Note: Descriptions are shown in the official language in which they were submitted.
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PROCESS FOR PREPARING OPTICALLY ACTIVE
~ CARBOXYLIC ACIDS
Brief Sl~mm~rv of the Invention
Related Applications
The following are related, commonly assigned applications
filed on an even date herewith: U.S. Patent Application Serial No. (D-
17378) and U.S. Patent Application Serial No. (D-17379), both of which
are incorporated herein by reference.
Technical Field
This invention relates to a process for preparing optically
- active carboxylic acids by oxidizing an optically active aldehyde with a
peracid in the presence of an amine and/or amine N-oxide catalyst to
produce the optically active carboxylic acid.
R~ckFround of the Invention
Asymmetric synthesis is of importance, for example, in
the pharmaceutical industry, since frequently only one optically active
isomer (enantiomer) is therapeutically active. An example of such a
pharmaceutical product is the non-steroidal anti-infl:~mm~tory drug
naproxen. The S enantiomer is a potent anti-arthritic agent while the
R enantiomer is a liver toxin. It is therefore oftentimes desirable to
selectively produce one particular enantiomer over its mirror image.
It is known that special precautions must be taken to
ensure production of a desired enantiomer because of the tendency to
produce optically inactive racemic mixtures, that is equal amounts of
each mirror image enantiomer whose opposite optical activities cancel
out each other, or partially optically active mixtures, that is other than
equal amounts of each enantiomer which may be looked at as mixtures
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of the optically inactive racemic mixture and the optically ratio
enantiomer which is in excess. In order to obtain the desired
enantiomer (or mirror image stereoisomer) from such a racemic
mixture, the racemic mixture must be separated into its optically
active components. This separation, known as optical resolution, may
be carried out by actual physical sorting, direct crystallization of the
racemic mixture, or other methods known in the art (see, for example,
U.S Patent 4,242,193). Such optical resolution procedures are often
laborious and expensive as well as destructive to the desired
enantiomer. Due to these difficulties, increased attention has been
placed upon asymmetric synthesis in which one of the enantiomers is
obtained in sigIuficantly greater amounts than the other enantiomer.
Efficient asymmetric synthesis affords a high degree of control in
stereoselectivity and, desirably, regioselectivity where applicable, e.g.,
branched/normal isomer ratio in alpha-olefin hydroformylation.
Disclosure of the Invention
This invention relates to a process for producing an
optically active carboxylic acid which process comprises oxidizing an
optically active aldehyde with a peracid in the presence of an amine
and/or amine N-oxide catalyst selected from the group consisting of a
substituted or unsubstituted alkyl amine, alkyl amine N-oxide,
aromatic amine, aromatic amine N-oxide, heterocyclic amine,
heterocyclic amine N-oxide and mixtures thereof, to produce the
optically active carboxylic acid, wherein said amine and/or amine N-
oxide catalyst has a basicity sufficient to catalyze said n~ ing of the
optically active aldehyde to the optically active carboxylic acid.
This invention also relates to a process for producing an
optically active carboxylic acid which process comprises: (1) reacting a
prochiral or chiral compound with carbon monoxide and hydrogen in
the presence of an optically active metal-ligand complex catalyst to
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produce an optically active aldehyde; and (2) oxidizing the optically
- active aldehyde with a peracid in the presence of an amine and/or
amine N-oxide catalyst selected from the group consisting of a
substituted or unsubstituted alkyl amine, alkyl amine N-oxide,
aromatic amine, aromatic amine N-oxide, heterocyclic amine,
heterocyclic amine N-oxide and mixtures thereof, to produce the
optically active carboxylic acid, wherein said amine and/or amine N-
oxide catalyst has a basicity sufficient to catalyze said 0xi~ ing of the
optically active aldehyde to the optically active carboxylic acid.
This invention further relates to a process for producing
an optically active carboxylic acid which process comprises: (1) reacting
a prochiral or chiral olefinically unsaturated organic compound with
carbon monoxide and hydrogen in the presence of an optically act*e
rhodium-ligand complex catalyst to produce an optically active
aldehyde; and (2) oxidizing the optically active aldehyde with a peracid
in the presence of an amine and/or amine N-oxide catalyst selected
from the group consisting of a substituted or unsubstituted alkyl
amine, alkyl amine N-oxide, aromatic amine, aromatic ~mine N-oxide,
heterocyclic amine, heterocyclic amine N-oxide and mixtures thereof, to
produce the optically active carboxylic acid, wherein said amine and/or
amine N-oxide catalyst has a basicity sufficient to catalyze said
oxidizing of the optically active aldehyde to the optically active
carboxylic acid.
Detailed Description
Forming Enantiomeric Aldehvde Mixture
This invention encompasses first providing a suitable
enantiomeric aldehyde mixture. Such mixtures can be provided by
such known processes as non-asymmetric processes (e.g., non-
asymmetric hydroformylation, non-asymmetric olefin isomerization or
non-asymmetric aldol condensation) followed by conventional
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--4--
resolution processes (e.g., chiral chromatography, kinetic resolution or
other known resolution methods). However, the enantiomeric aldehyde
mixtures are preferably provided by carrying out any known
conventional non-asymmetric syntheses of aldehyde mixtures in an
asymmetric fashion. In such preferred processes, the catalyst of a
conventional non-asymmetric synthesis is replaced by an optically
active metal-ligand complex catalyst and the process is conducted to
produce a suitable optically active aldehyde mixture. Illustrative of
such asymmetric processes include, for example, asymmetric
hydlofo~ ylation, asymmetric olefin isomerization and asymmetric
aldol condensation.
Preferably, the first step of the process of this invention
comprises forming an enantiomeric aldehyde mixture by asymmetric
hydroformylation. Such asymmetric hydroformylation processes
involve the use of an optically active metal-phosphorus ligand complex
catalyst and, optionally, free ligand to produce optically active
aldehydes by reacting a prochiral or chiral olefinic compound with
carbon monoxide and hydrogen. The optically active aldehydes
produced in this preferred first step of the process of this invention are
compounds obtained by the addition of a formyl group to an olefinically
unsaturated carbon atom in the starting material with simultaneous
saturation of the olefinic bond. The processing techniques of this
preferred first step of the process of this invention may correspond to
any of the known processing techniques heretofore employed in
conventional asymmetric syntheses reactions, including asymmetric
hydroformylation reactions. For instance, the asymmetric processes
can be conducted in continuous, semi-continuous or batch fashion and
can involve a liquid recycle operation if desired. This asymmetric
hydroformylation process step is ~1 efel ably conducted in batch fashion.
Likewise, the manner or order of addition of the reaction ingredients,
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catalyst and solvent are also not critical and may be accomplished in
any conventional fashion.
Alternatively, as the first step in the process of this
invention, asymmetric olefin isomerization can be carried out in
accordance with conventional procedures known in the art to produce
the enantiomeric aldehyde mixtures used in this invention. For
example, allylic alcohols can be isomerized under isomerization
conditions in the presence of an optically active metal-ligand complex
catalyst described herein to produce optically active aldehydes.
Also alternatively, as the first step in the process of this
invention, asymmetric aldol condensation can be carried out in
accordance with conventional procedures known in the art to produce
the enantiomeric aldehyde mixtures used in this invention. For
example, optically active aldehydes can be prepared by reacting a
prochiral aldehyde and a silyl enol ether under aldol condensation
conditions in the presence of an optically active metal-ligand complex
catalyst described herein.
In general, the above-mentioned asymmetric synthesis
processes are carried out in a liquid reaction medium that contains a
solvent for the optically active catalyst, preferably one in which the
reaction ingredients including catalyst are substantially soluble. In
addition, it may be desired that the asymmetric processes be effected in
the presence of free ligand as well as in the presence of the optically
active complex catalyst. By "free ligand" is meant ligand that is not
complexed with the metal atom in the optically active complex catalyst.
The prochiral and chiral starting materials useful in the
processes for producing the enantiomeric aldehyde mixtures employed
in the process of this invention are chosen depending on the particular
asymmetric synthesis process that is used. Such starting materials are
well known in the art and can be used in conventional amounts in
~ accordance with conventional methods. Illustrative starting material
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reactants include, for example, substituted and unsubstituted
aldehydes (for aldol condensation processes), prochiral olefins (for
hydroformylation processes) and ketones (for aldol condensation
processes) and the like.
Illustrative olefin starting material reactants useful in
certain of the asymmetric synthesis processes for producing the
enantiomeric aldehyde mixtures employed in this invention (e.g.,
asymmetric hydroformylation) include those which can be terminally
or internally unsaturated and be of straight chain, branched-chain or
cyclic structure. Such olefins can contain from 2 to 40 carbon atoms or
greater and may contain one or more ethylenic unsaturated groups.
Moreover, such olefins may contain groups or substituents which do
not essentially adversely interfere with the asymmetric syntheses
process such as carbonyl, carbonyloxy, oxy, hydroxy, oxycarbonyl,
halogen, alkoxy, aryl, haloalkyl, and the like. Illustrative olefinic
unsaturated compounds include substituted and unsubstituted alpha
olefins, internal olefins, alkyl alkenoates, alkenyl alkanoates, alkenyl
alkyl ethers, alkenols and the like, e.g., 1-butene, 1-pentene, 1-hexene,
1-octene, 1-decene, 1-dodecene, 1-octadecene, 2-butene, isoamylene, 2-
pentene, 2-hexene, 3-hexene, 2-heptene, cyclohexene, propylene
dimers, propylene trimers, propylene tetramers, 2-ethylhexene, 3-
phenyl-1-propene, 1,4-hexadiene, 1,7-octadiene, 3-cyclohexyl-1-butene,
allyl alcohol, hex-1-en-4-ol, oct-1-en-4-ol, vinyl acetate, allyl acetate, 3-
butenyl acetate, vinyl propionate, allyl propionate, allyl butyrate,
methyl methacrylate, 3-butenyl acetate, vinyl ethyl ether, allyl ethyl
ether, n-propyl-7-octenoate, 3-butenenitrile, ~-h~en~nni-le, styrene,
norbornene, alpha-methylstyrene and the like. Illustrative preferred
olefinic unsaturated compounds include, for example, p-
isobutylstyrene, 2-vinyl-6-methoxynaphthylene, 3-ethenylphenyl
phenyl ketone, 4-ethenylphenyl-2-thienylketone, 4-ethenyl-2-
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~uorobiphenyl, 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)styrene, 2-
~ ethenyl-5-benzoylthiophene, 3-ethenylphenyl phenyl ether,
propenylbenzene, isobutyl-4-propenylbenzene, phenyl vinyl ether, vinyl
chloride and the like. Suitable olefinic unsaturated compounds useful
in certain asymmetric syntheses processes of this invention include
substituted aryl ethylenes described in U.S. Patent 4,329,507, the
disclosure of which is incorporated herein by reference. Mixtures of
different olefinic starting materials can be employed, if desired, in the
asymmetric syntheses processes used as the first step in the process of
this invention. More preferably, the first step involves
hydroformylating alpha olefin~_cont~ining from 4 to 40 carbon atoms or
greater and internal olefins con~inin~ from 4 to 40 carbon atoms or
greater or mixtures of such alpha olefins and internal olefins.
nlustrative prochiral and chiral olefins useful in the
processes that can be employe~ to produce the enantiomeric aldehyde
mixtures that can be employed in this invention include those
represented by the formula:
/
E~2 R4
wherein R1, R2, R3 and R4 are the same or different (provided Rl is
dirr~ lt from R2 or R3 is different from R4) and are selected from
hydrogen; alkyl; substituted alkyl, said substitution being selected
from dialkylamino such as benzylamino and dibenzylamino, alkoxy
such as methoxy and ethoxy, acylosy such as acetoxy, halo, nitro,
nitrile, thio, carbonyl, carboxamid~, carboxaldehyde, carboxyl,
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carboxylic ester; aryl including phenyl; substituted aryl including
phenyl, said substitution being selected from alkyl, amino including
alkylamino and dialkylamino such as benzylamino and dibenzyl~rnin--,
hyd. o~y, alkoxy such as methoxy and ethoxy, acyloxy such as acetoxy,
halo, nitrile, nitro, carboxyl, carboxaldehyde, carboxylic ester,
carbonyl, and thio; acyloxy such as acetoxy; alkoxy such as methoxy
and ethoxy; amino including alkylamino and dialkyl~min-- such as
benzylamino and dibenzyl~mino; acylamino and diacyl~rnin- such as
acetylbenzylamino and diacetyl~minr); nitro; carbonyl; nitrile; carboxyl;
carboxamide; carboxaldehyde; carboxylic ester; and alkylmercapto such
as methylmercapto. It is understood that the prochiral and chiral
olefins of this definition also include molecules of the above general
formula where the R-groups are connected to form ring compounds,
e.g., 3-methyl-1-cyclohexene, and the like.
The optically active catalyst useful in producing the
aldehyde mixtures that are employed in this invention includes an
optically active metal-ligand complex catalyst in which the ligand is
optically active, ~ efe. ~bly optically pure. The permissible metals
which make up the optically active metal-ligand complexes include
Group VIII metals selected from rhodium (Rh), cobalt (Co), iridium (Ir),
ruthenil~m (Ru), iron (Fe), nickel (Ni), p~ ium (Pd), platinum (Pt),
osmium (Os) and mixtures thereof, with the p. efe~led metals being
rhodium, cobalt, iridium and ruthenium, more preferably rhodium and
ruthenium, especially rhodium. Other permissible metals include
Group IB metals selected from copper (Cu), silver (Ag), gold (Au) and
mixtures thereof, and also Group VIB metals selected from chromium
(Cr), molybdenum (Mo), tungsten (W) and mixtures thereof, and also
Group VA metals selected from arsenic (As) and antimony (Sb) and
mixtures thereof. Mixtures of metals from Group VIII, Group IB,
Group VIB and Group VA may be used in this invention. It is to be
noted that the successful practice of this invention does not depend and
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is not predicated on the exact structure of the optically active metal-
~ ligand complex species, which may be present in their mononuclear,
dinuclear and or higher nuclearity forms, provided the ligand is
optically active. Indeed, the exact optically active structure is not
known. Although it is not intended herein to be bound to any theory or
me~ h~ni.qtic discourse, it appears that the optically active catalytic
species may in its simplest form consist essentially of the metal in
complex comhin~t.ion with the optically active ligand and, in
hydroformylation, carbon monoxide, hydrogen and an olefin.
The term "complex" as used herein and in the claims
means a coordination compound formed by the union of one or more
electronically rich molecules or atoms capable of independent existence
with one or more electronically poor molecules or atoms, each of which
is also capable of independent existence. For example, the ~ ere~led
optically active ligands employable herein, i.e., phosphorus ligands,
may possess one or more phosphorus donor atoms, each having one
available or lln.~h~red pair of electrons which are each capable of
forming a coordinate covalent bond independently or possibly in
concert (e.g., via chelation) with the metal. As can be surmised from
the above discussions, carbon monoxide (which is also properly
~l~q.~ified as ligand) can also be present and complexed with the metal.
