallization (experiment 2 in FIG. 13). The chiral purity of
the first isolated solid ranged from 73% to 98%. A single
recrystallization was generally sufficient to obtain the desired
optical purity. A high overall yield was obtained when the mother
liquor reached a 20/80 ratio of (-)-CPTA to (+)-CPTA.
[0171] FIG. 14 shows the cooling profiles for the resolution
crystallizations listed in order of decreasing yield of (-)-CPTA.
Experiment number in FIG. 14 corresponds to the experiment number
in FIG. 13. The isolated yield of (-)-CPTA was determined using the
calculated yield of FIG. 13 and the percent of (-)-CPTA in the
isolated material. In general, longer hold times at low
temperatures led to an increase in yield.
[0172] Use of 0.45 molar equivalents of CAF D-Base consistently
gave 35-37% yield of material that was >98% optically pure
without the need for recrystallization.
Example 25
[0173] This example shows a method for separating (-)-CPTA from the
CAF D-Base.
[0174] To separate (-)-CPTA from the CAF D-Base, the diastereomeric
salt was mixed with 1,2-dichloroethane, and aqueous hydrochloric
acid was added to give a pH in the aqueous phase of less than about
2. The aqueous phase containing the hydrochloride salt of the CAF
D-Base was separated. After a water wash of the organic phase, the
bulk of the 1,2-dichloroethane was removed by distillation to
remove residual water. Complete solvent removal gave an oil.
Example 26
[0175] This example shows a method for esterifying (-)-CPTA without
any significant racemization. ##STR11##
[0176] (-)-CPTA was reacted with thionyl chloride in
1,2-dichloroethane at reflux to yield a corresponding acid
chloride. Reaction progress can be monitored by HPLC analysis. A
small amount of distillate was removed to remove excess thionyl
chloride. The mixture was cooled, and a large excess of vacuum
distilled N-acetylethanolamine was added. Stirring at ambient
temperature gave (-)-halofenate.
[0177] The esterification reaction mixture was quenched by adding
the reaction mixture to an aqueous potassium carbonate solution.
(-)-Halofenate was isolated by solvent exchange and crystallization
from the 6:1 heptane:2-propanol. Results are summarized in FIG.
15.
[0178] First crop isolated yields ranged from 47 to 59% and
averaged 55%. This isolated yield represents a reaction yield of 75
to 80% for this step. A second crop afforded a higher overall
yield; however, the product quality was poorer with the second crop
material.
[0179] Molar accountability of the CPTA loaded, found as isolated
halofenate, and halofenate and CPTA in the mother liquor, ranged
from 90 to 99%.
Example 27
[0180] This example shows a method for recovering and recycling
(+)-CPTA.
[0181] Heating CPTA in aqueous base caused racemization. The
remaining CPTA from the resolution step in Example 25 was
approximately 47% ee of the (+)-enantiomer, which also contains
residual CAF D-Base.
[0182] To recover and racemize the (+)-CPTA, the 2-propanol solvent
was removed and replaced with 1,2-dichloroethane. Washing with
water at a pH below about 2 removed the CAF-D-Base for subsequent
recovery. Aqueous sodium hydroxide was added, and the aqueous
solution heated to reflux. The 1,2-dichloroethane was either
removed by distillation prior to the addition of the basic
solution, or by a phase separation following addition of the basic
solution. An 89% yield of racemic CPTA was isolated from heptane
after heating an aqueous solution for four hours with 1.4 molar
equivalents of sodium hydroxide. Isolation of CPTA as a
crystallized intermediate provided a more consistent quality feed
for the resolution step.
[0183] The solubility of the sodium salt of racemic CPTA in water,
determined and expressed as the acid form, is shown in FIG. 16.
Addition of the isolated sodium salt to water gave a pH of about
9.5, and the solubility profile shown in the upper solubility
curve. Addition of a small amount of sodium hydroxide to give a pH
of about 12.6 decreased the aqueous solubility to that shown on the
lower curve.
Example 28
[0184] This example shows a method for producing CPTA from
(+)-halofenate.
