Note: Descriptions are shown in the official language in which they were submitted.
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Optically active 0-aminoketones, optically active 1,3-amino alcohols and
method for
the production thereof
Aminoalkylations of CH-acidic compounds have been known for about 100 years.
They are referred to as Mannich reactions and are one of the most important C-
C
bond forming reactions of organic chemistry.
N/R2 * a direct
R H H
Mannich PkN~
T reaction
Retro- R s
T Mannich 4
where Rs = H where R, * H R (NRz) reaction _
, R2 ,~Rx Mannich -base
N N + / s indirect
11
R H R H
or
preformed preformed preformed
imine iminium salt enolate equivalent
(e.g. enamine or
sityl enol ether)
In its original and most well-known form, the Mannich reaction is carried out
with
three reactants in the form of a "three-component coupling": an enolizable
ketone, a
nonenolizable aldehyde (frequently formaldehyde or an arylaldehyde) and an
amine
component (ammonia or a primary or secondary amine) react with one another to
form a (i-aminoketone. In this "Mannich base" the active hydrogen of the
enolizable
ketone has been replaced by an aminoalkyl substituent. This direct variant of
the
Mannich reaction is particularly industrially attractive, because the three
reactants
specified are usually readily available and inexpensive, and at least very
easily
obtainable. Also, these reactants are generally not sensitive (i.e. have good
storability) and therefore allow simple handling. Finally, the direct three-
component
coupling of commercially available reactants is a single-stage, i.e. the
shortest
conceivable, synthesis of 3-aminoketones.
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In addition, there are less industrially attractive indirect variants of the
Mannich
reaction in which preformed enolate equivalents (usually enamines or silyl
enol
ethers) are used. These compounds are generally not commercially available or
are
expensive. Their preceding preparation is an additional synthetic step. Also,
the
trimethylsilyl enol ethers in particular and, to a lesser extent, the
enamines, are acid-
and hydrolysis-sensitive, poorly storable and difficult to handle. Although
silyl enol
ethers having certain other silyl groups are more stable, they are more
expensive to
prepare. The high nucleophilicity of the preformed enolate equivalents has
advantages and disadvantages. On the one hand, it allows frequently mild
reaction
conditions and thus occasionally makes possible Mannich reactions which in the
direct variant are accompanied by too many secondary reactions. On the other
hand,
the aminomethylations of preformed enolate equivalents are frequently low
temperature reactions and therefore costly and inconvenient on the industrial
scale.
Further disadvantages of stereoselective variants using preformed enolate
equivalents are the use of industrially problematic Lewis acid catalysts, poor
solubilities of reaction components at the low temperature and, for this
reason, the
necessity of using large amounts of solvent (poor space/time yields) or the
use of
problematic or expensive solvents. Iminium salts in the Mannich reaction are
distinctly more reactive (more electrophilic) than imines. This brings
advantages and
disadvantages which are similar to those described above for preformed enol
equivalents.
Asymmetric Mannich reactions are described, for example, in M. Arend et al.
(Angew.
Chem. Int. Ed. Engl. 1998, 37, 1044-1070), which states on page 1067: "Despite
many studies, and some notable successes, penetration into enantiomerically
pure
Mannich bases is still only beginning. j...] When one thinks of the many in
situ
racemization-free routes to derivatization of the kinetic products (to, for
example,
amino alcohols, diamines, amines etc.), it becomes understandable that the
possibility of developing efficient and effective routes to products of
controlled
absolute configuration may indeed be realizable. Catalytic processes, which
are
established in many other areas of stereochemistry, are almost completely
untouched".
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The use of stoichiometric amounts of chiral auxiliaries in an asymmetric
Mannich
reaction is described, for example, by H. Ishitani et al. (J. Am. Chem. Soc.
2000, 122,
8180-8186). This method has no industrial relevance, since the chiral
auxiliary is
covalently bonded to the preformed imine (or more rarely to the preformed
enolate
equivalent), in order to conduct the Mannich reaction as a diastereoselective
addition. Synthesis, linking and, after completed Mannich reaction, removal of
the
chiral auxiliary require a plurality of additional synthetic steps. The
Mannich additions
were in addition frequently low temperature reactions, and the chiral
auxiliaries were
difficult to obtain or only available in an absolute configuration.
Catalytic asymmetric Mannich variants were summarized by S.E. Denmark & O.J.-
C.
Nicaise ("Catalytic Enantioselective Mannich-Type Reactions" in Comprehensive
Asymmetric Catalysis, E.N. Jacobsen, A. Pfaltz, H. Yamamoto, Eds.; Springer-
Verlag: New York, 1999; Vol. 2, Chapter 26.2.9; pages 954-958). The catalytic
variants are for the most part indirect Mannich reactions which limits their
industrial
attractiveness. Also, complicated chiral transition metal catalysts have to be
used.
Direct asymmetric three-component Mannich reactions using unmodified ketones
can
be induced by heteropolymetallic chiral catalysts based on lanthanides,
although, as
described in S. Yamasaki et al. (Tetrahedron Left. 1999, 40, 307-310), result
in only
moderate chemical yields ( 16%) and enantiomeric excesses (< 64% ee).
The first direct catalytic asymmetric three-component Mannich reaction which
comes
near to fulfilling the industrial demands was reported only recently (B. List,
J. Am..
Chem. Soc. 2000, 122, 9336-9337; cf. H. Groger & J. Wilken, Angew. Chem. Int.
Ed.
Engl. 2001, 40, 529 - 532 ). In this reaction, unmodified ketones are reacted
with
aryl- or alkylaldehydes and certain aniline derivatives with catalysis using
35 mol% of
(L)-proline in dimethyl sulfoxide or chloroform at room temperature to give
optically
active Mannich bases. The chemical yields were moderate to good (35-90%), and
the optical purities average to very good (73-96% ee).
Mannich bases and their derivatives have numerous industrial applications
which are
summarized in M. Arend et al. (Angew. Chem. 1998,110,1096-1122) on page 1045.
The most important field of use, in particular of chiral Mannich bases, is the
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preparation of active ingredients for drugs, for example the neuroleptic
Moban. On
this subject, it is stated in Arend et at. on page 1047: "The classical
Mannich reaction
is not suited to the enantioselective synthesis of p-amino ketones and amino
aldehydes. Thus, the majority of pharmaceutical products, which are derived
from the
Mannich reaction, are used in the form of racemates. The application of
enantiomerically pure Mannich bases is only possible when these are available
by
separation of the racemate. This problem becomes more severe when one takes
into
consideration the increasing importance of stereochemically pure
pharmaceuticals
(the avoidance of "isomer ballast" and of undesirable side effects)."
Racemic (i-amino ketones which can be described by a mixture of a compound of
the
formula (I) and its enantiomer
KNrR O
,,=H rac-(I)
RI H R5
R4
in which the substituents R1 = phenyl, R2 = H, R3 = phenyl, R4 = methyl and
R5 = phenyl, are described in T. Akiyama et at., Synlett 1999, 1045-1048;
in which R1 = p-tolyl, R2 = H, R3 = p-methoxycarbonylphenyl, R4 = methyl and
R5 = phenyl are described in N. Shida et at, Tetrahedron Lett. 1995, 36, 5023-
5026;
in which R1 = phenyl, R2 = H, R3 = p-chlorophenyl, R4 = methyl and R5 = phenyl
are
described in CA120: 257988;
in which R1 = tert-butyl or phenyl, R2 = R3 = R4 = methyl and R5 = phenyl are
described in E.G. Nolen et at., Tetrahedron Left. 1991, 32, 73-74.
Chiral 1,3-amino alcohols, like, for example, the analgesic tramadol, are
important as
active pharmaceutical ingredients, and also as chiral auxiliaries for
asymmetric
syntheses, documented, for example, in S. Cicchi et at. ("Synthesis of new
enantiopure 1i-amino alcohols: their use as catalysts in the alkylation of
benzaldehyde
by diethylzinc", Tetrahedron: Asymmetry 1997, 8, 293-301).
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The limited diastereoselective reduction of Mannich bases with LiAIH4 was
described
as early as 1985 by J. Barluenga et al. ("Diastereoselective synthesis of P-
amino
alcohols with three chiral centers by reduction of n-amino ketones and
derivatives" J.
Org. Chem. 1985, 50, 4052-4056).
5
Chiral 1,3-amino alcohols of the formula (II),
RAN/Rz
,,.H OH
(II)
R1 H R5
R4
i.e. with (SR,RS,SR) configuration could hitherto not be prepared with
industrially
usable diastereoselectivities from Mannich bases of the formula (I).
The assignment of (R) and (S) configuration is based on the priority rules of
Cahn,
Ingold and Prelog. This prioritization may be reversed when one or more of the
substituents is modified. The designation (SR,RS,SR) states that in this
compound
the middle stereocenter (which bears R4 as a substituent) has (R)
configuration when
the two outer stereocenters have (S) configuration (this is the configuration
drawn in
formula II), or else that the middle stereocenter has (S) configuration when
the two
outer stereocenters have (R) configuration (this is the mirror image of the
configuration drawn in formula II). The configuration of the stereoisomers
depends on
the selection of the chiral anion Y*" vide infra. The above-specified
configuration
designation (SR,RS,SR) relates to the model product as specified in the
examples,
but may be reversed in the case of other compounds or substituents. The
stereochemistry of the compound of the formula (11) is reported unambiguously
by the
structural formula (11).
A multistage enzymatic method for producing chiral 1,3-amino alcohols starting
from
racemic butane-1,4-diols is described in the US patent US 5,916,786.
The carbonyl reduction of a-chiral P-aminoketones using LiAIH4 (lithium
aluminum
hydride) or with hydrogen in the presence of platinum catalysts results
preferentially
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in the 1,3-amino alcohol dia-(II) whose hydroxyl configuration is
diastereomeric to
formula (II) when the amino substituent is tertiary
R3 2
N11-IR OHH
'H dia-(ll)
R1 H R5
R4
and an approximately equimolar mixture of the diastereomers (II) and dia-(Ii)
results
when the amino substituent is secondary (M.-J. Brienne et al., Bull. Soc.
Chim.
France 1969, 2395; A. Andrisano & L. Angiolini Tetrahedron 1970, 26, 5247).
The patent application EP 1117645 describes optically active 1,3-amino
alcohols of
the formula (II) where R1 = o-aminophenyl, R2 = H, R3 = R4 = 2-pyridyl and
R5 = phenyl or 3,5-dimethylisoxazol-4-yl which had previously been prepared by
a
classical optical resolution.
The present invention provides a compound of the formula (I) or its enantiomer
R, N/R O
,,.H
R5 (I)
R1 H
R4
where
R' is
1. hydrogen,
2. a tert-butyl group or
3. a carbocyclic or heterocyclic aryl radical R6, where the aryl radical R6 is
a
carbocyclic aryl radical having 5-14 carbon atoms or a heterocyclic aryl
radical
having 5-14 carbon atoms, where from 1 to 4 carbon atoms are replaced by N,
0 or S,
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where R6 is unsubstituted or bears from 1 to 5 substituents which are each
independently (C,-C7)alkyl, (C3-C7)cycloalkyl, alkanoyl (-CO-(C1-C7)alkyl),
aroyl
(-CO-(C5-C14)aryl), fluoro, chioro, bromo, iodo, hydroxyl, (C1-C7)alkoxy,
(C3-C7)cycloalkoxy, (C5-C14)aryloxy, (C1-C7)alkanoyloxy, (C5-C14)aroyloxy,
-O-CO-NHR, -O-CO-NRR', -0-CO-OR, -O-CO-SR, -O-CS-NHR, -O-CS-NRR',
-0-CS-OR, -0-CS-SR, -O-S02-(C1-C7)alkyl, -0-S02-(C5-C14)aryl, nitro,
-NH-CO-R, -NR'-CO-R, -NH-CO-OR, -NR'-CO-OR, -NH-CO-NHR, -NR'-
CO-NHR, -NR'-CO-NRR", di(C1-C7)alkylamino, di(C5-C14)arylamino,
N-(C1-C7)alkyl-N-(C5-C14)arylamino, (C1-C7)alkylthio, (C5-C14)arylthio,
(C1-C7)alkylsulfonyl, (C5-C14)arylsulfonyl, (C5-C14)arylsulfoxidyl, or an
unsubstituted aryl radical R6,
where R, Rand R" are each independently (C1-C7)alkyl, (C3-C7)cycloalkyl or
(C5-C14)aryl,
preferably an aryl radical having 6-10 carbon atoms, more preferably a
carbocyclic
aryl radical having 6-10 carbon atoms,
more preferably a radical from the group of phenyl, naphthyl, anthracenyl,
phenanthrenyl, pyridyl, quinolinyl, isoquinolinyl, benzoquinolinyl,
pyridazinyl,
pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, benzopyridazinyl,
benzopyrimidinyl,
benzopyrazinyl (quinoxalinyl), benzotriazinyl, pyridopyridinyl,
pyridoquinolinyl
(phenanthrolinyl), benzoquinoxalinyl (phenazinyl), pyrrolyl, benzopyrrolyl
(indolyl),
benzoindolyl, pyrazolyl, benzopyrazolyl, imidazolyl, benzimidazolyl,
triazolyl,
benzotriazolyl, tetrazolyl, imidazopyrimidinyl (9H-purinyl), furanyl,
benzofuranyl,
dibenzofuranyl, thiophene, benzothiophene, dibenzothiophene, isoxazolyl,
benzisoxazolyl, oxazolyl, benzoxazolyl, oxadiazolyl, benzoxadiazolyl,
thiazolyl,
benzothiazolyl, isothiazolyl, benzisothiazolyl, thiadiazolyl or
benzothiadiazolyl,
particularly preferably a radical R7 where R7 is defined as a radical from the
group of
phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl or benzoquinolinyl, where
R7 is
unsubstituted or is provided with up to 5 substituents which are each
independently:
(C1-C7)alkyl, (C3-C7)cycloalkyl, fluoro, chloro, bromo, (C1-C7)alkoxy,
(C3-C7)cycloalkoxy, (C5-C14)aryloxy, (C1-C7)alkanoyloxy, (C5-C14)aroyloxy, -0-
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CO-NHR, -O-CO-NRR`, -0-CO-OR, nitro, phenyl, naphthyl, pyridyl, quinolinyl,
isoquinolinyl, benzoquinolinyl,
especially preferably a carbocyclic or heterocyclic aryl radical R8 where R8
is defined
as a radical from the group of phenyl, naphthyl, pyridyl or quinolinyl, and
where R8 is
unsubstituted or provided with up to 5 substituents which are each
independently:
nitro, fluoro, chloro or bromo,
R2, R3 and R4 are each independently
1. hydrogen,
2. (C,-C7)alkyl,
where (C1-C7)alkyl is unsubstituted or substituted by an aryl radical R6,
3. (C3-C7)cycloalkyl or
4. an aryl radical R6, and
preferably each independently hydrogen or an aryl radical R7,
more preferably each independently hydrogen or an aryl radical R8,
R5 is an aryl radical R6,
preferably an aryl radical R7,
more preferably an aryl radical R8,
excluding a compound of the formula (I) in which R1 = o-aminophenyl or o-
nitrophenyl, R2 = H, R3 = 2-pyridyl, R4 = 2-pyridyl and R5 = phenyl or 3,5-
dimethylisoxazol-4-yl.
Preference is given to a compound of the formula (I) as described above,
excluding a
compound of the formula (I) in which R1 = o-aminophenyl or o-nitrophenyl, R2 =
H, R3
= 2-pyridyl optionally substituted by methyl, fluorine or MeO, R4 = 2-pyridyl
optionally
substituted by OH, CH2OH, MeO, CHO or NH2, and R5 = phenyl or heteroaryl,
where
phenyl and heteroaryl are optionally substituted by fluorine, chlorine,
bromine, iodine,
OH, NO2, (C,-C7)-alkyl, CHO, -(C=O)-(Cl-C8)-alkyl, (C1-C6)-alkylthio or
pyridyl.
Alkyl and alkoxy radicals may be branched or unbranched.
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Examples of (C,-C7)alkyl radicals are methyl, ethyl, propyl, isopropyl, n-
butyl,
isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl.
Examples of (C3-C7)cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl,
cycloheptyl, 2-methylcyclopentyl, 3-methylcyclohexyl.
The invention also provides a compound of the formula (II)
R~, N,R2
,
=,H OH
(II)
RI H R5
R4
where the R1, R2, R3, R4 and R5 radicals are each as defined in the compound
of the
formula (I), or its enantiomer or its salts,
with the exception of a compound of the formula (II) where R1 = o-aminophenyl
or o-
nitrophenyl, R2 = H, R3 = 2-pyridyl, R4 = 2-pyridyl and R5 = phenyl or 3,5-
dimethylisoxazol-4-yl.
Preference is given to a compound of the formula (II) as described above,
excluding
a compound of the formula (II) in which R1 = o-aminophenyl or o-nitrophenyl,
R2 = H,
R3 = 2-pyridyl optionally substituted by methyl, fluorine or MeO, R4 = 2-
pyridyl
optionally substituted by OH, CH2OH, MeO, CHO or NH2, and R5 = phenyl or
heteroaryl, where phenyl and heteroaryl are optionally substituted by
fluorine,
chlorine, bromine, iodine, OH, NO2, (C,-C7)-alkyl, CHO, -(C=O)-(C%-C8)-alkyl,
(C1-C6)-
alkylthio or pyridyl.
Over the entire application text, any stereochemical formula given refers
either to the
absolute configuration expressed by the stereochemical formula or its
enantiomer,
where the compounds are always present in an enantiomeric purity of greater
than or
equal to 90% ee, preferably greater than or equal to 95% ee, more preferably
greater
than or equal to 98% ee. This applies in particular to the compounds of the
formulae
(I), (II) and (III).
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Over the entire application text, a "classical optical resolution" is the
separation of the
image and mirror image of a racemic material by using a (substantially)
enantiomerically pure auxiliary to form diastereomeric salts which, owing to
differing
5 physical properties, for example different solubilities, are separated from
one another
without resulting in a (significant) conversion of the image to the mirror
image under
the conditions of the optical resolution. The maximum achievable yield of the
enantiomerically pure material by means of a classical optical resolution is
50%. It
differs fundamentally from the "dynamic optical cleavage" in which the image
and
10 mirror image interconvert under the conditions of the optical resolution
and thus
enable yields of the enantiomerically pure material of up to 100% to be
achieved.
Dynamic optical resolutions may in principle be kinetically controlled or
thermodynamically controlled. A group of reactions within the
thermodynamically
controlled dynamic optical resolutions are the crystallization-induced dynamic
optical
resolutions. The examples described in the present invention belong to this
group of
reactions.
It was found that, surprisingly, compounds of the formula (III) or their
diastereomers
(III A),
Y Y
H H
2
R3~ +,,- R N+,,'R2
N O
R R5 R R5
R4 H R4, H
(III) (III A)
salts of the f -aminoketones of the formula (I), whose cation has very high
enantiomeric excesses and very high diastereomeric purity (syn/anti ratio),
can be
prepared in high yield in a simple manner by direct four-component coupling
based
on a dynamic optical resolution.
The cation of (III A) is the enantiomer of the cation (Ill). However, since
the anion Y'
is homochiral, the compound (III A) is a diastereomer to the compound (Ill).
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The present invention therefore also provides a process for preparing a
compound of
the formula (III) or its diastereomer (III A),
Y
H
R N+.,-RO
R R5
R4 H
(III)
where the R1, R2, R3, R4 and R5 radicals are each as defined in the compound
of the
formula (I),
and where the Y anion is the conjugate base of an optically active, organic
Bronsted
acid (protic acid),
preferably an optically active, naturally occurring or industrially prepared
carboxylic
acid, for example (R)-(-)-mandelic acid, (S)-(+)-mandelic acid, D-(-)-tartaric
acid,
L-(+)-tartaric acid, (+)-di-0,0'-pivaloyl-D-tartaric acid [(+)-DPTA], (-)-di-
0,0'-pivaloyl-
L-tartaric acid, [(-)-DPTA], (+)-O,O'-dibenzoyl-D-tartaric acid, (-)-O, O'-
dibenzoyl-L-
tartaric acid, (-)-di-O,O'-benzoyl-L-tartaric mono(dimethylamide), (+)-O,O'-
dianisoyl-
D-tartaric acid [(+)-DATA], (-)-O,O'-dianisoyl-L-tartaric acid [(-)-DATA], (+)-
di-0,O'-p-
tolyl-D-tartaric acid, (-)-di-0,0'-p-tolyl-L-tartaric acid, D-(+)-malic acid,
L-(-)-malic
acid, L-(+)-lactic acid, D-(-)-lactic acid, (S)-(-)-2-
(phenylaminocarbonyloxy)propionic
acid, (R)-(+)-2-(phenylaminocarbonyloxy)propionic acid, D-(+)-gluconic acid, (-
)-
2,3,4,6-di-O-isopropylidene-2-keto-L-guIonic acid, (D)-(-)-quinic acid, (-)-
3,4,5-
trihydroxy-l-cyclohexene-1-carboxylic acid [shikimic acid], (S)-(+)-(2,2-
dimethyl-5-
oxodioxolan-4-yl)acetic acid, (+)-camphoric acid, (-)-camphoric acid, (1 R)-
(+)-
camphanic acid, (IS)-(-)-camphanic acid, (R)-(-)-O-acetylmandelic acid, (S)-
(+)-O-
acetylmandelic acid, (R)-2-phenoxypropionic acid, (S)-2-phenoxypropionic acid,
(S)-
(+)-(x-methoxyphenylacetic acid, (R)-(-)-a-methoxyphenylacetic acid, (R)-(+)-a-
methoxy-a-trifluoromethylphenyl acetic acid, (S)-(-)-a-methoxy-a-
trifluoromethyl-
phenylacetic acid, (S)-(+)-2-phenyl propionic acid, (R)-(-)-2-phenyl prop
ionic acid, (R)-
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(+)-2-chloropropionic acid, (S)-(-)-2-chloropropionic acid, (R)-(+)-N-(a-
methylbenzyl)-
phthalic monoamide, (S)-(-)-N-(a-methylbenzyl)phthalic monoamide, (R)-(-)-5-
oxotetrahydrofuran-2-carboxylic acid, (S)-(+)-5-oxotetrahydrofuran-2-
carboxylic acid,
D-(+)-3-phenyllactic acid, L-(-)-3-phenyllactic acid, L-(+)-a-
hydroxyisovaleric acid,
D-(-)-a-hydroxyisovaleric acid, (+)-menthyloxyacetic acid, (-)-
menthyloxyacetic acid,
(+)-mono-(1 S)-menthyl phthalate, (-)-mono-(1 R)-menthyl phthalate, (+)-trans-
5-
norbornene-2,3-dicarboxylic acid, (-)-trans-5-norbornene-2,3-dicarboxylic
acid, (R)-
(+)-methylsuccinic acid, (S)-(-)-methylsuccinic acid, (R)-(+)-6-hydroxy-
2,5,7,8-
tetramethylchroman-2-carboxylic acid [(R)-(+)-Trolox ], (S)-(-)-6-hydroxy-
2,5,7,8-
tetramethylchroman-2-carboxylic acid [(S)-(-)-Trolox ], (S)-(+)-2-(4-
isobutylphenyl)-
propionic acid [(S)-ibuprofen], (R)-(-)-2-(4-isobutylphenyl)propionic acid
[(R)-
ibuprofen], (+)-2-(6-methoxy-2-naphthyl)propionic acid [(+)-naproxen], (-)-2-
(6-
methoxy-2-naphthyl)propionic acid [(-)-naproxen], and also the available
natural or
unnatural a- or R-amino acids and their readily accessible derivatives, in
particular N-
acylated derivatives, +
or an optically active sulfonic acid, for example (1 S)-(+)-camphor-10-
sulfonic acid,
(1 R)-(-)-camphor-10-sulfonic acid, (-)-3-bromocamphor-8-sulfonic acid or (+)-
3-
bromocamphor-10-sulfonic acid,
or an optically active phosphoric acid, phosphinic acid or phosphonic acid
derivative,
for example (R)-(-)-1,1'-binaphthalene-2,2'-diyl hydrogen phosphate, (S)-(+)-
1,1'-
binaphthalene-2,2'-diyl hydrogen phosphate, (+)-phosphinothricin or (-)-
phosphinothricin,
or an optically active phenol, preferably (R)-(+)- or (S)-(-)-binaphthol,
which comprises
converting the compounds of the formulae (IV), (V), (VI) and (VII)
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13
O
O ~ R2
N R5 HY*
R' 4
H H
(IV) (V) (VI) (VII)
where the R1, R2, R3, R4 and R5 radicals in the compounds of the formulae
(IV), (V),
(VI) and (VII) are defined as in the compound of the forumal (I),
in one or more suitable solvents or without solvent to the compound of the
formula
(III),
by either reacting the compounds of the formulae (IV), (V), (VI) and (VII) at
the same
time in a direct Mannich reaction,
or initially reacting the compounds of the formulae (IV) and (V) to an imine
of the
formula (X) or to an aminal of the formula (XI) which can optionally be
isolated
_AR2 H`N12
R H
R H R/ 'H
(X) (Xl)
and then converting the compound of the formula (X) or (XI) with the addition
of the
compounds of the formula (VI) and (VII) to a compound of the formula (III).
The above-described reaction to give a compound of the formula (III) is
referred to
hereinbelow as process step 1.
In a preferred embodiment, the four components of the formulae (IV), (V), (VI)
and
(VII) and optionally a suitable solvent are introduced into a reactor and
stirred. The
sequence of addition is uncritical. On a large scale, in particular when (IV) -
(VII) are
solids, it is most practicable to initially charge these reactants in the
reactor and then
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14
to feed in the solvent, if necessary with cooling. The reaction mixture is
then heated
to the desired reaction temperature. In the normal embodiment, a solution is
initially
present. However, in particular when one or more of the four components is
sparingly
soluble, the process step may also be carried out in such a way that the
sparingly
soluble reactants only go into solution as the reaction advances. Owing to the
crystallization of the salts (III) and (Ill A) which sets in after a certain
time, the latter
case may result in a suspension being present over the entire course of the
reaction.
When the solution of the reactants (IV) - (VII) is initially clear and a
sample is taken
from the reaction mixture immediately after the crystallization of the salts
(111)/(111 A),
and this sample is filtered, the analysis shows that there is a small to
moderate, but
significant excess of the salt (III) over the diastereomeric salt (III A) in
the precipitate.
In contrast, the salts (I11) and (III A) are present in the filtrate in a
ratio of 1:1. In the
further course of the reaction, the amount of precipitate increases
continuously and
the ratio of (III) to (III A) rises continuously, while it remains in the
filtrate at 1:1.
Finally, the reaction changes to a steady state in which neither the amount of
precipitate nor the ratio of (III) to (111 A) rises further. The amount of
precipitate was
generally 85-95% of theory and the enantiomeric excess of the Mannich base (I)
in
the (111)/(111 A) precipitate was 90-99% ee.
Owing to the retro-Mannich tendency of (III) and (III A), it is generally not
possible to
determine the enantiomeric ratio by direct HPLC or DC analysis. Although
determination by NMR is possible in principle, it is too inexact owing to
signal
overlapping. The best determination method is to derivatize the samples with
optically pure (+)- or (-)- camphanic chloride (VIII A) or achiral pivaloyl
chloride
(VIII B) by HPLC:
CA 02484685 2004-11-03
R~ R
(III) N O
R1 R5
0 =,,
R4 H
R CI (IX)
(VIII A) : R = (-)-camphanyl
(VIII B): R = tert-Bu R\ R
N O
(III A)
R R5
R4
(IX A)
The N-acylated derivatives (IX) and (IX A) are stable and can no longer
undergo a
retro-Mannich reaction. The use of (-)-camphanic chloride has the advantage
that the
5 derivatives (IX) and (IX A) are diastereomers and can therefore be separated
on
conventional HPLC columns having an achiral stationary phase. However, the
method has the disadvantage that a (usually small) distortion of the
stereoisomeric
ratios (undesired kinetic optical resolution) may occur during the
derivatization, since
the reaction rates of (III) and (III A) with this acid chloride are not
identical. (III) and
10 (III A) have to react with the achiral pivaloyl chloride (VIII B) at the
same rate, so that
distortion of the stereoisomeric ratios can be ruled out in this case.
However, the
derivatization products (IX) and (IX A) in this case are enantiomers, so that
an HPLC
column having a chiral stationary phase is required for their separation. The
analyses
of a large number of samples show that the enantiomeric excesses determined
using
15 (-)-camphanoyl chloride are distorted to give ee values which are worse by
up to 4%
compared to the more reliable determinations using pivaloyl chloride.