The ultimate composition of the optically active complex catalyst may
also contain an additional ligand, e.g., hydrogen or an anion satisfying
the coordination sites or nuclear charge of the metal. Illustrative
additional ligands include, e.g., halogen (Cl, Br, I), alkyl, aryl,
substituted aryl, acyl, CF3, C2F5,
CN, R2PO and RP(O)(OH)O (wherein each R is alkyl or aryl), acetate,
acetylacetonate, SO4, PF4, PF6, NO2, NO3, 3 2 2
C6H~CN, CH3CN, NO, NH3, pyridine, (C2H~)3N, mono-olefins,
diolefins and triolefins, tetrahydrofuran, and the like. It is of course to
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- 10-
be understood that the optically active complex species is ~L~e.dbly
free of any additional organic ligand or anion that might poison the
catalyst and have an undue adverse effect on catalyst performance. It
is preferred in the rhodium-catalyzed asymmetric hydroformylation
reactions of this invention that the active catalysts be free of halogen
and sulfur directly bonded to the rhodium, although such may not be
absolutely nec~q.q~ry.
The number of available coordination sites on such metals
is well known in the art. Thus the optically active species may
comprise a complex catalyst mixture, in their monomeric, dimeric or
higher nuclearity forms, which are 5J~ efes dbly characterized by at least
one phosphorus-cont~inin~ molecule complexed per one molecule of
rhodium. As noted above, it is considered that the optically active
species of the preferred rhodium catalyst employed in this invention
during asymmetric hydroformylation may be complexed with carbon
monoxide and hydrogen in addition to the optically active phosphorus
ligands in view of the carbon monoxide and hydrogen gas employed by
the asymmetric hydroformylation process.
Moreover, regardless of whether the optically active
complex catalyst is formed prior to introduction into the reaction zone
or whether the active catalyst is prepared in situ during the reaction,
the asymmetric synthesis processes (and especially the asymmetric
hydroformylation processes) may, if desired, be effected in the presence
of free ligand.
The ligands employable in producing the enantiomeric
aldehyde mixtures useful in this invention include those optically
active ligands having the general formula:
- SU~ )TE SHEET (RULE 26)
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W X y
Z _ m
wherein each W is the same or different and is phosphorus, arsenic or
antimony, each X is the same or different and is oxygen, nitrogen or a
covalent bond linking W and Y, Y is an m-valent substituted or
unsubstituted hydrocarbon residlle, each Z is the same or different and
is a substituted or unsubstituted hydrocarbon residue, preferably a
hydrocarbon residue containing at least one heteroatom which is
bonded to W, or the Z substituents bonded to W may be bridged
together to form a substituted or unsubstituted cyclic hydrocarbon
residue, preferably a cyclic hydrocarbon residue cont~ining at least 2
heteroatoms which are each bon~ed to W, and m is a value equal to the
free valence of Y, preferably a val~;e of from 1 to 6, provided at least
one of Y and Z is optically active.
Referring to the above general formula, it is appreciated
that when m is a value of 2 or greater, the ligand may include any
combination of permissible cyclic hydrocarbon residues and/or acyclic
hydrocarbon residues which satisfy the valence of Y. It is also
appreciated that the hydrocarbon residues represented by Z may
include one or more heteroato~s and such heteroatom may be directly
bonded to W. The optically acti~e ligands included in the above
general structure should be easil~ ascertainable by one skilled in the
~ art.
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- 12 -
Illustrative optically active ligands employable in the first
step of the processes this invention include those of the formulae:
Z/C~W--O--Y
\0/
_ m
W O--Y
/
_Z _ m
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- 13-
Z W- Y
\0/
Z W O Y
\ N
_ I _ m
y~
wherein W, Y, Z and m are as defined hereinabove and Y"' is the same
or different and is hydrogen or a substituted or unsubstituted
hydrocarbon residue. Illustrative preferred optically active ligands
encompassed by the above formulae include, for example,
(poly)phosphites, (poly)phosphinites, (poly)phosphonites and the like.
Illustrative ~ er~ d optically active ligands employable
in this invention include the following:
(i) optically active polyphosphites having the formula:
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(Ar) o
(CH2)y
(Q) n
(CE. 2)y
(Ar) O _ m'
wherein each Ar group is the same or different and is a substituted or
unsubstituted aryl radical; Y' is an m-valent substituted or
unsubstituted hydrocarbon radical selected from alkylene, alkylene-
oxy- alkylene, arylene and arylene-(CH2)y-(Q)n-(CH2)y- arylene; each
y is the same or different and is a value of O or 1; each n is the same or
different and is a value of O or l; each Q is the same or different and is
a substituted or unsubstituted divalent bridging group selected from -
CR1R2-, -O-, -S-, -NR3-, -SiR4R5- and -CO-, wherein R1 and R2 are the
same or different and are hydrogen or a substituted or unsubstituted
radical selected from alkyl of 1 to 12 carbon atoms, phenyl, tolyl and
anisyl, and R3, R4 and R5 are the same or different and are a radical
selected from hydrogen or methyl; and m' is a value of from 2 to 6;
(ii) optically active diorganophosphites having the
formula:
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(Ar) O
(Cl2)y
(Q) n
(CE-2)y
(Ar) O
wherein Y" is a substituted or unsubstituted monovalent hydrocarbon
radical, and Ar, Q, n and y are as defined above; and
(iii) optically active open-ended bisphosphites having
- the formula:
(~r) O O Y"
(cE- 2)y
(Q) n P 0- Y' O P
(CE: 2)y
(Ar) O
wherein Ar, Q, n, y, Y' and Y" are as defined above and Y" can be the
same or different.
Tllustrative aryl radicals of the Ar and Y' groups of the
above formulae include aryl moieties which may contain from 6 to 18
carbon atoms such as phenylene, naphthylene, anthracylene and the
like. In the above formulae, preferably m is from 2 to 4 and each y and
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each n has a value of 0. However, when n is 1, Q preferably is a -
CRlR2- bridging group as defined above and more preferably
methylene (-CH2-) or alkylidene (-CHR2-), wherein R2 is an alkyl
radical of 1 to 12 carbon atoms (e.g., methyl, ethyl, propyl, iso~o~yl,
butyl, dodecyl, etc.), especially methyl.
The m-valent hydrocarbon radicals represented by Y' in
the polyphosphite ligand formula above are hydrocarbons cont:~inin~
from 2 to 30 carbon atoms selected from alkylene, alkylene-oxy-
alkylene, arylene, and arylene-(-CH2-)y-(Q)n-(-CH2-)y- arylene
radicals, wherein Q, n and y are the same as defined above- Preferably
the alkylene moieties of said radicals contain from 2 to 18 carbon
atoms and more preferably from 2 to 12 carbon atoms, while the
arylene moieties of said rz3-1icz~1~ preferably contain from 6 to 18 carbon
atoms.
The divalent bridging group represented by Y' in the
open-ended bisphosphite ligand formula above are divalent
hydrocarbons cont~inin~ from 2 to 30 carbon atoms selected from
alkylene, alkylene-oxy-alkylene, arylene and arylene-(-CH2-)y-(Q)n-
(-CH2-)y-arylene radicals, wherein Q, n and y are the same as defined
above. Preferably the alkylene moieties of said radicals contain from 2
to 18 carbon atoms and more preferably from 2 to 12 carbon atorns,
while the arylene moieties of said radicals preferably contain from 6 to
18 carbon atoms.
Hydrocarbon radicals represented by Y" in the above
phosphite ligand formulae include monovalent hydrocarbon radicals
cont~ining from 1 to 30 carbon atoms selected from alkyl radicals
including linear or branched primary, secondary or tertiary alkyl
radicals, such as methyl, ethyl, n-propyl, isopropyl, amyl, sec-amyl, t-
amyl, 2-ethylhexyl and the like; aryl radicals such as phenyl, naphthyl
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and the like; aralkyl radicals such as benzyl, phenylethyl, tri-
- phenylmethylethane and the like; alkaryl radicals such as tolyl, xylyl
and the like; and cycloalkyl radicals such as cyclopentyl, cyclohexyl,
cyclohexylethyl and the like. Preferably, ~' is selected from alkyl and
aryl r~rlic~l~ which contain from about 1 and 30 carbon atoms.
Preferably, the alkyl radicals contain from 1 to 18 carbon atoms, most
1~ efeL ably from 1 to 10 carbon atoms, while the aryl, aralkyl, alkaryl
and cycloalkyl radicals preferably contain from 6 to 18 carbon atoms.
Further, although each Y" group in the open-ended bisphosphite ligand
formula above may differ from the other, preferably they are identical.
The aryl radicals in the above forInulae may also be
substituted with any substituent radical that does not unduly
adversely affect the processes of this invention. Illustrative
substituents include radicals cont~ining from 1 to 18 carbon atoms
such as alkyl, aryl, aralkyl, alkaryl and cycloalkyl radicals; alkoxy
radicals; silyl radicals such as -Si(R9)3 and -Si(OR9)3; amino r~tlic~l.c
such as -N(R9)2; acyl radicals such as -C(O)R9; acyloxy radicals such
as -OC(O)R9; carbonyloxy radicals such as -COOR9; amido radicals
such as -C(O)N(R9)2 and -N(R9)COR9; sulfonyl radicals such as -
SO2R9; sulfinyl radicals such as -SoR9; sulfenyl radicals such as -SR9;
phosphonyl radicals such as -P(O)(R9)2; as well as halogen, nitro,
cyano, trifluoromethyl and hydroxy radicals and the like, wherein each
R9 can be a monovalent hydrocarbon radical such as alkyl, aryl,
alkaryl, aralkyl and cycloalkyl radicals, with the provisos that in
amino substitutents such as -N(R9)2, each R9 taken together can also
comprise a divalent bridging group that forms a heterocyclic radical
with the nitrogen atom, in amido substituents such as -C(O)N(R9)2
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- 18 -
and -N(R9)COR9, each R9 bonded to N can also be hydrogen, and in
phosphonyl substituents such as -P(O)(R9)2, one R9 can be hydrogen.
It is to be understood that each R9 group in a particular substituent
may be the same of different. Such hydrocarbon substituent radicals
could possibly in turn be substituted with a substituent such as
already herein outlined above provided that any such oc~:~ ~ ellce would
not unduly adversely effect the processes of this invention. At least
one ionic moiety selected from salts of carboxylic acid and of sulfonic
acid may be substituted on an aryl moiety in the above formulae.
Among the more preferred phosphite ligands useful in the
first step in the process of this invention are those ligands wherein the
two ~r groups linked by the bridging group represented by -(CH2)y-
(Q)n-(CH2)y- in the above formulae are bonded through their ortho
positions in r~l.qtinn to the oxygen atoms that connect the Ar groups to
the phosphorus atom. It is also preferred that any substituent radical,
when present on such Ar groups, be bonded in the para and/or ortho
position on the aryl in relation to the oxygen atom that bonds the
substituted Ar group to its phosphorus atom.
Illustrative monovalent hydrocarbon residues represented
by the Z, Y, Y" and Y"' groups in the above formulae include
substituted or unsubstituted monovalent hydrocarbon radicals
cont~ining from 1 to 30 carbon atoms selected from substituted or
unsubstituted alkyl, aryl, alkaryl, aralkyl and alicyclic radicals. While
each Z and Y" group in a given formula may be individually the same
or different, preferably they are both the same. More specific
illustrative monovalent hydrocarbon residues represented by Z, Y, Y"
and Y"' include primary, secondary and tertiary chain alkyl radicals
such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, neo-
pentyl, sec-amyl, t-amyl, iso-octyl, 2-ethylhexyl, iso-nonyl, iso-decyl,
octadecyl and the like; aryl radicals such as phenyl, naphthyl,
SUBSTITUTE SHEET (RULE 26)
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anthracyl and the like; aralkyl radicals such as benzyl, phenylethyl
- and the like; alkaryl radicals such as tolyl, xylyl, p-alkylphenyls and
the like; and alicyclic radicals such as cyclopentyl, cyclohexyl,
cyclooctyl, cyclohexylethyl, 1-methylcyclohexyl and the like. Preferably
the unsubstituted alkyl radicals may contain from 1 to 18 carbon
atoms, more preferably from 1 to 10 carbon atoms, while the
unsubstituted aryl, aralkyl, alkar.vl and alicyclic radicals preferably
contain from 6 to 18 carbon atoms. Among the more preferred Z, Y, Y"
and Y"' residues are phenyl and substituted phenyl radicals.
Illustrative divalent hydrocarbon residues represented by
Z, Y and Y' in the above formulae include substituted and
unsubstituted radicals selected fro~ alkylene, -alkylene-oxy-alkylene,
arylene, -arylene-oxy-arylene-, alicyclic radicals, phenylene,
naphthylene, -arylene-(CH2)y(Q)n(cH2)y-arylene- such as -phenylene-
(CH2)y(Q)n(cH2)y-phenylene- and-naphthylene-(CH2)y(Q)n(cH2~y-
naphthylene-r~-lic~lc7 wherein Q, y and n are as defined hereinabove.
More specific illustrative divalent radicals represented by Z, Y and Y'
include, e.g., 1,2-ethylene, 1,3-propylene, 1,6-hexylene, 1,8-octylene,
1,12-dodecylene, 1,4-phenylene, 1,8-naphthylene, 1,1'-biphenyl-2,2'-
diyl, 1,1'-binaphthyl-2,2'-diyl, 2,2'-binaphthyl-1,1'-diyl and the like.
The alkylene radicals may contain from 2 to 12 carbon atoms, while
the arylene radicals may contain ~rom 6 to 18 carbon atoms.
Preferably Z is an arylene radical, Y is an alkylene radical and Y' is an
alkylene radical.
Moreover, the above-described radicals represented by Z,
Y, Ar, Y' and Y" of the above formulae, may be further substituted with
any substituent that does not unduly adversely effect the desired
results of this invention. Illustrative substituents are, for example,
monovalent hydrocarbon radic~s having between one and about 18
carbon atoms, such as alkyl, aryl, alkaryl, aralkyl, cycloalkyl and other
radicals as defined above. In addition, various other substituents that
- SUD;~ 111 UTE S~ (RULE 26)
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-20 -
may be present include, e.g., halogen, preferably chlorine or fluorine, -
NO2, -CN, -CF3, -OH, -Si(CH3)3, -Si(OCH3)3, -Si(C3H7)3, -C(O)CH3, -
C(O)C2H5, -0C(O)C6H5, -C(O)OCH3, -N(CH3)2, -NH2, -NHCH3, -
NH(C H ) -CoNH2,-cON(cH3)2~-s(o)2c2H5~ OC 3~ 2 5
~C6H5~ -C(O)C6H5, -~(t-C4Hg), -SC2H~;, -OCH2cH2ocH3,
(OCH CH ) OCH3 -(OCH2CH2)30CH3~-SCH3~ S( ) 3 6 5
( )(C6H5)2 -P(o)(cH3)2~-p(o)(c2H5)2~-p(o)(c3H7)
P(~~C4Hg)2~ -P(o)(c6Hl3)2~ -P(O)CH3(C6H5), -P(O)(H)(C6H5),
NHC(O)CH3 and the like. Moreover, each Z, Y, Ar, Y and Y' group
may contain one or more such substituent groups which may also be
the same or different in any given ligand molecule. Preferred
substituent radicals include alkyl and alkoxy radicals cont.Siining from
1 to 18 carbon atoms and more preferably from 1 to 10 carbon atoms,
especially t-butyl and methoxy.