[0185] Addition of from 1 to 3 molar equivalents of sodium
hydroxide to about 10 wt % of 87% ee (+)-halofenate in water and
warming to 50 to 60.degree. C. resulted in a substantially complete
hydrolysis to CPTA. Partial racemization to give approximately 70%
ee (+)-CPTA occurred (Time=0 of FIG. 17). The solution was heated
to reflux, and the enantiomeric ratio monitored over time. With 3
molar equivalents of base, almost complete racemization (<3% ee
by the chiral HPLC analysis method) occurred in less than 2 hours
at reflex. The pH dropped from 12.8 to 12.6 over the course of the
racemization. A slightly longer reaction time was required with 2
molar equivalents (pH 12.6 to 11.6). With 1 molar equivalent,
racemization stopped at approximately 60 to 70% ee, with a final pH
of 9.4.
[0186] Use of 0.5 molar equivalents of sodium hydroxide left
approximately 40% of the halofenate unhydrolyzed after 2 hours at
60.degree. C.; heating to reflux overnight left approximately 1%
halofenate at a final pH of 4.8. This did not significantly
minimize racemization. The amount of CPTA produced was 72.6% ee of
the (+)-enantiomer.
Example 29
[0187] This example illustrates a method for recovering (-)-CPTA
from (-)-halofenate crystallization mother liquor.
[0188] As noted previously and shown in FIG. 15, the (-)-halofenate
crystallization mother liquor contains a large amount of
(-)-halofenate and (-)-CPTA. By hydrolysis of the (-)-halofenate,
additional (-)-CPTA can be generated as feed for the resolution
step.
[0189] Hydrolysis of a (-)-halofenate crystallization mother liquor
(88.3% ee of (-)-halofenate) at 50.degree. C. and a final pH of
12.7 rapidly gave 65.8% ee (-)-CPTA. The (-)-CPTA was recovered as
the CAF D-Base diastereomeric salt (96.4% ee) by addition of CAF
D-Base to a 2-propanol solution. From the amount of diastereomeric
salt initially loaded, 55 mol % was obtained as (-)-halofenate, 28%
was recovered as the (-)-CPTA/CAF D-Base salt, and 14 mol %
remained as CPTA in the mother liquor.
Example 30
[0190] This example illustrates a method for recovering CAF
D-Base.
[0191] The CAF D-Base is found in the acidic phase from separation
of (-)-CPTA from the diastereomeric salt, and from the acidic wash
step of the CPTA recovery from the resolution mother liquors.
Basification with aqueous sodium hydroxide to a pH greater than
about 12 resulted in precipitation with good recovery in a form
that was easily filtered. Results are shown in FIG. 18. Recovery
from the diastereomeric salt was generally greater than 90%;
recovery from the resolution mother liquor was lower.
Concentrations in the aqueous solution ranged from about 5 to
20%.
[0192] The enantiomeric purity of the CAF D-Base can be determined
by careful analysis of the melting point by DSC (D. Pitre, M.
Nebuloni, and V. Ferri; Arch. Pharm. (Weinheim) 324, 525 (1991)).
As the conglomerate of the (+)- and (-)-forms, e.g., racemate,
melts more than 20.degree. C. lower than the pure enantiomer,
melting point was found to be a sensitive method for assessing
enantiomeric purity. However, measurement of the enantiomeric
purity of two of the samples by chromatographic separation of a
derivative showed no loss of chiral purity. The enantiomeric purity
of the recovered CAF D-Base, near the detection limit of the HPLC
analysis method, was indistinguishable from the source
material.
Example 31
[0193] This example illustrates another method for preparing
racemic CPTA.
[0194] A 500-mL round-bottom flask in a heating mantel and fitted
with an overhead stirrer and condenser was charged with 73.28 g
(0.430 mol) of 4-chlorophenylactic acid, 70 ml, of
1,2-dichloroethane, and 41 mL (0.56 mol) of thionyl chloride. The
mixture was warmed at 50 to 55.degree. C. for 19 h. The reaction
mixture was analyzed by HPLC analysis. To the solution of acid
chloride was added 29 mL (0.57 mol) of bromine, and the solution
was warmed at 70 to 75.degree. C. for 20 h. The resulting
.alpha.-bromo product was cooled in an ice bath and 100 mL (1.31
mol) of 2-propanol was added dropwise. The maximum temperature
reached was 17.degree. C. After cooling to 4.degree. C., the
reaction mixture was added to water. The solution was warmed to
ambient temperature, and the aqueous layer was removed. The organic
phase washed with 37 mL of water. The separated 1,2-dichloroethane
solution was evaporated to give 134.1 g of an oil.
