Note: Descriptions are shown in the official language in which they were submitted.
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PROCESSES FOR PREPARING CHROMANYLBENZOIC ACIDS
Backarourad of the Invention
This invention relates to methods for preparing substituted chromanol
derivatives.
The substituted chromanol derivatives prepared using the methods of the
present invention
are disclosed in United States patent application Serial No, 09/511,475, filed
Feb. 23, 2000,
U.S. Patent Nos. 5,552,435 and 6,096,906, and PCT international application
publication nos.
WO 96/11925 (published April 25, 1996), WO 96/11920 (published April 25,
1996), and WO
93/15066 (published August 5, 1993). Each of the foregoing United States
patent
applications and patents and PCT international applications are incorporated
herein by
reference in their entirety.
The substituted chromanol derivatives prepared using the methods of the
present
invention are effective in inhibiting the action of LTB4, as disclosed in
United States Patent
No. 5,552,435. As LTB4 antagonists, the substituted chromanol are therefore
useful in the
treatment of LTB4-induced illnesses such as inflammatory disorders including
rheumatoid
arthritis, osteoarthritis, inflammatory bowel disease, psoriasis, eczema,
erythma, pruritis,
acne, stroke, graft rejection, autoimrnune diseases, and asthma.
The present invention provides several enhancements over the prior art methods
of
preparing substituted chromanol derivatives. As disclosed in Serial No.
09/511,475, 7
halochromanol intermediates to the substituted chromanol derivatives are
prepared by initial
formation of an acylated chiral auxiliary which then undergoes asymmetric
aldol condensation
with an aromatic aldehyde, followed by reductive cleavage of the chiral
auxiliary and
subsequent intramolecular cyclization. For the formation of the acylated
chiral auxiliary,.the
prior method set forth in Serial No. 09/511,475 uses pyrophoric, air sensitive
organolithium
reagents such as n-butyllithium, which requires the use of cryogenic
conditions. The present
invention instead uses more convenient and economical reagents such as DMAP
and
triethylamine. Rather than a reductive cleavage of the chiral auxiliary, the
present invention
uses a hydrolysis to cleave the chiral auxiliary, providing a significantly
higher recovery of the
auxiliary and permitting much simpler isolation by crystallization. In
addition, the present
invention provides higher yields of the pre-cyclization intermediate using
reagents that are
more readily available on a commercial scale (i.e., sodium borohydride and
boron trifluoride
diethyl ether complex) than those required bythe prior art process (lithium
borohydride).
Furthermore, the present invention offers significant practical advantages in
the
formation of the 7-arylchromanol used as a precursor to the substituted
chromanol. In
particular, use of an isopropyl benzoic ester rather than a neopentyl ester to
prepare a
berizene boronic acid intermediate required for Suzuki cross-coupling with the
7-
halochromanol was unexpectedly found to suppress the undesired formation of
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diisopropylamide and benzophenone (arising from condensation with a molecule
of starting
ester) side products observed in the method disclosed in Serial No.
09/511,475.
Transesterification of the ester is also avoided since the isopropyl ester is
reacted with
triisopropylborate in accordance with the new procedure described in the
present disclosure.
The choice of the isopropyl ester has proven to be a superior reactant in
further processing
since its higher stability suppresses hydrolysis to the carboxylic acid.
In addition, because of the use of the isopropyl ester and an improved choice
of
solvent, the present invention has the added advantage of cleaner formation of
the benzene
boronic acid intermediate and more facile product isolation by
crystallization. The cross-
coupling step of the present approach is additionally enhanced over the prior
art by use of a
more stable palladium phosphine catalyst and. a new solvent combination which
allows for
preparation of substituted chromanols on a significantly larger scale. The
present invention
further provides improvements in methods disclosed in Serial No. 09/511,475
for forming the
7-substituted chromanol penultimate intermediate by coupling a substituted
benzene boronic
acid and a substituted 7-halochromanol, rather than a substituted halobenzene
and a
substituted chromanol 7-boronic acid. The isopropyl ester has the added
advantage of higher
stability for the final ester hydrolysis step, thereby minimizing undesired
premature hydrolysis.