As an example of the increase with time of the proportion of the product (III)
at the
expense of (III A) in the precipitate of a four-component coupling reaction, a
reaction
was investigated in which R1 = o-nitrophenyl, R2 = 2-pyridyl, R3 = H, R4 = 2-
pyridyl,
R5 = phenyl and HY* = (+)-di-0,0'-pivaloyi-D-tartaric acid, and the solvent =
ethanol,
and the reaction temperature = 20-25 C.
CA 02484685 2004-11-03
16
O O
_0 O
0 O
O
NO2 0
H + (j2+ i I Y* (+)-dipivaloyl
N C tartrate
N
CLNH+O
NH+O 2 2
2 Y 2I - (\ Y*-
ONI I *- + ON
N I N
2 L -J 2
(XII) (XII A)
Table 1: Progress against time of the formation of an exemplary compound of
the
formula (III) as a ratio to its enantiomer
t [h] Content of (XII) Content of (XII A)
[%] [%]
21 62.68 37.32
46 67.27 32.73
62.5 69.67 30.33
130 78.40 21.60
154.5 83.68 16.32
177 86.74 13.26
202 89.99 10.01
225 94.89 5.11
297 96.91 3.09
322 97.67 2.33
CA 02484685 2010-09-08
17
In the precipitate (XII)/(XII A) there are two cations for each (+)-DPTA
anion. In this
experiment, the reaction mixture was stirred using a Teflon -coated magnetic
stirrer
bar in a round-bottom flask. The first sample taken after 21 hours contained
(111) and
(III A) in a ratio of 62.7:37.3. After 322 hours, the ratio was 97.7:2.3. This
corresponds to an enantiomeric excess of the underlying free base of 95.4% ee.
The
higher the reaction temperature, the more rapid the rise in the (XII)/(XII A)
ratio in the
precipitate of the four-component coupling, which also exhibits a distinct
dependence
upon solvents and upon the nature of the chiral Brensted acid (VII).
For optimum results, preference is given to carrying out the process step I
according
to the invention with the use of a stirrer which ensures particularly
efficient mixing
and comminution of solid particles in the reaction suspension.
The process step I may be carried out in water, with or without the addition
of
organic solvents and/or solubilizers, or, when one or more of the reactants
(IV) - (VII)
is liquid at the reaction temperature, may also be carried out in the absence
of
solvents ("neat").
A suitable solvent is water or an organic solvent, or a mixture of water with
an
organic solvent, optionally containing a solubility-enhancing additive, for
example a
phase transfer catalyst, where organic solvents may be present in 100% purity
or
technical quality, for example a C1-C8-alcohol, branched or unbranched,
preferably
methanol, ethanol, n-propanol, isopropanol or n-butanol, or a ketonic solvent,
preferably acetone or methyl ethyl ketone (MEK), or an ester, preferably ethyl
acetate
or n-butyl acetate, or an ether, preferably tetrahydrofuran, methyl tert-butyl
ether,
diisopropyl ether, 1,2-dimethoxyethane or diethylene glycol dimethyl ether
(diglyme),
or a hydrocarbon, aliphatic or aromatic, preferably toluene, or a
supercritical medium,
preferably supercritical carbon dioxide or a halogenated hydrocarbon,
preferably
dichloromethane, or a polar, aprotic solvent, preferably DMF, DMSO or NMP,
and water present in the reaction is optionally removed, for example, by
azeotropic
distillation or by adding water-binding additives, for example magnesium
sulfate or
activated molecular sieves.
CA 02484685 2004-11-03
18
The reaction is carried out at from -15 C to +140 C, preferably. at from +10 C
to
+100 C, more preferably at from +30 C to +70 C.
The process step 1 may be carried out at atmospheric pressure, under reduced
pressure (vide supra, for example for the purpose of distilling off an
azeotrope) or
under pressure, the latter for the purpose of reaction acceleration, in an
inert gas
atmosphere or under air.
The process step 1 according to the invention is carried out using 0.80-2.00
molar
equivalents of the reactants (IV) and (V), and also 0.80-4.00 molar
equivalents of the
chiral acid (VII), based in each case on reactant (VI). Preference is given to
carrying
out the process according to the invention using 0.95-1.30 molar equivalents
of the
reactants (IV) and (V), and also 1.00-2.00 molar equivalents of the chiral
acid (VII),
based in each case on 1.00 molar equivalents of the reactant (VI). Particular
preference is given to carrying out the process according to the invention
using
1.00-1.25 molar equivalents of the reactants (IV) and (V), and also 1.05-1.50
molar
equivalents of the chiral acid (VII), based in each case on 1.00 molar
equivalents of
the reactant (VI).
Table 2 shows the results of four-component couplings to give a compound of
the
formula (III) using (+)-dipivaloyl-D-tartaric acid [(+)-DPTA] as the chiral
acid (VII)
CA 02484685 2004-11-03
19
_ H3C D13
O O`N H3C
O
H O
HO p
N
4~
4, %H+ 0 H3
H3C CH3
2
Q'H2 O H3C NO
2
0
O
O Hs
0
H3C CH3
2
and using typical laboratory glass reaction vessels (up to 0.5 mol in
multineck round-
bottom flasks, above 0.5 mol in cylindrical jacketed reactors rounded at the
bottom)
equipped with motor-driven mechanical stirrers (up to 0.5 mol using a
precision glass
stirrer having Teflon paddles; above 0.5 mol using a steel turbine stirrer).
CA 02484685 2004-11-03
^ 0
J rco
.0
a) V
LO 00
Lf) N 00
00co co pNQ
oo a)
> 22==== o N rn
M
m
W W W tDS r^t70 r 00 OM
av UUUUUL N Lric Lriip 0)
00000O Nv. C) M~ O N N.0 N N
a) E L L L L L L 'C L co CU Ct co ca >% cc m
'0 10
Ct w0 r 0 0 '0'0 '0'V OM
:moo U i- Cl) U) LO .N A 0).m An . N- . - CD r r
^ C9 '011- O co M N CD
a)
__ L N co 0co C)) co
ML (~ - Cl)
N LC) a) c = O >.
O O LO C 0 O 00 0- r
_ L co 'C E NEE co
r r
C7 CO OU = j,0 Er -- M w
0
-64 co cu r- 0 70
75 Z -6
2
> O Cc9 m m 0 cu
c~ 2a) U) ati (DU') 0)M N~
0
oc~a E0
CL c,? U
cc cr qt
O ti
%~=; E NO p0 70 = O p0 NO MO
. lo: >+~ E E Mr Mr 0.0 in E Mr rr Nr
>' >
Q- .-. =_
N L
a -6 L
^ 1~1 E NO p0 0p NO Mp
E E M r c r) r M r r r N r
>+ >
a =~
N or
^cq'1 II E O NN ~N ~N ON ~N
m O f` Ln O
>~ E E d r M r M r r r N r
>
0
N a W M Cr)
II O O ch r
N >= E N ON ON LON ONON
0 `-'Z EE Mr Mr Mr l r-:
0 o
F Z N lco Lf)
CA 02484685 2004-11-03
tea)
>
2=C
a)
a) 00 CD
al 0) a)
::.
Cu
.. > ti O co
Ja)
tC'5 L6 0~ MCnCO NO
U') 00)j 'p CO 0)j pyj -D 0)0) nj CG
CL L .. tea)) N O
E CD L L L L L L ..
0 0 O O Nlf) O fit` O L
.gr N y ui N N r N r
co 'fl O O LO d 0)
0
0)
Z- ~? 0) 0) 0
U) U
0 :3
0 0 r r '- CCf
Q O .p C C
co
CN
(o O O CO a) ` U O
(D 0 0
0 C.)
tt 14t V) co 4 CO
C O O C
a) 0 0 0
O E ~o -c U) ci
cn ,~ a) r-- a) (0 co
O CJ
ro
> =`
a) ti N- 0
-rEo~o 0o No
- - E E N ~ N
N 0) r-_
LO M CO
^~I II E O jO NO 0
?E E N~ N~ co CL
_ -
N ~ ~ N ~
~'I E O ~N ~N ON
~ .~ T. E E o
- M N
>
O
CVa_w 0)) O 0)
_ II 0 0 0 O O co
0
N>W = E O d7 4N LjN
a) ZZ- - ZEE M r M=--
O cu I ~ Z ID IN CO
CA 02484685 2004-11-03
22
Four-component couplings corresponding to the above-described reactions were
carried out to give compounds of the formula (Ill) using S-(+)-mandelic acid.
01 OH
O
H O
I N I OH
+
+ a
N NH2
O
aN
N02 NH2 O H0
I\ I\
N
Table 3 shows the results of four-component couplings where R1 = o-
nitrophenyl,
R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, and R5 = phenyl, and in which S-(+)-
mandelic
acid was used as a Bronsted acid (VII):
CA 02484685 2004-11-03
O O O
m ^ r r O CO
cy)
V V
C C .. .. r T 0 T T
Z O
6) 0) O '~t r cc C)
Cl) A C A 0) 0) C) C7) 0)
J > M r co N N LC) co
CU "D LO LO G o = 'a 0) C )) 0) C 0) C) 0) C))
co CO d o0
C:> 't U")
a y CD ~ ~ 6 0) 't 0 0 CC) C) t- - C3)
3: > N~ I.- Goan-04 a r 'D ONN
a co O ,a? . C C? O "-
-c CA CA to
N O ti d LLL CO CO ..L . .. .. .. cu
o CO UC) L 0U) It rto 0 0 Lif) 0LLL p
Ov CA r.Cn0) CA CO NN'- N 04 C7 Nt7'tt)
V
CU ~,
m Z7 -O 0 CO ll~r C co C) c - co
O
.=..~ >. o rL. co N- (0 )) 0 C)) c; c~ C)) - C)
L
~ L L L L L
CO 0 .C O N LO CY) V,
tt d CD
c(V U C 0 0 0 0 0 U 0
0 : C0 CO d `Cfi CD to CD
c 2 04 2o 2`1 I I o
o E 0 00 C) 0 00 (1) - n ~ g LO 04~N - 2 it
Cq ~~~~~r W co -Ui iT W~COWW.....N
U 2
II .} -UD d) O O co 0 co CD
_^C. 0 6 C) L60 00 00 TO ~0 UO 00
c9 V E 0 N- ti r N co
O co O
....E (v E ENNr N TN ---'N (C)N 0) N NN
A >
N d O Ci) 0 0 LC) ) a) LO co
0
III 11 E p 0 0 0 0 0 M O Ci 0 M 0 N O O O
v M, V) . L() CD . q-I 4 6 0) O
..mac E E Nr Nr N- - CDT (OT 04 ~r rr
T 2
CIIi II E p NNmN ON NN ~N TN LO N
cv m cD O (09 r 0 W o rn N
T Mr Lor rr
>-CCc E E Nr Nr CAr o0r F-
0.
III E OW ~OpNO6O 6 LO 14, ~O 00
co >- :tz E O LO 0 Lo 0 r- N 1` Lo C; Ci 0) N N N
z E E c -Nr c - I`T !`T C')r U - Tr
~ O
1` 00
F- Z N m Lc) co
CA 02484685 2004-11-03
0
E Co M cf)
V
0
O
Z 't 0) 1- LO
> ~= rn 00 00 00 0)
._. to ..~ 0) 0) 0) 0) A
U C
(D J > 1` 0) ~t
? Q) - et d ~t N LO
o = it 'D C 0) 0) 0) 0) 0)
M
N co Lt) M N
O M
d: 00 0
a CU N- CONNO M'-tC00) co CD sT cy) 0)t-00)
> O0'L7 00)D)~ rrN O6 CN 2-0 OM d
QCo co LLLCo0)0) 000):DCO CD N. 0) 0) iw
L c~ ca C to cy
co L 0 Lq V Cl 5 co
L L t 0 L .C Co I-.. U) 0.C -C C L O CV
`. U-0 N r MU N N Co.? N to .~ N'0-CO I..~ O)
CD
.2-04- O
OD O N N N
0 co 0N) N- 0cli
) 000
O L L
C!) O L L L r" u) CD
CO N ti N- LC) r ti r
N ~-v U U U U ~~U U U
C m
U) co CO C)
0 C co
0 C0 C00 (00 OD O 0
;^ I Y I I' I Y 2 Y o I Y
75 Q W N 0 W p W N Q W Q W O O W O
Cq W .i co W t0 W W CO W W
U
II } -Op 0) I V- co
Ul) 0 .0 0 co E ono t!)0 0 000 0 L60
r r ~ r
E cco E E-CV M~- -r Nr rr Nr
>, >
U)
CL 0
N O a) 0 O rl- O
11 II 0 0 O O O O M O 0 0
c u~ E O 0 U)O CVO U)0 OO UO
.~~~ E E I~r Nr re- Nr rr Nr
>+
cr V)
Z _ T-- .t U) lc) 0
~
N~I 0 O O ON ~N It )N N~ 0 . co c~ LO
..i~ x E E 00r C) - rr Nr rr Nr
O
N
CY)
N O 0 . ~O Co 0 co U') LOLO 00
M> 11 _ E O C)N C; ON tO0 OO 00
CD ..- of z E E COr M rr Nr rr (N
(0 O O r N C')
Z O) r r ~- r r
CA 02484685 2004-11-03
O
v to
~t O
0
0
C! C) C6 'a 'Z7 000 0 V
A 0) C C C O O C
U v
CU J >_ tt Ln M CD M 2: (D Lc) m LO ct) f- 'C7 O) CA co Cn 0) (M C 0)
F-
U ~ `t O
J .= CflC')
Q_ Q) T O 0 )0)
> CA O)
O D.> 0D `+0+
CU E N C C) CU co N Irt ti N d'
= co
CD L6 4- I~ C 0 N N M Lc) r; N
U C7 0 ' V) 03 I~+ .2 O O C) Cn C7) IM
,.~ CC 0 T ti N N M CD
75 a) N
.~ '>+ o rt-= co N- O C)0 co 'co 00 cW
-C O t L .C .C .C
cn _c s
co O) w 0 co CD (0 ' ti CD
O 0 N r i" T N N
N c, U U 0 U U U U U U
0 0 0 m (00 0 0 0 0 0 C)
U co CO Cl) T to (0 (D CO 't It Co
.. _ = Q) N C
2 0 0 C C O O 0
C U
to
~o 0 W u p )0 W U) CL00momL r) t0ic ~I 0m
W..~N W-CD CN CCT COU)m
U_
11 -d) C
+ -O N O N 0 0 O co Ln 0
LO co LO 060 TLO6O ti03 TLC)
~ S) E CUC E E eM- O N C) N P N- co ' co O ~ co
N -N T T T () N ~t T r T
>, >
c~ C) 0 LO :=~ I II 0_. L6 c) MO p0 6O pj'0 N0U)O LOp
5. to 0 r Nq L) .LC)C?N0) .0 .. (N
N T N T T r T N T T T
CL II
0) 0 co C) CD It C)
= : O CDN NONO oO TO dN OO
~N M M T
O T (0V r rr
E E TT C'rm N` - Nr ~=-~- LO
0
N Q,- W O - O O O '[t - O
III 0 0 0 0
= 0 DOD O 0 TO C'r) 00 6 0
Ch = E p NC) pCN 0O0O NOON4 NO
(D IXZ E E Tr C')T NT NT rr LC)T NT TT
0
CC3 O U) CD -~ 03 C3) N
O r
}- Z T T r T r N N N
CA 02484685 2004-11-03
0
Lp ^ r
mZ
.-.c:_ C)
U) A
a)
U
co
j .C
Go a co
U
aD 0.fC E >
=L
cu
Ua C
cv-aoo
lq*
= o 5 (D
ri
o
N -V U)
C C cu O U
~cDXa
00 cTD.Q T
=_ 1
N 0
a~U
0C C ~~E
U (DD- rnItN 0
.r C
C N
m O
> 0
a) M
gm
(D cr
II ^
+'D O 4)O
- C
cc E oMO
>EcaEEC
N a O N O
ii E '
U-i
EE
>: >
a=
N 0 N 0
E E -'
j
L m
CL CT
W O
'
04 III O` E L00
acOfZEE r
Z N
CA 02484685 2004-11-03
27
Four-component couplings using (+)-DPTA, (S)-(+)-mandelic acid or (-)-malic
acid
were carried out in the ten reactors operated in parallel of an Argonaut
Surveyor
Reaction Screening System in accordance with the reaction conditions
summarized
in Tables 4 and 5 and in different solvents. In these reactors, mixing is
effected by
piston activated magnetic agitation. Mixing is distinctly more efficient than
that of
magnetic stirrer bars or of precision glass paddle stirrers and slightly more
efficient
than that of turbine stirrers.
Table 4 shows the results of four-component couplings using (+)-DPTA, (S)-(+)-
mandelic acid or (-)-malic acid:
CA 02484685 2004-11-03
O
'~ L O to N o 0) o t7 co
0) 0 M r t- r r 0 0) r O r
>- CL) O 0 N ti N L6 N ( N N
C o
O
N r r r
4-j .. U-)
^ N tiZ CR Z O?Z r rZ
L
Lf) LO LO LO
FD N N N N O co
E ti t` ti N cc
co cfl CD r r
(~ r r r r LO L
~ r r r r
C Or0)00 h+ '(O N 03' Co m
P- 00 to N- (0M c' co Lo C- LC) - N r co O 00 00 0 CO
0
C< 4NNCON 00 0 (0 00 rL() 'tN00 (0 00 N 00 N
X fr)MCr)Nr co'Ct=r0 cDM r rr It M C) N M
0
co
N
Oo 0)rN0 (0 F'- CON (0'-0M C0 It0 00 N C0 d ti
N M N 0) r 0) M co 0) (0 00 h O O r r 0) M
X 6 r-:MN- -X1)000 M(0(0 U) N- - d e- N e- r`
O
o co (0(0N-co 0)000) 00000 000001.0 C0 Co N- CO
MCDO~M (DC) C') (00) C') Co0)~ M COO C')
r r r r r
0 u) 0 O O 0 0
0 M If) M Lt) M
I--
_ = O 0 = 0
O 0 0 a) co
- Q)
0
-a . O 0
0 = "' 0
00 O =
= O
0) s
r d t~ N LO
C6 m
f-
CA 02484685 2004-11-03
'C7 = o ti o r o CO o N o
C7) L= N N N. N CD IL) N C0 CV
N N 00 O . r
Ul) CV
g> QC' T r T T 1S.{.
\~ . G .. G .. . .. G
~_ e-Z TZ N N Nz
S
O_O CD co Cl
O O
3 v E CD CD 00 CO CO
t6 ` Lo LO C3) CA 0)
O
C 0 M 0) M co C) LC) co LO N M N
a) W co V)
i d
C< N 0) N- C) CO 0 co O N~ O 0) co
X M 04 N M M N C. 0 Lf) LO Ln OD
1` N T LO N M LA 00 N. co N
. ~__r C 7 M CO Imo- O r M r i O O W O IL)
N NO o rn ti C7) ti O0
O O
X N.
U X co 1` co 0) Co CON-C) 14, IRT It eh 0)
M COCA~M O0)LO M000)~MCOC7)~M COCA
T r LO T T
;~ 0 0 0 0
M LO LC') LO I)
2 = Z
a) O co cl) : 0 0
U) W m
0
.O ^
0
0 2
0
a) L
LO co M to 0)
C3 CD
CA 02484685 2004-11-03
Table 5 shows four-component couplings using (S)-(+)-mandelic acid in various
solvents in the surveyor screening system:
Table 5
mol. eq. Mass Yield Solvent ee (HPLC) Ratio
mandelic acid [g] % of theory [%] (I) / (VII) ['H NMR]
2.00 2.51 86.0 EtOH,MEK 95.2 1:1
2.00 2.52 86.3 EtOH,toluene 94.4 11
2.00 2.39 81.8 EtOH, abs. 94.8 1 : 1
2.00 2.52 86.3 n-BuOH 96 11
2.00 2.75 94.2 i-PrOH 94 1:1
2.00 2.24 76.7 MeOH 98.6 1:1
2.00 1.49 51.0 MEK 97.4 1:1
2.00 1.92 65.8 Acetone 97.8 1:1
2.00 2.55 87.3 n-BuOAc 96.0 1:1
2.00 2.40 82.2 MeOH 98.6 1:1
1.1 2.35 80.6 MeOH 95.0 1:1
1.2 2.44 83.5 McOH 94.8 1:1
1.5 2.49 85.2 MeOH 95.2 1:1
2.0 2.57 88.0 MeOH 93.2 1:1
1.1 2.40 82.3 EtOH,MEK 91.2 1:1
1.2 2.48 85.0 EtOH,MEK 91.8 1:1
1.1 2.59 88.8 i-PrOH 92.0 1:1
1.2 2.69 92.2 i-PrOH 93.4 1:1
1.5 2.71 92.7 i-PrOH 93.0 1:1
2.0 2.40 82.2 i-PrOH 94.3 1:1
1.1 2.29 78.4 n-BuOAc 90.8 n.d.
1.2 2.53 86.6 n-BuOAc 94.0 n.d.
1.5 2.45 83.9 n-BuOAc 94.4 n.d.
2.0 2.57 88.0 n-BuOAc 96.0 n.d.
1.5 2.58 88.4 EtOH,MEK 93.6 n.d.
2.0 2.48 84.9 EtOH,MEK 93.0 n.d.
1.1 2.52 86.3 n-BuOH 92.4 n.d.
CA 02484685 2004-11-03
31
Table 5
mol. eq. Mass Yield Solvent ee (HPLC) Ratio
mandelic acid [g] % of theory [%] (I) / (VII) ['H NMR]
1.2 2.52 86.3 n-BuOH 95.4 n.d.
1.5 2.63 90.1 n-BuOH 96.4 n.d.
2.0 2.40 82.2 n-BuOH 95.0 n.d.
1.5 13.08 89.5 MeOH 91.2 n.d.
1.5 9.67 66.2 Acetone 94.6 n.d.
Unless otherwise stated in the tables, the product (lll) was isolated by
cooling the
suspension to room temperature, followed by filtration and washing of the
solid with a
little cold solvent.
In methanol at 60 C, the combined four-component coupling/dynamic optical
resolution proceeded very quickly. After only one hour, the underlying free
Mannich
base (I) of the precipitate (III)/(III A) had achieved an enantiomeric excess
of 92.6%
ee (Table 3, line 2) and, after a maximum of 3 hours, the reaction was
completed at
97.3% ee (Table 3, line 1). Owing to the more efficient mixing, up to 98.6% ee
was
obtained in the Surveyor Screening System (Table 5).
Owing to the not inconsiderable solubility at room temperature of (III) in
methanol, the
yields were at least 10% below those in ethanol. Even at only 30 C, the
reaction in
methanol was completed within 15 hours (Table 4). In ethanol, the reaction at
40 C
required 44-53 hours (Table 3, lines 4 and 5). Yields (up to 95.3% of theory)
and
enantiomeric excesses (approx. 95% ee) were high. At 60 C, the reaction in
ethanol
was completed after only approx. 4 hours when two equivalents of mandelic acid
were used. Yields (up to 92.6% of theory) and enantiomeric excesses (up to
97.5%
ee) remained high (Table 3, lines 6-8). When the reaction was carried out at
very high
concentration, the reaction rate fell somewhat, while yield and ee fell
marginally
(Table 3, line 9). Using 1.5 equiv. of mandelic acid, the reaction at 60 C in
ethanol
required approx. 7 hours and led to only slightly lower yields and ee values
(Table 3,
lines 10 and 11). Using 1.10 equiv. of mandelic acid (Table 3, lines 12 to 14)
and
using only 1.05 equiv. of mandelic acid (Table 3, lines 15 to 16), the
phenomenon
was again observed that an ee obtained at 60 C in ethanol distinctly worsened
on
CA 02484685 2004-11-03
32
cooling the suspension to RT (before filtering off the product with suction).
Standing
overnight may result in an ee reduction of 8% (line 16). However, when the
cooling of
the suspension and the filtering off with suction of (III) were effected
rapidly, an 88%
yield and 95.4% ee were obtained even when only 1.05 equiv. of mandelic acid
were
used (line 15). In the case of reactions using 2.0 equiv. of mandelic acid,
such ee
deteriorations on cooling did not occur. An aliquot of the reacted reaction
suspension
(60 C, ethanol) was withdrawn and stirred at room temperature for 72 hours.
The
enantiomeric excess and the syn/anti ratio afterwards were unchanged.
The reaction may be carried out with similar success in relatively long-chain
branched
or unbranched alcohols, for example isopropanol (Table 3, line 17, Table 5) or
n-
butanol (Table 3, lines 18 and 19; Tables 4 and 5). It also succeeds in
ketonic
solvents, for example acetone (Table 3, lines 20 and 21; Table 5) or methyl
ethyl
ketone (MEK, Table 5), in esters, for example ethyl acetate or n-butyl acetate
(Table 3, lines 22 and 23; Table 5) and in halogenated hydrocarbons, for
example
dichloromethane.
The reaction can in principle be carried out in ethers, for example
tetrahydrofuran,
methyl tert-butyl ether, diisopropyl ether, 1,2-dimethoxyethane, or diethylene
glycol
dimethyl ether (diglyme), in hydrocarbons, for example toluene, and also in
supercritical media, for example supercritical carbon dioxide. The use of
solubility-
enhancing additives, for example phase transfer catalysts or cosolvents may be
advantageous. The reaction can be carried out in polar, aprotic solvents, for
example
dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO) or
N-methylpyrrolidinone (NMP). The yields isolated in these solvents are
competitive
when the solubility of (III) in them is not too high.
The reaction tolerates a content of moisture. Comparison of Table 3, line 4
with line 5
and of Table 5, lines 1-3 shows that absolute ethanol offers no advantages
over
technical, or MEK- or toluene-denatured ethanol. In some examples, the
observation
was made that when solvents were used which form low-boiling azeotropes with
water (for example ethanol), continuous azeotropic distilling off of the water
of
reaction formed in the Mannich reaction at atmospheric pressure or under a
reduced
pressure leads to significant to moderate reaction acceleration. This may be
utilized
CA 02484685 2004-11-03
33
to optimize the space-time yield and, owing to the relatively short thermal
stress,
occasionally be used to improve the chemical purity and isolated yield of the
product.
Similar results can also be obtained by water-binding additives, for example
dried
magnesium sulfate or activated molecular sieves. However, the exclusion of
water
and/or the removal of the water of reaction formed are necessary neither for
the
practical quantitative progress of the four-component Mannich coupling, nor
for the
progress of the dynamic optical resolution. Tables 1-5 confirm that when the
necessary reaction times are accepted, the product (ill) may also be obtained
in very
high yield, chemical. purity and with high enantiomeric excess when undried
apparatus and undried solvents are used and the resulting water of reaction is
not
removed.
In accordance with Tables 2-5, the relative molar amounts of the four
reactants
(IV)-(VI) can be varied within considerable intervals without any resulting
negative
effects on yield, chemical purity or enantiomeric excess of the product (III).
Using
1.00 equivalents of the CH-acidic components (VI) as the basis in each case,
the
amounts of the remaining reactants used in the specific examples (Tables 1-5)
were
varied within the following intervals: aldehyde (IV): 1.00-1.20 equivalents;
amine (V):
1.05-1.25 equivalents, chiral acid (VII): 1.05-2.00 equivalents.
The most important factor for the efficiency of the dynamic optical resolution
in
process step 1 is a good choice of the chiral acid HY* of the formula (VII).
In all fields
of stereochemistry, there is now a consensus that there is no optimum chiral
auxiliary
per se or an optimum chiral ligand per se, nor can there be one. The extent of
asymmetry of reactions rather depends upon the specific reactant/auxiliary and
product/auxiliary interactions ("chiral recognition"). Which chiral acid (VII)
delivers an
optimum result within the process according to the invention thus depends on
the
specific nature of the substituents R1 to R5 and has to be determined,
generally
experimentally, in each case independently for each combination of the
reactants (IV)
to (VI). This may be achieved in the following way:
a) The racemic free Mannich base rac.-(I) is prepared. This may be effected
particularly simply by one of the two following alternative routes:
CA 02484685 2004-11-03
34
al) The four-component Mannich coupling is carried out in a similar manner to
process step 1, except that the reactants (IV), (V) and (VI) are used with
only
catalytic amounts of an achiral acid in a solvent in which the Mannich base
rac.-(I)
has only moderate solubility. In many cases, the use of approx. 1 mol% of
p-toluenesulfonic acid hydrate in the solvent ethanol has proven useful. The
free
Mannich base rac.-(1) then crystallizes out of the reaction mixture sometimes
in
very high yields and may be isolated by filtration. Example 3 describes a
corresponding procedure.
a2) The four-component Mannich coupling is carried out in a similar manner to
process step 1, except that the reactants (IV), (V) and (VI) are carried out
using
stoichiometric or greater than stoichiometric amounts of an achiral acid in
one of
the abovementioned solvents suitable for process step 1. In this case, a salt
similar to the formula (III) is obtained in which the cation is racemic and
the anion
Y" is achiral. This salt rac.-(III) is the converted to the free racemic
Mannich base
rac.-(I) in a similar manner to process step 2.
b) A solvent is found in which rac.-(I) is averagely to moderately soluble
(preferred
solubility approx. 1-5% by weight) and in which its retro-Mannich reaction
proceeds as slowly as possible. To select this solvent, various alternative
physical
or chemical methods are available:
b1) Rac.-(I) is dissolved in appropriate perdeuterated solvents and the retro-
Mannich
rates in each case are monitored by repeatedly analyzing the solutions by 1H
or
13C NMR at short time intervals;
b2) Rac.-(I) is dissolved in solvents to obtain real time monitoring of the
retro-
Mannich reaction with the aid of a ReactlR probe, or by analyzing the solution
in a
cuvette in a conventional two-beam IR instrument at regular time intervals,
using
in each case an identical cuvette filled with the pure solvent in the
reference
beam.
b3) Rac.-(I) is dissolved or suspended in aprotic solvents which are
compatible with
an amidation reaction using acid chlorides. Immediately after they are
prepared,
the solutions or suspensions are reacted with pivaloyl chloride (VIII B) to
give the
racemic pivaloyl derivative (IX)/(IX A). The slower the retro-Mannich reaction
in
the particular solvent, the higher the yield and purity of the amide (IX)/(IX
A)
achieved. Example 4 describes a corresponding procedure.