[0195] A 1-L round-bottom flask with an overhead stirrer was
charged with 34.0 g (0.515 mol) of 85% potassium hydroxide and 370
mL of 2-propanol. The mixture was warmed to 41.degree. C. using a
water bath to dissolve much of the solid. The mixture was cooled in
an ice bath, and 73.8 g (0.455 mol) of
.alpha.,.alpha.,.alpha.-trifluoro-m-cresol was added dropwise. The
maximum temperature reached was 13.degree. C. The solution was
cooled to 5.degree. C. before the dropwise addition of 134.1 g of
the oil obtained above. The material was rinsed in with 18 g of
2-propanol. The slurry was evaporated to a residue, then charged
with 250 mL of water and 42.8 g (0.535 mol) of 50% aqueous sodium
hydroxide. The mixture was heated to reflux for 1 h.
[0196] After cooling to ambient temperature, the mixture was
diluted with 250 mL of 1,2-dichloroethane, and the pH was decreased
to 0.3 by the dropwise addition of 71 g (0.72 mol) of 37%
hydrochloric acid. After a phase separation, the solvent was
removed from the 1,2-dichloroethane phase to give 202.2 g of
residue. The residue was treated with 131 g of heptane, and
evaporated to a residue of 164 g. The process was repeated with 97
g of heptane, giving 160 g of an oil. The residual oil was stirred
at ambient temperature with 257 g of heptane to give a slurry,
which was chilled in an ice bath before isolation of the solid by
filtration. The filter cake washed with 49 g of heptane, then dried
under a vacuum to give 125.58 g (0.380 mol, 88% yield) of CPTA.
Example 32
[0197] This example illustrates a method for preparing a racemic
mixture of compound 4 of Example 22.
[0198] A 50-mL round-bottom flask equipped with a magnetic stirrer
and reflux condenser was charged with 2.10 g (6.35 mmol) of racemic
CPTA, 21 g of 2-propanol, and 0.50 g (4.2 mmol) of thionyl
chloride. HPLC analysis after 90 minutes at reflux indicated 84.2
area % of 7 and 12.7 area % of CPTA. An additional 1.0 g (8.4 mmol)
of thionyl chloride was added to give less than 1 area % of CPTA.
The solution was cooled to ambient temperature and treated with 1.0
g (12 mmol) of solid sodium bicarbonate. The solvent was
evaporated, and the residue dissolved in 25 mL of toluene. After
washing with water (2.times.10 mL), the solvent was evaporated to a
residue of 2.31 g (6.2 mmol, 98% yield) of compound 4 of Example 22
(95.8 area % of 7, 2.4 area % of toluene).
Example 33
[0199] This example illustrates a method for determining solubility
of racemic CPTA.
[0200] A 100 mL water jacketed resin pot with a magnetic stirrer
was connected to a recirculating water bath and charged with 9.44 g
of racemic CPTA and 16.78 g of 1,2-dichloroethane. The bath
temperature was warmed to 35.degree. C., and the slurry was stirred
for one hour. The agitator was shut off, and the solid was allowed
to settle for 30 min. A 0.1360 g sample of the supernate was
removed and diluted to 25.00 mL with acetonitrile, and the solution
was assayed by HPLC analysis. Results for this and a series of
other measurements are shown in FIGS. 11 and 19. For analysis at
about 2.degree. C., a 0.54 g-sample of CPTA in 1.92 g of
1,2-dichloroethane was stored in a refrigerator overnight before
analysis of the supernate by HPLC analysis. The solubility of CPTA
in heptane, included in FIG. 19 shown in FIG. 12, was determined in
a similar fashion.