Summary of the Invention
The present invention relates to a process of preparing a compound of formula
X
having the structure:
C02H Rz OH
R
R3
X
or the enantiomer of said compound, wherein in said compound of formula x the
R3-
substituted benzoic acid moiety is attached at carbon 6 or 7 of the chroman
ring;
R~ is -(CHZ)qCHR5R6 wherein q is 0 to 4;
each Rz and R3 is independently selected from the group consisting of H,
fluoro,
chloro, C~-Cs alkyl, C~-C6 alkoxy, phenylsulfinyl, phenylsulfonyl, and -
S(0)~(C~-C6 alkyl)
wherein n is 0 to 2, and wherein said alkyl group, the alkyl moiety of said
alkoxy and
-S(O)~(C~-C6 alkyl) groups, and the phenyl moiety of said phenylsulfinyl and
phenylsulfonyl
groups are optionally substituted by 1 to 3 fluoro groups;
R5 is H, C~-C6 alkyl, or phenyl optionally substituted by the groups set forth
in the
definition of R2;
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R6 is H, C~-C6 alkyl, C3-Cg cycloalkyl, C6-Coo aryl, or 5-10 membered
heteroaryl,
wherein said aryl and heteroaryl groups are optionally substituted by 1 or 2
substituents
independently selected from phenyl, the groups set forth in the definition of
R~, and phenyl
substituted by 1 or 2 groups set forth in the definition of RZ;
which comprises treating a compound of the formula
~O O RZ OH
R'
R3 \ O
IX
or the enantiomer of said compound of formula IX in the preparation of the
enantiomer of said compound of formula X, wherein R', Ra, and R3 are as
defined above, and
the benzoate moiety is attached to position 6 or 7 of the chroman ring, with a
base.
In said process of preparing the compound of formula X, the compound of
formula IX
is preferably treated with an aqueous hydroxide base, R' is preferably benzyl,
4-fluorobenzyl,
4-phenylbenzyl, 4-(4-fluorophenyl)benzyl, or phenethyl, Rz is preferably
hydrogen or fluoro,
and R3 is preferably fluoro, chloro, or methyl optionally substituted by 1 to
3 fluorines. Most
preferably, said compound of formula IX is treated with a base comprising
aqueous lithium
hydroxide, said compound of formula IX is (3S,4R)-2-(3-benzyl-4-hydroxy-
chroman-7-yl)-4-
trifluoromethyl-benzoic acid isopropyl ester, wherein the compound of formula
X is (3S,4R)-2-
(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid.
In a further aspect of the present invention, said compound of formula IX, or
the
enantiomer of said compound, wherein R', R2, and R3 are as defined above, is
prepared by
treating a compound of the formula
R2 OH
R'
J
O
VII
or the enantiomer of said compound of formula VII in the preparation of the
enantiomer of the compound of formula IX, wherein R' and RZ are as defined
above and X is
halo or Ci-C4 perfluoroalkylsulfonate, attached at position 6 or 7 of the
chroman ring, with a
compound of the formula VIII:
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OH
Bo
~ ~OH
~O
R3
vlll
wherein R3 is as defined above, in the presence of a base or fluoride salt and
a
palladium catalyst.
In said process of making the compound of formula IX, or the enantiomer of
said
compound, preferred substituents for R', R2, and R3 are as stated above for
said process of
making the compound of formula X. In another preferred embodiment, X is halo
in formula
VIII, the base or fluoride salt is selected from sodium carbonate,
triethylamine, sodium
bicarbonate, cesium carbonate, tripotassium phosphate, potassium fluoride,
cesium fluoride,
sodium hydroxide, barium hydroxide, and tetrabutylammonium fluoride, the
palladium catalyst
is selected from tetrakis(triphenylphosphine)palladium(0),
dichlorobis(triphenyl-
phosphine)palladium(II), pal-ladium(II) acetate, allylpalladium chloride
dimer,
tris(dibenzylideneacetone)dipalladium(0), and 10% palladium on carbon. Most
preferably, the
base or fluoride salt is potassium fluoride, the palladium catalyst is 10%
palladium on carbon,
the compound of formula VII is (3S,4R)-(7-bromo-3-benzyl-4-hydroxy-chroman),
and the
compound of formula VIII is isopropyl 4-trifluoromethyl-benzoate 2-boronic
acid.
In a further aspect of the invention, the compound of formula VIII, wherein R3
is as
defined above, is prepared by hydrolyzing a compound of the formula
Oi~CH2)n
/ - - N-Ra
O'' CH
2)m
2o x1
wherein R3 is as defined above, the dashed line indicates an intramolecular
complex
between the B and N atoms, n and m are independently 2 to 5, and Rg is H or C~-
C6 alkyl. R8
is preferably H and preferred substituents for R3 are as stated above for said
process of
making a compound of formula VIII. Preferably, said hydrolysis is effected
with an aqueous
acid, such as hydrochloric acid, and n and m are each 2. Most preferably, said
compound of
formula ?CI is 2-[1,3,6,2]dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid
isopropyl ester.