The optically active ligands employed in the complex
catalysts useful in the first step of the process of this invention are
uniquely adaptable and suitable for asymmetric syntheses processes,
especially rhodium-catalyzed asymmetric hydroformylation. For
instance, the optically active phosphorus ligands may provide very
good rhodium complex stability in addition to providing good catalytic
activity for the asymmetric hydroformylation of all types of permissible
olefins. Further, their unique chemical structure should provide the
ligand with very good stability against side reactions such as being
hydrolyzed during asymmetric hydroformylation, as well as upon
storage.
The types of optically active ligands of the generic class
employable in the first step of the process of this invention can be
prepared by methods known in the art. For instance, the optically
active phosphorus ligands employable in this invention can be
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prepared via a series of conventional phosphorus halide-alcohol or
~rnine condensation reactions in which at least one of the alcohol or
~mine ingredients is optically active or optically pure. Such types of
condensation reactions and the manner in which they may be
conducted are well known in the art. Moreover, the phosphorus
ligands employable herein can be readily identified and characterized
by conventional analytical techniques, such as Phosphorus-31 nuclear
magnetic resonance spectroscopy and Fast Atom Bombardment Mass
Spectroscopy if desired.
As noted above, the optically active ligands can be
employed as both the ligand of the above-described optically active
metal-ligand complex catalyst as well as the free ligand that can be
present in the reaction medium of the processes of this invention. In
addition, while the optically active ligand of the metal-ligand complex
catalyst and any excess free ligand preferably present in a given
process of this invention are normally the same ligand, different
optically active ligands, as well as mixtures of two or more different
optically active ligands, may be employed for each purpose in any given
process.
The optically active metal-ligand complex catalysts of this
invention may be formed by methods known in the art. See, for
example, U.S. Patent Nos. 4,769,498,4,717,775, 4,774,361, 4,737,588,
4,885,401, 4,748,261, 4,599,206, 4,668,651, 5,059,710 and 5,113,022,
all of which are incorporated herein by reference. For instance,
efo.llled metal hydrido-carbonyl catalysts may possibly be prepared
and introduced into the reaction medium of an asymmetric syntheses
process. More preferably, the metal-ligand complex catalysts of this
invention can be derived from a metal catalyst precursor which may be
introduced into the reaction medium for in situ formation of the active
catalyst. For example, rhodium catalyst precursors such as rhodium
dicarbonyl acetylacetonate, Rh2O3, Rh4(CO)12, Rh6(CO)16, Rh(N03)3
Sl,~ 111 ~.JTE SHEET (RULE 26)
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and the like may be introduced into the reaction medium along with
the ligand for the in situ formation of the active catalyst. In a
preferred embodiment, rhodium dicarbonyl acetylacetonate is
employed as a rhodium precursor and reacted in the presence of a
solvent with a phosphorus ligand compound to form a catalytic
rhodium-phosphorus cornplex precursor which is introduced into the
reactor, optionally along with excess free phosphorus ligand, for the in
situ formation of the active catalyst. In any event, it is sufficient for
the purpose of this invention to understand that an optically act*e
metal-ligand complex catalyst is present in the reaction medium under
the conditions of the asymmetric syntheses and more preferably
asymmetric hydroformylation process.
Moreover, the amount of optically active complex catalyst
- present in the reaction medium need only be that minimum amount
necessary to provide the given metal concentration desired to be
employed and which will furnish the basis for at least that catalytic
amount of metal necessary to catalyze the particular asymmetric
syntheses process desired. In general, metal concentrations in the
range of from about 1 ppm to about 10,000 ppm, calculated as free
metal, and ligand to metal mole ratios in the catalyst rz~n~ing from
about 0.5:1 to about 200:1, should be sufficient for most asymmetric
syntheses processes. Moreover, in the rhodium catalyzed asymmetric
hydroformylation processes of this invention, it is generally preferred
to employ from about 10 to 1000 ppm of rhodium and more preferably
from 25 to 750 ppm of rhodium, calculated as free metal.
A further aspect of the first step of the process of this
invention involves the use of a catalyst precursor composition
consisting essentially of a solubilized metal-ligand complex precursor
catalyst, an organic solvent and free ligand. Such precursor
compositions may be prepared by forming a solution of a metal starting
material, such as a metal oxide, hydride, carbonyl or salt e.g., a
SU~;~ UTE SHEET (RULE 26)
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-23-
nitrate, which may or may not be in complex combination with an
optically active ligand, an organic solvent and a free ligand as defined
herein. Any suitable metal starting material
may be employed, e.g., rhodium dicarbonyl acetylacetonate, Rh203,
Rh4(CO)12, Rh6(CO)16, Rh(NO3)3, polyphosphite rhodium carbonyl
hydrides, iridium carbonyl, poly-phosphite iridium carbonyl hydrides
osmium halide, chlorosmic acid, osmium carbonyls, palladium hydride,
palladous halides, platinic acid, platinous halides, ruthenium
carbonyls, as well as other salts of other metals
and carboxylates of C2-C16 acids such as cobalt chloride, cobalt
nitrate, cobalt acetate, cobalt octoate, ferric acetate, ferric nitrate,
nickel fluoride, nickel sulfate, p~ lium acetate, osmium octoate,
iridiu~n sulfate, ruthenium nitrate, and the like. Of course, any
suitable solvent may be employed such as those employable in the
asymmetric syntheses process desired to be carried out. The desired
asymmetric syntheses process may of course also dictate the various
amounts of metal, solvent and optically active ligand present in the
precursor solution. Optically active ligands if not already complexed
with the initial metal may be complexed to the metal either prior to or
in situ during the asymmetric syntheses process.
The optically active catalyst used in the first step of the
process of this invention may optionally be supported. Advantages of a
supported catalyst may include ease of catalyst separation and ligand
recovery. Illustrative examples of supports include alllmin:~, silica gel,
ion-~h~nge resins, polymeric supports and the like.
The process conditions employable in the asymmetric
processes that can be employed in the first step of the process of this
invention are chosen depending on the particular asymmetric
synthesis process. Such process conditions are well known in the art.
- All of the asymmetric syntheses processes useful in this invention can
SUBSTITUTE SHEET (RULE 26)
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-24 -
be carried out in accordance with conventional procedures known in
the art. Illustrative reaction conditions for conducting the asymmetric
syntheses processes of this invention are described, for example, in
Bosnich, B., Asymmetric Catalysis, Martinus Nijhoff Publishers, 1986
and Morrison, James D., Asymmetric Synthesis, Vol. 5, Chiral
Catalysis, Academic Press, Inc., 1985, both of which are incorporated
herein by reference. Depending on the particular process, operating
temperatures can range from about -80~C or less to about 500~C or
greater and operating pressures can range from about 1 psig or less to
about 10,000 psig or greater.
The reaction conditions for effecting the p. ef~ d
asymmetric hyd~oroLlllylation process that can be employed in the first
step of the process of this invention may be those heretofore
conventionally used and may comprise a reaction temperature of from
about -25~C or lower to about 200~C and pressures r~nging from about
1 to 10,000 psia. While the preferred asymmetric syntheses process is
the hydroformylation of olefinically unsaturated compounds carbon
monoxide and hydrogen to produce optically active aldehydes, it is to
be understood that the optically active metal-ligand complexes may be
employed as catalysts in other types of asymmetric syntheses processes
to obtain good results.
As noted, the first step of the preferred process of this
invention involves the production of optically active aldehydes via
asymmetric hydroformylation of a prochiral or chiral olefinic
unsaturated compound with carbon monoxide and hydrogen in the
presence of an optically active metal-phosphorus ligand complex
catalyst and, optionally, free phosphorus ligand, especially an optically
active rhodium-phosphorus ligand complex catalyst.
While the optimization of the reaction conditions
necessary to achieve the best results and efficiency desired are
dependent upon experience in the utilization of this invention, only a
S~ ITE SHEET (RULE 26)
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- 25-
certain measure of experimentation should be necessary to ascertain
those conditions which are optimum for a given situation and such
should be well within the knowledge of one skilled in the art and easily
obtainable by following the more preferred aspects of this invention as
explained herein andlor be simple routine experimentation. For
instance, the total gas pressure of hydrogen, carbon monoxide and
olefinic unsaturated starting compound of the preferred asymmetric
hydroformylation process of this invention may range from about 1 to
about 10,000 psia. More preferably, however, in the asymmetric
hydroformylation of prochiral olefins to produce optically act*e
aldehydes, it is preferred that the process be operated at a total gas
pressure of hydrogen, carbon monoxide and olefinic unsaturated
starting compound of less than about 1500 psia, and more preferably
less than about 1000 psia. The minimum total pressure of the
reactants is not particularly critical and is limited predominately only
by the amount of re~ct~nts necessary to obtain a desired rate of
reaction. More specifically, the carbon monoxide partial pressure of
the asymmetric hydroformylation process of this invention is
preferably from about 1 to about 360 psia, and more preferably from
about 3 to about 270 psia, while the hydrogen partial pressure is
preferably about 16 to about 480 psia and more preferably from about
30 to about 300 psia. In general, the molar ratio of gaseous hydrogen
to carbon monoxide may range from about 1:10 to 100:1 or higher, the
more ~ efe~l ed hydrogen to carbon monoxide molar ratio being from
about 1:1 to about 1:10. Higher molar ratios of carbon monoxide to
gaseous hydrogen may generally tend to favor higher branched/normal
isomer ratios.
Further as noted above, the preferred asymmetric
hydroformylation process useful in the first step of the process of this
invention may be conducted at a reaction temperature from about -
25~C or lower to about 200~C. The preferred reaction temperature
SUBSTITUTE SHEET (RULE 26)
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- 26 -
employed in a given process will of course be dependent upon the
particular olefinic starting material and optically active metal-ligand
complex catalyst employed as well as the efficiency desired. Lower
reaction temperatures may generally tend to favor higher enantiomeric
excesses (ee) and branched/normal ratios. In general, asymmetric
hydroformylations at reaction temperatures of about 0~C to about
120~C are ~ ~r~ d for all types of olefinic starting materials. More
preferably, alpha-olefins can be effectively hydroformylated at a
temperature of from about 0~C to about 90~C while even less reactive
olefins than conventional linear alpha-olefins and internal olefins as
well as mixtures of alpha-olefins and internal olefins are effectively
and preferably hydroformylated at a temperature of from about 25~C to
about 120~C. Indeed, in the rhodium-catalyzed asymmetric
hydroformylation process of this invention, no substantial benefit is
seen in operating at reaction temperatures much above 120~C and such
is considered to be less desirable.
The processes employed in the first step of the process of
this invention are conducted for a period of time sufficient to produce
an enantiomeric aldehyde mixture. The exact reaction time employed
is dependent, in part, upon factors such as temperature, nature and
proportion of starting materials, and the like. The reaction time will
normally be within the range of from about one-half to about 200 hQurs
or more, and preferably from less than about one to about 10 hours.
The asymmetric synthesis processes, preferably
asymmetric hydroformylation processes, useful as the first step in the
process of this invention can be carried out in either the liquid or
gaseous state and involve a batch, continuous liquid or gas recycle
system or combination of such systems. A batch system is preferred for
conducting such processes. Preferably, such asymmetric
hydroformylation involves a batch homogeneous catalysis process
wherein the hydroformylation is carried out in the presence of both free
SlJ~;~ UTE SHEET (RULE 26)
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-27 -
phosphorus ligand and any suitable conventional solvent as further
- described herein.
The asymmetric synthesis processes, and ~ efe. dbly
asymmetric hyd. ofo~ ylation process, useful as the first step in the
process of this invention may be conducted in the presence of an
organic solvent for the optically active metal-ligand complex catalyst.
Depending on the particular catalyst and reactants employed, suitable
organic solvents include, for example, alcohols, alkanes, alkenes,
alkynes, ethers, aldehydes, ketones, esters, acids, amides, amines,
aromatics and the like. Any suitable solvent which does not unduly
adversely interfere with the intended asymmetric synthesis process
can be employed and such solvents may include those heretofore
commonly employed in known metal catalyzed processes. Increasing
the dielectric constant or polarity of a solvent may generally tend to
favor increased reaction rates and selectivity. Mixtures of one or more
different solvents may be employed if desired. The amount of solvent
employed is not critical to this invention and need only be that amount
sufflcient to provide the reaction medium with the particular metal,
substrate and product concentration desired for a given process. In
general, the amount of solvent when employed may range from about 5
percent by weight up to about 9~ percent by weight or more based on
the total weight of the reaction medium.
As noted above, the metal-ligand-catalyzed asymmetric
synthesis processes (and especially the asy~nmetric hydroformylation
process) useful as the first step in the process of this invention can be
carried out in the presence of free ligand, i.e., ligand that is not
complexed with the metal of the optically active metal-ligand complex
catalyst employed. While it is yL ~fe~ ~L ed to employ a free ligand that is
the same as the ligand of the metal-ligand complex catalyst such
ligands need not be the same in a given process, but can be different if
~ -desired While the asymmetric syntheses and preferably asymmetric
SUBSTITUTE SHEET (RULE 26)
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-28 -
hydroformylation process may be carried out in any excess amount of
free ligand desired, the employment of free ligand may not be
absolutely necessary. Accordingly, in general, amounts of ligand of
from about 2 to about 100, or higher if desired, moles per mole of metal
(e.g., rhodium) present in the reaction medium should be suitable for
most purposes, particularly with regard to rhodium catalyzed
hydroformylation; said amounts of ligand employed being the sum of
both the amount of ligand that is bound (complexed) to the metal
present and the ~mount of free (non-complexed) ligand present. Of
course, if desired, make-up ligand can be supplied to the reaction
medium of the asymmetric hyd~vfo~lllylation process, at any time and
in any suitable manner, to m~intslin a predetermined level of free
ligand in the reaction medium.
The ability to carry out the processes useful as the first
step of the process of this invention in the presence of free ligand can
be a beneficial aspect of this invention in that it removes the criticality
of employing very low precise concentrations of ligand that may be
required of certain complex catalysts whose activity may be retarded
when even any amount of free ligand is also present during the
process, particularly when large scale commercial operations are
involved, thus helping to provide the operator with greater proce.q.qinF
latitude.