Example 34
[0201] This example illustrates a method for resolving a racemic
mixture of CPTA.
[0202] A 1-L bottom-drain reactor was charged with 48.2 g (146
mmol) of CPTA, 16.4 g (77.3 mmol) of
(1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (CAF D-Base),
and 193 g of 2-propanol. The slurry was heated to 70.degree. C. to
give a solution, then cooled to 60.degree. C. and held for 1 h. The
resulting slurry was cooled at 0.25.degree. C./min to a jacket
temperature of 2.degree. C. and held for 14 h; the internal
temperature was 4.degree. C. The solid was isolated by vacuum
filtration and rinsed with 27 g of 2-propanol. The mother liquor
and wash solution was sampled for HPLC analysis, and the results
are shown in FIG. 13. The 50.48-g wetcake was reloaded to the 1-L
reactor with 193 g of 2-propanol, and the slurry warmed to a gentle
reflux with a jacket temperature of 85.degree. C. to give a
solution. The solution was sampled for HPLC analysis; the results
are listed in FIG. 13. A slurry formed upon cooling to 65.degree.
C. After warming to 68.degree. C. for 30 min, the slurry was cooled
to 40.degree. C. at 0.25.degree. C./min, then to 18.degree. C. at
0.4.degree. C./min, then to 2.degree. C. at 1.degree. C./min. (In
other preparations, linear cooling rates recorded in FIG. 14 were
used.) The solid was isolated by vacuum filtration, rinsed with 18
g of 2-propanol, and dried under vacuum to give 27.29 g (50.4 mmol,
34.5% yield) of (-)-CPTA/CAF D-Base. HPLC analysis results for the
isolated solid and mother liquor and wash are included in FIG.
13.
Example 35
[0203] This example illustrates preparation and resolution of
racemic CPTA from halofenate.
[0204] A 1-L round-bottom flask with an overhead stirrer was
charged with 129.75 g (0.312 mol) of racemic halofenate, 325 g of
water, and 32.6 g (0.408 mol) of 50% aqueous sodium hydroxide. The
slurry was heated to 60.degree. C. for 1 hour to give a solution,
then cooled. At a temperature of 40.degree. C., 328.5 g of
1,2-dichloroethane and 44 g (0.45 mol) of 37% hydrochloric acid
were added, and the two-phase mixture was cooled to 29.degree. C.
The pH of the aqueous phase was 0.85. The organic phase was
separated and washed with 250 mL of water, then evaporated to a
residue of 118.2 g. 2-Propanol (149 g) was added, and evaporated to
a residue of 131.2 g. The residue, containing theoretically 103.2 g
of racemic CPTA based on the amount of halofenate loaded, was
charged to a 1-L bottom-drain reactor with 33.10 g (0.1556 mol) of
CAF D-Base and 400 g of 2-propanol. The mixture was warmed to
67.degree. C. to give a light slurry, then cooled to 1.degree. C.
at 0.075.degree. C./min. The mixture was chilled to -7.degree. C.,
and the solid isolated by vacuum filtration and washed with 60 mL
of 2-propanol. HPLC analysis results of the isolated solid and the
492.8-g mother liquor and wash solution are shown in FIG. 13
(experiment 9). The 92.74-g wetcake was reloaded to the 1-L reactor
along with 477 g of 2-propanol, and the mixture heated to
75.degree. C. to give a solution. The solution was cooled to
5.degree. C. at 0.5.degree. C./min, and the crystallized solid
isolated by vacuum filtration, rinsed with 60 mL of 2-propanol, and
dried to give 51.81 g (0.0956 mol, 31% yield) of the (-)-CPTA CAF
D-Base diastereomeric salt. HPLC analysis results for the isolated
solid and 529.9 g of mother liquor and wash solution are included
in FIG. 13.
Example 36
[0205] This example illustrates a method for racemizing (+)-CPTA
and recovering racemic CPTA.