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In a further aspect of the invention, a process is provided for preparing a
compound
of formula Xa having the structure:
C02H RZ OH '
R
-NH2 (CH2)~-NHS
R3 ~ O
Xa
or the enantiomer of said compound, wherein R~, R2, and R3 are as defined for
compound of formula X and wherein n is 2 to 4; which comprises treating a
compound of
formula X as set forth above, with a compound of the formula NH2-(CH2)"NH~,
wherein n is 2
to 4.
In the context of the present invention, the term C~-C8 alkyl encompasses both
linear
and branched chain alkyl groups, including, but not limited to, methyl, ethyl,
n-propyl,
isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopentyl, and cyclohexyl. The
alkyl group may be
unsubstituted or substituted with one or more hydroxyl, halo, cyano, carboxyl,
alkylacyl,
arylacyl, alkoxycarbonyl, or alkylsulfoxide moieties. The term C~-C8 alkoxy,
as used herein,
encompasses ethereal moieties containing any of the C~-C8 alkyl groups, both
substituted and
unsubstituted. The term aryl, as used herein, encompasses, but not limited to,
phenyl,
biphenyl, naphthyl, pyridyl, indolyl, pyrazinyl, pyrimidinyl, furanyl,
benzofuranyl, benzopyridyl,
and thiofuranyl, and may be unsubstituted or substituted with one or more C~-
C$ alkyl,
hydroxyl, halo, cyano, carboxyl, alkylacyl, arylacyl, alkoxycarbonyl, or
alkylsulfoxide moieties.
The term aryloxy encompasses ethereal moieties containing any of the aryl
groups noted,
both unsubstituted and substituted. The terms aryl(Ci-C$)alkyl and aryl(CT-
C$)alkoxy
encompass moieties containing any of the C~-C$ alkyl groups, both substituted
and
unsubstituted and any of the aryl groups noted, both unsubstituted and
substituted.
Examples of groups termed aryl(C~-C8)alkyl include benzyl, tolylmethyl,
xylylmethyl,
fluorophenylmethyl, (4-ethylphenyl)methyl, 2-(2-pyridyl)ethyl, 3-(4-
hydroxyphenyl)cyclohexyl,
and the like. . Examples of groups termed aryl(C~-C8)alkoxy encompass, but are
not limited
to, benzyloxy, (3-tolyl)methyoxy, p-xylylmethoxy, 2-phenylethoxy, 3-
phenylbutoxy,
pyridylmethoxy, 3-phenyltetrahydrofuranyl, and the like.
Detailed Description of the Invention
The process of the present invention is illustrated in the following Schemes.
In the
discussion which follows, unless otherwise indicated, Ri, R~, R3, R4, R5, Rs,
R~, R8, X and Y
are as defined above. The following Schemes and the description which follows
also apply to
the enantiomeric forms of the respective compounds.
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SCHEME1
p O O
'Y ~
O N' \
O RZ O
N'
,O R III ~ ( -H
R4 Ila ?C v 'F
II
R2 OH O O z OH O
R
~ ~N
O ~C I ~ 'OH ~NH~R~R$ ,
R
X F R4 x F V
IV
O
N' \
~O
R4 Ila
R~ OH
R~ R~ OH
J R,
x O
V F ~ H
II ~ O
VI
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SCHEME 2
O
Y
R3
XIII
O
~O
R3
XII
OH
O
~ OH
~O
R
VIII
i(~ H~)n
._ ___.N_R8
~~ CH
( 2)m
R'
XI
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_g_
SCHEME 3
Oi~CH2)n
/ _ ___N-Re
O~~CH2)
m
XI
OH
O g'
~ ~OH
~O
R3
VIII R2 OH
R
_O
VII
~O O RZ OH
R'
R ~ O
IX
C02H R2 OH
R
O
R3
X
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_g_
SCHEME4
OH O OH O
/ _ OH Me (R) / - Me (R)
~ ~O ~
\ I F Bn Ph"NH2 \ ~ 13n Ph"NH3
Br Br
XIV XV XVI
In one aspect of the invention, the compound of formula VII, or the enantiomer
of said
compound, wherein R~ and RZ are as defined above, is prepared by treating the
diol having
formula VI:
RZ OH
R'
F OH
VI
or the enantiomer of said compound of formula VI in the preparation of the
enantiomer of said compound of formula VII, wherein R' and R~ are as defined
above, with a
base, optionally in the presence of added copper salts.