CA 02484685 2004-11-03
In the examples investigated hitherto, it has been found that the retro-
Mannich
tendency of the salts of structurally analogous Mannich bases with Bronsted
acids
(formula III) under identical conditions (same solvent, same temperature, same
Bronsted acid) is supported by electron-donating substituents in the aldehyde
5 component of the formula (IV). Electron-withdrawing substituents in the
aldehyde
component of the formula (IV) reduced the retro-Mannich tendency. The 1 H NMR
monitoring of the syn/anti-isomerization of a syn-Mannich salt of the formula
(III) via
retro-Mannich reaction at 300 K in DMSO-d6 solution can be seen in Example 28.
As
can be seen from Example 27, good choice of the reaction parameters in the
four-
10 component coupling results in Mannich salts in excellent yield with very
high
diastereomeric and enantiomeric purity of the underlying Mannich base even
when
the aldehyde component contains electron-donating substituents and the retro-
Mannich tendency is high.
15 In the above-described examples, it has been found that the retro-Mannich
reaction
of free Mannich bases rac.-(I) frequently proceeds very slowly in acetone.
c) A screening of all available optically active Bronsted acids HY* (VII) with
regard to
efficiency of a classical optical resolution is carried out with the solution
or
suspension of rac.-(I) in the solvent obtained according to b). To this end,
when
20 the substituents R' to R5 contain no basic centers, the freshly prepared
suspension of rac.-(I) is reacted with 1.0 molar equivalent of the acid (VII)
when
(VII) is a monobasic acid, or with 0.5 molar equivalent of the acid (VII) when
(VII)
is a dibasic acid. When the substituents R' to R5 contain basic centers, more
molar equivalents of the acid (VII) are correspondingly added. The mixture is
25 stirred for approx. 20 h at room temperature, the precipitated salt (III)
is isolated
by filtration and the enantiomeric ratio present in the underlying free base
(I) is
determined by derivatizing to (IX)/(IX A), followed by HPLC analysis (vide
supra).
The chiral Bronsted acids (VII) selected are those which deliver the highest
(IX):(IX A) ratios, preferably (IX):(IX A) >_ 95:5 5 in the screening. Example
6
30 describes a representative experimental procedure for such a screening.
d) Further selection may be effected among the optically active Bronsted acids
(VII)
selected according to c) in order to very substantially fulfill the following
criteria for
particularly preferred acids (VII):
- Y has a stable configuration under the reaction conditions;
CA 02484685 2004-11-03
36
- it leads to a maximum difference in solubility between its two
diastereomeric
salts (III) and (III A)
- it effects a very low solubility of the desired diastereomer of the formula
(III)
and a very high solubility of the undesired diastereomer of the formula (III
A)
- the racemate of the salt of the formula (Ill) (1:1 mixture of salt (III) and
its
mirror image) crystallizes as a conglomerate. A conglomerate consists of a
mixture of two mirror image crystal structures of which one crystal structure
corresponds to the crystal structure of the optically active salt (III). In
the
conglomerate, not only the enantiomeric molecules, but also the two crystal
structures as supramolecular constructions are mirror images of one another.
The two crystal structures in the conglomerate differ not only in the
chirality of
the molecules. The crystal packings, i.e. the three-dimensional periodic
arrangements/stackings of the molecules in the two crystal structures are also
mirror images.
it catalyzes the four-component Mannich reaction which leads to the formation
of (III) and (III A),
- it catalyzes the retro-Mannich reaction of the more soluble diastereomeric
salt
(III A), i.e. the cleavage of the salt (III A) to the enolizable ketone (VI)
and the
iminium salt R'CH=N+R2R3 Y.- or its dissociation products, the aldehyde (IV)
and the salt of the amine (V) with HY*.
When the free Mannich base of the formula (I) crystallizes as a conglomerate,
the
present invention also encompasses a special embodiment in which the three-
component coupling and the dynamic optical resolution may be carried out in
the
absence of a chiral auxiliary acid HY*. In this embodiment, the solution of
the three
components (IV), (V) and (VI), optionally in the presence of catalytic amounts
(approx. 1-10 mol%) of an achiral acid, for example p-toluenesulfonic acid, is
seeded
with crystals of optically pure free Mannich base. Owing to the conglomerate
effect
(preferential crystallization), only this antipode of the free Mannich base
can
crystallize out of the reaction solution and is continuously formed from the
mirror
image remaining in the solution. When this continued formation is rapid
compared to
the crystallization rate of the desired antipode, the boundary concentration
of the
wrong antipode at which it would also start to crystallize is never reached in
the
course of the reaction. For this reason, the precipitate at the end of the
reaction
consists exclusively of the desired antipode and the chemical yield may
approach
CA 02484685 2004-11-03
37
100%. This asymmetric transformation of the 2nd kind without the necessity of
a
chiral auxiliary is referred to by the term "total spontaneous resolution"
(E.H. Eliel,
S.H. Wilen "Stereochemistry of Organic Compounds", John Wiley, New York, 1994,
page 316 ; Y. Okada et al, J. Chem. Soc., Chem. Commun. 1983, 784 - 785).
In a further variant of the process step 1 according to the invention, the
imine (X) is
initially formed from the reactants (IV) and (V), and only then is the CH-
acidic ketone
(VI) added, which leads in the presence of a suitable optically active acid
(VII) to the
formation of the Mannich salt (111) with dynamic optical resolution. It will
be
appreciated that it is also possible to form the imine (X) from the aldehyde
(IV) and
the amine (V) in a known manner, catalyzed by an acid which may be achiral,
for
example approx. 1 mol% of p-toluenesulfonic acid hydrate, and to isolate the
imine.
Such a procedure is described in Example 9. The imine (X) may then be reacted
afterwards with the ketone (VI) and the optically active acid (VII) to give
the Mannich
salt (111).
Some of the disadvantages of the indirect Mannich reaction are avoided when a
solution of the imine (X) is initially formed by heating the aldehyde (IV) and
an at least
equimolar amount of the amine (V) in one of the abovementioned suitable
solvents,
more preferably n-butyl acetate, and azeotropically distilling off the
resulting water of
reaction, preferably under reduced pressure. Particular preference is given to
carrying out this reaction step in an apparatus/a reactor which has the
function of a
water separator, i.e. after condensation of the azeotropic vapor and
subsequent
phase separation, the organic solvent having a lower specific gravity flows
automatically back into the reactor, while the water is retained in the
separator. Once
the theoretical amount of water has separated, 0.80-2.00 equivalents of the CH-
acidic ketone (VI) and 0.80-4.00 equivalents of the chiral acid (VII) (based
in each
case on the aldehyde (IV)), preferably 0.95-1.30 equivalents of (VI) and 1.00-
2.00
equivalents of (VII), more preferably 1.00-1.25 equivalents of (VI) and 1.05-
1.25
equivalents of (VII), are added to the reaction solution, and it is optionally
further
heated until the enantiomeric purity in the precipitate (111)/(III A) which
appears after a
short time has reached its maximum owing to the proceeding dynamic optical
resolution.
CA 02484685 2010-09-08
38
As can be seen from Table 3 (No. 22, 23), when R' = o-nitrophenyl, R2 = 2-
pyridyl, R3
= H, R4 = 2-pyridyl, R5 = phenyl, HY = (S)-(+)-mandelic acid and the solvent
was n-
butyl acetate, the normal four-component coupling at 60 C resulted in the
Mannich
salt III in an isolated yield of 84.6% of theory and in 95.1 % ee. In
contrast, when the
n-butyl acetate solution of the imine (X) was initially formed in the manner
described,
the Mannich salt (I11) was obtained in a yield of 93.1 % of theory in 96.7% ee
when
heating to 60 C was effected immediately after adding (VI) and (VII). A
particularly
high yield of 93.4% of theory and 98% ee was achieved when heating was
initially
effected only to 40 C (commencing precipitation) after addition of (VI) and
(VII), and
the temperature was raised to 60 C only after 4 h. In contrast, the normal
four-
component coupling resulted in parallel formation and reaction of the imine
(X). In the
present example, an investigation in a Mettler reaction calorimeter RCI with
real time
monitoring of the progress of the reaction by ReactlR probe showed that in no
phase
of the four-component coupling was there any accumulation of more than 40% of
the
theoretical amount of the imine (X) in the reaction mixture. Furthermore, the
duration
of the thermal stress there on significant amounts of the imine (X) is
substantially
shorter.
In a further procedure variant of the process step 1 according to the
invention, the
aminal of the formula (XI) may also be initially formed (Example 10) and then,
either
after intermediate isolation or in the original reaction solution, be reacted
with the
ketone (VI) and the acid (VII), optionally with the addition of an additional
equivalent
of the aldehyde (IV), to give the Mannich salt (III). In this procedure
variant also, (III)
is isolated in optical yields which approach those of the four-component
coupling
(Tables 2 to 5).
In all of the procedure variants of the process step 1 according to the
invention
mentioned here, the high optical activity of the Mannich salt (111) is based
on the
occurrence of a dynamic optical resolution. The process step according to the
invention thus differs fundamentally from the four-component Mannich reaction
described by B. List (J. Am. Chem. Soc. 2000, 122, 9336-9337). The latter
concerns
a catalytic asymmetric Mannich reaction, i.e. the addition step of an enamine
resulting from the condensation reaction of the CH-acidic ketone (VI) with the
catalyst
(L)-proline, to the imine (X) which results from the condensation reaction of
the
CA 02484685 2004-11-03
39
aldehyde (IV) with the amine (V) with direct formation of the free Mannich
base (1) is
asymmetric. For this reason, only approx. 35 mol% of (L)-proline are used in
the List
reaction. The reaction product present in solution is already optically active
and,
according to the present level of understanding, the optical purity of the
product does
not fundamentally change during the progress of the reaction. In contrast, the
process step 1 according to the invention is not carried out with "catalytic"
amounts of
the chiral acid (VII): when less than 0.8 molar equivalent of a monobasic acid
(VII) or
less than 0.4 molar equivalent of a dibasic acid (VII) is used, the isolated
yields of the
Mannich salt (III) inevitably fall to less than 70% of theory and are then no
longer
industrially acceptable. Since the addition of the ketone (VI) to the imine
(X) of the
chiral acids (VII) which is formed in situ in the reaction mixture is not
significantly
asymmetrically induced, the ratio of the Mannich salts (111):(lll A) in the
solution is
about 1:1. The optical purity in the Mannich salt (11l) which has crystallized
out also
rises continuously over the entire course of the reaction.
The chiral acids (VII) of the process step 1 according to the invention may be
obtained virtually quantitatively in a simple manner and in unchanged optical
purity,
and be reused in the next batch. Multiple reuse of the chiral auxiliary (VII)
on
repeated batchwise performance of the process step 1 means that the Mannich
salt
(111) can be prepared with substantially less than 0.35 mol% of (VII) gross.
B. List (J.
Am. Chem. Soc. 2000, 122, 9336-9337) also reports that the reaction only
succeeds
with proline and fails with even very closely related analogs of proline.
In contrast, owing to its different type of mechanism, the process step 1
according to
the invention succeeds with a very wide variety of sometimes very structurally
different acids (VII). For example, Tables 2 to 5 show that the same Mannich
base
could be prepared in high optical purity using (S)-(+)-mandelic acid, (+)-
dipivaloyltartaric acid or (L)-(-)-malic acid. It is also of industrial
interest that (S)-(+)-
mandelic acid and (L)-(-)-malic acid have a price comparable to that of (L)-
proline, but
the enantiomeric compounds (R)-(-)-mandelic acid and (D)-(+)-malic acid are
substantially cheaper than (D)-proline. Significant advantages of the present
process
step 1 over the List reaction are the very wide variety of usable solvents,
the isolation
of the optically active Mannich salt (III) without workup (by simple
filtration), and the
CA 02484685 2004-11-03
high isolated chemical yields (85-95% of theory). These properties are all
confirmed
by the examples in Tables 2 to 5.
O NO2
H cNH2 (XIII) (XIV) (XV)
2-nitrobenzaldehyde 2-aminopyridine
O H
HO H N
N C'LNH+O N O
O I
C,LNHO
\ 2N I I
L-proline O2N 2 O
N, I i
(XVI) (XVII)
5
An asymmetric Mannich reaction experiment to give a compound of the formula
(III)
where R1 = o-nitrophenyl, R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl and R5 =
phenyl, and
where L-proline was used as the transferor of the chiral information, was
carried out
by weighing 493 mg (1.00 equiv.) of the ketone of the formula (XV), 294 mg
10 (1.25 equiv.) of 2-aminopyridine (XIV) and 453 mg (1.20 equiv.) of 2-
nitrobenzaldehyde (X111) into each of the 8 glass reactors of a Surveyor
Reaction
Screening System. Also, 101 mg (0.35 equiv.) of L-proline were weighed into
each of
reactors 1-5 and 7, and 576 mg (2.00 equiv.) of L-proline were each weighed
into
reactors 6 and 8. 10 ml of the solvent specified in the table were then added
in each
15 case. Reactors 1-6 were stirred at room temperature (22 C), and reactors 7-
8 at
40 C internal temperature. After the specified reaction times, withdrawn
samples
were derivatized with camphanoyl chloride (VIII A), and the resulting isomeric
amides
(XVII), (XVII A), the anti-isomer of (XVII), and the anti-isomer of (XVII A)
were
quantified by HPLC.
Table 6 shows the results of an attempted asymmetric Mannich reaction using
L-proline.
CA 02484685 2004-11-03
41
Table 6
Ratio %, HPLC
ent- trans- ent- t [h] T [ C] No. Solvent Molar equiv.
(XVII) (XVII) (XVII) trans- of L-proline
(XVII)
- 19 22
- 40.5 1 Aceton 0.35
- 53
- - - 131
49.7 47.8 1.2 1.2 19 22
51.1 47.6 0.6 0.7 40.5 2 Methanol 0.35
51.9 47.4 0.3 0.5 53
56.0 43.7 0.1 0.2 155
- - - 19 22
- - - 40.5 3 DMSO 0.35
53
131
- - 19 22
19.1 19.1 24.3 37.6 40.5 4 Dichloro- = 0.35
23.3 21.6 24.1 31.0 53 methane
24.9 22.6 23.1 29.4 131
50.5 49.5 - - 19 22
48.9 47.1 1.7 2.3 40.5 5 Ethanol 0.35
49.5 47.9 1.1 1.6 53
55.3 43.8 0.4 0.5 155
48.9 45.9 2.4 3.4 19 22
48.4 47.4 1.6 2.5 40.5 6 Ethanol 2.00
49.5 46.7 1.6 2.2 53
54.1 45.4 0.3 0.1 155
50.4 48.0 0.7 0.8 18 40
54.9 45.1 - - 131 7 Ethanol 0.35
49.8 48.7 0.6 0.8 18 40
52.6 44.7 2.4 0.3 131 8 Ethanol 2.00
Under the conditions explicitly described in J. Am. Chem. Soc. 2000, 122, 9336-
9337
and under closely related variants of these conditions, no preparatively
usable results
are achieved. Under the preferred conditions (35 mol% of (L)-proline in
acetone or
DMSO solvent at room temperature), neither the Mannich base nor its enantiomer
had been formed in significant amounts after reaction times of from 19 hours
to 131
hours (Table 6, No. 1 and 3). In the methanol and ethanol solvents not
specified by
CA 02484685 2004-11-03
42
List, the use of 35 mol% of (L)-proline at room temperature leads to the
formation of
the virtually racemic Mannich base within 19 hours (Table 6, No. 2 and 5).
Only on
continued stirring of the reaction mixture over 155 hours does the Mannich
base
formed attain a low, but significant enantiomeric excess (approx. 12% ee) with
the
simultaneous disappearance of the small amounts of the trans-isomer originally
present (Table 6, No. 2 and 5). An increase in the reaction temperature
(ethanol,
40 C) does not increase the enantiomeric excess of the Mannich base achieved
after
131 hours (Table 6, No. 7). Even using 200 mol% of (L)-proline in ethanol both
at
room temperature and at 40 C results in only a small optical purity of the
Mannich
base obtained (8-9% ee, Table 6, No. 6 and 8). When 35 mol% of (L)-proline are
used in a dichloromethane solvent at room temperature, there is approximately
twice
as much trans-isomer as the desired cis-isomer of the Mannich base up to a
reaction
time of 40 hours. Only after 131 h have the amounts of trans- and cis-isomer
become
equal. No significant enantiomeric excesses are achieved by either
diastereomer
over the entire period (Table 6, No. 4).
Conditions have also been found under which a f -aminoketone of the formula
(I) can
be obtained from the compound of the formula (III) without significant loss of
the
stereochemical purity.
The invention further provides a process for preparing an optically active P-
aminoketone (Mannich base) of the formula (I) or its mirror image
RkN/R O
R1 R5
R4 H
(I)
where the R1, R2, R3, R4 and R5 radicals are each as defined above,
which comprises
CA 02484685 2004-11-03
43
converting a compound of the formula (III) in a suitable solvent by adding a
suitable
base.
Suitable bases are organic amines, preferably (C1-C,o)trialkylamines,
preferably
(C 1 -C3)trial kyl a mines, for example triethylamine or
diisopropylethylamine, and also
alkali metal or alkaline earth metal hydrogencarbonates, carbonates or
hydroxides.
Suitable solvents are water or organic solvents, or a mixture of water with an
organic
solvent, optionally a solubility-enhancing additive, for example comprising a
phase
transfer catalyst, where organic solvents may be present in 100% purity or in
technical quality, and may be, for example, a C,-CB-alcohol, branched or
unbranched,
for example methanol, ethanol, n-propanol, isopropanol or n-butanol, or a
ketonic
solvent, for example acetone or methyl ethyl ketone (MEK), or an ester, for
example
ethyl acetate or n-butyl acetate, or an ether, for example tetrahydrofuran,
methyl tert-
butyl ether, diisopropyl ether, 1,2-dimethoxyethane or diethylene glycol
dimethyl
ether (diglyme), or a hydrocarbon, aliphatic or aromatic, for example toluene,
or a
supercritical medium, for example supercritical carbon dioxide or a
halogenated
hydrocarbon, for example dichloromethane, or a polar, aprotic solvent, for
example
DMF, DMSO or NMP.
(I) may be liberated from (III) within the temperature range from the melting
point to
the boiling point of the solvent (or solvent mixture), for example from -30 to
100 C,
preferably from 0 to 40 C, more preferably from 0 to 25 C.
The liberation of the Mannich base (I) from the optically active Mannich salt
(III) under
complete retention of configuration is a nontrivial process step, since it has
to be
carried out under conditions under which
1. there is no deprotonation of the C-H acidic a-position to the keto function
in (III) or
(I), since this would lead to the formation of the undesired anti-diastereomer
of (III)
or (I), and
2. there is no retro-Mannich cleavage of (III) or (I), since this would lead
to yield loss,
the formation of chemical impurities, the formation of the undesired anti-
diastereomer and also partial loss of the optical purity of the Mannich base
(I).
CA 02484685 2004-11-03
44
The liberation may in principle be carried out in those organic solvents,
preferably in
acetone, in which the retro-Mannich cleavage proceeds very slowly (vide
supra), with
the use of bases, preferably triethylamine, diisopropylethylamine, alkali
metal or
alkaline earth metal hydrogencarbonates or carbonates which can deprotonate
the N-
H acidic ammonium group, but not the C-H acidic a-position of (III) or (I).
The liberation may further be carried out in an aqueous medium, and using as
bases,
for example, alkali metal or alkaline earth metal hydrogencarbonates,
carbonates or
hydroxides, preferably under pH-stat conditions at a pH of approx. 8-9.
Preference is
given to sodium hydrogen carbonate or sodium hydroxide under pH-stat
conditions at
a pH of approx. 8-9, and particular preference is given to sodium hydroxide.
Since the solubility both of the Mannich salts (III) and of the free Mannich
bases (I) is
usually very low in weakly basic water, the liberation reaction leads to
conversion of a
suspension of the salt (III) to a suspension of free Mannich base (I). After
the end of
the reaction, the product (I) may therefore be isolated by simple
centrifugation or
filtration. Owing to the low solubility, only a very small proportion of the
reactant (III) is
ever present in solution, and only for a short time, since the free base (I)
formed
precipitates out again immediately. For this reason, the retro-Mannich
reaction plays
virtually no role in aqueous media. The isolated yield of free base (I) in the
cases
investigated was 95-100% of theory, the content of the anti-diastereomer under
the
optimized conditions at 0.7-1.5% was unchanged within the margin of error
compared
to that of the Mannich salt (III) used, and the enantiomeric excess of (I) in
the
optimized procedure fell by less than or equal to 2%, preferably 1 %, ee
compared to
the salt (III) (Table 7).
In the case of salts of the formula (III) which are insufficiently soluble in
pure water to
be deprotonated by bases such as NaOH or NaHCO3 or Na2CO3 at a usable rate to
give (I), one or more organic, water-miscible solvents may be added in amounts
of
< 25% by volume, preferably 1-10% by volume, more preferably 5-10% by volume
(for example methanol, ethanol, isopropanol, n-propanol, acetone, tetra
hydrofu ran).
Preference is given to adding 1-10% by volume of the cosolvent to the solvent
in
which the preceding four-component coupling (process step 1) has been carried
out,
as long as this solvent is water-miscible. Particular preference is given to
using
CA 02484685 2004-11-03
methanol, ethanol, n-propanol or isopropanol both as the solvent for the four-
component coupling and as the cosolvent for the liberation of (I) in the
aqueous
medium. Very particular preference is given to using the Mannich salt (III)
dampened
with alcohol, as obtained in the centrifugation, without preceding drying, for
the
5 liberation in the aqueous medium. Whether, and to what extent an organic
cosolvent
has to be added to the aqueous suspension of (III) depends upon the solubility
and
aqueous wettability of (III), and also upon the nature of its substituents R1
to R5 and
its anion Y Preference is given to minimizing the cosolvent addition to such
an
extent as can be reconciled with an acceptable liberation rate under pH-stat
10 conditions. An unnecessarily high cosolvent addition to the aqueous medium
may
reduce the isolated yields of free Mannich base (I) or make a more complicated
isolation of (I) necessary (distilling the cosolvent out of the reaction
suspension
before centrifuging off the solid for the purposes of complete precipitation
of (I) in the
suspension). Also, an unnecessarily high cosolvent addition may promote the
retro-
15 Mannich reaction during the liberation under pH-stat conditions and. thus
worsen
yields, chemical purity, diastereomeric purity and enantiomeric purity of the
product
M.
0
CiNHO
\ NH2 O 2
N I
I
(XVIII) (XVII)
The liberation of a Mannich base of the formula (I) is illustrated hereinbelow
using the
example of a reaction of a compound of the formula (I) where R' = o-
nitrophenyl,
R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl and R5 = phenyl (compound of the
formula
(XVII)), in which (XVII) has been liberated from the corresponding mandelate
salt of
the formula (XVIII) under various conditions.
CA 02484685 2004-11-03
46
Table 7 shows the results of the conversion of the compound (XVIII) to
compound
(XVI I):
CA 02484685 2004-11-03
C
a) L f0 C o ~t
N U O
cn u
L) LL
C E M
n U Z C r p) Lo
:3 (D 04
-0 > ou
LOX (1) > m rn C)
IL a) a>
a O v Lo
D>-
ci
E -(D =2: c6 _
a) C) N-
0 W V-0 >
= ~-v o to co
V > ca U o 0 c0 06
d7
O` X O >. C) o) O)
o c
0 0 0
0
a)Z
T
a >ca. ()Vv >m.ra)-o > .,.,Co a)3s
V Xz cam U Xz ca- a) XZ ca a >%
U) z a) A a N 'o - Z a) A N - z a) m 0
I (D (D
~ N - N U
ns N U C N N Lc): fa 0 'a
U)i 0~~ 3=`v U ) 0 -3-a U))0 L~ ~~ a)
C O N a C O N
fa T0 { L
ca = 0 S N CU = L N CC = N ,1
= a) C-6 ca L _ 3
m C ca 1.0- N U= a) c ca 4- t5
o a) (n .0
a a) a)o
a)
U)oo cn -oC~ c v -a~
x =. a) = o
w (( nc 'a a n ~ v U)cacn>>3 NC U) N
a) m a)
> 0 - C C C
0 (a 0 0 0
a) 0 00
Lo 0 0
to
O E r
Z
N z z voi =rnr =aoT7 =(0rn
m E cu ova 0~ O - c
a) cu
z z z
c: U) 0-0 c^ cn^
c
a) c
a t s
== cam? > > Q~ .. c cL ao .. cLa ao
=' m ca=- EN^E EN^ EN
U~ U~ o > L o \
m 'n Z a) > > U s a) U CO > a to C6.2:
ca V a) 'fl () a) V a) a) c a)
b a) a) a)
O ti If) N-
c~v N r)
z
CA 02484685 2004-11-03 (D c6
0 co U p N
U) 6
to o N o ti
c~`o0oZ ~ cci r c'i
U_^ G'L^
> u
00 x > (6
Q. ~ a >
o..` > 0 0
E a) :-. r cr)
a) -0 m 0) 0) co
_ _ o
C c
U z 0 o .r c U.L.