[0206] The resolution and recrystallization mother liquors from the
resolution of 103.2 g of CPTA described in Example 35 above,
containing 71.6 g (0.217 mol) of CPTA (44% ee of the
(+)-enantiomer) based on the yield and purity of the isolated
diastereomeric salt, was evaporated to a residue of 108.7 g. The
residue was treated with 176 g of 1,2-dichloroethane, 35.2 g of
water, and 6.8 g of 37% hydrochloric acid. The organic phase was
removed and evaporated to a residue to 79.0 g. Water (80 g) was
added, and the solvent evaporated to a residue of 78.1 g. The
residue was treated with 141.9 g of water and 24.6 g (0.308 mol) of
50% aqueous sodium hydroxide, and the solution was heated to reflux
for 4 hours to give a racemate by chiral HPLC analysis. The
solution was cooled and treated with 140 ml, of 1,2-dichloroethane
and 32.0 g (0.325 mol) of 37% hydrochloric acid. The organic phase
was removed and evaporated to a residue of 80.1 g, which was
treated with 250 mL of heptane in a 40.degree. C. water bath to
give a slurry. The solid was isolated by vacuum filtration and
dried to give 63.83 g (0.193 mol, 89% yield) of racemic CPTA.
Resolution of a sample gave results consistent with those of fresh
CPTA (entry 10 of FIG. 13).
Example 37
[0207] This example illustrates a method for isolating (-)-CPTA
from the diastereomeric salt.
[0208] A 500-mL flask with a magnetic stirrer was charged with 40.0
g (73.7 mmol) of (-)-CPTA/CAF D-Base, 100 g of 1,2-dichloroethane,
40 g of water and 7.6 g (77 mmol) of 37% hydrochloric acid. After
complete dissolution of the solid, the lower organic phase was
removed and washed with 10 mL of water. The pH of the combined
aqueous phase was 0.9.
[0209] HPLC assay of 128.2 g of the organic phase found 24.32 g
(73.6 mmol, 99.8% of theory) of (-)-CPTA as a solution in
1,2-dichloroethane.
Example 38
[0210] This example illustrates a vacuum purification of
N-acetylethanolamine.
[0211] A 50-mL round-bottom flask equipped with a magnetic stirrer,
heating mantel and a short path distillation head was charged with
29.09 g of N-acetylethanolamine and placed under a vacuum of
approximately 0.8 torr. Bubbles formed as the liquid was heated,
although no condensate was collected. Distillate was collected at a
head temperature of approximately 130.degree. C. to afford 26.71 g
(92% recovery) of N-acetylethanolamine as a clear liquid.
Example 39
[0212] This example illustrates a method for producing
(-)-halofenate.
[0213] A 500-mL round-bottom flask with a magnetic stirrer was
charged with 35.5 g (65.4 mmol) of the (-)-CPTA/CAF D-Base
diastereomeric salt (99.4% ee), 89.0 g of 1,2-dichloroethane, and
35.5 mL of water. To the slurry was added 6.7 g (68 mmol) of 37%
hydrochloric acid, and the mixture was stirred at ambient
temperature to give two clear phases. The lower organic phase was
removed and washed with 7.0 g of water. The organic phase was
evaporated to a residue of 26.13 g, then dissolved in 55.6 g of
1,2-dichloroethane and placed in a 250-mL round-bottom flask in a
heating mantel with a magnetic stirrer and fitted with a
reflux/distillation head. HPLC assay of the solution found 22.06 g
(66.7 mmol, 102% of theory) of CPTA. To the solution was added 7.5
mL (100 mmol) of thionyl chloride, and the solution was heated to
reflux for 2 hours. Heating was continued to collect 6.1 g of
distillate. The solution was cooled to ambient temperature, then
chilled in an ice bath for the addition of 25.85 g (251 mmol) of
distilled N-acetylethanolamine (KF analysis 1176 and 1288 ppm
water). The temperature rose to about 26.degree. C. after the
addition. The solution was added slowly with stirring to 9.90 g
(71.6 mmol) of potassium carbonate in 36 g of water chilled in an
ice bath. The maximum temperature reached was 15.degree. C. The
reaction mixture was rinsed in with 5 mL of 1,2-dichloroethane. The
lower organic phase was removed and washed with 37 mL of water. The
solution was evaporated to give an oil (32.84 g). The oil was
treated with 54 g of heptane, and the solvent was removed to give
31.56 g of a solid residue. To the solid was added 76 g of heptane,
and the solvent was removed to give 29.19 of a solid residue. The
solid was dissolved in 28 mL of 2-propanol at 40.degree. C., then
diluted with an additional 28 mL of 20 propanol and 334 mL of
heptane. Cooling to ambient temperature gave a thin slurry. A thick
slurry formed upon cooling in an ice bath. After stirring for 2
hours, the solid was isolated by vacuum filtration, rinsed with 29
g of heptane, and dried to give 14.21 g (34.2 mmol, 52.3% yield) of
(-)-halofenate. No (+)-halofenate was detected by chiral HPLC
analysis (>99.8% ee).