As indicated above, the aldehyde-forming processes useful
in this invention can be conducted in a batch or continuous fashion,
with recycle of unconsumed starting materials if required. The
reaction can be conducted in a single reaction zone or in a plurality of
reaction zones, in series or in parallel or it may be conducted batchwise
or continuously in an elongated tubular zone or series of such zones.
The materials of construction employed should be inert to the starting
materials during the reaction and the fabrication of the equipment
should be able to withstand the reaction temperatures and pressures.
SUBSTITUTE SHEET (RULE 26)
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Means to introduce and/or adjust the quantity of starting materials or
- ingredients introduced batchwise or continuously into the reaction
zone during the course of the reaction can be conveniently utilized in
the processes especially to maintain the desired molar ratio of the
starting materials. The reaction steps may be effected by the
incremental addition of one of the starting materials to the other.
Also, the reaction steps can be combined by the joint addition of the
starting materials to the optically active metal-ligand complex
catalyst. When complete conversion is not desired or not obtainable,
the starting materials can be separated from the product and then
recycled back into the reaction zone. The processes may be conducted
in either glass lined, stainless steel or ~imilAr type reaction equipment.
The reaction zone may be fitted with one or more internal and/or
external heat ~ hAn~er(s) in order to control undue temperature
fluctuations, or to prevent any possible "runaway" reaction
temperatures.
The aldehyde-forming processes useful as the first step in
the process of this invention are useful for preparing mixtures of
substituted optically active aldehydes. The aldehyde-forming processes
useful in this invention stereoselectively produce a chiral center.
Illustrative optically aldehydes prepared by the processes of this
invention include, for example, substituted aldehydes. Illustrative
preferred optically active aldehyde compounds prepared by the
asymmetric hy~;llofollllylation process of this invention include, for
example, S-2-(p-isobutylphenyl)propionaldehyde, S-2-(6-methoxy-2-
naphthyl)propionaldehyde, S-2-(3-benzoylphenyl)-propionaldehyde, S-
2-(p-thienoylphenyl)propionaldehyde, S-2-(3-fluoro-4-
phenyl)phenylpropionaldehyde, S-2-[4-(1,3-dihydro-1-oxo-2H-isoindol-
2-yl)phenyl]propionaldehyde, S-2-(2-methylacetaldehyde)-5-
benzoylthiophene and the like. Illustrative of suitable optically active
aldehyde (including derivatives of the optically active aldehydes) and
SUBSTITUTE SHEET (RULE 26)
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- 30-
prochiral and chiral starting material compounds include those
permissible optically active aldehyde and prochiral and chiral starting
material compounds which are described in Kirk-Othmer, Encyclopedia
of Chemical Technology, Third Edition, 1984, the pertinent portions of
which are incorporated herein by ~ ~rt~ ellce, and The Merck Index, An
Encyclopedia of Chemicals, Drugs and Biologicals, Eleventh Edition,
1989, the pertinent portions of which are incorporated herein by
reference.
The aldehyde-forming processes useful as the first step in
the process of this invention can provide optically active aldehydes
having very high enantioselectivity and regioselectivity. Enantiomeric
excesses of plefe. ~bly greater than 50%, more preferably greater than
75% and most ~ er~l ~bly greater than 90% can be obtained by such
processes. Branched/normal molar ratios of ~ ef~ dbly greater than
5:1, more preferably greater than 10:1 and most preferably greater
than 26:1 can be obtained by such processes.
In the process of this invention, the aldehyde mixtures
may be separated from the other components of the crude reaction
mixtures in which the aldehyde mixtures are produced by any suitable
method. Suitable separation methods include, for example, solvent
extraction, cryst~lli7~tion, distillation, vaporization, wiped film
evaporation, falling film evaporation and the like. It may be desired to
remove the optically active products from the crude reaction mixture as
they are formed through the use of trapping agents as described in
published Patent Cooperation Treaty Patent ApplicationWO 88/08835.
A preferred method for separating the enantiomeric aldehyde mixtures
from the other components of the crude reaction mixtures is by
membrane separation. Such membrane separation can be achieved as
set out in U.S. Patent No. 5,430,194 and copending U.S. Patent
Application Serial No. 08/430,790, filed ~ay 5, 1995, both incorporated
herein by reference.
SUBSTITUTE SHEET (RULE 26)
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In the process of this invention, the enantiometric purity
- of mixtures of optically active aldehyde isomers may be improved by
crystallization as described in said U.S. Patent No. ~,430,194.
The generic scope of this invention includes a process for
preparing optically active carboxylic acids by oxidizing an optically
active aldehyde with a peracid in the presence of an amine and/or
amine N-oxide catalyst to produce the optically active carboxylic acid.
The generic scope of this invention is not intended to be limited in any
manner by any particular reaction for forming enantiomeric aldehyde
mixtures.
Oxidation
Once the requisite mixture of enantiomeric aldehydes has
been provided, the next step of the process of this invention involves
oxidizing the optically active aldehyde with a peracid in the presence of
an amine and/or amine N-oxide catalyst to produce an optically active
carboxylic acid. Suitable solutions can be provided by using liquid
aldehydes or by melting solid aldehydes. However, suitable solutions
usually consist of the aldehydes dissolved in an a~. o~;ate solvent
(e.g., in the solvent in which the first step of the process of this
invention was conducted). Any solvent which will dissolve the
aldehyde mixture and is unreactive with peracids may be used.
Examples of suitable solvents are ketones (e.g., acetone), esters (e.g.,
ethyl acetate), hydrocarbons (e.g., toluene), nitrohydrocarbons (e.g.,
nitrobenzene), ethers (e.g., tetrahydrofuran (THF) and 1,2-
dimethoxyethane) and water. A mixture of two or more solvents can be
employed to m~imi~e the purity and yield of the desired aldehyde.
Tlie solution used may also contain materials present in the crude
reaction product of the aldehyde-forming reaction (e.g., catalyst, ligand
and heavies). Preferably, however, the solution consists essentially of
~ only the aldehyde and the solvent. The concentration of the aldehyde
SUBSTITUTE SHEET (RULE 26)
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in the solvent solution will be limited by the solubility of the aldehyde
in the solvent.
The oxidizing agent useful in the process of this invention
is a peracid. Illustrative peracids include, for example, peracetic acid,
performic acid, perpropionic acid, perbenzoic acid and the like. The
preferred oxidizing agent is anhydrous peracetic acid. Such peracid
oxidizing agents are well known in the art and can be used in amounts
described below and in accordance with conventional methods.
The oxidizing agent is employed in an amount sufficient
to permit complete oxidation of the optically active aldehyde.
Preferably, the o~ inF agent stoichiometry can range from about 1 to
about 10 molar equivalents with respect to optically active aldehyde,
~ ef~. ably from about 1 to about 2 molar equivalents with respect to
optically active aldehyde, and most preferably from about 1 to about
1.3 molar equivalents with respect to optically active aldehyde.
The catalysts useful in the oxidation step of the process of
this invention include primary, secondary and tertiary ~mine.~ and
amine N-oxides and mixtures thereof. The catalysts have sufficient
basicity to catalyze the oxidation of an optically active aldehyde to an
optically active carboxylic acid. The catalysts are desirable in that
little or no rac~mi7~tion of the optically active aldehyde occurs.
Illustrative primary, secondary and tertiary amine and amine N-o2~ide
catalysts include, for example, aliphatic amines, aliphatic amine N-
oxides, aromatic :~mines, aromatic amine N-oxides, heterocyclic
amines, heterocyclic amine N-oxides, supported polymeric ~mines,
supported polymeric amine N-oxides and the like, including mixtures
thereof. Illustrative aliphatic amines include substituted and
unsubstituted alkyl amines such as butylamine, diethylamine,
triethylamine and the like including the N-oxides thereof. Illustrative
aromatic amines (those in which nitrogen is attached directly to an
aromatic ring) include substituted and unsubstituted anilines and the
SUBSTITUTE SHEET (RULE 26)
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N-oxides thereof, e.g., aniline, toluidine, diphenyl~mine, N-ethyl-N-
methyl.qniline, 2,4,6-tribromo~nilin~ and the like. Illustrative
heterocyclic amines (those in which nitrogen makes up a part of an
aromatic or non-aromatic ring) include sub~,l,il u~ed and' unsubstituted
pyridines, pyrimidines, pyrrolidines, piperidines, pyrroles, purines and
the like including the N-oxides thereof. Preferred oxidation catalysts
include, for example, 2,6-lutidine N-oxide, 4-methoxypyridine N-oxide
and 2,5-lutidine N-oxide. Amine N-oxide catalysts are preferred
oxidation catalysts and can affect, e.g., decrease, the amount of formate
byproduct formed in the oxidation process of this invention. The amine
and/or amine N-oxide catalyst ~. efer dbly has a high boiling point so as
to reduce or elimin~te amine impurities resulting from the catalyst in
the product.
As indicated above, the catalysts have sufficient basicity
to catalyze the oxidation of an optically active aldehyde to an optically
active carboxylic acid. Such basicity can result from the catalyst
functioning as a Lewis base or a Bronsted-Lowry base. The catalysts
should be basic enough to promote decomposition of any aldehyde-
peracid adduct but relatively unreactive with regard to oxidation by
peracid. The basicity of the catalysts should also be sufficient to favor
the oxidation reaction to optically active carboxylic acids over any
competing aldehyde rz~cemi~:~tion reactions.
In an embodiment of this invention, if the amine and/or
~mine N-oxide catalyst has ~rce~:sive basicity causing optically active
aldehyde rac~mi~çltion, the optically active aldehyde racemization can
be suppressed by ~tltling a weak organic acid to the reaction mixture.
Various weak organic acids, e.g., aliphatic and aromatic carboxylic
acids, may be employed in the process of this invention. The weak
organic acids should be sllfficient to moderate basicity of the catalyst to
suppress racemization. Preferred weak organic acids have a pKa 3-6
and include, for example, acetic acid. The weak organic acid is
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employed in an amount sufflcient to moderate basicity of the catalyst
to ~ ss racemi7~tion~ preferably l equivalent with respect to the
catalyst.
The ~mine and/or amine N-oxide catalyst is employed in a
catalytically effective amount, i.e., an amount sufficient to catalyze the
oxidation reaction. Preferably, the amine and/or amine N-oxide
stoichiometry can range from about 0.1 to about 10 molar equivalents
with respect to optically active aldehyde, preferably from about 0.5 to
about 2 molar equivalents with respect to optically active aldehyde,
and most preferably from about 0.7 to about 1.2 molar equivalents
with respect to optically active aldehyde. The amine and/or amine N-
oxide stoichiometry can affect the amount of formate byproduct formed
in the process of this invention.
The catalysts used in the oxidation step of the process of
this invention may optionally be supported. Advantages of a supported
catalyst may include ease of catalyst separation. Illustrative examples
of supports include all77nin~, silica gel, ion-e~rch~nFe resins, polymeric
supports and the like.
The process conditions employable in the oxidation step of
the process ofthis invention are chosen to minimi7e aldehyde
racemization and reduce formate byproducts.
The mode of addition of reaction ingredients in the
oxidation step of the process of this invention is not narrowly critical.
The mode of addition should be such that an optically active carboxylic
acid is obtained. As an illustration, if the peracid is added to a mixture
of optically active aldehyde and amine and/or ~nline N-oxide catalyst,
the oxidation must be carried out before base-catalyzed racerni7S7tion
occurs.
The oxidation step of the process of this invention may be
conducted at a reaction temperature from about -25~C or lower to
about 60~C. Lower reaction temperatures may generally tend to
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minimi7e formate byproduct formation. To minimi7e aldehyde
- rac~mi~t.ion, the temperature should not exceed about 10~C during
exothermic peracid addition when using amines as catalysts. When
using amine N-oxides as catalysts, temperatures should not exceed
about 25~C to minimi7e methyl ketone formation when oxidizing
alpha-methyl substituted benzylic aldehydes. In general, oxidations at
reaction temperatures of about -10~C to about 25~C are plefe~ed.
The oxidation step of the process of this invention is
conducted for a period of time sufficient to produce an enantiomerically
enriched carboxylic acid mixture. The exact reaction time employed is
dependent, in part, upon factors such as temperature, nature and
proportion of starting materials, and the like. The reaction time will
normally be within the range of from about one-half to about 200 hours
or more, and ~ere~ably from less than about one to about 10 hours.
The oxidation step in the process of this invention can be
carried out in the liquid state and can involve a batch or continuous
liquid recycle system. A batch system is preferred for conducting such
processes. Preferably, such oxidation involves a batch homogeneous
catalysis process wherein the oxidation is carried out in the presence of
any suitable conventional solvent as further described herein.
The oxidation step of the process of this invention may be
conducted in the presence of an organic solvent. Depending on the
particular catalyst and reactants employed, suitable organic solvents
include, for example, alcohols, alkanes, ethers, aldehydes, esters, acids,
amides, amines, aromatics and the like. Any suitable solvent which
does not unduly adversely interfere with the intended oxidation
process can be employed and such solvents may include those
heretofore commonly employed in known processes. Mixtures of one or
more different solvents may be employed if desired. Solvents which
partially or totally dissolve the aldehyde and do not react with peracids
~ may be useful. Organic esters are preferred solvents. Water and
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water/ethanol mixtures may also be useful solvents. The amount of
solvent employed is not critical to this invention and need only be that
amount sufficient to provide the reaction medium with the particular
substrate and product concentration desired for a given process. In
general, the amount of solvent when employed may range from about 5
percent by weight up to about 95 percent by weight or more based on
the total weight of the reaction medium.
As indicated above, the carboxylic acid-forming process of
this invention can be conducted in a batch or continuous fashion, with
recycle of unconsumed starting materials if required. The reaction can
be conducted in a single reaction zone or in a plurality of reaction
zones, in series or in parallel or it may be conducted batchwise or
continuously in an elongated tubular zone or series of such zones. The
materials of construction employed should be inert to the starting
materials during the reaction and the fabrication of the equipment
should be able to withstand the reaction temperatures and pressures.
Means to introduce and/or adjust the quantity of starting materials or
ingredients introduced batchwise or continuously into the reaction
zone during the course of the reaction can be conveniently utilized in
the processes especially to maintain the desired molar ratio of the
starting materials. The reaction steps may be effected by the
incremental addition of one of the starting materials to the other.
Also, the reaction steps can be combined by the joint addition of the
starting materials to the amine and/or amine N-oxide catalyst. The
processes may be conducted in either glass lined, stainless steel or
simil~r type reaction equipment. The reaction zone may be fitted with
one or more internal and/or external heat exch~nger(s) in order to
control undue temperature fluctuations, or to prevent any possible
"runaway" reaction temperatures.