2.5,- o 0 0 CD
ax CQ',,u ~, ~ E Ex
0 co
O c
a).2 L 2 0 0
N
cm (D z
a)
_M F- 0
or o ,tea'
_ 0 z =ox
~Z
co N _Za)0a)0 -a 0 3C
IT a) = U)N C0 N'ate)tea`) N a) (pO r0CU .- 2 'a .0 viN of oO
c O MD (D N a .0 n a) (n 'O +r O CU 3 U C"
a) cot c cot- c m ca=- 0 N=
E mCCcor aC~CCOS a)cva)
c0- C) -U)0 c ccia)-vim)C cci. OR ?=3
m co0a) con(D o co ~
X U~ `oO)_3 ~vNm
W coN (na)~~ U) v,ca )0
C , m a) m
> o= C C C
0 M" c c 0
c
E = cn 0 L O 0
N
0
U
-S z z z
a) p > N M N N
to E :3 =CEO m co V7 = U')
co 0 0 r- ~- O ai
M (D C13 cC .... M
Z z Z
c U) (n U)
a) () Q a) C. C C C C
0C = E . L- C o 2 cL o iZ o
-
t55; 0 C9 C o cu r-+ E N =~ E N .~ .. E N
a) X (n Z U .` v .` o U co > CO o m
C ~- () a) a) a) .1 L) 0
cu -0 a) 'v 0) a) v- a) a) s- () a)
a) (1) a) a) a)
c- 0
N N. ti
v > E r ao
cav E
o v LO 0
Z
CA 02484685 2004-11-03
C i
O U C' Cr) N --
cl) r~-+ 0 O O O
U Y
EO=~~ M Q)
O O Z r- ao
.. .N Uv
D c O LO
O X a) > N O)
a a>
=o a.` N N Co
0" x a) cu -0 m 0) CC) 0)
IL
0) 0)
~> cu , O co Os'W - 0 OL'ca >et
p u Vim. OX LO U 0X
CL x n +L' Co q, E c0 a) E
CU CU
O C
u Z 0-!Z I- 0c:)
O'D CT
m CL
L) XZ m t -Z f r) -~ XZ Co Cl)
to z CL Z L- faNC NC M C NO2caNC03.
cn O I- N O Q cn O I- y- U) O `~ O O a)
O ~~ w 0-W ~0..f--~ N c
c cat-~ O ~O COI ` 0 3 c"a2 f 5, 3-v
O C fa -0 (D s Z a) C ca 'a O n a) c ca Co 4) L6
" - - rn
ccCLa)_a) cc=wo U) -0 cn
"D a
x coCc~aOocnca oa)ccnMcl)
Cl)
w
C N a) a)
O - C C C 0
~O 0 0 C
E O N O N O N
O 2 2 2
Z z z
^ N N N ^
E'S Ln~ LU =LLO
CO E 00)' Oo) Ornr
Z z z
c ^ L cn cn cn
-. m a) c'. (D r~ c cs c cr c
c
L- CL
~> cOm am E a) E04 EN EN
> Ica
m X cnZ O'r- c: c0.)~ t0C),a 0 O.
c`a -a a) V a) (D . ai
c - 0
t- F- r-
m E
oo ao ao
m
O~ X E
rn
CO O co
-- Z
CA 02484685 2004-11-03
C I a) 0 a) N U C Ln O)
C-4 - o c;
(D C^
C) N to
a; 20
cc 0 o Z u c6 a0 =-
_ V
= 07 (D 04
xa) > L ip co 0)
` 0)
(L a) 6. >
0
0 .L LO co 0 C
2Xa )imi" > rn 0) c o^
a c E_
c cu
Cc :3 0) r
U .-. .~. (y L) X
0 0 Co C) 8 C
0> 0 N 0 L6 Ln M
X 0 0) C) E
2 N -- E
o c
o^
ai 00
C Z
C _ Q
V A v
F- A -c
> Lo Ln o > co. +Ln a3 3~ > V++ 00--o
XZ ( _ XZ cow U) W X co, L)
O N ZNN0.3 .Z8 Noa)'a=za)LciC0
N C
LO 2:~ caN o m a) o 0 LM= NQ 0U a
O r.+ a) o. R Q a) N w o cl)
+.+
= ~ >,= c(n 'a u ~_ ~ ~ >,w 3w coo= coo N o
0cCoo0)lri3 Ccolci0 m 3v
E 'a C aC V N~ 0 C aC .~ 0= c CL-0 C L
0 cu (n .0 0 0 0
.0 cn .0
Q) a) (1)
c c c
0 C E 0 c 0
a) 0 LO 0 to E O N O N O N
Q
Z z
N ^ N ^
UMo
N o> L L
m E OQi OC) z
z z -
^ N '0
cn
C= ^ a) a CL o C C. o C C.C C
co ~ co a x .. CL
> >
E L-
o2 ao cu cu EN L EN -- EN
co x c) z a) > > ' cd > o co (p > co ca =?
a) cZa) a) a) )g vrna rna
c=_ o ti ti ti
ti m E
ao ao ao
E
c
m O 0 - N
f" Z
CA 02484685 2004-11-03
C I Q)
0 a) c N C o LA M
N r.+ tC U, O O
N O a) ~ o LO a .- C)
N Z'.r m L r
~; \ CU >
OL X O > C6 Q)
a) a >
0
O o ~ap.L > 0 C 9 C
a)= G
CL >
E
Y j Y C
C9 CT D)X
L) u
CO O C CO
et U
O tCf a) o O OD N .Fu ui CC) co m
X (D 0) E a) E
L L.
O
a) O M p
0
o
u r
Z
L L T
O ^= C00) 'LO (v) C ^= O .tQ
=0. c' a== =0 Cu N ci 0 =OLD a
a m U) >U~ =-o> m
XZ`O v) = X~ XZLn Co
co Z cU 3 o 3 =Z cvQ Cn0_ZLV 0 3 "a 'a V CN=O O 'O CD Np C1,= CtfN+- O n'O't
3
a) a) Ch o
a) ~.
CU a) (6 a) L O N Co O N 76 0) u)
Cm 5, U) - o Ca - M 3.
a) c a t, 3 E C a) 0
o m rn N 3
c ) r- CL Cl) L C N - ma c
o
xa w EU a= ~U n 3 zo EU =
w o Cn o o
a) CC c C N
:.. ~. 0 0
O Q C
>= 0L() 0Lo 0LC)
o f = N = N
C/)
N
z
N 0 N
N Co =moo UcY) o =moo
m C Q 0 N 0 0)'-
C Z Z Co
tn 'n
c _^ a)> > (D c C C
c o C Co d o.. m C
O" > P
M EL
CDXcZ(D a`) a)-g--- )a ~t"Qj )
-a a) V _ a) a) a) a) ()
() a) a) a) a) a)
' C = 0 X E p CO 06
O tO
F- Z `- r
CA 02484685 2004-11-03
- L
O N
ca U C- N
= OY N+-' Ou O Q
U Lt_
~C.-. ~tAt`O
O O~ c N
co p C z E L L L e- ~--
m c)
cn 04
TO
O O O Q) O
-p In CG
O`
aN) > oN O O O
>
x a) U m-0 m
>
17 ^
~ ~ Z' LO
CO CO
> 52 N o O c6 06 00
O X O =~+ t7) 0) W
CL .(n
O py N 0
CL) O LL ~+ a Co Q O Q
m NMO f`
LQ
Z m 0)
U)
c) N
L r
O 0 co Ur TOCN~ C (O A C "D
>Vc oM t-a>Vc 00 ~ 5>V ~ao U-a
N X cOcU oO x cu v=)0, m m-= ui
a) Zcoo N-Z coo NZ'a'-n N
'0 Q CL L= O CL-_ I p O ^
C4 :3
E a~.E~o.pa~a.E~o~p~a).E~~p-a
c ac 0 Esc C.~ N 2 c ci (D o -c
co U) (D O N M M O O cn c4 cn N cn
) Un vi~Un cnCD
x v= cn
LLJ 0 0
N :D c N U N C U.) N U LC)
co co O E Q O Q O N O CV
E 0 O 0 O N O N
co
22 2
M C)
CU O O
cn OQ O OUMO OOMO
E NNN NON tt1~N
to Z Z Z
C U) cn co cn Ch
' t1 L L CO CO
, L- t t1\ " fl.c m iZc O
co Q
UZ N= E -2!
C >v> N~ j N cco >: ^ E c0,
cn r- L) 0_ 0
X ? tU CD tD CD CA CO Q Cfl O Q
t`tf -0 a) '0 Cl) a) r- 0) r a)
-'
O a) a)
N tU
0
N 0 f9 -
X E Co 00
CD p O N- co
F- Z ~ ~ =-
CA 02484685 2004-11-03
- L.
C
ONO V co
CO C
O
ca .
= cY N o 0 0 0
U~
E N u I- 0 N
N O Z O r r
U V
`..
O O O I- CO
CO Cn
OL X O > to a) a) a)
Oo.>
u
mCL 's >
2 X C >
ME = 'O p U) U)
2 5v ca w a Or CD m
a. A
O C
0 n
O 0
O
L o 0 0 0
C z u r r r
- 0 cri o a)=czN ao ~2 N at
'a 0-0
X
U N O N I O X I L 3 X I O` O O 0 3: -0 C
N cl)
Co Z O O L ~ W '0 O -0 .a'O Ca W .a to n, c -
Lf)
O 0 .~ .. I N O -
N~yy N 3~ 0 "T L-
- `~0 ~~.cr~ 3-a
CD (D (D
LL N A N
C N=_~. N m O M O NI O ON 06 a OC
E E ~~ E~~ EU, o aLI
w o I ao L ai C C m 00
O Ccov cica) ccaU)O...=.o= U)U)Oc~a~v iU)
xa 3g~ZCF-a= ~caN
w z Z N
c
> CO co U-) Co ~j Co co
Cl) cow' WN Wr 111
~= Cp
(D 00 > E O N O N 0 c
CO
C) N
a) t 0-11
N N
C/) o 0C'O I~:rn I"000
U E It,N Oro O
E O Z ca 0 ca v =-
z z
o .. o
C L Cn Co CO C')
(D c
C1 L L t
CM = c => > > co Q. o C`a 0. D M CU Q o c 11
U > U > Ca CO ~ o m CO .-. o m ctj
O"C"O O O O CO CL CO CL
E a O "O r `.- v C` N
O O O
O N > E ti C'7 N- 04
X E O N
I- Z T- N 04
CA 02484685 2004-11-03
a)
04 U C o M
c: M = O O p
U LL
E (D
/010 O Z V V
o ; N N co
LO EL rn rn rn
a=` > co co
oXmEvcc rn 0)
a. a)`~ >
O m Nu a) o rn oi cc;
rn
c rn
o
a) o-~`ti=moo a0oo0)) o oo
m E".c o E s acoo
N oZ m aCONON0)=- O c tncn Q. N
.2 cl) v- ti m N
XU amio 0a = 2~ 50 o0
_ = s-0 N o
~
o a*1 0
m a) cA O =0 X m cn X m N t -t3
,n v caZ o c+c m m co~Z cc s0=Z=v Vi W cu CO "a
U o 0 0L v cn
(a m o a),o o cnp cu. -3v CT c N m 4) 4) CL N m r.+ ( o a
a)Otntc)v)NV0 C-4 =a~CVNA . avaCOmN2
cCLU-j ~spN cti~U~ -c =0~oN
m cn oaDVO- m <n c, rn U) m cn m
x co a) *, m
w Cu cu (n
C V) c.- C
U? m O E O a 0' < 0
E C4 t1)
0 0 0
vOi o Uoo U"!o Ur-o
m E cm CUM CCU co N
Z Z Z
o õ o 0
C ^ L N C co cn N
cc>a-> a>cLoarn C, ma~0
M 0 M m EMS: E--:: o ECD (D X c Z a) co
O `. `) >_ o u
(D (D CO cn 2
2 (D (D
a) CU a) o a) ()
a) a) a)
c~ 4) M > E N 00)) ti
0 X E LO cry
m
0 N N N
CA 02484685 2004-11-03
0) a- cb
= C Y M
U)
0 i c;
C L
O OZ
+- .y o Z
O O O Lo
-O > 'd '~'-. ~t cV
2 (D > co
d. X O O_ > O O
O c M .-L a) Co ) cc 2X0) U-0 > O O
17 ^
M- o co M
-0 > cu o O M O
X o "L rn rn
a
O c0 a) C O c o L O c 0
co co )ccfi0 0 Q. E 'ML 'Q'L
N ~~o E L
DMZ cu cis cOLU')LLO
O CD cV co co
"a U) Lo 0
O _"a0 CO- 0 3 _ co =~ O
cc a) Cc >, 'D > m~ EF-
>
N XZ cn n =-0 1 ,-1 0
.=,N=== f~4,N=OZ=d
ca W a 3 ~ uJ N a v a)
a)
coo ac)Cc0 ccoitQa)a)
c ~O oo 0 ~~s c >'= M
W C14 E -v C V c Q-' =o W "a
c F- a) N
0 c OE. a~ c `LnOL0i o
x 0c -E o 0N_ 2 cu ci v ~
3 E
cn N
w
O
co
C co C Lo c:
> p E -c -c
Cl) cc W oi w
) O U') O co
o = O = c
rl
_ Z Z ^
a) p > NNcn N~
E v0 0 CY)
O
Z Z "
c ^ L cn cfl U)
a) am c Lo (n r:
M 0)
CU c:
c0
c) > U O. O co O E II',- II E Mco L6
X cn z O U U O j \ U O .>
` 'O a) V Q c..
.. m a) W
a)
M co
N
z N co
CA 02484685 2004-11-03
56
In the reactions described in Table 7, 0.95-1.10 equiv. of 2N sodium hydroxide
solution were added all at once at 0 C or room temperature to a suspension of
(XVIII)
in pure water, which resulted in the quantitative liberation of (XVII), which
was,
however, accompanied by the formation of from 5 to 10% of the anti-
diastereomer of
(XVII) (No. 1-5 and 8-11). Depending on the specific reaction conditions, the
reduction in the enantiomeric excess of (XVII) was either only minimal (No.
1), slight
(No. 2, 4, 5, 9-11) or distinct (No. 3 and 8). Immediately after the entire
amount of
sodium hydroxide solution had been added in one portion, the hydroxide ion
concentration was therefore so high that not only did the desired
deprotonation of the
ammonium function of the Mannich salt (XVIII) occur, but the undesired
deprotonation of its C-H-acidic a-position to the carbonyl group also occurred
to a
considerable extent.
Since the resulting enolate ion of (XVII) is not reprotonated
stereospecifically, but to a
similar extent on both sides of the enolate plane, both (XVII) and its anti-
isomer are
formed. When the stirring time after the sodium hydroxide solution addition
was
limited to 1 hour at room temperature, only 1.3-3.7% of the anti-isomer was
formed
(No. 6. and 7), but the degree of liberation in this time was only approx.
20%, and in
one of the experiments, the enantiomeric excess of the salt (XVIII) (96.2% ee)
also
fell by 7% to only 89.0% in the free base (XVII) (No. 6).
When 2 equivalents of sodium hydrogencarbonate were added at 0 C instead of
sodium hydroxide solution to the aqueous suspension of the mandelate (XVIII),
only
2.4% of liberation occurred within 14 hours (No. 12), but the product filtered
off with
the suction as the (XVIII)/(XVII) mixture contained no increased amount of
anti-
isomer. Equally, only 11-13% of liberation occurred when 1 equivalent of 2N
sodium
hydroxide solution was metered very slowly into the purely aqueous suspension
of
(XVIII) over 5 hours at 0 C (No. 13 and 15).
However, the addition of 5 or 10% by volume of acetone to the liberation using
2
equivalents of NaHCO3 effected quantitative formation of the free base (XVII)
with
complete retention of the enantiomeric purity and without significant increase
of the
anti-isomer, not only at 0 C (No. 14, 16, 17, 22), but also at 10 C (No. 23),
at room
temperature (No. 18), and at 40 C (No. 24). Marginally even better results
were
CA 02484685 2004-11-03
57
achieved using sodium hydrogencarbonate in water/ethanol (10:1) at room
temperature (No. 19).
Equally good results were achieved when 0.95-1.00 equivalent of 2N sodium
hydroxide solution was metered at pH 8.5 (using an autoburette under pH-stat
conditions) into the suspension of (XVIII) in water/ethanol (10:1) (No. 20,
21, 25, 26).
Retention of the enantiomeric and diastereomeric purity appeared to be
slightly better
at room temperature (No. 20 and 21) than at 40 C (No. 25 and 26).
The process step 2 according to the invention offers the possibility of
substantially
recovering in unchanged enantiomeric purity the optically active acid HY* of
the
formula (VII) used during the four-component coupling from the weakly basic,
aqueous mother liquor of the liberation reaction. The preferred method for
this
purpose depends upon the solubility, and also on the chemical and optical
stability of
the chiral acid in aqueous acidic media. In the case of acids (VII) which are
very
insoluble in water at approx. pH 3, it is generally sufficient to acidify the
mother liquor
and centrifuge off or filter off the precipitated solid (VII). When an a-amino
acid has
been used as the chiral acid (VII), it is generally sufficient to acidify the
aqueous
mother liquor of the liberation step to the isoelectric point of the a-amino
acid and
then to centrifuge off or filter off the solid. When the chiral acid (VII) has
a not
inconsiderable water solubility, as in the case, for example, of tartaric
acid, malic acid
or mandelic acid, or there is a risk of partial racemization under too
strongly acidic
conditions, the preferred recovery method is frequently extraction from the
weakly
acidified aqueous mother liquor. For example, the recovery of (S)-(+)-mandelic
acid
by ethyl acetate extraction succeeds in 88% yield, > 99,5% chemical purity and
100% ee.
In the event of very high water solubility, mineral acid sensitivity or a high
cost of the
chiral auxiliary, other recovery methods, for example freeze drying of the
neutralized
aqueous mother liquor of the liberation reaction, also come into
consideration.
Furthermore, a simple reduction method has been found by which (i-aminoketones
of
the formula (I) or their salts of the formula (III) can be reduced with very
high
diastereoselectivity to 1,3-amino alcohols without losing the stereochemical
purity
CA 02484685 2004-11-03
58
already present in the compounds of the formula (I) or (III) or having to use
any chiral
auxiliaries.
The present invention therefore also provides a process for preparing an
optically
active 1,3-amino alcohol of the formula (II) or its mirror image
RZI -R2
N H OH
R R5
R4 H
(II)
where the R', R2, R3, R4 and R5 radicals are each as defined above,
which comprises reducing a compound of the formula (I) or a compound of the
formula (III) with a suitable reducing agent.
The compound of the formula (II) may then be worked up by methods known per
se.
The conversion of a compound of the formula (I) to a compound of the formula
(II) is
referred to hereinbelow as process step 3.
The conversion of a compound of the formula (III) to a compound of the formula
(II) is
referred to hereinbelow as process step 4.
Suitable reducing agents are borane or borohydride reagents, optionally in the
presence of a chiral catalyst.
The process step 3 according to the invention achieves a distinct
diastereoselection
in the reduction of the keto group of optically active a-aminoketones (I) in
favor of
1,3-amino alcohols of the formula (II) when using borane or borohydride
reagents.
The diastereoselective reduction of (I) to (II) may be achieved using achiral
reducing
agents (principle of simple diastereoselection) or in the presence of
optically active
CA 02484685 2004-11-03
59
catalysts, and in the latter case, the enantioselectivity of the catalytically
active
reagent overlaps the simple diastereoselection and usually dominates. In the
case of
reduction in the presence of optically active catalysts, high diastereomeric
excesses
are achieved when the enantioselectivity of the chiral catalyst coincides with
the
simple diastereoselectivity of the reduction (matched case). Lower
diastereomeric
excesses are obtained when the catalyst has the opposite absolute
configuration and
its enantioselectivity therefore counteracts the simple diastereoselectivity
(mismatched case).
Examples of achiral reducing agents (principle of simple diastereoselection)
include:
1. a borane-sulfide complex, for example borane-dimethyl sulfide or borane-1,4-
thioxane complex;
2. a borane etherate, for example boron-tetrahydrofuran complex;
3. catecholborane;
4. a borane-sulfide complex or a borane etherate or catecholborane in the
presence of a Lewis acid, for example titanium chloride triisopropoxide
(iPrO)3TiCl;
5. a borane-amine complex, for example borane-ammonia, borane-tert-butylamine,
borane-N,N-diethylaniline, borane-N-ethyldiisopropylamine, borane-N-
ethylmorpholine, borane-N-methylmorpholine, borane-morpholine, borane-
piperidine, borane-pyridine, borane-triethylamine or borane-trimethylamine
complexes;
6. a borane-amine complex in the presence of a Lewis acid, for example
titanium
chloride triisopropoxide (iPrO)3TiCl;
7. a borane-phosphine complex, for example borane-tributylphosphine or borane-
triphenylphosphine complexes;
8. a combination of a borohydride, preferably sodium borohydride or
tetraalkylammonium borohydride, with a reagent which leads to in situ
generation of borane. Examples of such combinations include sodium
borohydride/iodine, sodium borohydride/boron trifluoride diethyletherate,
sodium
borohydride/chlorotrimethylsilane; tetraalkylammonium borohydride/alkyl halide
(for example methyl iodide) in dichloromethane or the biphasic mixture of an
alkyl bromide (for example n-butyl bromide) and a saturated aqueous solution
of
sodium borohydride and catalytic amounts (approx. 10 mol%) of a quaternary
CA 02484685 2004-11-03
onium salt as a phase transfer catalyst (B. Jiang, Y. Feng, J. Zheng
Tetrahedron
Lett. 2000, 41, 10281);
9. a borohydride of a mono- or bivalent metal cation, for example sodium
borohydride, lithium borohydride or zinc borohydride, or a tetraalkylammonium
5 borohydride, in the presence or absence of a cerium(III) salt, for example
CeCl3,
as an additive;
10. diborane (B2H6).
The following reductions, for example, may be used in the presence of one or
more
10 optically active catalysts:
1. a borohydride of a mono- or bivalent metal cation, preferably sodium
borohydride, in the presence of catalytic amounts of an optically active
aldiminato cobalt(II) complex, for example (1 S,2S)-N,N'-bis[3-oxo-2-(2,4,6-
trimethyl benzoyl)butylidene]-1,2-diphenylethyl enediaminato cobalt(II) (S)-
MPAC,
15 in the presence or absence of tetrahydrofurfuryl alcohol as a coligand.
This
reagent combination was described by T. Makaiyama et at., Synlett 1996, 1076.
It leads to a catalytic enantioselective borohydride reduction of carbonyl
groups.
In the case of the present novel application for reducing Mannich bases (I),
the
natural diastereoselectivity of sodium borohydride may be enhanced by the
20 coinciding enantioselectivity of the reagent.
2. a borohydride of a mono- or bivalent metal cation, preferably sodium
borohydride, catalyzed by a rhodium complex which results from the
coordination of two molecules of optically pure 1,3-amino alcohol (II) per
molecule of [(p5)-pentamethylcyclopentadienyl]rhodium dichloride dimer. It is
25 possible and advantageous in this case to choose the substituents R, to R5
in
the chiral ligand (II) in such a way that they are identical with those of the
resulting reduction product (II), so that the sodium borohydride reduction
proceeds autocatalytically. Such catalysts are similar to the CATHyTM
catalysts
from AVECIA (WO 98/42643), but differ in the following points:
30 - CATHyTM catalysts are prepared from the cyclopentadienylrhodium chloride
dimer and chiral 1,2-amino alcohols, for example cis-1-amino-2-indanol. In the
present application, chiral 1,3-amino alcohols are used.
- CATHyTM catalysts were used for enantioselective transfer hydrogenations in
which secondary alcohols, preferably isopropanol, or triethylamine/formic acid
CA 02484685 2004-11-03
61
mixtures functioned as hydrogen donors. In contrast, a borohydride, preferably
sodium borohydride, functions as the reducing agent in the present
application.
- CATHyTM catalysts were used for enantioselective transfer hydrogenations of
different prochiral ketones, but not for the redution of the keto group in
racemic
or optically active Mannich bases (for example (I)) or their salts (for
example
(III)).
Preferred reducing agents are a borane-sulfide complex, a borane etherate,
sodium
borohydride or a sodium borohydride complex comprising an in situ catalyst
which is
obtained by the coordination of the [(p5)-pentamethylcyclopentadienyl]rhodium
dichloride dimer to the optically active 1,3-amino alcohol (II).
Particularly preferred reducing agents are a borane-dimethyl sulfide complex
or
borane-tetrahydrofuran complex.
Owing to its titer stability on storage at room temperature and also to its
industrial
availability in high concentration (94-95% liquid), very particular preference
is given to
the borane-dimethyl sulfide complex.
The reaction is carried out using 0.3-10.0 molar equivalents of one of the
reducing
agents specified, preferably using 0.5-4.0 molar equivalents, more preferably
using
1.0-2.5 molar equivalents.
Process steps 3 and 4 may be effected, for example, in an aromatic hydrocarbon
(for
example toluene, cumene, xylene, tetralin, pyridine), a saturated hydrocarbon
(for
example cyclohexane, heptane, pentane), an ether (for example anisole,
tetrahydrofuran, tert-butyl methyl ether, diisopropyl ether, 1,2-
dimethoxyethane, 1,4-
dioxane), a chlorinated hydrocarbon (for example dichloromethane, chloroform,
chlorobenzene), an amide (for example N-methylpyrrolidone, N,N-
dimethylacetamide), an ester (for example isobutyl acetate, butyl acetate,
isopropyl
acetate, propyl acetate, ethyl acetate) or a sulfoxide or sulfone (for example
dimethyl
sulfoxide or sulfolane) as the solvent. The last three classes of solvent are
not inert
toward the borane. Preference is given to carrying out the reaction in
toluene,
CA 02484685 2004-11-03
62
cumene, tetrahydrofuran or anisole. Particular preference is given to toluene,
cumene, or THF.
The reduction reaction is carried out in the temperature range from -70 C to
the
boiling point of the solvent used, preferably 120 C, preferably at from -10 C
to +40 C,
more preferably at from 0 C to +25 C.
There exist the options of
a) adding the solution of the borane complex to the suspension or solution of
the
Mannich base (I) (normal addition), or
b) adding the suspension or solution of the Mannich base (I) to the initially
charged
solution of the borane complex (inverse addition).
The duration of the reduction reaction depends upon the specific reactant
(nature of
the substituents R1 to R5), upon the reaction temperature selected and the
solubility
of the reactant in the solvent. It is from approx. 30 minutes to 3 days,
preferably from
I to 5 hours, more preferably 1-2 hours.
When the particularly preferred reducing agents, borane-dimethyl sulfide or
borane-
THF complex are used, the primary product of the reaction is a diastereomer
mixture
of oxazaborinanes which, if desired, can be easily isolated. The formula (C)
is
attributed to its strongly dominating component on the basis of its HPLC
behavior, its
molar mass determined by HPLC/MS (M+H+: m/z = 437.3) and its smooth conversion
to the 1,3-amino alcohol (II) under the action of methanol/methanesulfonic
acid.
CA 02484685 2004-11-03
63
R3 R2 R2 H H H ~H
131-13 R\N 0 R-,, NiBb
R R4 R R1 R5 -R2H R1 R5
H 11
R4 H R4 H
(1) (A) (B)
H
R. B\ solvolytic workup R3 H H
N 0 z.B. McSO3H / MeOH N O H H
R1 - R5 - H2, B(OCH3)3 RI Rs
R4 H R4 H
(C) (II)
Table 8 summarizes the results of an exemplary reaction of the aminoketone
(XVII)
(compound of the formula (I) where R1 = o-nitrophenyl, R2 = 2-pyridyl, R3 = H,
R4 = 2-pyridyl and R5 = phenyl) to the 1,3-amino alcohol (XIX) or its
diastereomer
dia-(XIX):
N~ 1
NO 2 HN 0 1) Reduction
I \ I \ 2) Workup
N,
(XVI I)
N~ 1 N/
NO2 HN OH NO2 HN OH
N, Ni
\ I \ I
(XIX) dia-(XIX)
CA 02484685 2004-11-03
a)
a .0
O
tC U a)
'0 co
a) Mn O O
} O CL V c C C c .~
N ti
a)
0 = X
0 0
E 2
N h N
cn 06 fa0 Q) ti f`
CD N
C6 4 N
r
M M C")
O.~
00 f~
w X X crj
Cc RR rn M S o I- co
M O 00 CD I- co 0)
a a a
0
c V p '0 a c
CU -0 a
Y ^ ~ O (D Z > > w =
N O M
:3 a) 0 0
o ~0 axC o pc >o zto 02
X~z QoL)Z z vox N v~
Co
cr-
.C
w aom~ ~ c - F
D) c M N rn
oc
co. 0
.` 'O c ` ~ o N
(q ~'QU v Opt N O + r 0 ON
a) _
>> SE p E p E LL =E
~o 0It Oo a)o a) C=) u5LO
F-
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()
a) )
O N N a) a)
(n , c yi c w LL
cc co 0 m c C4- ~7
)_>% ('7 7+- Mo E o C
a) M- N r E = 0o= ON = oLo oio E
co l0 a) NZ r.c Z r~- m .Oco m .0 N Mr M_N
E p CU O
E u) m E m E E
` E o Eo0 E E c- E
m 00 a) cu N _ N N co U
C _U c "It U) L O tom 5-0 6- U M p"O V-
co C (D 0
`~ ^ x o E>-"' E Q& > E a) E E E E
L) W ._ c r a) a) X E a)
ao ac iX ~~ oEU? W ~ a) L ~,- ~~ a. 04 s E E
m a CU - i_ ~ O 0 U E - U co 0 i 0 Z 0 i U') EU')
04 cY cD
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CA 02484685 2004-11-03
CL
'C7 o
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N C 7
O 2 O 'p U) N- LC) -C3 O '~t ti
O a_U .. co CD CO m
C . -
vi
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a ti o ~ ~ 0 0 0
E
E E m r ti r co 0 N CY)
Cn ._ .~ r tt ti CV (0 LCD
O
U) G) N O O 0 O r tt N
:p LO O co c m ~t N M C'7 Lri
~- .~ .. .... C X CO ..