[0214] HPLC assay of 294.1 g of the mother liquor and wash found
11.2 g of halofenate and 1.26 g of CPTA. The solvent was
evaporated, and 12.47 g of the residue was dissolved in 14 mL of
2-propanol. Addition of 84 mL of heptane gave a slurry after
stirring overnight at ambient temperature. The slurry was chilled
in an ice bath and the solid was collected, rinsed with 9 g of
heptane, and dried to give 5.64 g (13.6 mmol, 20.7% yield, 89.9%
halofenate and 3.9% CPTA by HPLC analysis, 99.6% ee) of
(-)-halofenate. HPLC assay of 81.74 g of the mother liquor and wash
found 3.66 g (8.8 mmol, 13.5%) of halofenate and 0.93 g (2.8 mmol,
4.8%) of CPTA.
Example 40
[0215] This example illustrates a method for isolating racemic CPTA
sodium salt.
[0216] The mother liquors from a resolution crystallization and
recrystallization containing in theory 63.9 g (0.193 mol) of CPTA
based on the resolution recovery was evaporated to a residue of 91
g. The residue was dissolved in 146 g of 1,2-dichloroethane and
treated with 28.6 g of water and 6.3 g of 37% hydrochloric acid at
40.degree. C. The 219 g organic phase was evaporated to a residue
of 71.86 g. To the residue was added 120 g of water and 21.5 g
(0.269 mol) of 50% sodium hydroxide. The solution was heated to
reflux, then allowed to cool to ambient temperature to give a thick
slurry. The solid that formed upon cooling was isolated by vacuum
filtration, rinsed with 25 mL of water, then dried to give 31.78 g
(0.0901 mol, 46.7% recovery) of the sodium salt of CPTA. Chiral
HPLC analysis found that the material was racemic. HPLC assay of
the 188.6 g mother liquor and wash found 28.3 g (0.0856 mol, 44.4%)
of CPTA.
Example 41
[0217] This example illustrates a method for determining the
solubility of racemic CPTA sodium salt.
[0218] A 100-mL water jacketed resin pot with a magnetic stirrer
was connected to a recirculating water bath and charged with 3.48 g
of the racemic CPTA sodium salt and 20.0 g of water. The bath
temperature was warmed to 35.degree. C., and the slurry was stirred
for one hour. The agitator was shut off, and the solid was allowed
to settle for 30 min. The pH was 9.4. A 0.3036 g-sample of the
supernate was removed and diluted to 25.00 mL with acetonitrile,
and the solution was assayed by HPLC analysis. Analysis was
repeated at 47.degree. C. and at 19.degree. C. An additional 3.01 g
of CPTA sodium salt was added to maintain a slurry at the higher
temperature, and 25 g of water was added to give a thinner slurry
at the lower temperature. The pH was increased to 12.7 at ambient
temperature by the addition of 50% aqueous sodium hydroxide, and
the analysis was continued at 13.5, 25, 34, and 42.degree. C.
Results are shown in FIGS. 16 and 20.
Example 42
[0219] This example illustrates hydrolysis and racemization of
(+)-halofenate.