The carboxylic acid-forming process of this invention is
useful for preparing mixtures of substituted optically active carboxylic
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acids. Illustrative optically active carboxylic acids prepared by the
process of this invention include, for example, substituted carboxylic
acids. Illustrative preferred optically active carboxylic acid compounds
prepared by the oxidation process of this invention include, for
example, S-2-(p-isobutylphenyl)propionic acid, S-2-(6-methoxy-2-
naphthyl)propionic acid, S-2-(3-benzoylphenyl)-propionic acid, S-2-(p-
thienoylphenyl)propionic acid, S-2-(3-fluoro-4-phenyl)phenylpropionic
acid, S-2- [4-(1 ,3-dihydro- 1-oxo-2H-isoindol-2-yl)phenyl] propionic acid
and the like. Illustrative of suitable optically active carboxylic acids
which can be prepared by the processes of this invention include those
permissible optically active carboxylic acids which are described in
Kirk-Othmer, Encyclopedia of Chemical Technology, Third Edition,
1984, the pertinent portions of which are incorporated herein by
~efe~allce, and The Merck Index, An Encyclopedia of Chçmic~l.c, Drugs
and Biologicals, Eleventh Edition, 1989, the pertinent portions of
which are incorporated herein by ~ ef~ lce.
The carboxylic acid-forming process of this invention can
provide optically active carboxylic acids having very high
enantioselectivity and regioselectivity. Enantiomeric excesses of
preferably greater than 60%, more pref~l ably greater than 85% and
most preferably greater than 95% can be obtained by such processes. A
number of important pharmaceutical compounds can be prepared by
such oxidation processes including, but not limited to, S-naproxen, S-
ibuprofen, S-ketoprofen, S-suprofen, S-flurbiprofen, S-indoprofen, S-
tiaprofenic acid and the like.
Illustrative of carboxylic acid-forming reactions and
permissible derivatization reactions include, for example, reactions
that involve the following reactant/aldehyde intermediate/product
combinations:
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Aldehyde
Reactant Intermediate Product
2-vinyl-6-methoxy- S-2-(6-methoxy-2- S-naproxen
naphthalene naphthyl)-
propionaldehyde
2-vinyl-6-methoxy- S-2-(6-methoxy-2- S-naproxen
naphthalene naphthyl)- sodium
propionaldehyde
p-isobutylstyrene S-2-(p-isobutylphenyl)- S-ibuprofen
propionaldehyde
p-isobutylstyrene S-2-(p-isobutylphenyl)- S-ibuprofen-L-
propionaldehyde lysinate
4-ethenylphenyl- S-2-(p-thienoylphenyl)- S-~u~ fen
2-thienylketone propionaldehyde
4-ethenyl-2-fluoro- S-2-(3-fluoro-4-phenyl)- S-flurbiprofen
biphenyl phenylpropionaldehyde
4-(1,3-dihydro-1-oxo- S-2-[4-(1,3-dihydro-1- S-indoprofen
2H-isoindol-2-yl)- oxo-2H-isoindol-2-yl)-
styrene phenyl] propionaldehyde
2-ethenyl-5- S-2-(5-benzoyl-2 S-tiaprofenic
thienyl )-
benzoylthiophene propionaldehyde acid
3-ethenylphenyl S-2-(3-phenoxy)propion- S-fenoprofen
phenyl ether aldehyde
propenylbenzene S-2- S-phenetamid, S-
phenylbutyraldehyde butetamate
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phenyl vinyl ether S-2-pheno2~y~0~ional- pheneticillin
dehyde
vinyl chloride S-2-chl~l o~1 o~ional- S-2-chloro-
dehyde propionic acid
5-(4-hydroxy)benzoyl- 5-(4-hydroxy)benzoyl-1- ketorolac
3H-pyrrolizine formyl-2,3-dihydro- or derivative
pyrrolizine
3-ethenylphenyl R-2-(3-benzoylphenyl)- R-ketoprofen
phenyl ketone propionaldehyde
4-ethenyl-2-fluoro- R-2-(3-11uoro-4-phenyl)- R-flurbiprofen
biphenyl phenylpropionaldehyde
The optically active derivatives of the products of the
process of this invention have a wlde range of utility that is well known
and documented in the prior art, e.g. they are especially useful as
pharmaceuticals, flavors, fragrances, agricultural chemicals and the
like. Illustrat*e therapeutic applications, include, for example, non-
steroidal anti-infl~mm~tory drugs, ACE inhibitors, beta-blockers,
analgesics, bronchodilators, spasInolytics, antihistimines, antibiotics,
antitumor agents and the like. ~
As used herein, the following terms have the indicated
mç~ning~
Chiral - compounds ~hich have a non-superimposable
mirror image.
Achiral - compounds which do not have a non-
superimposable mirror image.
Prochiral - compounds which have the potential to be
converted to a chiral compound in a particular process.
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Chiral center- any structural feature of a compound that
is a site of asymmetry.
Racemic - a 60/50 mixture of two enantiomers of a chiral
compound.
Stereoisomers - compounds which have identical chemical
constitution, but differ as regards the arrangement of the atoms or
groups in space
F'ln~ntiomers - stereoisomers which are non-
superimposable mirror images of one another.
Stereoselective - a process which produces a particular
stereoisomer in favor of others.
Enantiomeric excess (ee~ - a measure of the relative
amounts of two enantiomers present in a product. ee may be
calculated by the formula [amount of major enantiomer - amount of
minor enantiomer]/[amount of major enantiomer + amount of minor
enantiomer] and converted to percent.
ODtical activitv - an indirect measurement of the relative
amounts of stereoisomers present in a given product. Chiral
compounds have the ability to rotate plane polarized light. When one
enantiomer is present in excess over the other, the mixture is optically
active.
Optically active mixture- a mixture of stereoisomers
which rotates plane polarized light due to an excess of one of the
stereoisomers over the others.
Opticallv pure compound- a single enantiomer which
rotates plane polarized light.
Re~ioisomers - compounds which have the same molecular
formula but differing in the connectivity of the atoms.
Regioselective - a process which favors the production of a
particular regioisomer over all others.
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IsoBHA chloridite - 1,1'-biphenyl-3,3'-di-t- butyl-5,5'-
dimethoxy-2,2'-diylchlorophosphite.
(IsoBHA-P)~-2R.4R-pentanediol - A ligand having the
formula:
,~o p,l, (~p o ~\
Me(~(~ ~ OMe
OMe OMe
-
The latter ligand can be produced from Iso BHA chloridite
by the process described in Example 1 of above-mentioned PCT Patent
Application 93/03839. The complete chemical name of this ligand is
(2R, 4R)-Di[2,2'-(3,3'-di-tert-butyl-5,5'-dimethoxy-1,1'-biphenyl)]-2,4-
pentyl diphosphite.
For purposes of this invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements, CAS
version, ~nr~hook of Chemistry and Physics, 67th Ed., 1986-87, inside
cover. Also for purposes of this invention, the term "hydrocarbon" is
contemplated to include all compounds having at least one hydrogen
and one carbon atom. In a broad aspect, the hydrocarbons include
acyclic and cyclic, branched and unbranched, carbocyclic and
heterocyclic, aromatic and nonaromatic organic compounds which can
be substituted or unsubstituted.
As used herein, the term "substituted" is contemplated to
include all permissible substituents of organic compounds. In a broad
aspect, the permissible substituents include acyclic and cyclic,
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branched and unbranched, carbocyclic and heterocyclic, aromatic and
nonaromatic substituents of organic compounds. Illustrative
substituents include, for example, those described hereinabove. The
permissible substituents can be one or more and the same or different
for appropriate organic compounds. For purposes of this invention, the
heteroatoms such as nitrogen may have hydrogen substituents and/or
any permissible substituents of organic compounds described herein
which satisfy the valencies of the heteroatoms. This invention is not
intended to be limited in any manner by the permissible substituents
of organic compounds.
As used herein, the following symbols have the indicated
me~ning.c
L liter
mL milliliter
wt% weight percent
mL/min milliliters per minute
ppm parts per million by weight
g grams
mg milli~rams
psi pounds per square inch
~C degrees centigrade
b/n branched to normal isomer ratio
cc cubic centimeter
DSC Differential Sc~nning Calorimeter
GC Gas Chrom ~to~raphy
HPLC High Performance Liquid Chromatography
mm millimeter
mmol millimoles
TLC Thin Layer Chromatography
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The following Examples are provided to illustrate the
- process of this invention.
Example 1
Improving ~,n~ntiomeric Puritv of an Aldehvde
Throu~h Crvstallization in Acetone
A solution consisting of 6-methoxy-2-vinylnaphthalene
(395 g), Iso(BHA-P)2-2R,4R-pentanediol (6.041 g), Rh4(CO)12 0.862 g)
and acetone (1500 mL) was charged to a 1 gallon reactor which was
pressurized to 250 psi with 1:1 H2/CO. The reaction mixture was
stirred at ambient temperature for four days to effect
hydroformylation. The crude reaction product so produced was
removed from the reactor and an aliquot removed to determine the
composition of the product.
GC analysis of the aliquot of the crude reaction product
indicated that 98.8% of the olefin starting material had been converted
to aldehydes and that a 95:1 ratio of 2-(6-methoxy-2-
naphthyl)propionaldehyde to 3-(6-methoxy-2-naphthyl)-
propionaldehyde had been obtained. Oxidation of the aldehydes in the
aliquot followed by chiral High Performance Liquid Chromatography
(HPLC) analysis of the resulting carboxylic acids indicated that an 81Yo
ee of the desired S-aldehyde Li.e., S-2-(6-methoxy-2-naphthyl)-
propionaldehyde] was produced.
The above-mentioned oxidation and HPLC analysis were
conducted as follows: 3 mL of the crude reaction product was diluted in
50 mL of acetone and mixed with 0.3 g of potassium permanganate and
0.32 g of magnesium sulfate. The mixture so formed was stirred at
room temperature for 30 minutes to effect oxidation of the aldehydes in
the crude reaction product to the corresponding carboxylic acids. Then
the acetone was removed under reduced pressure. The residue so
produced was extracted three times with 50 mL of hot water and the
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three aqueous solutions so obtained were combined, filtered and
washed with 50 mL of chloroform. The aqueous layer was then
acidified with HCl to a pH of 2 at which time a white, solid precipitate
formed. The precipitate was filtered, washed with water and dried to
isolate the carboxylic acids. The carboxylic acids were analyzed by
chiral HPLC on a CHIRACELTM OD-H column which could separate
the two enantiomers of the resulting 2-(6-methoxy-2-
naphthyl)propionic acid.
The remainder of the crude reaction product was stored at
-22~C overnight and during that time crystals formed. These crystals
were filtered, washed with cold acetone and dried under vacuum to
yield 111 g of off-white crystals and a first filtrate. Analysis of the
crystals indicated that the b/n isomer ratio had been increased to
>250:1. Oxidation of the aldehydes to carboxylic acids and chiral
HPLC of the resulting carboxylic acids indicated a 93% ee of the S-
enantiomer had been obtained.
The first filtrate was stored overnight at -22~C and
additional crystals formed. These crystals were filtered, washed with
cold acetone and dried under vacuum to yield a second filtrate and 70 g
of white crystals with an b/n isomer ratio of 260:1 and a 93~ ee of the
S-enantiomer.
The second filtrate was stored at -22~C overnight and
again crystals formed. Filtration, washing and vacuum drying of these
crystals resulted in isolation of 60 g of a crystalline aldehyde product
having an b/n isomer ratio of 200:1 and an ee of 92% S-enantiomer.
F.~mple 2
Im~rovin~ Enantiomeric Puritv of Aldehvdes
Throu~h Crvst~ tion in Ethvl Acetate
A solution consisting of 6-methoxy-2-vinylnaphthalene (60
g), Iso(BHA-P)2-2R,4R-pentanediol (1.25 g), Rh4(CO)12 (0.131 g) and
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ethyl acetate (180 g) was charged to a 300 mL reactor which was
pressurized to 250 psi with 1:1 H2/CO. The reaction mixture so formed
was stirred at ambient temperature for four days to effect
hydroformylation. The crude reaction product was removed from the
reactor and an aliquot removed to determine the composition of the
product.
GC analysis of the aliquot indicated that 99% of the olefin
starting material had been converted to aldehydes and that a 59:1
ratio of 2-(6-methoxy-2-naphthyl)propionaldehyde to 3-(6-methoxy-2-
naphthyl)propionaldehyde had been obtained. Oxidation of the
aldehyde products followed by chiral HPLC analysis of the resulting
carboxylic acids indicated that an 80% ee of the desired S-aldehyde
[i.e., S-2-(6-methoxy-2-naphthyl)propionaldehyde] was produced.
- The remainder of the crude reaction product was then
stored at -22~C overnight, during which time crystals formed in the
container. These crystals were filtered, washed with cold acetone and
dried under vacuum to yield 32 g of off white crystals. Subsequent
analysis of these crystals indicated that the b/n isomer ratio had been
increased to >129:1. Oxidation of the crystalline aldehyde and chiral
HPLC of the resulting carboxylic acid indicated a 92% ee of the S-
enantiomer had been obtained.
Example 3
Membrane Separation of An Aldehvde
from Acetone Solution
A. A crude hydroformylation reaction product .cimil:~r
to the crude reaction product produced in Example 1 above was
processed through a membrane to remove the rhodium and ligand.
The crude reaction product contained 2-(6-methoxy-2-
naphthyl)propionaldehyde (30 wt%) dissolved in acetone (70 wt%) .
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T~e crude reaction product also contained rhodium (263.3 ppm) and
ligand.
The membrane was arranged and used as follows: Three
2 inch circles were cut from an 8 inch x11 inch sheet of MPF-60
membranes (Lot #021192, code ~107) which are sold by Membrane
Products Kiryat W~ m~nn Ltd. and which are believed to be within
the scope of above-mentioned European Patent Application 0 532,199
A1. These circles were placed into three Osmonics membrane holders.
The crude reaction product (feed) was placed into a 2L Hoke cylinder
under nitrogen. The feed was pumped to 500 psi at a flow rate of about
380 mLlmin. The feed flowed through a 60 micron filter and then was
split into three streams which went to the membranes. Flowmeters
were used to ensure that the flow was split equally to the holders. The
permeate from the membranes was combined and collected under
nitrogen. The raffinate flowed to a back pressure regulator and was
then returned to the Hoke cylinder.
About 1500 g of the crude reaction product was permeated
and the rhodium content of the resulting first permeate was about 69.4
ppm. The membrane and equipment were washed with acetone and
the acetone was discarded.
The above-described membrane separation was repeated
on the 1500 g of the first permeate (which contained 69.4 ppm
rhodium) and 1000 g of a solution (contz3ining 19.2 ppm rhodium) was
separated as a second permeate. The composition of the second
permeate was 80% acetone and 20% solids. The b/n isomer ratio of the
solids was 64:1 and it contained 1.4% normal isomer, 9.9% R-isomer,
and 88.7~c S-isomer [i.e., S-2-(6-methoxy-2-naphthyl)-
propionaldehyde]. The enantiomeric excess (ee) of the crystalline
solids was 80.7%. The second permeate so obtained was then
concentrated and crystallized as described below.