X X -c ll~ c (a O .c O 0) CA to
N
OxX OL OIL Lt7 h CD CO CO
~' .... C~) U) 0 qG a 0) 0)
C)) Q) O) O)
171
O
4t7 0 )) O aa)) O 4)) 0 a~i 0a) 0 (1) 4) O cn V)
a) 0-0 ) O a) o o~Z a() y o~ o2 g o2 0
U) cl) U)
Ch
04 C) M C~ C M C m M M
U)
CO
m
E O o L o 0 O O o L o o
E V 0Lo Uti ULo ;LO UN LC) UL to
C/) cu ON Or 004 ON ON c:) 04 ON + CV
a N W^ C^ a'^ 0) Cl) a) C
E c E E E E Cl) E
O ~ E = Ln (D U 5 LO a) 75 LO ( (D O 6 LO LOO
O O
U)
N> c E
UoCLI) E 0LI E 0LO 0U) E oU) E cU) E oU) E ou) E
m L e o COvi S, N M S , N CriS, Ln N01 M c, i C) C, )SN C701 N vi crlr
U U ^
:8 R
- -a)ooa3mo>a) Cl)
_>~- d75 C o Lo o caOo a)EXa)2 oX0) 2
L)^ EE E EE Eo-ovo Eoao E o E~
() a) E a) E a) E E dD 't o E ~COO~NO E_NO
Ca a) o E 0 DLO ~Lr) 0 0. 0 C). 0 LI)0LI) ~ O O LI ~
CD X- U) m La Ew co (CS ECAr - )0 Cf)r0)O
m o O F~: N co d
F- Z N- co C7) r r c- r
CA 02484685 2004-11-03
0 0
o 0 0 aa) ) CaQON a~~
O = () \ \ \ \ c o 0 0 0 = \ \ \
op 04
loth 0 CA O O^ o ~i Co
N O o Co
L O O O O CO CO m) O (V S O U.) ~- C N
0 d .~ .. A I'- A Co r r Co O Q) (V
vi
a)
0 0 o 0
Lo Ne
E
T7 T7 C1 ^ 0)
ti CO
co co r) et ,t Co
' LCD O .- M O OA
M M M Co LC)
O
. X X O Co CO CO C) 0
mXX
co 0) co 0) co LO rn rn rn
S S = ~2 S S = ~S I I O I I Q I Q
Ma.O MQ'0 MQ'0 Mu0 MQO M~O Mo'O
O a)Q) 0 4) a) 0 a)a, 0 a)U O 4) Q) O0 0(D OO DUO
0 0: O ~U) )LO ~LO2+C%1 + jNM+
CD
CD
F- H~ F-
cu a) cu
Ca_ 0.C OL OM
o OL O ,r
E o L U LO LCD
C e- o N V UUf UN Vt
C/). Cn + 004 0 s 004 C) 004 ON
~- ~ ~- ~ - E Cl) - Cl) -
E E E E E E E
>> >O ~O zO mO mf, E ~O =O
O O LO LO O O LO O N S CO O CO O M
O C C C
Cn Q) +N+ E C
C+r
"'a? C- E E E ^ E
m .,
m CCi O U .-. U .-. r U .- U U r U C U C
o- v o
> E
-\
rD Q-0OU) OLX)LO LO V) LO LO Lou) LOLnLC) NLOLC) NU)LO
m co a) CD (V~ c d ci d C-4-0)d CVSO NS) O NS, O
. > Q) _ > Q) - > a) 04 _ > Q) 04 > a) 04 õ > O . > O 004
C pX a)S pX a)S pX a)S pX a)S EX a)S pX mS pX a,I
N E o o E o o E' o E' E o\ \ E 0\ \
(`j^ ' fi b do o ~o ~mcn Edo CC-f)
0 0 6 1 OOLI)O OOtr) U7 OO LO cooOCO M OON"~ OON
0O X
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m O Ln CO ti M Q) O
f- Z 04
CA 02484685 2004-11-03
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to ? O o c o= e c o= \ \ o= o o a' _
O 'D 1` OO o C~) Lf
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a) 2 Ue-LTOLC) 0 0 0lqT COOON O~O
0 L1 CO 0)r- COC)e- ) N-C)-- COO -C)
vi
a)
O E
E o 0 0 0
~- ~ N N- co
O
co 0) It It
cfl co CO O
'D ... CO LO Lt) CO
O
U) C) O
mXX rn It rn rn
~SU M'S2U
a M 5IO M 52U co
O ~Oo0 ~Oo O X00 O ~Oo
0 ~N~+l)Ln~+ PLC) 0 ~Ln2+ 04
cu Cc Cc
ti
Co
m'0. CO ocu ocu oC
E~ UL U~ U~ Or
La 004 0 .. a) E a)" 4) ^ 4) t --
c E E E
> N m O O m c=)
O> _O O O O co
(Q) U) N
p O Q' E' 9)
E
co > T C - U C - U C U c
O; p v\ c v\ ~' O U\ O
0 o L6
Q'O N '7 E Lo "t LLB IT +~ O Un O
= 4'
m cu a) Co N- O N 9 E (V 04
C C C C C C
O L O O
O O O O 3 3
o> m N "> a) N ~-o > QQ 04 o> a)= D;n
EX a)2 oX a)2 pX (1)2 EX a)
~ Ego o Ego y c Ego o a) cl) u 0
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00
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CA 02484685 2004-11-03
a)
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o 0~am2 016- 16- 0 . ao~ aQ) na)
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0 Q. CO O M r-.- -- M rl 0) CO o - (r) (D C) - M
vi
a)
O
d o 0 0 o O
(/) .~ Ø. r~ (D (O
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:~ .. LO U) to to I,-
0 ^ ^
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X X cm O0) Off) Qom) ON)
U 0 0 0
U
0
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(0 0 (-o O > O3 O > (C O f~C O
= v
a m 0-00 M =
O O M O M O M O
0) (D
gU
o to2V tn2V m LO 0 o2V~ o
cc' ~cN RCN cN RCN ~ :VN
co
co
N F- F-
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w Q'
F- F- W F-
cu (D LL m of cc
cm 16- (D .c 0.c O O L 0
0. LO E c UN UN 0(y Vto Us
cl) O O
- a) o= a)= o= a)= o=
aa)) E aa)i E aa)) E Cl) E aai E CC) E
>? o :3 0 :3 O :3 O :3 o
6 0 -6 co oCD 'It
cn i F- F- F- .~ F-
U
a) rn rn
O
U) m
c"I > C C C C C
-; -- O L) L)
IV) to to o E ' o E ' o E
m N a) N N c (V C C (V m N N LO qq, a: N N m N
C C C C N 75 E
O ;E o +_ > a) ~ > a) 0 m ~ _ > a) ~ E > a) 0 o > a) p a)
C 6X a)= o'o oX a)= a) o c oX a)= EX a)= EX
0 o o o _ o o c o 0
\\ to t/) E \\ to v) E o\\ \
aD ~> EocDM ca EoiDM a) ca E Ei00 io000D orn C c=-
X 0CL( > u 000tri > Jr-0otr; o0tric`) o0ri0 00
U) Q'- ~e-0) 0 . (ON to e- 00 .C (0- for 00 LO -00 N A 000 Q'
(6 O
N 00 (M M
Z N N N
CA 02484685 2004-11-03
`)
'D O O O
C I (S CL (D CL 0) CL N CL
0 0 0
p D 0 0 0 0 0 0 0 0 0 0 Vol
0 4 co 1, .0- ~ r '- NN O co C 3
7- z
co
O co O` O' OiOM CDCACAM C)C)OM 4Cn0
~- 0 a (- C) . . rr- C) C) IRT 03 0)-v- e- F-. 0)
U , p
N N B C -L E w- m
46 0 O O
E O. d O co V> 2'D x
Cn E r r r c x O O E
r r r c6 ..i t1 Ct) .1 r
.. D C) CD C)
Cf) Cf) LI)
O ..
C 57< 57< co
rn rn rn
U 0 U
~C O > a)C.J ~CCON
04 =
=cf) O M O M D=
O M
O a~i Q) O ~O0 m~O N0
O U-) CO 04 0) -12
Co U.) C O
Z:
Ci
O = (D a) Cvi C Lo Cyi C
04
Q)
CD _ _ 'fl
U V _c o
F- UU M= 0 0 E04
M (D
m 0c:) m E+-.NLo
C)co E OL O NN Or
E 00 U U W 0 t
co ('U Or ON r.~ cl: 3 U) x CD a
E a E C E C E E
>? :3 o U- LO
O co CO O . N
CU
O N
c j v o C o C o C 2
- - -~ E - E - E Mom o
EMT 'ODO~N Unv~ CDU a) o o
CO Ca N CaN01 N 04 04 2 C)Z co
O > --- _^_
E X E >
O - 0 o >
> N
c EX a)= E~ m EX a)2 EX a =
N 0 o 0 O Lo 0 0 0 0 E 0 o 0
N tt0C) . N '? 0)V;N O~N
~
00 Q)> (HO)MO 6 C) OC)O LO 0)M~ u=)C)MO
IV- A 0) 0 N A a) r A C) O r A C) O
co M 04 C) C)
CA 02484685 2004-11-03
C.
O U C N
CL
N
L- C cV
O (D 0 aa a~0
o c
Q Q) \ = e e e_ 0 y
0 0 0
N c
O 0)Lo I- NM N
>- 0 QU1-00)'-C) CO00)00)C) X m
a)
C a
a)
cl E a
O O Ca
E -- o c 3
f/) EEO. N r r `
O 0
L
Cn U
'~ 0 O
^ ti F c '~
=i0 :~ LO LO
o X X ch M 0
v N
5-< 57< t : a)
~. rn rn m v C
co
i-. .-. (CC ) ( )
p
0 Ln
CL cf)
0 acri Oa) O acri Oa cc C LO
LO Cl) N N
C
CL =3
X- 0 LO Cn C L ca co C _Q Ex _ E C .0
0
rn~ E 2-
Uo(tn ? omE 5X =E c 0 c a)
E 0 0 .: 0 N to C04 '-' N r..; O U = ~ r 0 O>
a) O p 2 u-) L v .0 ' v0,
Cn N V- O a) O N N W U N F T C a) - C 0
_ 0 C 0 c CCf lB
E C ca c
Co L C O
c ) C C. O O
E E E
m 00 V- 0 m OE L a) L~ '
U) 0 1q, H 00 6 M cn (D m
O w
x X o õ= 0 Z X
p X X N y z D X
a) x x C%4
a) CU M 0 V C C1 tl 0 0) O
i .> - (D ca c E 8 C Z
= 4? ~~CO~r CD~r U U 0 8 Z
m cu a) CON - O CV O a. J 0 0 O N N
CL C c .-
_ _ - C9 C U
(D L-
CO 0 0 'p. c o
M d n .O M O L
O O 2 M. w UO
-6 0 > a O> aj~N
6 6 C C 0. C2 '
E
C E X 0 Z E X N= z z 0 0 a) Z
CO
U_ O o 0 o E o 0 0 .N. U U E E Cho Cep Q. CD O 0) ~ N 0 d= N C D Ca a) O 0 -0
L O
CO 0 LO CD MO L6 C7)cr)p a) 0 () M
X r A 0) O h A 0) 0 E C C .C .C 0 0 =-
C9 LO O
F- M U 0
Z Co
CA 02484685 2004-11-03
X
X
U
O
x
0)
L: . 0
O O
3 3 M
O
w G7
3 3
c c
0 0
c
u L)
x x ~
4) Cl) "D -D cc
o
cu c
o c
c cu
_ = 0
O O
W U)
Z
N
O o 0
> > C
'5 :O
U)) ate) V
ti c9
0 O
0 0
C C =
O O
cu c0 N
C C `-
o o 0 o
0 -0
U) CO 7
cco m LO E
N c0
.D L 0 U
N
.D L
co a)
c0 co a) U)
Q o N cu
a
U) Lo U)
ca CO
3 3
a)
U U 4
2 2 ch Cr
Z Z 4- a)
N N O z
L L 0
.~ .. C
4) (D
X X O N
'O O
X X a) a
0 0 C C
O O O C
U U -c
L
X O
X
O O C
a) a) '3 E
~- F- O o
m L^
CA 02484685 2004-11-03
72
The results show that this method allows the carbonyl group to be reduced with
high
stereoselectivity (up to >97:<3; see No. 9 and 11) and the retro-Mannich
reaction of
the reactant (I) is very substantially suppressed under the reaction
conditions, so that
the stereochemical information already present in the reactant is virtually
entirely
retained.
An example of a workup method known per se for reductions with borane or
borohydride reagents is the solvolytic cleavage and/or a crystallization.
The solvolytic cleavage of the oxazaborinane (C) initially formed in the
reduction of (I)
to the 1,3-amino alcohol (II), and its isolation from the reaction mixture
leads to the
greatest possible extent of removal of stereoisomers: the enantiomer ent-(11),
3
HO H l-,,N,.R
Rs R1
H Ra
ent-(I1)
the diastereomer dia-(Il)
RANHO H
R1 R5
R4 H
dia-(Il)
and the enantiomer of the diastereomer ent-dia-(II)
CA 02484685 2004-11-03
73
HO HzNRs
R5 R1
H R4
ent-dia-(I I )
Optionally, within the workup of the reaction solution of the product of the
formula (II),
a crystallization proceeding in high yields may be carried out which
completely
removes the small amounts of stereoisomers of (II) contained in the crude
reaction
solution. In this way, it was possible to prepare 1,3-amino alcohols of the
formula (II)
in very high purity (> 99.5% chemical purity, -100% de, > 99% ee) in 2-3
stages from
usually commercially obtainable starting materials while achieving high
overall yields,
sometimes above 70% of theory.
The solvolytic cleavage may be achieved by a variety of different procedures:
a) Preference is given to carrying out the cleavage using 1-4 equivalents of a
strong
acid, more preferably methanesulfonic acid or sulfuric acid, in an excess of a
low
molecular weight alcohol, more preferably methanol, at 0-60 C, more preferably
15-40 C (Table 8, No. 6-36). Under these conditions, the boron from (C) is
converted to a volatile trialkyl borate ester, in the particularly preferred
case to the
volatile trimethyl borate B(OCH3)3 with forms an McOH-B(OMe)3 azeotrope with
methanol of boiling point 59 C which contains approx. 70% of B(OMe)3 in the
azeotropic mixture (M. Couturier et al., Tetrahedron Left. 2001, 42, 2285).
Particularly when the borane reduction has been carried out in the
particularly
preferred solvents such as toluene or cumene, the boric ester solvate and
excess
methanol can be easily distilled off quantitatively after completed solvolysis
by
applying a vacuum. The 1,3-amino alcohol of the general formula (II) is
present in
protonated form and therefore generally has good water solubility. Therefore,
when water is added to the toluenic or cumenic distillation residue, the salt
of (II)
is in most cases virtually quantitatively extracted into the aqueous phase.
The
toluenic or cumenic phase then removes most reaction by-products, for example
retro-Mannich products and their reduction products. When the product-
containing, aqueous acidic solution is then rendered strongly basic, for
example
with aqueous sodium hydroxide solution, the free 1,3-amino alcohol (II)
CA 02484685 2004-11-03
74
precipitates out and can easily be isolated. However, particular preference is
given to isolating (II) by crystallizing one its salts while the small amounts
of
stereoisomers contained in the crude product remain in the mother liquor. The
optimum anion and solvent for such crystallization depend upon the nature of
the
substituents R1 to R5 in (II) and therefore have to be determined
independently for
each 1,3-amino alcohol of the formula (II). When R1 = o-nitrophenyl, R2 = 2-
pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl, for example, the optimum
crystallization of the dihydrochloride of (II) proved to be from 1-butanol.
The
dihydrochloride was obtained in 99.3-100% ee and a chemical purity of
99.1-99.9% in a yield of 74-84% of theory, based on the Mannich base (I) used
(Table 7, No. 19-29, 31-35). This crystallization can even compensate for an
untypically low enantiomeric purity of the Mannich base (I) used. In the
experiment of Tab. 7, No. 32, (I) of only 90.5% ee was used. Despite this,
(II)
dihydrochloride was isolated in 76.8% yield with 99.4% ee and 99.7% chemical
purity.
b) Alternatively, the solvolysis of (C) may be carried out using an excess of
a strong
aqueous acid, preferably 2-normal to concentrated hydrochloric acid or aqueous
}
methanesulfonic acid, at 0-100 C, preferably 0-40 C, after distilling off the
organic
solvent of the borane reduction beforehand. This workup was applied in Table 9
(No. 4-7, 9-14 and 16-18) and in Table 10 (No. 5-8). Under these conditions,
the
boron from (C) is converted to boric acid B(OH)3 which is only sparingly
soluble in
aqueous acidic reaction mixtures, in particular when cooled to 0-10 C, and
very
substantially crystallizes out and can therefore be easily removed. In
contrast, the
1,3-amino alcohol is present in protonated form and therefore generally has
good
water solubility. When the product-containing, aqueous acidic solution is
rendered
strongly basic, for example with aqueous sodium hydroxide solution, after
removing the boric acid, the free 1,3-amino alcohol (II) precipitates out and
can be
easily removed. Appropriate typical procedures are described in Examples 23
(corresponding to Tab. 9, No. 18) and 24 (corresponding to Tab. 10, No. 5).
However, preference is given, as is the case in a), to isolating (II) by
crystallizing
one of its salts. This is achieved by rendering the aqueous acidic product-
containing solution basic in the presence of a suitable organic water-
immiscible
solvent, for example n-butanol. The free 1,3-amino alcohol (II) is virtually
quantitatively extracted into this organic phase which is then heated and, by
CA 02484685 2004-11-03
adding a suitable aqueous acid, for example concentrated hydrochloric acid, a
salt of (II) is formed which crystallizes out on gradual cooling of the
butanolic
solution.
c) A further alternative solvolysis method for (C) is the addition of an
excess of the
5 solution of an alkali metal hydroxide or alkaline earth metal hydroxide,
followed by
heating to 30-100 C, preferably to 50-70 C. The free 1,3-amino alcohol (II)
may
then be extracted with an inert organic solvent, while the alkali metal borate
or
alkaline earth metal borate formed remains in the aqueous phase. An
appropriate
typical procedure is described in Example 25 (corresponding to Table 10, No.
3).
10 d) A further alternative solvolysis method for (C) is the addition of an
organic
complexing agent (for example diethylenetriamine) which forms a strong chelate
complex with the boron. Preference is given to applying this method in the
following form:
Methanol is initially charged in the solvolysis reactor at 20-60 C, preferably
at
15 40-50 C, under an inert gas atmosphere. The preferably toluenic reduction
mixture (comprising substantially (C) and excess borane) at 20-60 C,
preferably
40-50 C, is gradually metered into the initially charged methanol. On
completion
of metered addition, the complexing agent, for example diethylenetriamine, is
metered in and the solvolysis mixture is stirred until the solvolysis of (C)
to form
20 (II) is quantitative. Water is then fed to the reaction mixture, preferably
at 60-70 C.
The organic (toluenic) phase is then separated from the aqueous phase, and
washed with water, preferably at 60-70 C. The boron-amine chelate and excess
methanol are removed with the aqueous phase. The amino alcohol of the formula
(II) can be isolated from the toluenic phase by known processes. Depending on
25 the specific nature of the substituents R' to R5, direct crystallization by
gradual
cooling of the warm, concentrated toluene solution may also be advantageous.
However, it may also be advantageous to transfer (II), as described under a),
into
another more polar solvent, for example n-butanol, followed by the
crystallization
of a suitable salt of (II), for example a hydrochloride.
30 e) A further alternative cleavage method for (C) to form the 1,3-amino
alcohol (II) is
the solvolytic cleavage by adding hydrogen peroxide solution. This method is
only
advantageous for those products (II) which are not easily oxidized by hydrogen
peroxide. Also, since the reaction of boranes and some oxazaborinanes of the
CA 02484685 2004-11-03
76
formula (II) with hydrogen peroxide may be extremely exothermic, the workup
methods a) and d) are frequently preferred over e).
Process step 4 is carried out with the same reducing agents and under the same
reaction conditions (molar equivalents of reducing agents, solvents which can
be
used, reaction temperature and duration, method of adding) and workup methods
as
have already been described for process step 3.
The following special features apply to process step 4:
- Mannich salts of the formula (III) are generally distinctly more polar than
the
free Mannich bases of the formula (I). The solubility of the Mannich salts
(III) in
nonpolar solvents (toluene or less polar) is in most cases no longer
sufficient
for a viable reaction rate with the reducing agent. Preferred solvents for the
reduction of the Mannich salts (III) are therefore relatively polar solvents
in
which (III) has better solubility, and particular preference is given to
tetrahydrofuran.
Particularly preferred counterions Y*- in the Mannich salts (III) are chiral
carboxylates or dicarboxylates. These counterions Y*" are generally not
completely inert toward boranes, borane complexes or activated borohydrides
and are themselves gradually reduced by the reducing agents used. This
consumption has to be taken into account by an appropriate increase in the
equivalents of reducing agents.
As is described for process step 3, an oxazaborinane (C) is formed as the
primary
reaction product and is then converted by one of the above-described
solvolysis/workup procedures to the desired 1,3-amino alcohol of the formula
(II).
In Table 9, the results of diastereoselective carbonyl reductions of the (S)-
(+)-
mandelate salt (XVIII) (compound of the formula (III) where R1 = o-
nitrophenyl,
R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl and R5 = Ph) to the 1,3-amino alcohol
(XIX) are
compiled by way of example:
CA 02484685 2004-11-03
77
Q
\ / 0 = /
OH 1) BH3 Me2S,
NO2 +NH2 0 THE
2) HCI
N~
(XVIII)
NO2 NH OH NO2 NH OH
N~ N~
(XIX) dia-(XIX)
CA 02484685 2004-11-03
o
O 3 LA 0 4) a) 'o
L- L
0 CL
'O a) O a) \ \ p
N >> N 'a fl 0 0 0 to 0. Nx
} O V C C r r r 'p CA M X
0 a) (D
co cu
O CO m
N N It
(D 0)
O rC .r c
OL
..
E T j O o 0 o f 7 ca
J p C 5 A) m F, v ca CD CO r
00 = O W O N er- O CL V C CV u) Lo
O C =` 0 O 0
fn A -0 O CL
X a
r e}
o X O to r N N CV)
_X
o co U ~E .= cf) co . Lo v d v
co a C ~t co N N- o LO LO Lr) tO
ir x0 rn rn 0) rn 0) 0) 0) 0) 0)
X m
L
co a V > V > >U C C ^ ^ _ >=V^ U
Y 2 c Z =_ ~= E 0U E pU E= E O o-~= E 2 E
N a) N a) N a) O Or pEj CD CO N 4) 0 C) o CO
CO O CO r -~ v O. O LO
V) U) C) c")
0 + N p OL'e- L 0m = O C 0 CO ~ cu O
U') E + Pc V + r U N (~ U') LO o LO
a) 0OCj OCõ) ON oN 001
+r r
a a c i E ELL EUEU E U- E U E u-E U. E U E
> >o =0=02020 m =Ln =L$) 'It) =Ln
!~ ON ~~N~N~~ co ~co
~co ~co
~(n O U
N^E ^C ^ ^C ^C c .-.c E ^~ ^c ^C
a) > N .c (0 - CO .C Cp - to co CC) .-
'So oE 0EC ECDLo of c E -a C) of of
.=- Lo
= aft Ln V) Lo LO u) Lo co LO co 0 C6 LO C) C:,
CO CO
a)
c o~ ~o ~
O d o 0 o o o f o E E E E E
a E~ E E E E -.f 8f E E E E E
E E=- Er- E=-V7 I, Ln 0Ln O Ln 0) 0)
am) E N 0 N 0 CN 0) N 0 u) L u) co Ch co M co M Ch co
0) 0) CD
0 On r r r r r r
()
Z .- N Ch I't u) c0 I- co 0)
CA 02484685 2004-11-03
U V .0
-0 O
...X o
10-
.0 0 Q) 0 O l p CO .C '0 y p co O O 'C N OO CA r U
CL. 0 r r C.1C r ^-0
A V: CL
m fC co Ch C
0 0) C
to ,_ C
0
0 C
O X O
EUE ac" o o o cu
J CO V7 O cq ti L[)
O o d m r) c0 v M C')
E
0 v cu 0
a)
O E
X
`-- X O X D) Co 0) LO co N N O
0 C =E "'r c-; C6 M M M 6 cyi >
o Q)
R a O r r- Lo N C 'V)*
X j C)) C) 0) 0) co 0) CO
E E
co
O ~
CL U U U >2U U U~c~ E
Y = E E_ E ~O= E_ E= E' m a
o ZM =Ln cip ~~ ~g 0 uo VO W o
co E N CM OCp N p COpLD CLn CO 'C3 a
N N N V UM v C U U O N v) 0
CO
C N E :3
0 0 0 +r 0 0 +- 0 C O C O
L CV - cu - co ..... C8 - Lo - m .... X
Q-~ U .C UsOs0t U=U'LU CD
C~ E o 0 00 cc:) Lt~ o U') o to Q
w oNOM NONN Or OrC? E in
_ U
a) Cc
u_Eu_E u_LEL_E u_Eu_u_E
> LC)'C =0202 U') LO L~' X
H0F-0 HOH ~''- co
Lo
~vo X
U)
>, cu
C/) ) E
N.-. C .-.C C C C ^C ^c E
CU > C c9 cu ca = co co cc co co a 40 -
Er 0 Epo oO po.0 o.oo=oop d. m
= 00 MN- CO T- Mr C
CO v N Cu
O O
'O U
0
C EQ)o0 EQ) Q) OQ)OQ)OQ) L-
o
Eo EEE E a
E E~ E~ E~ o
co E ~a rn LC) E Lo E LO O Ln E to E to E LO E
a~ E ci6vO O, (0 V LO c6 6N 6 C
CL 0) N C) N C) N 0) C) C) 0) 0)
O Q)
N E
.Cu E
Z r r co "lo l(o r U v .0
CA 02484685 2004-11-03
Quantitative conversions of the Mannich base to components of the salt (XVIII)
were
achieved down to 3.0 equivalents of reducing agent (Table 9, No. 8-11, 16 and
18).
While hardly any conversion to (XIX) was achieved in toluene (Table 9, No. 1),
there
was substantial to complete conversion in THE (Tab. 9, No. 2-18). In the case
of the
5 carbonyl reduction, diastereoselectivities (ratio of (XIX)/dia-(XIX)) of up
to 96.8:3.2
were achieved (Table 9, No. 4 and 18). The isolated yields of (XIX) were 78-
83% of
theory, and these products also contained 3-4% of the diastereomer dia-(XIX)
and
almost 2% of the enantiomer of (XIX) (Table 9, No. 9 and 18), since there was
in this
case no crystallization step of the dihydrochloride of (XIX) similar to
process step 3,
10 section a). Including the crystallization of the dihydrochloride, the
enantiomerically
and diastereomerically pure amino alcohol (XIX) (> 99% ee, > 99% de, > 99%
chemical purity) was obtained in a yield of 70-75% of theory, based on the
mandelate
(XVIII) used.
15 In Table 10, the results of diastereoselective carbonyl reductions of (+)-
dipivaloyl-
tartaric acid salt (XII) (compound of the formula (111) where R1 = o-
nitrophenyl,
R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = Ph and HY* = (+)-
dipivaloyltartaric acid) to
the 1,3-amino alcohol (XIX) are summarized by way of example:
CA 02484685 2004-11-03
81
rCLNH~ H3C CH3
H3C O
p
NO O /CH3
N, H3C CH3
2
(XI I )
1cIINH NH
NO2 Q H
+ NO2 H
N~
(XIX) dia-(XIX)
CA 02484685 2004-11-03
'n
0
0) a) o
O N f7
5- C,
Co U) 0
U N-
O W
N
co CY)
O a) LO OD N
V Ud cm v Or-
ca
E Mo
O O X O X E X cC
O X c
L-m c..0 x: 75 x O Mco N C
U U O N p '0 0 r- U C N o
N t0 O. OR \- X
NON (N II
-ow
as a) x N v &)coX 2cco co viU)It~IC) xV
to cm,) a 4 Ern Ui O
co
p ^U O O~ MN N
0XX t5 -
M0
J c0 X O ~ co
x X 2 O ~- CO
vvv~ N to Q)
N N a) L
Z3 O N 0 O
O U O N
N U M V
N a co '0 W Q _c0D
co 1. ~ E
- U) a)
to .0 c,4 ~4 4-7:
E c
E c
(`) U `) 0 U) 0 c
0 Mr E 0 aa))E 00 0 ~V 4) o V0
F^F- cY) N cr Qcf) Oc')
> U-
c
O a)~ Ec E
OO M CC N U7 w O
V) 04M 30O NW O
a)
m
C
woo 7 04
s +~= 0) >
C L U W ff z ff
a) ca 'a M 5
a) (D .01 ~n cr
a) O U) c N m m O W a) C13 m
CC c0 E a Z Z m ~) to 4D _.a
O E
E a) X O E a)
r_ E 0 S2 ~ c O E o o E 0 o E 0 o
O (6 = c 0 V 00 = tOn N (D E a) c a) NO O N r a) C) p! co = a)
.~ N C +r g N .~ N
a) X ,~ ca co o s Iri X .. Iv co c O) .~ c>s o ca r- co co U')
a)o COL N 0 -0 t-- U-) h OMr- X
-, O~.QO
O
r)
Z 04
CA 02484685 2004-11-03
O 'o
U o 0
O
V o N co
06
ae-ocu co co
O N
ca 0 fl ~ cm,-'eO pV a) 'O 1 r' MO
U) a >_:=O=.0 U) 00~ co
00U
0 0 ^~ ^
M CL Xai Xai
0 0 0) \o ~o
J J 0 co 00 1 c0
z = a) E 0
N U)
;>, V O G= N N
0 J V w t. co
w:XXa co x O
OCxX=: E N
= N = O C N
3: (~ C
ONOC.crn~N CO oflz=
~
_ D E.z= d C 2
CL ~-0 o O T o o a o E Lo o^ C
ce) y O Lo CIO~ X QO ~j=Lo M X
z a 'Ct ca . (p 0. c) . 0 v lfl l6 ..~ t0 a C7 S O 0
2 E f- E
7 E
O
cc C in C O r0. `_ =~
oU CO E0oaE
CL 00o 04
'0 O .O o ca N
E E OH o O O o O
F-'}- QOmw QOtON OtL'ON
LL u-
m
c E E
> E 0 C)
O O O
CO
> d
^ ^ ~ -.