[0220] A 250-mL round-bottom flask equipped with a magnetic stirrer
and heating mantel was charged with 7.28 g (17.5 mmol) of
(+)-halofenate (86.9% ee), 72.2 g of water, and 4.21 g (52.6 mmol)
of 50% aqueous sodium hydroxide. The slurry was heated to 50 to
60.degree. C. The pH of the resulting solution was 12.8. Chiral
HPLC analysis showed 80.4% of (+)-CPTA and 10.5% of (-)-CPTA. The
solution was heated to reflux for 90 minutes. Chiral HPLC analysis
showed 49.6% of (+)-CPTA and 47.0% of (-)-CPTA. The pH was 12.6.
After cooling to ambient temperature, approximately 50 mL of
1,2-dichloroethane was added, and the pH was adjusted to 0.8 by the
addition of 7.3 g (74 mmol) of 37% hydrochloric acid. The organic
phase was evaporated to a residue of 6.0 g. The residue was treated
with 25 mL of heptane, warmed to dissolve the oil, and then cooled
in an ice bath. The solid was collected by vacuum filtration and
dried to give 5.10 g (15.4 mmol, 88% yield) of racemic CPTA. Data
for this and two similar hydrolyses are shown in FIGS. 17 and
21.
[0221] Similarly, heating 6.75 g (16.3 mmol) of (+)-halofenate with
0.65 g (8.1 mmol) of 50% aqueous sodium hydroxide in 67.5 g of
water for 2 hours at 60.degree. C. gave 37.5% of halofenate and
54.2% of CPTA. Heating to reflux overnight gave 92.1% of CPTA and
1.1% of halofenate, with a final pH of 4.8. Chiral HPLC analysis
found an 80.3/12.8 ratio of (+)/(-)-CPTA.
Example 43
[0222] This example illustrates preparation of (-)-halofenate with
recovery of the (-)-CPTA/CAF D-Base diastereomeric salt from the
(-)-halofenate crystallization mother liquors.
[0223] A 1-L round bottom flask with magnetic stirring was charged
with 50.0 g (92.3 mmol) of the (-)-CPTA/CAF D-Base diastereomeric
salt (97.1% ee), 124 g of 1,2-dichloroethane, 50 mL of water, and
9.6 g (98 mmol) of 37% hydrochloric acid. The organic phase was
separated and washed with 50 mL of water, then placed in a 250-mL
round-bottom flask in a heating mantel with a magnetic stirrer. A
reflux/distillation head was attached, and the solution was heated
to remove 35.4 g of distillate by distillation. After cooling to
40.degree. C., the solution was diluted with 25 mL of
1,2-dichloroethane, and 11 mL (150 mmol) of thionyl chloride was
added. After heating at reflux for 2 hours and removing 22.6 g of
distillate, the solution was cooled in an ice bath for the dropwise
addition of 38.6 g (374 mmol) of distilled N-acetylethanolamine.
The reaction temperature rose from 7 to 18.degree. C. during the
addition. After stirring overnight at ambient temperature, the
solution was added with stirring to 12.7 g of potassium carbonate
in 51 mL of water chilled in an ice bath. The organic phase was
removed and washed with 51 g of water. The organic phase (85.2% of
halofenate and 6.1% CPTA by HPLC analysis) was evaporated to an oil
of 44.3 g, treated with 133 g of heptane, then evaporated to a
solid of 43.3 g. The solid residue was dissolved in 61.5 g of
2-propanol and charged to the 1-L bottom-drain reactor along with
320 g of heptane, warmed to 50.degree. C., and cooled at 3.degree.
C./min to 20.degree. C., then at 1.degree. C./min to -3.degree. C.