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A portion of the second permeate produced as described
above was concentrated by evaporating acetone at 18~C and 25 inches
of mercury pressure to produce a concentrated solution contSlining 70%
acetone and 30% solids. The concentrate so obtained was charged into
a crystallizer described below. The cryst~ er consisted of a jacketed,
250 cc vertical cylinder (A) fitted with a stirrer (B) and an internal
filter (C). Cryst~lli7~t.ion was initiated by cooling the jacket to -14~C
thus cooling the contents of the cylinder to near -14~C. In order to
dissolve the small crystals that formed on the inner surface of the
cylinder and to enhance crystal size, the cryst~ r was reheated to
3~C and again cooled to -14~C using cooler (D). This procedure was
repeated three times. Since the internal filter (C) clogged, the solid
crystals formed in the cylinder and liquid were removed from the
crystallizer and separated in a laboratory vacuum filter. The resulting
filter cake was washed with one part by weight of cold acetone (0~C)
per two parts (by weight) of wet solids (filter cake). The resultant
crystalline filter cake contained 13% acetone and 87% crystalline solids
and had a b/n isomer ratio of 386:1. The solids cont~ined 0.3 normal
isomer, 2.4% R-isomer and 97.3% S-isomer. The enantiomeric excess of
the solids was 95.2%. Sc~nning Electron Microscope (SEM) photos
indicated that solid particles were uniform and about 100 microns in
size.
B. The concentration and cryst~lli7~tion procedure of
A above was repeated with another portion of the second permeate
obtained in the above-described membrane separation and the crystals
produced had a b/n isomer ratio of 446:1 and contained of 0.2~o normal
isomer, 2.7% R-isomer, and 97.1% S-isomer. The ee of the crystals was
94.6%.
C. The wet filter cakes produced via the procedures of
A and B above were combined and dissolved in two parts by weight of
acetone per part by weight of the combined wet filter cake. The
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solution so obtained was crystallized using the crystallization
procedure of A above, separated and washed per the procedure of A
above. The resultant crystals had a b/n isomer ratio of 921:1 and
contained 0.1 normal isomer, 1.3% R-isomer, and ~8.6% S-isomer. The
ee of the crystals was 97.4%.
D. The wet crystalline filter cake produced by
procedure of C above was dissolved in two parts (by weight) of acetone
per part of the combined wet cake and crystallized using the
cryst~lli7~t.ion procedure of A above, separated and washed according
to the procedure of A above. The final crystals so obtained had a b/n
isomer ratio of 1836:1. The crystal contained 0.05% normal isomer,
.6Yo R-isomer, 99.35% S-isomer and 4 ppm rhodium. The ee of the
crystals was 98.8%. The melting point of the crystals was 72.5~C
determined in a Differential Scs~nning Calorimeter (DSC).
Example 4
Refinin~ An Aldehvde from Ethvl Acetate Solution
A. A crude hydroformylation reaction product was
used that was ~qimil~qr to the crude reaction product produced in
Example 2 above and that was composed of 62.9% ethyl acetate and
37.1% solids cont~ining 2-(6-methoxy-2-naphthyl)propionaldehyde.
The solids had a b/n of 42:1 were composed of 2.3Yo normal isomerr
1~.7% R-isomer and 86% S-isomer [i.e., S-2-(6-methoxy-2-naphthyl)-
propionaldehyde] and had an ee of 76%. The crude reaction product
was crystallized as follows:
B. Seven successive 250 ml charges of the crude
reaction product were cooled to -7~C in the crystallizer used in
Example 3 above. The crystals and liquid resulting from the
cryst~lli7~tion were separated on an external vacuum filter and the
crystals were washed with 0.5 parts of ethyl acetate per part of wet
cake. The resultant composite cake from the seven crystallizations
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contained 24% ethyl acetate and 76% crystalline solids. The b/n isomer
ratio of the crystalline solids was 123:1 and the solids contained 0.8%
normal isomer, 6.0% R-isomer, and 93.2% S-isomer. The ee of the
crystalline solids was 87.9%.
C. The wet filter cake from step B. above was
dissolved in two parts by weight of ethyl acetate per part (by weight) of
wet filter cake. The solution was cooled to -13~C in the laboratory
cryst~lli7~r used in Example 3 above. The contents of the cryst~ er
were then reheated to 3~C and again cooled to -13~C. This cool-reheat
cycle was repeated two times to ~nh:~n~e the crystal size. The solid-
liquid mixture so produced was separated in an external vacuum filter
and the wet filter cake 50 produced was washed with 0.5 parts of cold (-
10~C) ethyl acetate per part of wet filter cake. The resultant cake
cont~ined 25% ethyl acetate and 755'o crystalline solids. The
crystalline solids had a b/n isomer ratio of 483:1 and had, a normal
isomer content of .2%, a R-isomer content of 1.6% and a S-isomer
content of 98.2%. The ee of the crystalline solids was 96.8%.
Example 5
Refinin~ of An Aldehvde from Acetone
Solution in a Fallin~ Film Crvstallizer
Crude hydroformylation reaction product that was ~unil~r
to the crude reaction product produced in F',7~mple 1 above and that
contained 70% acetone and 30% solids was refined in a laboratory
falling film cryst~lli7er. The solids in the crude reaction product had a
b/n isomer ratio of 69:1 and the solids composition was 1.4% normal
isomer, 8.9% R-isomer, and 89.7% S-isomer [i.e., S-2-(6-methoxy-2-
naphthyl)propionaldehyde]. The enantiomeric excess of the solids was
~ 81.9%.
The crude reaction product was concentrated by
evaporating 30% by weight of the solution. The resulting concentrate
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consisted of 57% acetone and 43% solids. This was crystallized in a
laboratory falling film cryst~ er by the following procedure.
The crystallizer consisted of a kettle (A), a jacketed
column (B) {the column was a one meter long jacketed vertical tube
having a one inch diameter internal opening} and (D) means for
pumping (i.e., circ~ ting) liquid from the kettle to the film device (C)
at the top of the falling film cryst~lli7er. The jacket of the cryst~lli7:er
was affixed to a supply of coolant (E) which flowed co-current with the
falling film. That is, both the falling film and the coolant in the jacket
flowed downward in a co-current fashion. The crystallizer used is
si~nil:~r in principle of operation to those described in above-mentioned
U.S. Patent 3,621,664.
Two thousand milliliters of the concentrate produced as
described above were charged to the kettle (A) of the falling film
cryst~ er used in this l~ mple 5. The concentrate in the kettle was
circulated briefly down through the column (B) to wet the inside walls
and then circulation was discontinued. Since the walls of the column
were maintained at -20~C by circlll~tinf~ coolant, a thin frosting of
solids quickly formed on the inner walls of the column. The flow
through the falling film crystallizer was resumed depositing crystals on
the inside of column wall. After the kettle temperature was reduced to
-16~C, the recirculation flow was stopped. During the cooling, a slight
amount of heat was added to the kettle by a heating mantle (F) to
prevent cryst,~lli7~t.ion in the kettle. To compensate for this heating,
the recirc~ ting liquid was cooled slightly by circulating coolant from
bath (G) to coolers (H). After cryst,~ tion was complete, the residual
liquid in the kettle was emptied and the solids inside the cryst~ r
walls were washed with 50 cc of wash liquid that was added from the
top of the column and this wash liquid was discarded. The composition
of the kettle residue was 61% acetone and 39% solids. The solids in the
kettle had a b/n isomer ratio of 60:1 and contained 1.6% normal
- SUBSTITUTE SHEET (RULE 26)
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isomer, 12.8% R-isomer and 85.6% S-isomer. The ee of the kettle solids
was 74.0%.
600 cc of reagant grade acetone was added to the kettle
and circulated to the falling film device at 20~C and then down the
inside wall of the column to dissolve the solids adhering to the inside of
the column. This was a very quick and efficient techni~ue for
recovering adhering solids and is a unique method for recovery of solids
from the falling film cryst~lli7~r.
The acetone solution recovered from the column wall
contained 78% acetone and 22% crystalline solids. The crystalline
solids had a b/n isomer ratio of 111:1 and contained 0.9% normal
isomer, 6.9% R-isomer and 92.2% S-isomer. The crystalline solids ee
was 86.1%.
-
Example 6
Refinin~ of An Aldehvde from Acetone Solution Utili~in~ Coolin~
Crvstallization
Three 2 inch circles from an 8.5 inch x 11 inch sheet ofMPF-50 membranes (LOT #021192 code 5102). These were placed into
three Osmonics membrane holders. Feed was placed into a 2L Hoke
cylinder under nitrogen. The feed was pumped to 500 psi at a flow rate
of about 380 mL/min. The feed flowed through a 60 micron filter ~nd
then was split into three streams which went to the membranes.
Flowmeters were used to ensure that the flow was split equally. The
permeate froIn the membranes was combined and collected under
nitrogen. The raffinate flowed to a back pressure regulator and then
was returned to the Hoke cylinder.
The feed was a 4 L batch of a crude hydroformylation
~ reaction product cont~ining 2-(6-methoxy-2-naphthyl)-
propionaldehydes (30 wt%) in acetone (70 wt5~o). The mixture also
contained rhodium (389.3 ppm) and Iso(BHA-P)2-2R,4R-pentanediol.
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About 3325 g of this solution was permeated through the membrane
and the resulting permeate solution had a rhodium content about 36.3
ppm. The system was emptied, cleaned with acetone and the waste
discarded.
The 3325 g of the permeate solution conts~ining 36.3 ppm
rhodium was placed back into the Hoke cylinder and about 1439 g of
this solution was again permeated through the membrane. The
resulting permeate solution contained about 5.6 ppm rhodium.
The 1439 g of the solution cont~ining 5.6 ppm rhodium
was placed back into the Hoke cylinder and passed back through the
membrane for the third time. About 935 g of this solution was
permeated through the membrane and the resulting permeate had
about 1.2 ppm rhodium. This permeate was then used as a feed for the
crystallization process described below.
Recovery and r~fining of S-2-(6-methoxy-2-naphthyl)-
propionaldehyde aldehyde from the permeate obtained as described
above was accomplished by the sequence of operations described below.
In sllmm~ry, the perIneate feed solution was batch crystallized by
cooling to - 10~C. The slurry so obtained was filtered to remove
crystals and the crystals were washed with one half gram of acetone
per gram of wet solids. The filtrate and was were combined and the
solution concentrated to 40 percent solids by evaporating acetone, The
cryst~ tion, filtration and w~hing was repeated on this
concentrated solution. The crystals from this second stage were
combined with crystals from the first crystallization and dissolved in
one and one half parts by weight of acetone per part of wet solids. This
solution was processed in the same manner as the original permeate
feed solution. The solids that were recovered and washed from both
crys~ F.tion stages were again combined and dissolved in acetone.
The final recrystallization was also conducted in the manner as
described above in this Example. The refined crystalline solids from
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this last stage represented the final product (i.e., S-2-(6-methoxy-2-
naphthyl)propionaldehyde). The final ee was 96.8. The yield of S-2-(6-
methoxy-2-naphthyl3propionaldehyde as a fraction of that supplied in
the feed was 26.8 percent.
Example 7
A. Naproxen Aldehvde Meltin~ Point Diagram
Experimental melting point data was obtained using the
crystallizer described in Example 3 above. Samples were obtained
during cryst~ tion tests in acetone solutions. The solid samples
were removed from the slurry by filtration. The samples were then
slowly heated in a Perkin/Elmer DSC7 to obtain the melting point.
The data are tabulated in Table 1.
The melting point of pure S enantiomer (S-2-(6-methoxy-
2-naphthyl)propionaldehyde) is discernible. It is difficult to develop a
complete liquidus curve for a variety of reasons. A problem with
melting point deterTnin~tion of such solid samples is that N isomer is
present in sufficient concentration to depress the mixture melting
point.
Table 1
Naproxen Aldehvde Melting Point Data
Sample Composition Meltin~ Point. ~C
%S %R %N
98.2 1.7 0.1 73.5
94.3 5.0 0.7 66.1
98.2 1.6 0.2 72.7
94.8 4.7 0.5 69.4
87.4 10.8 1.8 63.7
- 95.5 4.0 0.5 72.5
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88.1 8.7 3.2 57.2
92.3 7.0 0.7 66.9
B. Naproxen Aldehvde Solubilitv
Solubility data for solids in acetone solvent were obtained
by visually obt~inin~ a "cloud" point for a solution of known
composition by slowly cooling the solution. After obt~ining a "cloud"
point the solution was slowly heated until a "clear" point was observed.
The "clear" point represents the saturation temperature of the solution
and the "cloud" point the temperature at which massive spontaneous
nucleation occurs. The data are shown in Table 2.
Naproxen aldehydes [i.e., R- and S-2-(6-methoxy-2-
naphthyl)propionaldehyde] are very soluble in acetone. The solubility
of these aldehydes is very sensitive to temperature and a high degree
of solution subcooling is required to nucleate the solution.
Table 2
Naproxen Aldehvde Solubilitv Data in Acetone
Solids Ratio Clear Cloud
(wt% )SolidslLiquid Point. ~C Point. ~C
29.0 0.41 6 -17
35.3 0.56 15 -9
30.0 0.43 11 -6
22.0 0.28 1 -15
47.0 0.89 25 5
Example 8
Recoverv of S-Naproxen Aldehvde from Acetone Solution
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A crude reaction product of an asymmetric
~ hydroformylation reaction was produced with low ee (62%) to
experimentally investigate the quality of S-naproxen aldehyde [i.e., S-
2-(6-methoxv-2-n~pht.hyl)propionaldehyde] that can be recovered from
solutions with high concentrations of corresponding isomeric R- and N-
aldehydes. Using the cooling cryst~qlli7~tion procedure described in
Example 3 above (i.e., the solution is cooled to -15~C, reheated to 0~C
and this technique repeated three times before a final cool down to
minus 15), a feed solution cont~ining 77.6% S-isomer, 18.2% R-isomer
and 4.2% N-isomer and having an enantiomeric excess (ee) of 62% was
processed. The resulting crystals were recovered on a vacuum filter
and washed with cold acetone. The composition of the crystals was
9~.5% S-isomer, 4.0% R-isomer, and 0.5% N-isomer giving an
enantiomeric excess of 92%. The filtrate recovered from the
cryst~ tion procedure described above in this Example and having a
solids concentration of 6~;.5% S-isomer, 26.8% R-isomer and 7.7% N-
isomer was concentrated to ~;3% solids by evaporating acetone under
vacuum. The concentrate so obtained was crystallized using the
crvst~ tion procedure described above in this Example. The
composition of the crystalline solids obtained by the latter
cryst~lli7~tion was 92.3% S-isomer, 7.0% R-isomer and 0.7% N-isomer.