.N. 0) COL N > 0) > 0) O
a) cu 'D C^ O 'C O-
a) 0) 0) O N C m = y = = O
N~'EOf m m Cal
-- = o O o
-6 a) E E a)
C E N x 0 C O O E O 0 E N
C U c c O .- o
c~C E o.0- O C O) co C N y C O o
O M C O . (~ O1E O C e-0=0 C O=~- C N~-
N 000))
a) 0 .0 co) o ~03 2-0cn 0. 00)) -XN 0 .
z ]ED
CA 02484685 2004-11-03
N ^
o
_N O m t: ch O
CY)
c 0 00
o U a~
0 >'
.. cQ
.. C N O D)o
t N 'D
a 0 J O v
00- U) c~
m cu
.0 (n
04
^ _ ^ X ca
Cl) Q -wX c
C
O -D 1C O X O ' to
O
J J U 0 0 0 o M 00 0 o N
a. a N x O cj c") co -
e- co x^ loll O
22: .~ rn ~)NTOO?ri a
U
N C V N
0 N
0 N
m _x - r- co
ca ?5
X X 2" N 2 C)
U 13
o '6 7 c U E~ E
O o c_ o o O N 0 0M om
E c O 1~cI cr ) O L C m O CU () D) 2)
0 U) M O C %- co ... N C O E O= _N C N =C L E
~U ~p ~O
co Y ` ~ N N
C
O O C c) o U) 'D O 0 N O= O to C M O Z C
= O Z' o, N U
in M co =- cII m .,.+ Z 0 U T cC '* a 0 0 U v o d >
C F- C
E
LO
c`C C T c 0 C p
~0t
0 a) 20 0 o :5
E to Qo Er 0 < LO LO
{E I- oQ o -
LL
C ~ I=-
(D E
0
O
(l)
> C) ^
co co .
0) c c N^ N D
_ O V O > N
m a) cc -0
CD 0 N C N M ch '-
f6 E AM ~ m ~. m M
E ai a)
cE L 0 L m ~E L a~
E V c C E U
_ =C =~ U CD 'C c O E a) C
O m - ,~ (D m C a) w O N JS r- N U) M 9 C N U7
X n UU . 0- XN O 2-0 rn 04 v N om m rn
cc 0
r- z ti OD
CA 02484685 2004-11-03
O -p
a) a)
.
r- m O
N N
~ o U co
O >+
-. ca
U) '2
-c '2 0) O O 'a (D 'o 0)0)
ID-
0- CU M 11,
X
O V ^
o X
^0- X (D
a)
O `4) U
JJ f0 NN
o ui ao
rn o
co
cc,
XXaCU o0 .N
Ix XX% - E y C
2 00
I
v o a) O
ow p
0 0 ~ :3 0 LO w
4- L
0 O ch ~. N N 3 p) L-
v- O 0)_ LL 0 -
47- W 0 0 v
4- a) E 0
oN~-0OO02 0
LO o Y Q)U
;5E aU~E -0 0 t5 to
co\i N .0 co Q. CD Z = of c a 3 -c a) 0
~ >
0
I
E N
in C 0
0 CL
CL 0 E
Ot
0 -0 LO CD
O it b N
U-
2
I-
0 E
0 `O
04
U)
-a)
:3 U)
0) cr N .>
?Ccmm0~0 a )
a) CD U = U~
co E a
m 04
4-
O
c E c m c o
o E s
cu E a) 0
m
c c. Lo 57< m co
La5u,o x oc0 - 0 N 0
o
Z Z 0)
CA 02484685 2004-11-03
86
The use of sodium borohydride in butanol/water resulted in only a little of
the desired
product (XIX) (Table 10, No. 1). Although the conversion was better using
sodium
borohydride in ethanol in the presence of catalytic amounts of a quaternary
ammonium salt, the diastereoselectivity was only very low.(Table 10, No. 2).
When
the borane-dimethyl sulfide complex was used as the reducing agent, excellent
conversions and diastereoselectivities were achieved in THE (Tab. 9, No. 5-9),
while
there was no reaction in methyl tert-butyl ether (Tab. 9, No. 4). The ratio of
(XIX) to
dia-(XIX) (diastereoselectivity of the carbonyl reduction) in the crude
reaction mixture
after solvolysis of the intermediate (C) was up to 98:2 (Table 10, No. 9). In
the
isolated products (XIX) (yield 84-89% of theory, based on the salt (XII)
used), the
diastereomeric ratio was up to 99.2:0.8 and the enantiomeric purity 95.2% ee,
although the charge of Mannich salt (XII) used had an optical purity of only
93.2% ee
which was moderate for the four-component coupling, and although the workup
procedure included no crystallization step of the dihydrochloride of (XIX)
from butanol
(Table 10, No. 9). With regard to the chemical purity, no UV-active impurities
apart
from dia-(XIX) could be detected by HPLC, and the (XIX) content of the
isolated
product according to an HPLC assay (based on a purified reference standard of
(XIX)) was 97.9%.
The present invention allows compounds of the formulae (I), (II) and (III) to
be
prepared in high yields with high stereoselectivity starting from achiral,
commercially
obtainable reactants (IV), (V) and (VI) which are inexpensive or very easy to
prepare
by a short route using inexpensive, readily available auxiliaries (VII) and
mild reaction
conditions which are easy to realize from a technical point of view. The
process
described in the present invention is therefore particularly suitable for the
industrial
production of optically active compounds of the formulae (I) and (ll).
The following scheme provides an overview of the process according to the
invention:
CA 02484685 2004-11-03
87
O Process RAH', R2 Y
O R3 R2 step 1 N O
+ N + R5 + HY*
I R~ Rs
R1 H H R4
R4 H
(IV) (V) (VI) (VII) (III)
R& ,R2
N O
Process step 2
(III) R' R5 Process
R4 H step 4
(I)
RZ, /-R2
N H OH
Process step 3
(I) R R5
R4 H
(II)
The abovementioned tables and exemplary reactions contain a total of 162
examples
which illustrate the wide variety of possible variations of reaction
parameters within
the process according to the invention. Of these 162 examples recorded in the
tables, the particularly representative procedures have been described in
detail.
These procedures are preferred embodiments of the process according to the
invention. However, they do not in any way limit the subject matter of the
invention.
In the examples which follow, methods, ways of working and procedures are
described which it is necessary to know in order to be able to reproduce or
verify the
subject matter of the invention without problems and are intended to
illustrate the
process steps according to the invention without limiting the subject matter
of the
invention.
Example 1:
Determination of the enantiomeric excess of Mannich bases of the general
formula (I)
or of Mannich salts of the general formula (III) where R' = o-nitrophenyl,
CA 02484685 2010-09-08
88
R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl and HY = (S)-(+)-mandelic
acid, by
derivatizing with (-)-camphanoyl chloride.
mg of the Mannich base (I) specified in the title or its salt (Ili) are
weighed into a
5 10 ml volumetric flask and admixed with 200 mg of (-)-camphanoyl chloride. 1
ml of
triethylamine is added and the mixture is made. up to exactly 10 ml using
approx. 9 ml
of acetonitrile (HPLC grade). The mixture is dissolved within 30 seconds in an
ultrasound bath. 1 ml of the initially light yellow solution is transferred to
an HPLC vial
and, after a 10 min delay time, 8.0 pI thereof are injected to a Machery-Nagel
CC
10 250 mm x 4 mm Nucleosil 100-5 C18/5 um HD HPLC column. The elution is
effected
at a flow rate of 1.00 ml/min with a linear gradient composed of the two
following
eluents:
Eluent 1: Water/acetonitrile/trifluoroacetic acid = 900/100/1.00
Eluent 2: Water/acetonitrile/trifluoroacetic acid = 100/900/0.75
at the following gradient variation:
Time (in min) 0 2 22 26 27
Eluent 1 (in % by volume) 75 75 35 35 75
Eluent 2 (in % by volume) 25 25 65 65 25
The detection is effected at 254 nm. The derivatization products are eluted at
the
following retention times:
Corresponding amide of the general formula (IX A) (resulting from the
undesired
enantiomer of (I)): 19.59 min.
Amide of the formula (IX) (resulting from the desired enantiomer of (I)):
20.50 min.
Amide resulting from the anti-diastereomer of (1): 23.12 min.
Amide resulting from the anti-diastereomer of (I)-enantiomer: 24.09 min.
A peak at retention time 20.01 min. is also visible which results from a
derivatization
component.
The enantiomeric excess (1) is determined with the aid of the chromatogram as
follows: the sum of peak areas of (IX) and (IX A) is set to 100%. The
proportions of
CA 02484685 2010-09-08
89
(IX) and (IX A) are calculated (for example (IX) = 97.0%, (IX A) = 3.0%). The
proportion of (IX A) is deducted from the proportion of (IX).
In the example specified, the free Mannich base (I), or the underlying-Mannich
base
(I) of the Mannich salt (111) had an enantiomeric purity of 94.0% ee.
Example 2:
Determination of the enantiomeric excess of Mannich bases of the general
formula (I)
or of Mannich salts of the general formula (III) where R' = o-nitrophenyl,
R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl and HY = (S)-(+)-mandelic
acid, by
derivatizing with pivaloyl chloride.
In a 2 ml HPLC vial, 1 mg of the Mannich base (I) specified in the title or
its salt (III) is
dissolved. in 20 pi of pivaloyl chloride, 100 pl of triethylamine and 500 p1
of acetonitrile
(HPLC grade). After exactly 5 minutes, the reaction is stopped by adding 500
pl of
water. The vial is immediately sealed with the septum cap, placed in the
autosampler
of the HPLC instrument and, after a 10 min delay time, 5 pl thereof are
injected onto
a Merck Darmstadt 250 mm x 4 mm 5pmCHIRADEX column (R-Cyclodextrin)
(Order No. 1.51333.0001, Cartridge No. 971324). The elution is effected
isocratically
at a flow rate of 1.00 ml/min using the following eluent mixture:
Eluent 1: 1% of triethylamine in acetic acid (pH 4.1)
Eluent 2: 100% of acetonitrile
Eluent 1 : Eluent 2 = 82.5:17.5.
Detection is effected at 254 nm.
Figure 1 shows a typical chromatogram starting from the Mannich base of the
general
formula (I) with the substituents specified in the title and an enantiomeric
purity of
95.3% ee.
Figure 2 shows a chromatogram of a corresponding racemic Mannich base of the
general formula (I) with the substituents specified in the title.
CA 02484685 2004-11-03
Example 3:
Preparation of the free racemic Mannich base rac.-(I) [R' = o-nitrophenyl,
R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl] by catalysis of the three-
component coupling with 1 mol% of p-toluenesulfonic acid
5
70 ml of abs. ethanol, 5.91 g (30 mmol) of 1-phenyl-2-(pyridin-2-yl)ethanone,
3.53 g
(37.5 mmol) of 2-aminopyridine, 5.44 g (36.0 mmol) of 2-nitrobenzaldehyde and
57 mg (0.30 mmol) of 4-toluenesulfonic acid monohydrate are introduced in
succession under nitrogen into a 250 ml four-neck flask equipped with a
precision
10 glass stirrer. The solution is stirred at 25 C under nitrogen. After
approx. 18 hours,
the crystallization of the product rac.-(I) commences. At this juncture, TLC
(n-Heptane/EtOAc) shows a conversion of approx. 40%. After a total of 96
hours, a
thin layer chromatogram (TLC) shows virtually quantitative conversion. The
precipitate is filtered off with suction, washed with mother liquor and then
with 10 ml
15 of ethanol, and dried at 30 C under reduced pressure. 11.9 g (28.0 mmol;
93.2% of
theory) of yellow crystals are obtained.
The integral of the 1H NMR spectrum (CDCI3, measured immediately after
dissolution) shows a ratio of the desired compound to the anti-diastereomer of
97:3.
20 Example 4:
Reaction of rac.-(I) with pivaloyl chloride in acetone to give the amide rac.-
(IX)
[R' = o-nitrophenyl, R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl, R =
tert-Bu]
In a 500 ml four-neck flask, 15.02 g (35.4 mmol) of the racemic Mannich base
rac.-(I)
25 from Example 3 are initially charged at 0 C under nitrogen. 90 ml of
acetone are then
fed in with cooling to 0 C internal temperature, and then 6.44 g (53.3 mmol)
of
pivaloyl chloride and 13.82 g (106.9 mmol) of diisopropylethylamine are
metered in in
parallel from two dropping funnels. After stirring at 0 C for three hours,
HPLC
analysis shows 95.9% of the desired rac.-(IX), 1.1 % of the corresponding
trans-
30 diastereomer and 1.9% of unconverted rac.-(I). 40 ml of acetone are
distilled off
under reduced pressure (bath temperature < 35 C). 200 ml of water are fed in
to the
residue and then stirred at 0 C internal temperature for a further 2 hours.
The
precipitate is filtered off with suction, washed on the filter with 20 ml of
ice-cold ethyl
acetate and then dried at 40 C under reduced pressure. 16.4 g (32.2 mmol, 91 %
of
CA 02484685 2004-11-03
91
theory) of a light yellow crystalline solid is obtained, m.p. 162 C. The HPLC
purity is
99.4%.
Example 5:
Classical optical resolution of rac.-(I) [R1 = o-nitrophenyl, R2 = 2-pyridyl,
R3 = H,
R4 = 2-pyridyl, R5 = phenyl] using (S)-(+)-mandelic acid in acetone
6 ml of acetone were added to 503.9 mg (1.19 mmol) of rac.-(I) from Example 3
and
359.0 mg (2.36 mmol, 1.98 equiv.) of (S)-(+)-mandelic acid. The reaction
mixture was
magnetically stirred in a tightly sealed flask at 25 C for 20 hours, and the
precipitate
was filtered off with suction and dried under reduced pressure. 446 mg (0.773
mmol)
of the corresponding mandelate salt (III) were obtained which, according to 1H
NMR,
consisted of Mannich base (I) and mandelic acid in a ratio of 1:1.00.
Derivatization of
a sample with (-)-camphanoyl chloride and subsequent HPLC analysis according
to
Example 1 delivered a ratio of the amide (IX A) to the amide (IX) of.5.0 to
95Ø The
enantiomeric excess of the Mannich base (I) in the mandelate salt (III) was
therefore
90% ee.
Example 6:
Classical optical resolution of rac.-(I) [R1 = o-nitrophenyl, R2 = 2-pyridyl,
R3 = H,
R4 = 2-pyridyl, R5 = phenyl] using L-(-)-malic acid in acetone
6 ml of acetone were added to 504.2 mg (1.19 mmol) of rac.-(I) from Example 3
and
161.5 mg (1.20 mmol, 1.01 equiv.) of L-(-)-malic acid. The reaction mixture
was
magnetically stirred in a tightly sealed flask at 25 C for 20 hours, and the
precipitate
was filtered off with suction and dried under reduced pressure. 400 mg (0.716
mmol)
of the corresponding malate salt (III) were obtained which, according to 1H
NMR,
consisted of Mannich base (I) and malic acid in a ratio of 1:1.04.
Derivatization of a
sample with (-)-camphanoyl chloride and subsequent HPLC analysis according to
Example 1 delivered a ratio of the amide (IX A) to the amide (IX) of 2.4 to
97.6. The
enantiomeric excess of the Mannich base (I) in the malate salt (III) was
therefore
95.2% ee.
CA 02484685 2004-11-03
92
Example 7:
Classical optical resolution of rac.-(I) [R' = o-nitrophenyl, R2 = 2-pyridyl,
R3 = H,
R4 = 2-pyridyl, R5 = phenyl] using (-)-di,O,O'-pivaloyl-D-tartaric acid [(-)-
DPTA] in
acetone
6 ml of acetone were added to 506.2 mg (1.19 mmol) of rac.-(I) from Example 3
and
379.2 mg (1.19 mmol, 1.00 equiv.) of (-)-DPTA. The reaction mixture was
magnetically stirred in. a tightly sealed flask at 25 C for 20 hours, and the
precipitate
was filtered off with suction and dried under reduced pressure. 557 mg of the
corresponding DPTA salt (III) were obtained which, according to 'H NMR,
consisted
of Mannich base (I) and DPTA in a ratio of 1:0.57. Derivatization of a sample
with (-)-
camphanoyl chloride and subsequent HPLC analysis according to Example 1
delivered a ratio of the amide (IX A) to the amide (IX) of 97.6 to 2.4. The
enantiomeric
excess of the corresponding Mannich base (I) in the DPTA salt (III) was
therefore
95.2% ee.
Example 8:
Attempted classical optical resolution of rac.-(I) [R' = o-nitrophenyl, R2 = 2-
pyridyl,
R3 = H, R4 = 2-pyridyl, R5 = phenyl] using (S)-(+)-mandelic acid in ethanol
6 ml of ethanol were added to 500 mg (1.18 mmol) of rac.-(I) from Example 3
and
358.5 mg (2.36 mmol, 2.00 equiv.) of (S)-(+)-mandelic acid. The reaction
mixture was
magnetically stirred in a tightly sealed flask at 20-25 C for 18 hours, and
the
precipitate was filtered off with suction, washed with a little ethanol and
dried under
reduced pressure. 590 mg (1.02 mmol) of the corresponding mandelate salt (III)
were
obtained. HPLC analysis according to Example 1 delivered a ratio of the amide
(IX A)
to the amide (IX) of 47.9 to 52.1. The enantiomeric excess of the Mannich base
(I) in
the mandelate salt (Ill) was therefore only 4% ee.
Example 9:
Synthesis of the imine (X) from the aldehyde (IV) and the amine (V)
[R' = o-nitrophenyl, R2 = 2-pyridyl]
CA 02484685 2010-09-08
93
50 ml of toluene are added to 9.97 g (106 mmol) of 2-aminopyridine, 15.12 g
(100 mmol) of 2-nitrobenzaldehyde and 190.3 mg (1 mmol) of 4-toluenesulfonic
acid
monohydrate, and the reaction mixture is heated to reflux for 1 h under
nitrogen while
azeotropically distilling off the toluene/water azeotrope on a water
separator. The
mixture is then cooled to room temperature and the corresponding imine (X)
where
R' = o-nitrophenyl and R2 = 2-pyridyl crystallizes out. The product is
filtered off with
suction and dried under reduced pressure. 18.2 g (80 mmol, 80% of theory) of
yellow
crystals are obtained. According to 'H NMR (300 MHz, CDCI3; measured
immediately
after dissolution), 80% of the product is the imine (X) [S = 7.24 (m, 1 H),
7.38 (d, 1 H),
7.63 (td, 1 H), 7.70 - 7.83 (m, 2H), 8.06 (dd, 1 H), 8.36 (dd, 1 H), 8.53 (dm,
1 H), 10.28
(s, 1 H)] and 10% each are the reactants 2-aminopyridine and 2-
nitrobenzaldehyde.
IR (KBr): v = 1513 (s), 1435 (m), 1352 (m), 1339 (s), 788 (m) cm''. MS (DCI):
C12H9N302 (M = 227), m/z = 228 (100%, M + H+).
Example 10:
Synthesis of the aminal (XI) from the aldehyde (IV) and the amine (V)
[R' = o-nitrophenyl, R2 = 2-pyridylj
9.97 g (106 mmol) of 2-aminopyridine and 15.12 g (100 mmol) of 2-
nitrobenzaldehyde are dissolved under nitrogen in 53 ml of dichloromethane in
a
250 ml four-neck round-bottom flask equipped with a precision glass stirrer,
thermometer, water separator and reflux condensor, and the internal
temperature
falls to 12 C. 1.5 g of strongly acidic ion exchanger (Amberlite IR 120,
Merck) are
introduced and the reaction mixture is then heated to reflux at a bath
temperature of
75 C. In the water separator, approx. 1.5 ml of water collect (theory: 1.8 ml
from the
reaction plus 0.8 ml from the ion exchanger). After 5.5 hours, no more water
separation can be discerned. When the stirrer is switched off, a clear
solution which
is hardly any darker than the original reactant solution can be seen above the
settled
ion exchange resin. After standing at RT overnight, a considerable amount of
yellow
crystals have precipitated. The suspension is heated to reflux and sufficient
dichioromethane is added (approx. 100 ml) to just completely dissolve the
crystals in
the heat of boiling. The batch is hot-filtered through a fluted filter in
order to remove
the ion exchanger. The filtrate is admixed with 250 ml of toluene and the
dichioromethane is evaporated off under reduced pressure (beginning: 400 mbar,
CA 02484685 2004-11-03
94
end: 100 mbar) at a bath temperature of 40 C. Toward the end of the
concentration,
a pale yellow solid precipitates out. Improvement of the vacuum to 15 mbar
then
removes 2/3 of the toluene. The suspension is stored tightly sealed in a
refrigerator at
approx. 0 C overnight, which completes the crystallization of the product. The
solid is
filtered off with suction, washed with 20 ml of cold toluene and dried under
reduced
pressure at 40 C. 14.50 g (45.1 mmol, 45.1 % of theory) of pale yellow solid
are
obtained, melting point 134-135 C, after a further recrystallization from
toluene,
melting point 140-142 C. 1H NMR (300 MHz, DMSO-d6): 8 = 6.53 (tm, 2H), 6.58
(d,
2H), 7.20 (d, 2H), 7.30 - 7.44 (m, 3H), 7.53 (td, 1 H), 7.67 (td, 1 H), 7.78
(dt, 1 H), 7.88
(d, 1 H), 7.94 (m, 2H). IR (KBr): v = 3227 (m), 3074 (m) and 3020 (m), 1599
(s), 1576
(m), 1532 (s), 1459 (m), 1435 (s), 1320 (m), 1149 (m), 771 (m) cm 1. MS (DCI):
C17H15N502 (M = 321), m/z = 228.1 (100%, M + H+ - aminopyridine), 94.8
(aminopyridine).
Example 11:
Recovery of (S)-(+)-mandelic acid from the aqueous mother liquor of the
liberation of
Mannich base (I) from a Mannich salt of the formula (III) [R1 = o-nitrophenyl,
R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl, HY* = (S)-(+)-mandelic
acid]
The Mannich base (I) having the substituents specified in the title was
liberated from
256.5 g (445.0 mmol) of the corresponding Mannich salt (III) in 1280 ml of
water and
128 ml of ethanol using 222.0 ml of 2 N sodium hydroxide solution (444.0 mmol)
at
pH-stat 8.5, filtered off with suction, washed with 3 x 150 ml of water and
dried under
reduced pressure to obtain 188.52 g of (I) (444.1 mmol, 99.8% of theory).
The yellow aqueous mother liquor (pH 7.62) which had previously stood at room
temperature for 5 days was washed initially with 2 x 250 ml of methyl tert-
butyl ether,
then with 250 ml of ethyl acetate. The washing phases mentioned were all
distinctly
yellow, and after concentrating to dryness under reduced pressure, contained
0.21 g,
0.06 g and 0.04 g of residue, and were all discarded. The aqueous mother
liquor
(pH 7.83) which was now only very pale yellow was adjusted to the pKa value of
mandelic acid (pH 3.85) (calibrated glass electrode) using 12 ml of 37%
hydrochloric
acid. The solution became cloudy, but no mandelic acid precipitated out.
Extraction
was effected using 500 ml of ethyl acetate. After concentrating to dryness
under
reduced pressure, this "extract 1" comprised 14.10 g (92.67 mmol, 20.8% of
theory)
CA 02484685 2004-11-03
of residue. A further 19 ml of 37% hydrochloric acid were then added dropwise
to the
aqueous phase with stirring which resulted in the pH falling from 4.2 to 2.44
and
cloudiness occurring again. Extraction was effected using 500 ml of ethyl
acetate.
After concentrating to dryness under reduced pressure, this "extract 2"
comprised
5 29.57 g (194.35 mmol, 43.7% of theory) of residue. 18.5 ml of 37%
hydrochloric acid
were added dropwise to the aqueous phase with stirring, which resulted in the
pH
falling from 2.99 to 1.08. Extraction was effected using 500 ml of ethyl
acetate. After
concentrating to dryness under reduced pressure, this "extract 3" comprised
12.62 g
(82.94 mmol, 18.6% of theory) of residue. The aqueous phase (pH 1.4) was
extracted
10 once more with 500 ml of ethyl acetate. After concentrating to dryness
under reduced
pressure, this "extract 4" comprised 3.71 g (24.38 mmol, 5.5% of theory) of
residue.
The melting points (DSC measurements) of all four residues (extracts 1 to 4)
were
from 133.2 C to 133.5 C. According to 1H NMR spectra (400 MHz, DMSO-d6), all
four
residues consisted of mandelic acid of high purity. A sample of each residue
was
15 derivatized to the methyl ester with a solution of diazomethane in diethyl
ether, and
analyzed by GC to find the enantiomeric excess using a capillary column with a
chiral
phase [50 m x 0.25 mm ID fused silica capillary column coated with 0.25 Jim of
Lipodex-E (Ser. No. 723369, column No. 20174-32). Oven temperature: 115 C
isothermal, injector: 200 C, detector: 220 C, flow rate: 2.0 ml of He/min.
Split: 1:100.
20 The retention time of the (S)-(+)-mandelic acid (as the methyl ester) was
24.73 min. A
racemic comparative sample was used to determine that the retention time of
(R)-(-)-
mandelic acid (as the methyl ester) was 25.90 -min]. In none of the residues
(extracts
I to 4) could (R)-(-)-mandelic acid be detected. A total of 60.0 g (394.35
mmol, 88.6%
of theory) of (S)-(+)-mandelic acid were therefore recovered at 100% ee.
25 For a recovery of (S)-(+)-mandelic acid on the industrial scale, there is
thus the
possibility of continuously extracting the aqueous mother liquor, for example
in a
countercurrent process with, for example, ethyl acetate, by maintaining the pH
within
the range from 2.5-1.0 by continuously adding 37% hydrochloric acid.
30 Example 12:
Synthesis and isolation of the mixture of oxaborinanes having the main
component of
the formula (C) [R1 = o-nitrophenyl, R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl,
R5 = phenyl]
CA 02484685 2004-11-03
96
In a 250 ml four-neck flask equipped with precision glass stirrer, internal
thermometer
and septum, the suspension of 6.37 g (15 mmol) of a Mannich base (I) [R1 = o-
nitrophenyl, R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl] in 75 ml of
toluene
was cooled to an internal temperature of +1 C using an ice bath. Within 2
minutes,
4.47 ml (45 mmol, 3.0 equiv.) of borane-dimethyl sulfide (95% in dimethyl
sulfide)
were added via a syringe which resulted in a maximum internal temperature
increase
of +3 C. The cooling bath was removed and the suspension heated to +18 C
within
minutes. The light yellow suspension was stirred vigorously at this
temperature for
45 min.
HPLC analysis of the suspension [injection of 8.0,u1 of a solution in
acetonitrile onto a
250 x 4 mm steel column. Nucleosil 100-5 C18, 5 Nm, flow rate 1..0 ml/min.,
det.
254 nm, eluent A: water (900 ml)/acetonitrile (100 mI)/trifluoroacetic acid
(1.00 ml),
eluent B: water (100 ml)/acetonitrile (900 ml)/trifluoroacetic acid (0.75 ml);
elution with
a linear gradient: 0-2 min (75% A, 25% B), 22-26 min (35% A, 65%.B), 27 min
(75%
A, 25% B)] showed that all but 2% of the Mannich base (I) had reacted ((I) and
the
retro-Mannich products forming on the column give a broad peak having
shoulders at
tret 3-4 min). In addition to the toluene peak (tret 20.8 min), several minor
peaks and
3% of the 1,3-amino alcohol (Il) (tret 12.4 min), two peaks of relatively long
retention
time were detected ("peak 1" tret 25.5 min, "peak 2" tret 28.6 min) whose
total peak
area amounted to 93% of all peaks (apart from toluene). Between these two
peaks,
the base line was not reached again (remains on a plateau) which implies a
conversion of the compound "peak 1" to the compound "peak 2" on the column.
The suspension was cooled to +5 C and rapidly admixed with 5 ml of water, then
stirred at RT for 5 min. The suspension was filtered via a Buchner funnel. The
very
pale yellow solid was washed with toluene (2 x 10 ml) and dried at +45 C/150
mbar
under nitrogen. 6.22 g (14.26 mmol based on the formula (C), 95% of theory) of
colorless powder were obtained.