The solution became hazy at 27.degree. C., and a thick slurry
formed at 15.degree. C. The solid was isolated by vacuum
filtration, washed with 40 mL of heptane containing 5 mL of
2-propanol, and dried to give 21.01 g (50.6 mmol. 55% yield, 98.93%
by HPLC) of (-)-halofenate (99.9% ee). The 395.7 g mother liquor
and wash solution, containing 14.65 g (35.3 mmol) of halofenate
(88.3% ee) and 1.78 g (5.4 mmol) of CPTA by HPLC assay, was
evaporated to a residue of 21.57 g. The residue was heated to
50.degree. C. with 100 mL of water and 5.0 g (63 mmol) of 50%
aqueous sodium hydroxide to give a solution. HPLC analysis after
about 10 minutes found 83.6% of CPTA and 0.3% of halofenate. The
solution was cooled, diluted with 50 mL of 1,2-dichloroethane, and
the pH decreased from 12.7 to 1.6 with 7.3 g (74 mmol) of 37%
hydrochloric acid. After washing with 30 mL of water, the 72.9 g
organic phase, containing 11.32 g (34.2 mmol) of CPTA by HPLC
assay, was evaporated to a residue, treated with 36 g of heptane,
then evaporated to a residue of 14.9 g. The oily residue was
dissolved in 38 g of heptane with heating. Cooling gave an oil. The
solvent was removed and the residual oil dissolved in 34.8 g of
methylcyclohexane. An oil formed with cooling. The solvent was
removed and replaced with 45.6 g of 2-propanol. Chiral HPLC
analysis found 65.8% ee of (-5)-CPTA (a (+)/(-)-ratio of
16.9/81.6). To the solution at ambient temperature was added 6.50 g
(30.6 mmol) of CAF D-Base. A thick slurry rapidly formed. The
slurry was warmed to 40.degree. C. with stirring, then cooled in an
ice bath and the solid isolated by a vacuum filtration, washed with
7 g of 2-propanol, and dried to give 13.91 g (25.7 mmol) of
(-)-CPTA/CAF D-Base diastereomeric salt, which corresponds to 28%
recovery of the 50.0 g of salt initially loaded. The (+)/(-)-CPTA
ratio was 1.77/97.86. HPLC assay of the 45.34-g mother liquor and
wash solution found 4.34 g (13.1 mmol) of CPTA, which corresponds
to 14 mol % of the 50.0 g of salt initially loaded.
Example 44
[0224] This example illustrates a process for recovering CAF D-Base
from CPTA/CAF D-Base salt.
[0225] A 1-L round-bottom flask with a magnetic stirrer was charged
with 80.16 g (0.148 mol) of the (-)-CPTA/CAF D-Base salt, 237 g of
1,2-dichloroethane, and 80 mL of water. To the slurry was added
15.2 g (0.154 mol) of 37% hydrochloric acid, giving two clear
phases. The pH of the aqueous layer was 1.2. The lower organic
layer was removed and washed with 16 mL of water. The combined
aqueous phase (140.7 g) was treated with 12.9 g (0.161 mol) of 50%
aqueous sodium hydroxide to reach a pH of 12.1. The resulting
slurry was filtered and the solid was rinsed with 25 mL of water
and dried to give 30.79 g (0.145 mol, 98% recovery) of CAF D-Base
(mp 160.4-161.0.degree. C.).
Example 45
[0226] This example illustrates a process for recovering CAF D-Base
from the resolution mother liquor.
[0227] A 60.0 g sample of racemic CPTA was resolved with 20.88 g of
CAF D-Base in 240 g of 2-propanol as described above to give a 74.7
g wetcake. The wetcake was recrystallized in 218 g of 2-propanol to
give 32.35 g (32.8% yield) of (-)-CPTA/CAF D-Base salt. The mother
liquor and wash solutions from the crystallization and
recrystallization, theoretically containing 40.32 g of CPTA and
8.23 g (38.8 mmol) of CAF D-Base from the amount of salt obtained,
was evaporated to a residue of 72.9 g. The residue was dissolved in
265 g of 1,2-dichloroethane, 50 mL of water, and 4.0 g (40.6 mmol)
of 37% hydrochloric acid. The aqueous layer was separated, and the
pH was increased from 0.6 to 12.3 by the addition of 3.88 g (48.5
mmol) of 50% aqueous sodium hydroxide. The resulting slurry was
filtered and the solid was collected and rinsed with water to give
7.12 g (33.6 mmol, 87% recovery) of CAF D-Base (mp
162.4-163.0.degree. C.).
[0228] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
modifications or changes in light thereof will be suggested to
persons skilled in the art and are to be included within the spirit
and purview of this application and scope of the appended claims.
All publications, patents, and patent applications cited herein are
hereby incorporated by reference in their entirety for all
purposes.
* * * * *