The enantiomeric excess of those solids was 85.9%. The composition of
the solids in the final filtrate was ~4.1% S-isomer, 37.6% R-isomer and
8.3% N-isomer.
Example 9
Improving Enantiomeric Purity of
2-(p-Isobutylphenvl)propionaldehvde Throu~h Melt Crvstallization
~ A solution was prepared consisting of p-isobutylstyrene
(100.2 g), Iso(BHA-P)2-2R,4R-pentanediol (0.8~ g), and Rh4(CO)12
(0.091 g). 100 mL of the mixture so formed was charged to a 300 mL
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reactor which was pressurized with 1:1 H2/CO. The mixture was
stirred at 25~C for 46 hours at 130 psi to effect hyd~ of Orl. ~ylation. The
crude reaction product was removed from the reactor and an aliquot
removed to determine the composition of the product.
GC analysis on a beta-cyclodextrin chiral c~pill~ry column
(Cyclodex-B~M) indicated that 99.4% of the olefin starting material had
been converted to aldehydes and that a 42:1 ratio of 2-(p-
isobutylphenyl)propionaldehyde to 3-(p-isobutylphenyl)propion-
aldehyde had been obtained. Oxidation of the aldehyde products
followed by chiral gas chromatography of the resulting carboxylic acids
indicated that an 85+5 ~o ee of the desired S-aldehyde [i.e., S-2-(p-
isobutylphenyl)propionaldehyde] was produced.
A portion (25 mL, 23.54 g) of the crude product was flash
- distilled to separate the products from the catalyst. The first cut (12.4
g) was obtained at 89-92~C head temperature at a pressure of 1 mm of
Hg. A second cut (9.4 g) was obtained at 83-4~C at 0.6 mm of Hg, and a
small amount was left as residue. The second cut was partially frozen
and some liquid (3.27 g) was withdrawn, first with a pipet and then a
fritted glass filter stick with the liquid at -12 to -17~C.
Oxidation of portions of the liquid and crystals with
sodium chlorite followed by chiral gas chroIn~qto~raphy of the resulting
carboxylic acids indicated 92+1 and 75+2 % ee for the S-aldehyde in
the crystals and and liquid respectively. The ratios of the
concentrations of other impurities in liquid to their concentrations in
the crystals averaged 2.2 and the b/n ratio in the crystals was 54:1.
The oxidation with sodium chlorite referred to above was
conducted as follows:
A mixture of 0.28 gram of aldehyde and 2.0 mL of distilled
water was cooled to 0~C and stirred. Aqueous sodium s~llfAm~te (3 mL
of 1 M, adjusted to pH ~ with phosphoric acid) and sodium chlorite
(0.61 mL of 20%) solutions were added. After 15 minutes, the cooling
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bath was removed and the solution was stirred for an additional 15
minutes as it was allowed to warm to room temperature. The pH was
adjusted to 9.5 with 0.5 mL of 1 N sodium hydroxide and the material
rinsed with water into a separatory funnel. The solution was ~:h~ken
with added dichloromethane (10 mL) to extract neutral compounds.
The aqueous layer was separated and acidified to pH<2 with
concentrated hydrochloric acid. The cloudy mixture that formed was
extracted with 20 mL of dichloromethane, toluene was added as an
internal standard, and a small sample was taken to determine the
yields of branched and normal acids by gas chromatography. The
r~m~ining solution was dried over anhydrous mz-gne.cium sulfate and
filtered. The dichloromethane was removed with a rotary evaporator
under vacuum (~150 mm Hg) with the bath at 60~C. The residue (0.02
g)was dissolved in toluene and analyzed by chiral gas chr~ m~to~raphy.
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Example 10
Refinin~ of An Aldehvde from Acetone Solution Ut.ili7in~ Cooling
CrYstallization and Non-Solvent Addition
Crude hydroformylation reaction product (47 g) that was !:irni1~r
to the crude reaction product produced in ~.x~mple 1 above and that
contained 70.5 g of acetone was partially refined in a laboratory
crystallizer in a manner .qimil~r to Example 6. The solids in the
partially refined reaction product had 97.6~% S-isomer [i.e., S-2-(6-
methoxy-2-naphthyl)propionaldehyde]. The partially refined product
was further precipitated by ~ ling non-solvent (water) at the final
cryst~lli7er condition. The quantity of water added was 0.5 cc per cc of
crystallized slurry. The quality of the S-isomer recovered after vacuum
filtration and w~.ching with 150 cc of water was 97.87%. The quantity
of material recuve~ ed was 40 g. By repeating this procedure four
times, product quality increased to 99.10% ( 98.2% ee) with a recovery
of 28 g.
Example 11
Refinin~ of An Aldehvde from Acetone Solution Utili7in~ Vacuum
Cooling
Crude hydroformylation reaction product (666 g) that was
simil~r to the crude reaction product produced in Example 1 abovç and
that contained 40% acetone and 60~o solids was added to a
cryst~lli7~tion apparatus designed to provide vacuum cooling as
described below. The solids had a b/n ratio (2-(6-methoxy-2-
naphthyl)propionaldehyde to 3-(6-methoxy-2-naphthyl)-
propionaldehyde) of 82.76:1 and a 76% ee of the S-isomer [i.e., S-2-(6-
methoxy-2-naphthyl)propionaldehyde]. The apparatus consisted of a
jacketed one liter kettle equipped with stirrer, condenser and vacuum
pump. The solution was cooled to 5~C, where crystals formed, and then
to 0~C by slowly reducing the vacuum to a final reading of 50 mm
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absolute. The contents of the kettle were m~intqined at 0~C for 15
- minutes and then heated to 8~C by increasing system pressure to 150
mm and warming the kettle jacket to 10~C to heat the contents.
Conditions in the kettle were m~int~ined at 8~C for 10 minutes,
vacuum was again reduced to 50 mm and the kettle temperature
reduced to 0~C. This heat back technique was employed to dissolve
fine crystals and re-deposit the supersaturation onto existing crystals
thereby enh~ncing the crystal size. After main~ining kettle
temperature at 0~C for 10 minutes the contents were separated in a
laboratory centrifugal filter and washed with cold acetone. About 60 g
of dry solids were recovered with a b/n ratio of 440:1 and an ee of
92.3%.
- E~ample 12
Oxidation Of (S)-2-(6-Methoxv-2-naphthvl)propionaldehyde To S-
Naproxen Using Lutidine/Acetic Acid As Catalvst
To a stirred solution of 16.67 g (77.8 mmol) of (S)-2-(6-methoxy-
2-naphthyl)propionaldehyde (naproxen aldehyde) in ethyl acetate (78
mL) cooled in a wet-ice bath (ca. 2~C) was added concurrently 4.67 g
(77.8 mmol) of gl~ci~l acetic acid and 8.33 g (77.8 mmol) of 2,6-
dimethylpyridine (2,6-lutidine). To this solution was then added
slowly dropwise 8.87 g (116.7 mmol) of a 23.7 weight percent solu~ion
of peracetic acid in ethyl acetate, at a rate slow enough such that the
reaction temperature did not exceed 10~C (ca. 1 hour). After the initial
exotherm, the temperature returned to 2~C, and the reaction was
maintained at this temperature for an additional 3.5 hours.
Conversion of aldehyde at this time was ca. 99%, as monitored by GC
(DB-1 colllmn). The cold reaction solution was then transferred into a
separatory funnel, was diluted with ethyl acetate (300 mL), and was
washed with a 5% aqueous solution of sodium thiosulfate (Na2S2O3,
~ 100 mL). The ethyl acetate layer was further washed with two
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portions of water (110 mL each), and the combined water washes were
back-extracted with ethyl acetate (100 mL). The cornbined ethyl
acetate layers were extracted with two portions of a 5% aqueous
solution of sodium hydroxide (NaOH, 110 mL each). The combined
NaOH solutions of sodium napr- ~nAte were acidified to pH=1 with a
10% aqueous solution of hydrochloric acid, precipitating the naproxen
acid. The mixture was cooled in a wet-ice bath, and then was vacuum
filtered through a #4 VVh~Tn~n filter. The white solid thus obtained
was dried in a vacuum oven overnight at 45~ C (25 mm Hg), giving
15.85 g (88.5~o) of naproxen. HPLC analysis of this material (Chiracel
OD-H column) indicated an 'S' acid content of 99.2%, the same as the
starting aldehyde as measured following KMnO4 oxi~ .ion-
Example 13
Oxidation Of (S)-2-(4-Isobutvlphenvl)propionaldehyde To (S)-Ibuprofen
Usin~ Lutidine/Acetic Acid As Catalvst
To a stirred solution of 109 g (573 mmol) of 2-(4-isobutylphenyl)-
propionaldehyde (ibuprofen aldehyde) in ethyl acetate (512 mL) cooled
in a wet-ice bath (ca. 2~C) was added concurrently 34.4 g (573 mmol) of
Fl~iAl acetic acid and 61.4 g (573 mmol) of 2,6-dimethyl pyridine (2,6-
lutidine). To this solution was then added slowly dropwise 276 mL
(8~;9 mmol) of a 23.7 weight percent solution of peracetic acid in ethyl
acetate, at a rate slow enough such that the reaction temperature did
not exceed 7~C (ca. 1 h 40 min). After the initial exotherm, the
temperature returned to 2~C, and the reaction was rn~int~ined at this
temperature for an additional 2 hours. Conversion of aldehyde at this
time was ca. 99~o, as monitored by GC (DB-1 column). The cold
reaction solution was then transferred into a separatory funnel, was
diluted with ethyl acetate (650 mL), and was washed with a 7%
aqueous solution of sodium thiosulfate (Na2S2O3, 500 mL). The ethyl
acetate layer was further washed with two portions of water (750 mL
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each), and the combined water wasXes were back-extracted with ethyl
acetate (300 mL). The combined ethyl acetate layers were extracted
with three portions of a 5% aqueous solution of sodium hydroxide
(NaOH, 750 mL twice, then 500 mL). The combined NaOH solutions
were acidified to pH=1 with a 10% aqueous solution of hydrochloric
acid. The resulting solution was extracted with three portions of
dichloromethane (500 mL twice, then 300 mL), and the extract was
dried over anhydrous Na2SO4. The extract was filtered and
concentrated in vacuo to give 109 g (92.2%) of ibuprofen as an off-white
solid. HPLC analysis of this material indicated an 'S' acid content of
83%, the s~rne as the starting aldehyde as measured following KMnO4
",~;,l~t.ion.
Example 14
Oxidation Of (S)-2-(6-Methoxv-2-naphthvl)propionaldehvde To S-
Na~ Usin~ Lutidine N-Oxide As Catalvst
To a stirred solution of 3.32 g (15.5 mmol) of (S)-2-(6-methoxy-2-
naphthyl)propionaldehyde (98.8% pure by GC) in n-butyl acetate (15.5
mT.) cooled in a wet-ice bath (ca. 2~C) was added 1.91 g (15.5 mmol) of
2,6-dimethylpyridine N-oxide (2,6-lutidine N-oxide). To this solution
was then added slowly dropwise 1.77 g (23.2 mmol) of a 20.4 weight
percent solution of peracetic acid in ethyl acetate, at a rate slow
enough such that the reaction temperature did not exceed 10~C (ca. 30
min). After the initial exotherm, the temperature returned to 2~C, and
the reaction was maintained at this temperature for an additional 2
hours. Conversion of aldehyde at this time was ca. 99%, as monitored
by GC (DB-1 column). The reaction solution was transferred into a
separatory funnel, was diluted with n-butyl acetate (70 mL), and was
washed with a 5% aqueous solution of sodium thiosulfate (Na2S2O3,
15 mL). The butyl acetate layer was further washed with water (50
mL), and the combined water washes were back-extracted with n-butyl
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acetate (30 mL). The combined butyl acetate layers were extracted
with two portions of a 5% aqueous solution of sodium hydroxide
(NaOH, 65 mL each). The combined NaOH solutions of sodium
naproxenate were acidified to pH=1 with a 5% aqueous solution of
hydrochloric acid, precipitating the na~o~ell acid. The mixture was
cooled in a wet-ice bath, and then was vacuum filtered through a ~1
Whs3t.mAn filter. The filter cake was washed with cold water (50 mL)
and the white solid thus obtained was dried in a vacuum oven 60 hours
at 55~C (25 mm Hg), giving 3.51 g (98.4%) of naproxen.
Example 15
Oxidation Of (S)-2-(6-Methoxv-2-n~l~h~hvl)propionaldehvde To S-
Naproxen Usin~ Pvridine N-Oxide/Acetic Acid As Catalvst
To a stirred solution of 2.00 g (9.3 mmol) of (S)-2-(6-methoxy-2-
n~phthyl)propion~l~ehyde in ethyl acetate (10 mL) cooled in a wet-ice
bath (ca. 2~C) was added concurrently 0.89 g (9.3 mmol) of pyridine N-
oxide and 0.66 g (9.3 mmol) of acetic acid. To this solution was then
added slowly dropwise 5.8 mL (14.0 mmol) of a 20.4 weight percent
solution of peracetic acid in ethyl acetate, at a rate slow enough such
that the reaction temperature did not exceed 10~C (ca. 16 minutes).
After the iIlitial exotherm, the temperature returned to 2~C, and the
reaction was maintained at this temperature for an additional 4 hours.
The reaction solution was transferred into a separatory funnel, was
diluted with ethyl acetate (15 mL), and was washed with a 0.1 N
aqueous solution of sodium thiosulfate (Na2S2O3, 25 mL). The ethyl
acetate layer was further washed with water (10 mL), and the
combined water washes were back-extracted with ethyl acetate (10
mL). The combined ethyl acetate layers were extracted with two
portions of a 5% aqueous solution of potassium hydroxide (KOH, 65 mL
then 25 mL). The combined KOH solutions of potassium naproxenate
were acidified to pH=l with a 5~Yo aqueous solution of hydrochloric acid,
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precipitating the naproxen acid. The mixture was cooled in a wet-ice
bath, and then was vacuum filtered through a #1 Wh:ltT~ n filter. The
filter cake was washed with cold water (20 mL) and the white solid
thus obtained was dried in a vacuum oven 18 hours at 55~C (25 mm
Hg), giving 1.72 g (80.0%) of naproxen.