In DSC, this powder showed a weak endothermic peak at 104.6 C (-9.5 J/g) and a
very strongly exothermic (1718 J/g) decomposition peak at 166.8 C (onset at
157 C).
CA 02484685 2004-11-03
97
For "peak 1", HPLC-MS (API positive) gave M+H+: m/z = 437.3 which corresponds
to
the empirical formula C25H21BN4O3 (molecular weight 436.28) of the formula
(C). For
"peak 2", the following mass peaks were detected: m/z= 488.3, 449.2 and 439.3.
This
is possibly the boric acid adduct of the 1,3-amino alcohol (II) [C25H22N403 x
H3BO3,
molecular weight 488.3]. Boric acid and amino alcohol (II) are the expected
hydrolysis
products of the oxazaborinane (C) in aqueous acidic medium.
Finally, a sample of the colorless powder (C) is solvolyzed using 3.0 equiv.
of
methanesulfonic acid in an excess of methanol at +20 C. HPLC analysis of the
reaction mixture showed the virtually complete disappearance (< 1 %) of "peak
1" and
"peak 2" with simultaneous continuous growth of the peak of the amino alcohol
(II)
(94%) and its diastereomer dia-(Il) (tret 8.2 min, 4%). A similar workup to
Example 19
delivered the dihydrochloride of the pure amino alcohol (II) (100% ee, 99.5%
de) in a
yield of 75% of theory.
Example 13:
Synthesis of the optically active Mannich salt of the formula (III) [R1 = o-
nitrophenyl,
R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl] by four-component
coupling with
dynamic optical resolution at room temperature; monitoring of the variation of
ee with
time (Table 1); use of (+)-dipivaloyltartaric acid as the chiral auxiliary [HY
= DPTA] and ethanol as solvent (Table 2, No. 5):
60 ml of ethanol (denatured with toluene) were initially charged with stirring
into a
100 ml three-neck round-bottom flask equipped with a precision glass stirrer,
nitrogen
feed and bubble counter, and 4,63 g (23.5 mmol, 1.00 equiv.) of 2-
pyridylmethyl
phenyl ketone, 2.77 g (29.4 mmol, 1.25 equiv.) of 2-aminopyridine, 4.26 g
(28.2 mmol, 1.20 equiv.) of 2-nitrobenzaldehyde and 7.48 g (23.5 mmol, 1.00
equiv.)
of (+)-dipivaloyltartaric acid were introduced in succession. After approx. 10
min, a
clear, yellow solution was formed which began to become cloudy approx. 15 min.
later. Seed crystals (10 mg) of enantiomerically pure (+)-DPTA salt were added
which
resulted in a yellow suspension which was stirred at room temperature under a
nitrogen atmosphere for 14 days. At each of the times visible from Table 1,
small
aliquots of the reaction suspension were withdrawn, the solids contained
therein were
separated from the mother liquor by microfiltration and derivatized with (-)-
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camphanoyl chloride as described in Example 1, and analyzed by means of HPLC.
The variation of ee with time observed is reported in Table 1. On the 14th
day, the
ratio of the desired enantiomer to the undesired enantiomer was 97.67:2.33,
corresponding to 95.34% ee. The suspension which was now white was filtered,
and
the filter residue was washed with the mother liquor and then twice with 10 ml
of
ethanol each time. The solid was dried at 45 C under high vacuum for 2 hours.
11.45 g (9.81 mmol, 83.6% of theory) of the white salt were obtained which,
according to 'H NMR and titration contained two Mannich base cations per DPTA
dianion. It can be estimated that the actual yield was distinctly above 90% of
theory,
since the 10 intermediate sample withdrawals consumed significant amounts of
product.
Example 14:
Synthesis of the optically active Mannich salt of the formula (III) [R' = o-
nitrophenyl,
R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl] by four-component
coupling with
dynamic optical resolution at +40 C. Use of (+)-dipivaloyltartaric acid as the
chiral
auxiliary [HY* = (+)-DPTA] and ethanol as solvent (Table 2, No. 6):
In a 250 ml four-neck round-bottom flask equipped with a precision glass
stirrer,
nitrogen feed, and reflux condensor with bubble counter, 5.06 g (25.65 mmol,
1.00 equiv.) of 2-pyridylmethyl phenyl ketone were dissolved in 60 ml of
absolute
ethanol. Within 10 min, 2.99 g (31.76 mmol, 1.24 equiv.) of 2-aminopyridine,
4.61 g
(30.53 mmol, 1.19 equiv.) of 2-nitrobenzaldehyde and 8.08 g (25.38 mmol,
0.99 equiv.) of (+)-DPTA were added in succession at an internal temperature
of
40 C, and each addition was effected after waiting for just the, amount of
time
required for the solid to go completely into solution. A clear yellow solution
was
obtained which transformed into a yellow suspension after 25 min. The reaction
mixture was then stirred at 40 C overnight. Samples taken intermediately and
derivatized showed that the enantiomeric excess of the solid was 55.7% ee
after 4.16
hours and 93.0% ee after 20 hours. After 23 hours, the heating bath was
removed
and the suspension cooled to 23 C within 15 minutes, and the precipitate was
filtered
off with suction, washed twice with 10 ml of ethanol and then dried at 45 C
under
high vacuum. 14.89 g (12.76 mmol, 25.52 mmol of the Mannich base (I)
containing
the substituents specified in the title, 99.5% of theory) were obtained as a
very pale
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yellow solid. According to 1H NMR and titration, the salt consisted of (I) and
DPTA in
a ratio of 2:1. The enantiomeric excess was 95.9% ee.
Example 15:
Synthesis of the optically active Mannich salt of the formula (III) [R1 = o-
nitrophenyl,
R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl] by four-component
coupling with
dynamic optical resolution at +60 C. Use of (S)-(+)-mandelic acid as the
chiral
auxiliary [HY* = (+)-MDLA] and ethanol as the solvent (Table 3, No. 7):
In a 2 liter jacketed reactor (connected to a circulation thermostat) equipped
with a
temperature sensor and mechanical turbine stirrer, 97.2 g (492.8 mmol, 1.00
equiv.)
of 2-pyridylmethyl phenyl ketone were dissolved in 1200 ml of ethanol
(denatured
with methyl ethyl ketone) at room temperature. Over the course of 15 min, the
internal temperature was increased to 40 C. At this temperature, 55.66 g
(591.4 mmol, 1.20 equiv.) of 2-aminopyridine, 89.37 g (591.4 mmol, 1.20
equiv.) of 2-
nitrobenzaldehyde and 149.96 g (985.6 mmol, 2.00 equiv.) of (S)-(+)-mandelic
acid
were added in succession. Immediately afterwards, the internal temperature of
the
reaction mixture was increased to 60 C and a clear solution was obtained. This
heating procedure lasted 30 min., and 15 min. later, the first precipitate
formation
could be observed. Sample withdrawal/derivatization/HPLC analysis according to
Example 1 allowed an enantiomeric excess of the precipitate of 91.5% ee after
2 h,
93.0% ee after 3.5 h and 94.4% ee after 4.5 h to be determined. The reaction
mixture
was cooled to 20 C within 2 h. The precipitate was filtered off with suction,
washed 3
times with 50 ml of ethanol, and then dried at 40 C under a vacuum of 50 mbar
to
constant weight. 262.4 g (455.2 mmol, 92.4% of theory) of the mandelate salt
(III)
with the substituents specified in the title were obtained. The melting point
was
153-154 C. According to 1H NMR, it contained the corresponding Mannich base
(I)
and mandelic acid in a ratio of 1:1. The enantiomeric purity was 94.4% ee by
derivatization with camphanoyl chloride and 97.5% ee by the more exact method
of
pivaloyl derivatization according to Example 2.
Example 16:
Synthesis of the optically active Mannich salt of the formula (lll) [R' = o-
nitrophenyl,
R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl] by four-component
coupling with
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dynamic optical resolution at +40 C. Use of (S)-(+)-mandelic acid as the
chiral
auxiliary [HY* = (+)-MDLA] and acetone as the solvent (Table 3, No. 20):
In a 2 liter jacketed reactor (connected to a circulation thermostat) equipped
with a
temperature sensor and mechanical turbine stirrer, 97.2 g (492.8 mmol, 1.00
equiv.)
of 2-pyridylmethyl phenyl ketone were dissolved at room temperature in 1200 ml
of
acetone. Over the course of 15 min, the internal temperature was increased to
40 C.
At this temperature, 55.66 g (591.4 mmol, 1.20 equiv.) of 2-aminopyridine,
89.37 g
(591.4 mmol, 1.20 equiv.) of 2-nitrobenzaldehyde and 149.96 g (985.6 mmol,
2.00 equiv.) of (S)-(+)-mandelic acid were added in succession which resulted
in a
clear solution which was stirred further at 40 C. After 4.5 h, the first
formation of
precipitate could be detected. After 24 h, sample
withdrawal/derivatization/HPLC
analysis according to Example 1 gave a 97.0% ee of the precipitate. The
suspension
was cooled to an internal temperature of 25 C within 2.5 h. The suspension was
filtered off with suction, washed 3 times with 50 ml of acetone and dried at
40 C
under a vacuum of 50 mbar. 250.4 g (434.4 mmol, 88.2% of theory) of the
mandelate
salt (III) with the substituents specified in the title were obtained as an
almost
colorless solid having a melting point of 156-158 C. According to 'H NMR, it
contained the corresponding Mannich base (I) and mandelic acid in a ratio of
1:1.
The enantiomeric purity was 95.7% ee by derivatization with camphanoyl
chloride
(Example 1) and 97.0% ee by the more exact method of piv-derivatization
(Example 2).
Example 17:
Synthesis of the optically active Mannich salt of the formula (III) [R' = o-
nitrophenyl,
R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl] by coupling with Schiff
base
preformed in situ with dynamic optical resolution at 40 -60 C; use of (S)-(+)-
mandelic
acid as the chiral auxiliary [HY = (+)-MDLA] and n-butyl acetate as the
solvent
(Table 3, No. 23):
In a 1 liter four-neck round-bottom flask equipped with a water separator with
fitted
reflux condenser, precision glass stirrer, nitrogen feed and vacuum
connection, the
solution of 25.87 g (275 mmol) of 2-aminopyridine and 37.75 g (250 mmol) of
2-nitrobenzaldehyde in 500 ml of n-butyl acetate was heated to reflux at 100
mbar
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and a bath temperature of 70 C (50-60 C internal temperature) which resulted
in
approx. 4.7 ml of water separating in the water separator within 2.2 h.
The mixture was then left to stand overnight at 22 C under a nitrogen
atmosphere.
49.2 g (250 mmol) of 2-pyridylmethyl phenyl ketone were then added with
stirring
and, once it had all dissolved, 45.6 g (300 mmol) of (S)-(+)-mandelic acid
were added
and heated to an internal temperature of 40 C. Precipitate formation was
observed
after 5 min. After 3 h at 40 C, further heating was effected to 60 C and
stirring was
continued at this temperature for 24 h. The suspension was cooled to 25 C with
stirring, and the precipitate was filtered off with suction, washed twice with
50 ml of
n-butyl acetate and dried at 50 C under reduced pressure. 134.6 g (233.4 mmol,
93.4% of theory) of the mandelate salt (III) with the substituents specified
in the title
were obtained. According to 1H NMR, it contained the corresponding Mannich
base
(I) and mandelic acid in a ratio of 1:1. The enantiomeric purity was 95.4% ee
by
derivatization with camphanoyl chloride (Example 1) and 98.0% ee by the more
exact
method of pivaloyl derivatization (Example 2).
Example 18:
Typical procedure for Table 8: diastereoselective reduction of the optically
active free
Mannich base (I) [R1 = o-nitrophenyl, R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl,
R5 =
phenyl, corresponding to a compound of the formula (XVII)] to the
enantiomerically
pure 1,3-amino alcohol (XIX) and subsequent workup (Table 8, No. 29):
In a 500 ml four-neck flask equipped with a precision glass stirrer, dropping
funnel
and internal thermometer, 21.39 g (50.39 mmol, 1.0 equiv.) of the Mannich base
(XVII) (chem. purity > 99%, 95.6% ee, 0.36% of H2O) were suspended in 160 ml
of
toluene under a nitrogen atmosphere and cooled using an ice bath to an
internal
temperature of +1 C. At this temperature, 10.18 g (125.97 mmol, 2.5 equiv.)
of
borane-dimethyl sulfide complex (94% in dimethyl sulfide) were added dropwise
within 25 min, and the internal temperature rose to +2 C. Once addition had
been
completed, the mixture was heated to +20 C within 30 min and stirred further
at this
temperature which resulted in the yellow suspension turning beige. Reaction
monitoring after 15 min (HPLC as in Example 12) indicated the virtually
complete
consumption of (XVII) with the formation of an equilibrium of the
corresponding
oxazaborinanes of the general formula (C) and oligomers thereof. After a total
stirring
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time of 1.5 h at 20 C, 70 ml of methanol were added dropwise within 10 min at
an
internal temperature of the reaction mixture of between +15 C and +22 C with
ice
bath cooling. During this addition, gas development was observed. 6.5 ml
(100.78 mmol, 2.0 equiv.) of methanesulfonic acid were then added dropwise
within
10 min at an internal temperature of +20 C with ice cooling, and vigorous gas
development and exothermicity was observed. Toward the end of the addition, a
yellow solution was formed which was stirred at average to high speed at an
internal
temperature of +40 to +45 C. After a stirring time of 1.25 h, reaction
monitoring by
HPLC at 254 nm indicated a total of 6.1 % of "retro-Mannich" decomposition
products,
complete disappearance of the intermediate oxazaborinanes and a
diastereoselectivity of the reduction of 94.3:5.6. After a total of 1.75 h at
40-45 C, the
mixture was concentrated on a rotary evaporator at a bath temperature of +40
C/350
to 150 mbar to remove 78 ml of distillate (methanol, trimethyl borate, some
toluene).
The resulting biphasic mixture (toluene and separated yellow oil) were admixed
with
30 ml of 2N hydrochloric acid and extracted. The yellow, aqueous acidic phase
was
removed and the toluene phase re-extracted with 5 ml of 2N hydrochloric acid
plus
10 ml of water. According to HPLC, the toluene phase then contained no more
product (XIX) and was discarded. The combined aqueous acidic product-
containing
aqueous phases were dissolved in 200 ml of 1-butanol and admixed at an
internal
temperature of +20 C within 10 min with 95 ml (190 mmol, 3.77 equiv.) of 2N
sodium
hydroxide solution in a 500 ml four-neck flask equipped with a precision glass
stirrer
and dropping funnel to obtain an orange-yellow emulsion which was stirred for
a
further 5 min. The product-containing, orange-yellow butanol phase (upper) was
removed from the colorless, clear aqueous phase (lower, pH 10), and 85 ml of 1-
butanol/water were distilled off azeotropically on a rotary evaporator at a
bath
temperature of +50 C and from 250 to 45 mbar. The resulting concentrated
solution
of (XIX) in butanol was heated under nitrogen in a 500-ml four-neck flask
equipped
with a precision glass stirrer, dropping funnel and internal thermometer to an
internal
temperature of +45 C, and admixed within 5 min with 11.1 ml (110 mmol, 2.18
equiv.)
of 30% hydrochloric acid via the dropping funnel which resulted in an internal
temperature rise to +48 C and a yellow solution. This solution was cooled to
an
internal temperature of +20 C within 1 h, which resulted in the onset of the
crystallization of the white dihydrochloride and the formation of a pasty
suspension.
The mixture was then further cooled to +5 C within 10 min and stirred for a
further
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15 min at this temperature. The viscous suspension was then filtered via a
Buchner
funnel to obtain a white filter cake and a yellow filtrate. The filter cake
was washed
with 2 x 20 ml of 1-butanol, suction-dried and then dried in a vacuum drying
cabinet
at 40 C/100 mbar. 20.22 g (40.48 mmol calculated as (XIX) - 2 HCI) of white
crystalline solid were obtained. According to HPLC, it contained 99.8% of
(XIX) and
< 0.1 % of the diastereomer dia-(XIX). The enantiomeric purity was 100% ee.
According to titration (acid/base and also chloride titration) and 1H NMR,
(XIX) was
present as the dihydrochloride. According to 1H NMR, 11.5% by weight
(corresponding to 87.5 mol%) of 1-butanol were present. Even on extended
drying at
40-50 C under high vacuum, the butanol could not be removed. This behavior was
observed in all dihydrochlorides of Table 8 which had been precipitated from 1-
butanol. The butanol contents were without exception 85-97 mol%, so that the
product may be regarded as the monobutanol solvate of (II)-dihydrochloride.
The
yield was 80.3% of theory when the product weight was calculated as (XIX)-
dihydrochloride neglecting the butanol content and is based on the weight of
the
reactant (XVII) used without taking into account its incomplete enantiomeric
purity
(93.4% ee) [known as the telquel yield].
Example 19:
Diastereoselective reduction of the optically active free Mannich base (I) [R1
= o-.
nitrophenyl, R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl,
corresponding to a
compound of the formula (XVII)] to the enantiomerically pure 1,3-amino alcohol
(XIX);
use of borane-dimethyl sulfide complex as the reducing agent according to
Table 8,
No. 33; optimized workup.
In a 1 1 four-neck round-bottom flask equipped with a precision glass stirrer,
dropping
funnel and internal thermometer, 63.63 g (150 mmol, 1.0 equiv.) of the Mannich
base
(XVII) (chem. purity > 99%, 93.4% ee, 0.02% of H2O) were suspended under a
nitrogen atmosphere in 400 ml of toluene and cooled to an internal temperature
of
+1 C using an ice bath. At this temperature, 31.60 g (391.1 mmol, 2.6 equiv.)
of
borane-dimethyl sulfide complex (94% in dimethyl sulfide) were added dropwise
within 15 min which resulted in an internal temperature rise to +4 C. Once
addition
had been completed, the mixture was heated to +20 C within 30 min and then
stirred
further at this temperature which resulted in the yellow suspension turning
beige.
CA 02484685 2004-11-03
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Monitoring of the reaction after 2.5 h (HPLC system as in Example 12)
indicated the
virtually complete consumption of (XVII) with the formation of an equilibrium
of
oxazaborinanes. After a total stirring time of 4 h at 20 C, 190 ml of methanol
were
added dropwise within 10 min at an internal temperature of the reaction
mixture
between +15 C and +22 C with ice bath cooling. During this addition, gas
development was observed. 31.1 ml (478.9 mmol, 3.19 equiv.) of methanesulfonic
acid were then added dropwise within 20 min, likewise within an internal
temperature
interval of from +15 C to +22 C, and vigorous gas development was observed.
Once
2/3 of the total amount of acid had been introduced, a yellow solution was
obtained.
Once addition had been completed, the dropping funnel was rinsed using a
further
53 ml of methanol and stirring was continued at from +20 C to +22 C. After a
stirring
time of 1 h, HPLC reaction monitoring at 254 nm indicated a total of 5.4% of
Mannich
base (XVII) and "retro-Mannich" decomposition products, 5.3% of dia-(XIX) and
88.4% of (XIX), and also complete disappearance of the intermediate
oxazaborinanes. The diastereoselectivity in the crude reaction solution was
therefore
94.4:5.6. The mixture was stirred overnight at room temperature (internal
temperature
of +18 - +22 C) and concentrated the next day on a rotary evaporator at a bath
temperature of +40 C and from 400 to 150 mbar to a final volume of 380 ml to
remove methanol, trimethyl borate and some of the toluene. The resulting
biphasic
mixture was admixed with 212 ml of water at an internal temperature of from
+10 C
to +25 C. After stirring had been continued for 5 min, there was a phase
separation.
The toluene phase was discarded. The yellow, acidic product-containing aqueous
phase (approx. 330 ml) was dissolved in 303 ml of 1-butanol and admixed within
10 min with 61.72 g (509.2 mmol, 3.39 equiv.) of 33% sodium hydroxide solution
at
an internal temperature of from +10 C to +15 C in a 1 1 four-neck flask
equipped with
a precision glass stirrer and dropping funnel to obtain an orange-yellow
emulsion.
Once the addition was complete, the mixture was stirred for a further 5 min.
The
product-containing, orange-yellow butanol phase (approx. 390 ml, upper) was
removed from the virtually colorless clear aqueous phase (lower, approx. pH 9)
and
concentrated on a rotary evaporator at a bath temperature of +50 C and from
300 to
50 mbar to such an extent that 115 ml of distillate (1-butanol/water) were
azeotropically removed. The resulting concentrated solution of (XIX) in
butanol was
heated to an internal temperature of +49 C under nitrogen in a 500 ml four-
neck flask
equipped with a precision glass stirrer, dropping funnel and internal
thermometer and
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admixed within 5 min via the dropping funnel with 39.24 g (322.9 mmol, 2.15
equiv.)
of 30% hydrochloric acid which resulted in an internal temperature rise to +53
C and
a yellow solution. This solution was cooled to an internal temperature of +20
C within
15 min which resulted in the onset of crystallization of the white
dihydrochloride and
the formation of a pasty suspension. After a stirring time of 30 min at +20 C,
the
mixture was cooled to +1 C within 30 min and stirred at this temperature for
a further
1 h. Filtration was then effected through a Buchner funnel to obtain a white
filter cake
and a yellow filtrate. The filter cake was washed with 2 x 60 ml of 1-butanol,
suction-
dried and then dried in a vacuum drying cabinet under a gentle nitrogen stream
at
40 C and 50 mbar. 62.7 g (125.55 mmol) of (XIX) - 2 HCI were obtained as a
white
crystalline solid. According to HPLC, it contained 99.68% of (XIX) and 0.14%
of the
diastereomer dia-(XIX). The enantiomeric purity was 100% ee. According to
titration
and 1H NMR, (XIX) was present as dihydrochloride. According to 'H NMR, 11.5%
by
weight (corresponding to 87.5 mol%) of 1-butanol were present. The yield was
83.7%
of theory when the product weight (62.7 g) is calculated as (XIX)-
dihydrochloride
neglecting the butanol content and is based on the weight of the reactant
(XVII) used
without taking into account its incomplete enantiomeric purity (93.4% ee)
[known as
the telquel yield]. When the butanol content of (XIX)-dihydrochloride is taken
into
account, and the racemic proportion (6.6%) of the reactant (XVII) used which
had
been removed in the workup is subtracted, then the yield was 79.4% of theory.
When
the yield corrected for butanol is based on the all the reactant (XVII), then
the yield
was 74.1 %.
Example 20:
Diastereoselective reduction of the optically active free Mannich base (I) [R1
= o-
nitrophenyl, R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl,
corresponding to a
compound of the formula (XVII)] to the enantiomerically pure 1,3-amino alcohol
(XIX)
with borane generated in situ from chlorotrimethylsilane and sodium
borohydride
(Table 8, No. 34)
In a 500 ml four-neck round-bottom flask equipped with a precision glass
stirrer,
reflux condenser, internal thermometer and septum, 1.70 g (45.0 mmol, 3.0
equiv.) of
sodium borohydride were suspended in 215 ml of tetrahydrofuran. After adding
4.89 g (45.0 mmol, 3.0 equiv.) of chlorotrimethylsilane (by syringe), the
suspension
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was stirred at average to high speed at an internal temperature of 50 C for 45
min,
and a finely crystalline white solid precipitated out. The suspension was then
cooled
to +1 C and admixed within 5 min with 6.36 g (15.0 mmol, 1.0 equiv.) of the
Mannich
base (XVII), which resulted in an internal temperature rise to +3 C and a pale
yellow
suspension. The mixture was heated to 20 C within 15 min and stirring was
continued at this temperature. HPLC monitoring after 30 min indicated
virtually
complete conversion of (XVII) to the oxazaborinane (C). After a total stirring
time of
2 hat 20 C, 25 ml of methanol were added dropwise to the mixture at from 10 to
C within 5 min. 3.1 ml (47.9 mmol, 3.19 equiv.) of methanesulfonic acid were
then
10 added within 5 min. The mixture was then stirred further at an internal
temperature of
C. HPLC monitoring after 15 min showed 23% of (XVII) and 72% of (C). After a
stirring time of 30 min, a further 50 ml of methanol and 3.1 ml (47.9 mmol,
3.19 equiv.) of methanesulfonic acid were added to the mixture at 20 C. The
mixture
was then stirred at an internal temperature of 40-43 C. Further HPLC
monitoring after
15 30 min indicated the complete conversion of (C) to (XIX) (85.1 %), dia-
(XIX) (5.4%),
and also (XVII) and retro-Mannich decomposition products (8.5% in total).
After a
total stirring time of 1 h at 40-43 C, the yellow suspension was filtered to
remove
salts and the filtrate fully concentrated on a rotary evaporator at 40 C and
from 400 to
20 mbar. The remaining yellow, viscous oil was stored overnight at +4 C in 50
ml of
20 water. The aqueous product phase was dissolved in 60 ml of 1-butanol in a
250 ml
four-neck round-bottom flask equipped with a precision glass stirrer, dropping
funnel
and internal thermometer under nitrogen and admixed within 5 min with 11.96 g
(98.7 mmol, 6.58 equiv.) of 33% aqueous sodium hydroxide solution at from 15
to
22 C. The orange-yellow suspension was stirred for 5 min and the yellow
butanol
phase separated from the colorless aqueous phase (pH 13-14). The butanol phase
was concentrated at 50 C and from 200 to 20 mbar to such an extent that 22 ml
of
distillate (butanol/water) were azeotropically removed. The resulting
concentrated
butanolic solution was heated to an internal temperature of 47 C in a 100 ml
four-
neck flask equipped with a precision glass stirrer, dropping funnel and
internal
thermometer under nitrogen and admixed within 5 min with 4.00 g (33.0 mmol,
2.20 equiv.) of hydrochloric acid which resulted in an internal temperature
rise to
50 C and a clear orange-red solution. This was cooled to 15 C within 15 min
which
resulted in the onset of crystallization of the white dihydrochloride and a
pasty
suspension being obtained. After a stirring time of 30 min, the mixture was
cooled
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further to 1 C within 15 min and stirring was continued at this temperature
for one
hour. The precipitate was filtered off with suction, washed twice with 10 ml
of butanol
and dried at 40 C and 50 mbar under a gentle nitrogen stream. 5.60 g (11.21
mmol,
74.8% of theory) of white solid were obtained which, according to HPLC, had
> 99% ee, and consisted of 99.6% of (XIX) and 0.2% of dia-(XIX). 'H NMR
indicated
a 1-butanol content of 12.0%. The water content (Karl-Fischer titration) was
0.99%.
The chloride titration gave 1.97 equiv. of chloride ions per mole of (XIX).
Example 21:
Liberation of the Mannich base (I) [R1 = o-nitrophenyl, R2 = 2-pyridyl, R3 =
H, R4 =
2-pyridyl, R5 = phenyl, corresponding to a compound of the formula (XVII)]
from the
mandelate salt (XVIII) [Y (S)-(+)-mandelic salt] with NaHCO3 in water/acetone
according to Table 7, No. 23:
In a 2 liter jacketed reactor (connected to a circulation cryostat) equipped
with a
temperature sensor and mechanical turbine stirrer, 228.6 g (396.6 mmol, 1.0
equiv.)
of mandelate salt (XVIII) (95.6% ee of the Mannich base (XVII) present) were
suspended at room temperature in 1143 ml of water under a nitrogen atmosphere
and with stirring. The white suspension was then cooled to an internal
temperature of
+10 C. 66.64 g (793.24 mmol, 2.0 equiv.) of sodium hydrogencarbonate were
added,
followed after 5 min by 114 ml of acetone. The suspension which was gradually
becoming yellow was stirred at an internal temperature of +10 C. The
conversion
was monitored by taking samples, filtration and 1H NMR of the solid. After 4.5
hours,
15.4% of mandelic acid were still present, and after 7.4 hours still 9.1%.
After stirring
overnight, no more mandelic acid was detected. The suspension was filtered off
with
suction and the filter cake washed 3 times with 50 ml of water each time. The
solid
was dried in a vacuum drying cabinet at 40 C and approx. 50 mbar. 168.25 g
(396.4 mmol, 99.95% of theory) of the free Mannich base (XVII) were obtained
as a
yellow powder, 96.8% ee (camph. method according to Example 1) or 96.2% ee
(piv.
method according to Example 2), m.p. 153-154 C, residual water content
according
to Karl-Fischer titration: 0.32% by weight. 1H NMR and HPLC confirm that it is
a
single compound which contains no more mandelic acid. 1H NMR also showed that
the content of the anti-diastereomer of (XVII) was less than 1 %.
CA 02484685 2004-11-03
108
Example 22:
Liberation of the Mannich base (I) [R1 = o-nitrophenyl, R2 = 2-pyridyl, R3 =
H, R4 =
2-pyridyl, R5 = phenyl, corresponding to a compound of the formula (XVII)]
from the
mandelate salt (XVIII) [Y* = (S)-(+)-mandelic acid salt] with 2N sodium
hydroxide at
pH-stat 8.5 in water/ethanol according to Table 7, No. 21
The reaction was carried out in a 10 liter jacketed reactor (connected to a
circulation
cryostat) equipped with a temperature sensor and mechanical bell stirrer to
which a
Metrohm 718 STAT-Titrino autotitrator was connected. The autotitrator was
filled with
1150 ml of 2.00 N sodium hydroxide solution, and was controlled via a glass
electrode dipping into the reaction suspension and set to the following
parameters:
maximum metering rate 20 ml/min, minimum metering rate 4 ml/min, recording
time
interval every 60 sec., pHmax 8.5. The dropping tip of the autotitrator dipped
into the
reaction suspension. The jacket temperature of the reactor was controlled in
such a
manner that the temperature of the reaction suspension was maintained within
the
20-25 C range.
At room temperature, 1311.3 g (2.274 mol, 1.0 equiv.) of mandelate salt
(XVIII)
(94.4% ee of the Mannich base (XVII) present, approx. 1.3% of the anti-
diastereomer
of (XVII)) were suspended at room temperature in 5686 ml of water under a
nitrogen
atmosphere and with stirring, and 569 ml of ethanol (denatured with methyl
ethyl
ketone) were added. The pH of the suspension (before the beginning of the
titration)
was 4.8. After switching on the titrator, the pH briefly reached a maximum of
pH 9.7.
After only 30 sec., the reaction suspension had changed in color from pale
yellow to
intense yellow. The initially high metering rate slowed appreciably with time.
After 4
hours, 92% of the theoretical amount of sodium hydroxide solution had been
metered
in. The mixture was stirred overnight under pH-stat conditions (pH 8.5). The
next
morning, the metered addition had come to a standstill. The pH of the
suspension
was 8.72 and a total of 1139.6 ml (100.2% of theory) had been added by
titration.
The suspension was filtered off with suction, and the filter cake was washed 4
times
with 500 ml of water. The solid was dried in a vacuum drying cabinet under a
nitrogen
stream at 40 C and approx. 100 mbar for 28 hours, then at 25 C and 100 mbar
for 70
hours and finally at 40 C for a further 20 hours under high vacuum (10-2
mbar).
960.9 g (2.26 mol, 99.5% of theory) of the free Mannich base (XVII) were
obtained as
CA 02484685 2004-11-03
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a fine light yellow powder, 95.6% ee (piv. method according to Example 2),
m.p. 150-
152 C, residual water content according to Karl-Fischer titration: 0.35% by
weight.
'H NMR and HPLC confirmed that it is a single compound which contains no more
mandelic acid. 1H NMR also showed that the content of the anti-diastereomer of
(XVII) was approx. 1.2%.
Example 23:
Diastereoselective reduction of the optically active mandelate salt (III) [R'
_
o-nitrophenyl, R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl, HY* = (S)-
(+)-
mandelic acid, corresponding to a compound of the formula (XVIII)] to the 1,3-
amino
alcohol (XIX) according to Table 9, No. 18; solvolysis of the oxazaborinane
using
hydrochloric acid
In a 1 1 four-neck round-bottom flask equipped with a precision glass stirrer,
dropping
funnel with fitted bubble counter, internal thermometer and nitrogen feed,
30.0 g
(52.0 mmol, 1.0 equiv.) of the mandelate salt (XVIII) (96.5% ee of the Mannich
base
(XVII) present) were suspended in 400 ml of THE and cooled to +1 C by means
of an
ice bath. 15.5 ml (156 mmol, 3.0 equiv.) of borane-dimethyl sulfide complex
(95%)
were added dropwise within 10 min under a nitrogen atmosphere at a reaction
temperature of from +1 to +3 C. Once the addition had been completed, the ice
bath
was removed and the reaction mixture brought to 23 C within 15 min, and then
stirred for a further 1.5 hours. Sample taking/HPLC analysis showed that the
conversion of (XVIII) to oxazaborinane (C) had been completed after only 1
hour. The
reaction mixture was cooled again to 1 C with the ice bath and then 25 ml of
water
were slowly added dropwise at a maximum internal temperature of 12 C. This
resulted in vigorous gas development and the solution became pale yellow.
Stirring
was continued at room temperature until gas development was complete (30 min).
A
white solid precipitated out. The THE was distilled out of the reaction
mixture at 40 C
and approx. 100 mbar. Toward the end of distillation, a full water jet vacuum
(approx.
20 mbar) was applied for 5 min. After cooling to +5 C, 200 ml (2400 mmol) of
conc.
hydrochloric acid (37%) were slowly added dropwise at a maximum internal
temperature of the reaction mixture of 20 C, and the mixture was then stirred
at 40 C
for 1 hour. The 1,3-amino alcohol (XIX) went into solution as the
hydrochloride and
boric acid precipitated out. The suspension was left to stand overnight in a
CA 02484685 2004-11-03
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refrigerator at 4 C in order to complete the crystallization. The boric acid
was filtered
off with suction and washed with 40 ml of water. After drying under reduced
pressure,
it weighed 7.23 g (116.9 mmol, 75% of theory). The acidic filtrate had a total
volume
of 250 ml. In a 1 I four-neck flask equipped with a precision glass stirrer
and dropping
funnel, 96 g (2400 mmol) of sodium hydroxide solution were dissolved in 520 ml
of
water, cooled to 13 C, and then said acidic filtrate was slowly added dropwise
within
60 min at a maximum internal temperature of 15 C. The crude 1,3-amino alcohol
(XIX) precipitated out in roughly crystalline form. The suspension was stirred
at room
temperature for a further 1 hour, and the precipitate was filtered off with
suction and
washed with 250 ml of water (the precipitate which formed when the washing
water
ran into the filtrate consisted predominantly of polar impurities and was
therefore
discarded). The crude (XIX) was dried in a vacuum drying cabinet at 40 C and
approx. 100 mbar. 20.7 g (48.54 mmol, 93.4% of theory) of pale yellow solid
was
obtained. It was suspended in 100 ml of diisopropyl ether and stirred
vigorously at
55 C for 1 hour. The solid was filtered off with suction, washed with.100 ml
of
diisopropyl ether and dried under reduced pressure at 40 C and approx. 100
mbar.
17.5 g (41.0 mmol, 78.9% of theory) of pale yellow powder were obtained which,
according to HPLC analysis, was 95% pure and contained 3.1 % of the
diastereomer
dia-(XIX) and 1.8% of by-products.
Example 24:
Diastereoselective reduction of an optically active Mannich salt (III) [R' _
o-nitrophenyl, R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl, HY* = (+)-
DPTA] to
the 1,3-amino alcohol of the general formula (II), corresponding to a compound
of the
formula (XIX) according to Table 10, No. 5; solvolysis of the oxazaborinane
with
hydrochloric acid.
In a 250 ml four-neck round-bottom flask equipped with a precision glass
stirrer,
septum, bubble counter, internal thermometer and nitrogen feed, 10.0 g (8.57
mmol;
according to 1H NMR determination of the ratio of the compound (XVII) to DPTA,
containing 16.08 mmol of (XVII); 1.0 equiv.) of the DPTA salt (III) (95.1% ee
of the
Mannich base (XVII) present) were suspended in 100 ml of THE, then cooled to
an
internal temperature of from 0 to 5 C. 7.63 ml (80.45 mmol, 5.0 equiv.) of
borane-
dimethyl sulfide complex (95%) were added dropwise within 15 min by syringe
under
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nitrogen. The ice bath was then removed and the suspension heated to room
temperature. After 20 min at room temperature, there was a clear solution.
Taking a
sample and HPLC analysis showed that (III) had been quantitatively converted
to the
oxazaborinane (C) and that only a few by-products had been formed. 45 ml of
water
were added dropwise within 15 min (gas development, vigorous foaming), which
resulted in an internal temperature rise to 40 C. 10 ml of 37% hydrochloric
acid were
added dropwise within 15 min, and then the internal temperature was increased
to
60 C. After 15 min at 60 C, HPLC analysis indicated that no more boron
compound
was present and that (XIX) had formed as the main product. 30 ml of 33% sodium
hydroxide solution were used to adjust the pH to 13, and the reaction mixture
was
then cooled to room temperature and extracted twice with 100 ml of
dichloromethane.
The combined organic extracts were evaporated to dryness under reduced
pressure
and the residue (solid foam) was dried in a vacuum drying cabinet at 40 C and
50 mbar. 8.11 g of pale yellow powder were obtained which, according to an
HPLC
assay, had a purity of 75.1 %, based on a pure reference standard of (XIX).
The yield
of (XIX) was therefore 6.09 g (14.28 mmol, 88.8% of theory). The HPLC 100%
purity
was 94.8%, the ratio of (XIX) to dia-(XIX) was 97.8:2.2, and the enantiomeric
purity
was 96.8% ee.
Example 25:
Diastereoselective reduction of an optically active Mannich salt (III) [R1 =
o-nitrophenyl, R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl, HY* = (+)-
DPTA] to
the 1,3-amino alcohol of the general formula (II), corresponding to a compound
of the
formula (XIX) according to Table 10, No. 3; solvolysis of the oxazaborinane
using
potassium hydroxide solution
In a 250 ml four-neck round-bottom flask equipped with a precision glass
stirrer,
septum, bubble counter, internal thermometer and nitrogen feed, 10.0 g (8.57
mmol;
according to 1H NMR determination of the ratio of the compound (XVII) to DPTA,
containing 16.08 mmol of (XVII); 1.0 equiv.) of the DPTA salt (III) (95.1% ee
of the
Mannich base (XVII) present) were suspended in 100 ml of THF, then cooled to
an
internal temperature of from 0 to 5 C. 7.63 ml (80.45 mmol, 5.0 equiv.) of
borane-
dimethyl sulfide complex (95%) were added dropwise within 15 min by syringe
under
nitrogen. The ice bath was removed and the reaction mixture stirred while
heating to
CA 02484685 2004-11-03
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room temperature. After 30 min, there was a clear solution. Taking a sample
and
HPLC analysis showed the complete conversion of the reactant to 91 % of
oxazaborinane and 9% of (XIX). 45 ml of water were added dropwise within 15
min,
followed by 45 ml of 20% aqueous potassium hydroxide solution within 15 min.
This
resulted in gas development, vigorous foaming and an internal temperature rise
to
40 C. The reaction mixture was heated to 60 C and the solvolysis of the
oxazaborinane to the 1,3-amino alcohol (XIX) was followed by HPLC monitoring.
After 3 hours at 60 C, the ratio (C)/(XIX) was 53.3:46.7, after 10 hours
19.4:80.6, and
after 16 hours 6.9:93.1. The solvolysis was aborted at this point and the
reaction
mixture cooled to room temperature. Extraction was effected twice with 100 ml
of
dichloromethane and the combined organic extracts were washed with 50 ml of
saturated sodium chloride solution. The dichloromethane solution was then
evaporated to dryness under reduced pressure and the residue was dried under
reduced pressure at 40 C and 50 mbar. 7.05 g of pale yellow powder were
obtained
which, according to an HPLC assay, had a purity of 77.2% based on a pure
reference
standard of (XIX). The yield of (XIX) was therefore 5.44 g (12.76 mmol, 79.3%
of
theory). The HPLC 100% purity was 93.0%, the ratio of (XIX)/dia-(XIX)
98.5:1.5, and
the enantiomeric purity 95.2% ee. 5.5% of unsolvolyzed oxazaborinane (C) were
still
present.
Example 26:
Diastereoselective reduction of an optically active Mannich salt (III) [RI _
o-nitrophenyl, R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl, HY* = (+)-
DPTA] to
the 1,3-amino alcohol of the general formula (II), corresponding to a compound
of the
formula (XIX) according to Table 10, No. 9; solvolysis of the oxazaborinane
using
methanol/methanesulfonic acid
In a 250 ml four-neck round-bottom flask equipped with a precision glass
stirrer,
septum, bubble counter, internal thermometer and nitrogen feed, 15.33 g
(13.13 mmol; according to 1H NMR determination of the ratio of the compound
(XVII)
to DPTA, containing 25.30 mmol of (XVII); 1.0 equiv.) of the DPTA salt (III)
(93.2% ee
of the Mannich base (XVII) present) were suspended in 125 ml of THF, then
cooled
to an internal temperature of from 0 to 5 C. 4.86 ml (63.94 mmol, 2.5 equiv.)
of
borane-dimethyl sulfide complex (95%) were added dropwise within 15 min by
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syringe under nitrogen. The ice bath was removed and the reaction mixture
stirred
while heating to room temperature. After 45 min, there was a clear solution.
After 2 h,
no more reactant could be detected by HPLC. At 5 C, 20.9 g of methanol were
added
dropwise within 15 min, immediately followed by 4.92 g of methanesulfonic
acid. The
yellow solution was heated to an internal temperature of 35 C and the
solvolysis of
the oxazaborinane (C) was followed by HPLC monitoring. After 4.5 h, 3.7% of
(C),
94.2% of (XIX) and 2.1 % of the diastereomer dia-(XIX) were detected. After
6.5 h at
35 C and standing of the solution overnight at room temperature, 1.8% of (C),
96.9%
of (XIX) and 1.8% of dia-(XIX) were detected. The yellow, clear solution was
evaporated under reduced pressure on a rotary evaporator to a residue of 22.95
g
(yellow oil plus solid) and dissolved in 15 ml of methanol to give a clear
solution
(ultrasound bath, 35 C). This highly concentrated methanol solution was added
dropwise within 15 min into the solution of 10 ml of 25% ammonia solution in
75 ml of
water (25 C), and (XIX) precipitated out immediately. The suspension was
stirred at
room temperature for 1 hour, then filtered off with suction. According to an
HPLC
assay against a pure reference standard of (XIX), this crude product had a
purity of
88% and a (XIX)/dia-(XIX) ratio of 98.1:1.9. It was resuspended in a solution
of 1 ml
of conc. ammonia solution in 75. ml of water and stirred vigorously at room
temperature for two hours, then filtered off with suction and dried at 45 C
and
150 mbar. 11.0 g (25.79 mmol, 101.9% of theory) of a light yellow powder
which,
according to an HPLC assay against a standard, had a purity of 96.1 % (i.e.
corrected
yield: 97.9% of theory), 93.2% ee and an unchanged (XIX)/dia-(XIX) ratio of
98.1:1.9.
This roughly purified (XIX) was stirred vigorously in 66 ml of boiling
diisopropyl ether
for 30 min, stirred for a further hour under ice bath cooling, then filtered
off with
suction and dried at 50 C under high vacuum (10"2 mbar). 9.50 g (22.28 mmol,
88.1 %
of theory) of light yellow powder were obtained which, according to an HPLC
assay
against a standard, had 97.9% purity (i.e. corrected yield: 86.2% of theory),
95.2% ee
and an (XIX)/dia-(XIX) ratio of 99.2:0.8.
Example 27:
Synthesis of the optically active Mannich salt of the formula (III) [R' = p-
tolyl, R2 =
2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl] by four-component coupling
with
dynamic optical resolution at room temperature; use of (S)-(+)-mandelic acid
as the
chiral auxiliary [HY* = (+)-MDLA)] and ethanol as the solvent:
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In a 100 ml three-neck flask equipped with a precision glass stirrer, 30 ml of
ethanol
(denatured with methyl ethyl ketone) were initially charged. At room
temperature
(22 C), 2.32 g (11.76 mmol, 1.00 equiv.) of 2-pyridylmethyl phenyl ketone,
1.40 g
(14.70 mmol, 1.25 equiv.) of 2-aminopyridine, 1.75 g (14.11 mmol, 1.20 equiv.)
of
4-tolylaldehyde and 3.65 g (23.52 mmol, 2.00 equiv.) of (S)-(+)-mandelic acid
were
added in succession under an N2 atmosphere. The mechanical stirrer was
switched
on and after a few minutes a clear yellow solution formed. After 1 h,
considerable
amounts of precipitate had formed. The suspension was stirred further at room
temperature. After 40 h and 64 h of reaction time, samples of the suspension
(each
containing approx. 50 mg of precipitate) were withdrawn and the precipitate in
it
filtered off with suction in each case. The syn/anti ratio was determined by
1H NMR
spectroscopy (measured immediately after dissolving the sample in DMSO-d6).
The
diastereomeric ratio can in principle be calculated from the integrals of a
plurality of
signals, most simply from the methyl singlet which for the syn-isomer is at
5 = 2.15 ppm, and for the antiisomer at 5 = 2.11 ppm. The optical purity of
the
Mannich base was determined by chiral phase HPLC analysis after piv.
derivatization
using the procedure described at the end of Example 27.
For both samples, the syn/anti ratio calculated from the NMR integrals was
95:5.
Taking into account the period of 3.5 min which was required after dissolving
the
sample for introducing the sample into the NMR instrument, sample shimming and
data accumulation, an original syn/anti ratio of the precipitate of > 99: < 1
is
extrapolated from the kinetics (Example 28) of the syn/anti-isomerization. In
both
cases, the molar ratio of Mannich base to mandelic acid was exactly 1:1. The
enantiomeric excess of the Mannich base was 96.0% ee in the sample after 40 h
and
97.0% ee in the sample after 64 h.
The precipitate of the reaction mixture was filtered off with suction, washed
with
mother liquor and then with a little ethanol, suction-dried and dried under
high
vacuum. 5.66 g (10.4 mmol, 88.2% of theory) of pale yellow powder were
obtained.
Taking into account the two samples taken previously (approx. 100 mg), the
yield
was 90% of theory.
1H NMR (400 MHz, DMSO-d6): 8 = 2.15 (s, 3H), 5.02 (s, 1H, CHOH of the
mandelate
anion), 5.65 (d, 1 H), 5.95 (t, 1 H), 6.32 (d, 1 H), 6.37 (t, 1 H), 6.89 (d, 1
H), 6.99 (d, 2H),
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7.20 (m, 2H), 7.25-7.48 (m, 11 H), 7.50-7.60 (m, 2H), 7.68 (td, 1 H), 7.87 (d,
2H), 7.92
(-d, 1 H), 8.46 (-d, 1 H).
13C NMR (100.62 MHz, DMSO-d6): 8 = 20.52 (CH3), 55.20 (CH), 60.55 (CH), 72.44
(CHOH of the mandelate anion), 107.84 (CH), 111.87 (CH), 119.10 (CH), 121.80
(CH), 126.60-128.70 (12 signals, CH), 133.13 (CH), 135.40 (C), 136.50 (CH),
136.63
(CH), 138.95 (C), 140.20 (C), 147.25 (CH), 148.87 (CH), 156.10 (C), 157.90
(C),
174.20 (CO2-), 196.8 (C=O).
Derivatization and ee determination:
20 l of pivaloyl chloride, followed by 10 jd of triethylamine are added to 2-
5 mg of the
Mannich salt in a Reacti-Vial . The solution is sonicated for 2 min in an
ultrasound
bath. 500 l of acetonitrile (HPLC grade) are added and 1 l of the solution
is injected
onto a Chiralpak AS 250 mm x 4.6 mm column. Isocratic elution at 25 C and
1.0 ml/min of the eluent 50% isopropanol/50% n-hexanel0.1% trifluoroacetic
acid and
UV detection at 254 nm. The main isomer (98.5%) was eluted at t(ret) 12.14
min, and
the mirror image (1.5%) at t(ret) 7.34 min. An appropriately derivatized
racemic
comparative sample delivered 50% of each peak.
Example 28:
Syn/anti-isomerization of the Mannich base mandelate from Example 26 in DMSO-
d6
solution at 300K. Kinetics and equilibrium location of the retro-
Mannich/Mannich
reactions:
8 mg of the product from Example 27 were dissolved in DMSO-d6 as rapidly as
possible in a 1H NMR tube at room temperature. The sample was immediately
introduced into the NMR instrument (400 MHz, 300.0 K), shimmed rapidly and
analyzed. The first spectrum was obtained 3.5 min after the sample
dissolution. It
showed the syn- and anti-isomers of the Mannich salt in a ratio of 95.1:4.9.
Further
spectra of the solution were each obtained at an interval of 3-4 min. They
showed a
continuous increase of the anti-isomer at the expense of the syn-isomer. The
variation can be seen from the graphics and the table of the appendix. 69 min
after
dissolution of the Mannich salt, the NMR monitoring was aborted at a syn/anti
ratio of
50:50. A repeat measurement 20.5 hours after dissolution of the Mannich salt
indicated a syn/anti ratio of 41.5:58.5. After a total of 44.5 hours, this
ratio was
unchanged. The thermodynamic equilibrium of the two isomers is thus achieved
in
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less than 20 h and the anti-isomer is preferred in solution. In contrast, the
four-
component coupling (Example 27) results in the crystallization of virtually
pure syn-
isomer, apparently owing to lower solubility. Even the spectrum obtained 3.5
min after
sample dissolution indicates (in addition to the syn- and anti-isomers of the
Mannich
salt) the presence of the retro-Mannich products 2-pyridylmethyl phenyl ketone
(formula VI; singlet at S = 4.53 ppm) and tolylaldehyde (or corresponding
imine)
(formula IV or X, singlets at 8 = 2.40 and 9.12 ppm) in small but significant
amounts.
The best fit curve between the measurement points of the graph was obtained by
3rd
order polynomial formation. Extrapolation of these curves to time t = 0 shows
that the
solid had a syn/anti ratio of > 99:< 1.
NMR Time after cis- trans-
Measurment sample isomer isomer
No. dissolution [%] [%]
[min]
1 3.5 95.1 4.9
2 6.5 92.5 7.5
3 10.5 89.0 11.0
4 13.5 85.0 15.0
5 17.5 81.7 18.3
6 20..5 77.3 22.7
7 24.5 76.8 23.2
8 27.5 71.8 28.2
9 31.5 68.0 32.0
10 34.5 66.2 33.8
11 37.5 63.8 36.2
12 41.5 61.7 38.3
13 44.5 60.1 39.9
14 48.5 58.7 41.3
51.5 56.8 43.2
16 55.5 54.5 45.5
17 58.5 53.6 46.4
18 61.5 52.9 47.1
19 65.5 52.0 48.0
68.5 50.5 49.5
21 1230 41.5 58.5
22 2670 41.6 58.4
Example 29:
15 Synthesis of the optically active Mannich salt of the formula (III) [R1 = o-
chlorophenyl,
R2 = 2-pyridyl, R3 = H, R4 = 2-pyridyl, R5 = phenyl] by four-component
coupling with
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dynamic optical resolution at room temperature; use of (S)-(+)-mandelic acid
as the
chiral auxiliary [HY* = (+)-MDLA)] and ethanol as the solvent:
In a 50 ml two-neck flask equipped with a magnetic stirrer bar, 30 ml of
ethanol
(denatured with methyl ethyl ketone) were initially charged. At room
temperature
(20 C), 2.32 g (11.76 mmol, 1.00 equiv.) of 2-pyridylmethyl phenyl ketone,
1.41 g
(14.70 mmol, 1.25 equiv.) of 2-aminopyridine, 2.03 g (14.11 mmol, 1.20 equiv.)
of
2-chlorobenzaldehyde and 3.65 g (23.52 mmol, 2.00 equiv.) of (S)-(+)-mandelic
acid
were added in succession under an N2 atmosphere. The magnetic stirrer was
switched on and a yellow, slightly cloudy solution formed. After a reaction
time of
30 min, the cloudiness had distinctly increased, and after 1 h, considerable
amounts
of precipitate had already appeared. The mixture was stirred at room
temperature
over the weekend. After a total of 3, 4, 5, 6 and 7 days of reaction time,
samples
(each of approx. 50 mg) were taken. Derivatization with pivaloyl chloride and
similar
HPLC analysis to Example 27 gave the following enantiomeric excesses: 97.2%
ee,
97.4% ee, 97.6% ee, 98.2% ee, 98.4% ee. The main isomer was eluted at
t(ret) = 9.38 min, and the mirror image at t(ret) = 6.31 min. An appropriately
derivatized racemic comparative sample delivered 50% of each of these peaks.
In 'H NMR spectra (400 MHz, DMSO-d6) of the samples, the anti-isomer could not
be
detected (i.e. syn/anti >>99:1), and likewise no o-chlorobenzaldehyde or its
imine.
Traces of the retro-Mannich product 2-pyridylmethyl phenyl ketone could be
detected.
The precipitate of the reaction batch was filtered off with suction, washed
with mother
liquor and then with a little ethanol, suction-dried and dried under high
vacuum.
5.77 g (10.19 mmol, 86.7% of theory) of pale yellow powder were obtained.
Taking
into account the five previously taken samples (approx. 250 mg), the isolated
yield
was 90.4% of theory.
'H NMR (400 MHz, DMSO-d6): S = 5.02 (s, 1 H, CHOH of the mandelate anion),
5.73
(d, 1 H), 6.22 (t, 1 H), 6.38 (d, 1 H), 6.40 (t, 1 H), 6.90 (d, 1 H), 7.14 (t,
2H), 7.18 (-td,
1 H), 7.25-7.30 (m, 2H), 7.30-7.38 (m, 3H), 7.38-7.45 (m, 4H), 7.45-7.57 (m,
3H), 7.67
(td, 1 H), 7.87 (m, 3H), 8.48 (dd, 1 H).
13C NMR (100,62 MHz, DMSO-d6): 5 = 52.65 (CH), 58.92 (CH), 72.41 (CHOH of the
mandelate anion), 107.37 (CH), 112.25 (CH), 122.35 (CH), 124.66 (CH), 126.60-
129.29 (9 signals, CH), 132.83 (CH), 133.02 (C), 136.30 (C), 136.71 (CH),
136.77
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(CH), 139.68 (C), 140.22 (C), 147.37 (CH), 148.90 (CH), 156.36 (C), 157.44
(C),
174.09 (CO2-), 196.43 (C=O).
Example 30:
Synthesis of the racemic Mannich salt of the formula (III) [R1 = phenyl, R2 =
2-pyridyl,
R3 = H, R4 = 2-pyridyl, R5 = phenyl] by four-component coupling at room
temperature;
use of (S)-(+)-mandelic acid as the chiral auxiliary [HY* = (+)-MDLA)] and
ethanol as
the solvent:
In a 100 ml three-neck flask equipped with a precision glass stirrer, 30 ml of
ethanol
(denatured with methyl ethyl ketone) were initially charged. At room
temperature
(22 C), 2.32 g (11.76 mmol, 1.00 equiv.) of 2-pyridylmethyl phenyl ketone,
1.41 g
(14.70 mmol, 1.25 equiv.) of 2-aminopyridine, 1.51 g (14.11 mmol, 1.20 equiv.)
of
benzaldehyde and 3.65 g (23.52 mmol, 2.00 equiv.) of (S)-(+)-mandelic acid
were
added in succession under an N2 atmosphere. The mechanical stirrer was
switched
on and after a few minutes a yellow, slightly cloudy solution formed. After 20
min, a
precipitate had formed. The suspension was stirred further at room temperature
for 3
days. A sample was taken in a similar manner to Example 27 and derivatized
with
pivaloyl chloride. The analysis was effected isocratically on a Chiralpak AD
250 mm x 4.6 mm column using a 25% isopropanol/75% n-hexane/0.1 %
trifluoroacetic acid eluent. The image and mirror image, as in an
appropriately
derivatized racemic reference sample, were eluted in a 50:50 ratio [t(ret) =
12.25 and
14.46 min]. 1H NMR showed that the Mannich mandelate salt was present in high
purity. Diastereomer and retro-Mannich products could be detected in very
small
amounts in the NMR solution (DMSO-d6).
The reaction mixture was then heated to 60 C for 7 h, then allowed to cool .to
RT, and
the solid was filtered off, washed with a little ethanol and dried under high
vacuum.
5.55 g (10.44 mmol; 88.8% of theory) of pale yellow powder was obtained. The
1H NMR spectrum was unchanged. Derivatization resulted in the Mannich base
remaining unchanged in racemic form. In contrast to Examples 27 and 29, (S)-
(+)-
mandelic acid in an ethanol solvent does effect formation of the Mannich base
from
the reactants (IV), (V) and (VI), and also crystallization of the mandelate
salt, but no
dynamic optical resolution.
CA 02484685 2004-11-03
119
1H NMR (400 MHz, DMSO-d6): s = 5.02 (s, 1 H, CHOH of the mandelate anion),
5.68
(d, 1 H), 5.99 (t, 1 H), 6.32 (d, 1 H), 6.37 (t, 1 H), 6.97 (d, 1 H), 7.07 (t,
1 H), 7.15-7.25
(m, 5H), 7.41 (t, 2H), 7.50-7.60 (m, 3H), 7.70 (t, 1H), 7.87 (d + m, 3H), 8.47
(d, 1 H).