Example 16
Oxidation Of (S~-2-(4-IsobutYlphenYl)propionaldehvde To (S)-Ibuprofen
Usin~ Lutidine N-Oxide As Catalvst
To a stirred solution of 10.0 g (52.6 mmol) of 2-(4-
isobutylphenyl)propionaldehyde (ib~ oren aldehyde) in n-butyl
acetate (53 mL) cooled in a wet-ice bath (ca. 2~C) was adLded 6.5 g (52.6
mmol) of 2,6-dimethylpyridine N-oxide (2,6-lutidine N-oxide). To this
solution was then added slowly d~ o~wise 29 mL (78.8 mmol) of a 20.0
weight percent solution of peracetic acid in ethyl acetate, at a rate slow
enough such that the reaction temperature did not exceed 10~C (ca. 25
minutes). After the initial exotherIn, the temperature rleturned to 2~C,
and the reaction was maintained at this temperature for an additional
4 hours. The cold reaction solution was then transferred into a
separatory funnel, was diluted with n-butyl acetate (100 mL), and was
washed with a 1% aqueous solution of sodium thiosulfate (Na2s2o3
100 rnT.) The butyl acetate layer was further washed with two
portions of water (100 mL each), and the combined water washes were
back-extracted with n-butyl acetate (100 mL). The combined butyl
acetate layers were extracted with two portions of a 5% aqueous
solution of sodium hydroxide ~NaOH, 100 mL each). The combined
NaOH solutions were acidified to pH=1 with a 10% aqueous solution of
hydrochloric acid. The resulting solution was extracted with two
portions of dichloromethane (100 mL each), and the extract was dried
over anhydrous Na2SO4 The extract was filtered and concentrated in
vacuo to give 10.3 g (94.6%) of ibuprofen as an off-white solid.
SUBSTITUTE SHEET (RULE 26)
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E:xample 17
Oxidation Of (S)-2-(6-Methoxv-2-naphthvl)propionaldehvde To S-
Naproxen With Peracetic Acid (1.5 Equivalents) Using 4-
Methvlmorpholine N-Oxide (1.0 Equivalent) As Catalvst
To a stirred solution of 3.0 g (14.0 mmol) of (S)-2-(6-methoxy-2-
naphthyl)propionaldehyde (ca. 95% pure by GC) in n-butyl ~et~te
(14.0 mL) cooled in a wet-ice bath (c~. 2~C) was added 1.64 g (14.0
mmol) of 4-methylmorpholine N-oxide. To this solution was then
added slowly dropwise 7.7 mL (21.0 mmol) of a 23.0 weight percent
solution of peracetic acid in ethyl acetate, at a rate slow enough such
that the reaction temperature did not exceed 5~C (highly exothermic,
ca. 60 minutes). TLC analysis of the reaction mixture 10 minutes post
- peracetic acid addition indicated that coll~/e~ ~ion of the aldehyde was
complete, and a sample (0.5 mL) was withdrawn for GC analysis. The
reaction solution was transferred into a separatory funnel with the aid
of n-butyl acetate (25 mL), and was washed with a 1 M aqueous
solution of sodium thiosulfate (Na2S2O3, 5 mL). The butyl acetate
layer was further washed with water (50 mL). The butyl acetate
solution of naproxen acid was then extracted with two portions of a 5~o
aqueous solution of sodium hydroxide (NaOH, 50 mL each). The
combined NaOH solutions of sodium napro~ren~te were acidified with
stirring to pH=l with a 5% aqueous solution of hydrochloric acid (105
mL), precipitating the naproxen acid. The mixture was vacuum
filtered through a #l Whs~.n~n filter, and the solids were washed with
cold water (5 mL). The white solid thus obtained was dried in a
vacuum oven 14 hours at 55~C (25 mm Hg), giving 2.52 g (78.2%, not
including withdrawn sample) of na~ o~ell. Chiral phase HPLC
analysis indicated a ratio of S: R naproxen of 50.1: 49.9 (racemic).
SUBSTITUTE SHEET (RULE 26)
CA 02234983 1998-04-16
WO 97/14669 PCTrUS96/16903
- 65 -
Example 18
Oxidation Of (S)-2-(6-Methoxv-2-naphthvl)propionaldehvde To S-
Naproxen With Peracetic Acid (1.5 Equivalents) Using 4-Methoxy-
pvridine N-Oxide (1.0 Equivalent) As Catalvst
To a stirred solution of 3.0 g (14.0 mmol) of (S)-2-(6-methoxy-2-
n~phthyl)propionaldehyde (ca. 95% pure by GC) in n-butyl acetate
(14.0 mL) cooled in a wet-ice bath (ca. 2~C) was added 1.75 g (14.0
mmol) of 4-metho~y~y~ idine N-oxide. To this solution was then added
slowly dropwise 7.7 mL (21.0 mmol) of a 23.0 weight percent solution of
peracetic acid in ethyl acetate, at a rate slow enough such that the
reaction temperature did not exceed 5~C (highly exothermic, ca. 60
minutes). TLC analysis of the reaction mixture 10 minutes post
peracetic acid addition indicated that conversion of the aldehyde was
- complete, and a sample (0.5 mL) was withdrawn for GC analysis. The
reaction solution was transferred into a separatory funnel with the aid
of n-butyl acetate (25 mL), and was washed with a 1 M aqueous
solution of sodium thiosulfate (Na2S2O3, 5 mL). The butyl acetate
layer was further washed with water (50 mL). The butyl acetate
solution of naproxen acid was then extracted with two portions of a 5%
aqueous solution of sodium hydroxide (NaOH, 50 mL each). The
combined NaOH solutions of sodium napr-)~enzlte were acidified with
stirring to pH=1 with a 5% aqueous solution of hydrochloric acid (105
mL), precipitating the naproxen acid. The mixture was vacuum
filtered through a #1 Wh:lt.m~n filter, and the solids were washed with
cold water (5 mL). The white solid thus obtained was dried in a
vacuum oven 14 hours at 55~C (25 mm Hg), giving 2.75 g (85.4%, not
including withdrawn sample) of naproxen. Chiral phase HPLC
analysis indicated a ratio of S: R naproxen of 88.5: 11.4 (77.1 %ee),
the same ratio as the starting aldehyde within experimental error.
SlJBSTITUTE SHEET (RULE 26)
CA 02234983 1998-04-16
W O 97/14669 PCT~US96/16903
- 66-
Example 19
Oxidation Of (S)-2-(6-Methoxy-2-naphthvl~propionaldehvde To S-
Naproxen With Peracetic Acid (1.1 Equivalents) Using 4-MethoxY-
pvridine N-Oxide (0.5 Equivalents) As Catalvst At 2-5~C
To a stirred solution of 5.0 g (23.3 mmol) of (S)-2-(6-metho~y-2-
nApht.hyl)propionf~lrl-?hyde (ca. 95% pure by GC) in n-butyl acetate
(24.0 mL) cooled in a wet-ice bath (ca. 2~C) was added 1.46 g (11.67
mmol) of 4-metho~y~.idine N-oxide. To this solution was then added
slowly dropwise 1.95 g (26.67 mmol) of a 23.0 weight percent solution
of peracetic acid in ethyl acetate, at a rate slow enough such that the
reaction temperature did not exceed 6~C (highly exothermic, ca. 45
min). TLC analysis of the reaction mixture 30 minutes post peracetic
acid addition indicated that co~lve~;jion ofthe aldehyde was complete.
The reaction solution was transferred into a separatory funnel with the
aid of n-butyl acetate (50 mL), and was treated with a 1 M aqueous
solution of sodium thiosulfate (Na2S2O3, 1.3 mL). A sa~nple (0.5 mL)
was withdrawn for GC analysis. The butyl acetate layer was washed
with water (50 mL, twice), and the wahings were back-extracted with
n-butyl acetate (20 mL). The combined butyl acetate solutions of
naproxen acid were then extracted with two portions of a 5% aqueous
solution of sodium hydroxide (NaOH, 60 mL each). The combined
NaOH solutions of sodium napr~ n~te were acidified with stirring to
pH=1 with a 5% aqueous solution of hydrochloric acid (125 mL),
precipitating the naproxen acid. The mixture was cooled in a wet-ice
bath, vacuum filtered through a #1 Wh~tn ~n filter, and the solids
were washed with cold water (5 mL). The white solid thus obtained
was dried in a vacuum oven 14 hours at 55~C (25 mm Hg), giving 4.91
g (91.4%, not including withdrawn sample) of naproxen. Chiral phase
HPLC analysis indicated a ratio of S: R naproxen of 88.6: 11.4 (77.2
%ee), the same ratio as the starting aldehyde within experimental
error.
- SllJ~;~ ITE SHEET(RULE 26)
CA 02234983 l998-04-l6
WO 97/14669 PCTrUS96/16903
- 67 -
Example 20
Oxidation Of (S)-2-(6-Methoxv-2-naphthyl)propionaldehvde To S-
Naproxen With Peracetic Acid (1.1 Equivalents) Using 4-Methoxv-
pvridine N-Oxide (0.5 Equivalents) As Catalvst At -25~C
To a stirred solution of 1.0 g (4.67 mmol) of (S)-2-(6-methoxy-2-
naphthyl)propionaldehyde (ca. 95% pure by GC) in n-butyl acetate (5
mL) cooled in a CO2/CCl4 bath (-25~C) was added 292 mg (2.3 mmol) of
4-metho~y~ylidine N-oxide. To this solution was then added slowly
dropwise 391 mg (5.1 mmol) of a 23.0 weight percent solution of
peracetic acid in ethyl acetate, at a rate slow enough such that the
reaction temperature did not exceed -18~C highly exothermic, ca. 20
minutes). TLC analysis of the reaction mixture 10 minutes post
peracetic acid addition indicated that conversion of the aldehyde was
complete. The reaction solution was then treated with a 0.1 M aqueous
solution of sodium thiosulfate (Na2S2O3, 11 mL). A sample (0.5 mL)
was withdrawn from the organic layer for GC analysis. The reactor
contents were transferred to a separatory funnel using n-butyl acetate
(20 mL), and the butyl acetate layer was washed with water (50 mL).
The butyl acetate solution of naproxen acid was then extracted with
two portions of a 5% aqueous solution of sodium hydroxide (NaOH, 30
mL each). The combined NaOH solutions of sodium napro~n~te ~rere
acidified with stirring to pH=1 with a 5% aqueous solution of
hydrochloric acid (65 mL), precipitating the naproxen acid. The
mixture was vacuum filtered through a #1 Wh~tm~n filter. The white
solid thus obtained was dried in a vacuum oven 14 hours at 55~C (25
mm Hg), giving 0.804 g (74.7%, not including withdrawn sample; 85%
corrected for withdrawn sample) of naproxen. Chiral phase HPLC
analysis indicated a ratio of S: R naproxen of 88.7: 11.3 (77.4 %ee),
the same ratio as the starting aldehyde within experimental error.
.
SlJ~a 1 1 1 UTE SHEET (RULE 26)
CA 02234983 1998-04-16
WO 97/14669 PCTAUS96/16903
- 68-
Example 21
Oxidation Of (S)-2-(6-Methoxv-2-naphthvl)propionaldehvde To S-
Naproxen With Peracetic Acid (1.5 Equivalents) Usin~ 4-
MethYlmorpholine N-Oxide (1.0 Equivalent) / Acetic Acid (1.0
Equivalent) As Catalvst
To a stirred solution of 3.0 g (14.0 mmol) of (S)-2-(6-methoxy-2-
naphthyl)propionaldehyde (ca. 94~o pure by GC) in n-butyl acetate
(14.0 mL) cooled in a wet-ice bath (ca. 2~C) was added 0.84 g (14.0
mmol) of glacial acetic acid followed by 1.64 g (14.0 mmol) of 4-
methylmorpholine N-oxide. To this solution was then added slowly
d. o~wise 7.7 mL (21.0 mmol) of a 23.0 weight percent solution of
peracetic acid in ethyl acetate, at a rate slow enough such that the
reaction temperature did not exceed 5~C. The reaction mixture was
stirred at 2~C for 4 hours, then excess peracetic acid was neutralized
by the addition of a 1.0 M aqueous solution of sodiuIn thiosulfate
(Na2S2O3, 10 mL). The solution was transferred into a separatory
funnel with the aid of n-butyl ~cet~te (26 mL), and the aqueous layer
was separated and discarded. The butyl acetate solution of na~l o~ell
acid was then extracted with two portions of a 5% aqueous solution of
sodium hydroxide (NaOH, 50 mL each). The combined NaOH solutions
of sodium naproxenate were acidified with stirring to pH=2 with a 5%
aqueous solution of hydrochloric acid (100 mL), precipitating the
na~l o~ell acid. The mixture was cooled in a wet-ice bath and was
vacullm filtered through a #2 Wh:~t.m~n filter. The white solid thus
obtained was dried in a vacuum oven 14 hours at 55~C (25 mm Hg),
giving 2.58 g (80.0~o) of naproxen. Chiral phase HPLC analysis
indicated a ratio of S: R naproxen of 78.0: 22.0 (partial r~c~ fion;
this batch of aldehyde was known to give acid with S: R content of
88.1: 21.9).
SUBSTITUTE SHEET (RULE 26)
CA 02234983 1998-04-16
WO 97/14669 PCTrUS96/16903
- 69 -
Example 22
Oxidation Of (S)-2-(6-MethoxY-2-naphthyl)propionaldehvde To S-
Naproxen With Peracetic Acid (3.0 Equivalents) Usin~
TriethanolAmine (1.0 Equivalent) / Acetic Acid (1.0 Equivalent) As
Catalvst
To a stirred solution of 1.0 g (4.67 mmol) of (S)-2-(6-methoxy-2-
naphthyl)propionaldehyde in absolute ethanol (5.0 mL) cooled in a wet-
ice bath (ca. 2~C) was added 0.27 mL (0.28 g, 4.67 mmol) of gl~..i~l
acetic acid followed by 0.62 mL (0.70 g, 4.67 mmol) of triethanol~min~?.
To this solution was then added slowly ~ o~wise 2.25 mL (7.0 mmol) of
a 23.0 weight percent solution of peracetic acid in ethyl acetate, at a
rate slow enough such that the reaction temperature did not exceed
10~C. The reaction mixture was stirred at 2~C for 2 hours, then an
- additional 2.25 mL (7.0 mmol) of the peracetic acid solution was added
to complete the conversion of the aldehyde (4 hours total). The solution
was transferred into a larger flask with the aid of ethanol (5 mL),
heated to 50~C, and was diluted with water (40 mL). The solution was
cooled in a wet-ice bath causing precipitation, and was vacuum filtered
through a #2 Wh~t.m~n filter. The light purple solid thus obtained was
washed with 20 mL water and was dried in a vacuum oven 14 hours at
55~C (25 mm Hg), giving 0.79 g (73.5~o) of naproxen. Chiral phase
HPLC analysis indicated a ratio of S: R naproxen of 95.8: 4.2, the
s~me as that obtained by an independent oxidation method.
Although the invention has been illustrated by certain of
the preceding examples, it is not to be construed as being limited
thereby; but rather, the invention encompasses the generic area as
hereinbefore disclosed. Various modifications and embodiments can be
made without departing from the spirit and scope thereof.
SUBSTITUTE SHEET (RULE 26)