In said process of making the compound of formula VII, or the enantiomer of
said
compound, preferred substituents for R' and R2 are as stated above for said
process of
making the compound of formula VIII. In another preferred embodiment, the base
is
potassium tert-butoxide, sodium bis(trimethylsilyl)amide, potassium
bis(trimethylsilyl)amide,
cesium carbonate, or sodium hydride. Most preferably, the base is potassium
tert-butoxide
and the compound of formula VI is (1 R,2S)-2-benzyl-1-(4-bromo-2-fluoro-
phenyl)-propane-
1,3-diol.
In a further aspect of the invention, the compound of formula VI, or the
enantiomer of
said compound, wherein R' and RZ are as defined above, is prepared by treating
a compound
of the formula:
OH .NH2R7R$
v
or the enantiomer of said compound of formula V in the preparation of the
enantiomer
of the compound of formula VI, wherein R', R~, and X are as defined above, and
R' and R8
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are independently hydrogen, C~-C6 alkyl, benzyl, phenyl substituted by R~, C3-
C8 cycloalkyl, or
C6-Coo aryl, with a hydride reducing agent.
In said process of making the compound of formula VI, or the enantiomer of
said
compound, preferred substituents for R', RZ, and X are as stated above for
said process of
making the compound of formula VII. In another preferred embodiment, the
reducing agent is
sodium borohydride in the presence of boron trifluoride diethyl ether complex
or boron
trifluoride tetrahydrofuran complex, borane tetrahydrofuran complex, or borane
dimethyl
sulfide complex. Most preferably, the compound of formula V is (2R,3R)-
benzylammonium-2
benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionic acid, and the reducing
agent is
sodium borohydride in the presence of boron trifluoride tetrahydrofuran
complex.
In a further aspect of the invention, the compound of formula V, or the
enantiomer of
said compound, wherein R' and R2 are as defined above, is prepared by treating
a compound
of the formula
OH O O
_ N'
R, O
F
R
IV
or the enantiomer of said compound of formula IV in the preparation of the
enantiomer of the compound of formula V, wherein R', R2, and X are as defined
above, and
R4 is C~-C8 alkyl, aryl or aryl(C~-C8)alkyl with a base in the presence of a
peroxide, then with a
reducing agent, and finally with ari amine of the formula NHR'R8, where R' and
R8 are
independently hydrogen, C~-C6 alkyl, benzyl, phenyl substituted by R~, C3-C8
cycloalkyl, or C6-
Coo aryl,.
In said process of making the compound of formula V, or the enantiomer of said
compound, preferred substituents for R', R2, and X are as stated above for
said process of
making the compound of formula VI, and R4 is benzyl. In another preferred
embodiment, the
base is lithium hydroxide and the peroxide is aqueous hydrogen peroxide, or
the base in the
presence of a peroxide may be lithium hydroperoxide; the reducing agent is
sodium sulfite or
sodium thiosulfate, and the amine is benzylamine, dicyclohexylamine or 2-
methylbenzylamine. Most preferably, the compound of formula IV is [4R-
[3(2R,3R)]]-4-benzyl-
3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one,
the base is
lithium hydroxide, the peroxide is aqueous hydrogen peroxide, and the reducing
agent is
sodium sulfite, and the amine is benzylamine.
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In a further aspect of the invention, the compound of formula V, or the
enantiomer of
said compound, wherein R', RZ and X are as defined above, and at least one of
R' and R8 is
a chiral moiety, is prepared by treating a compound of the formula
RZ OH O
~OH
R'
X F
Va
or the enantiomer of said compound of formula Va in the preparation of the
enantiomer of the compound of formula V, wherein R', R~ and X are as defined
above, with a
chiral amine of the formula NHR'R8, where R' and R8 are independently
hydrogen, C~-CB
alkyl, benzyl, phenyl substituted by R2, C3-Ce cycloalkyl, or C6-Coo aryl, and
at least one of R'
and R8 is a chiral moiety.
In said process of making the compound of formula V, or the enantiomer of said
compound, preferred substituents for R', R~, and X are as stated above for
said process of
making the compound of formula VI. In another preferred embodiment, the
compound of
formula V is (2R,3R)-[R-a-methylbenzylammonium)-2-benzyl-3-(4-bromo-2-fluoro-
phenyl)-3
hydroxy-propionate, and the chiral amine is R-a-methylbenzylamine.
fn a further aspect of the invention, the compound of formula IV, or the
enantiomer of
said compound, wherein R', R2, R4 and X are as defined above, is prepared by
treating a
compound of the formula
O O
N'
R, / " O
R4
III
or the enantiomer of said compound of formula III in the preparation of the
enantiomer of the compound of formula IV, wherein R' and R4 are as defined
above with a
compound of the formula II:
Rz O
'H
X ~F
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wherein Rz and X are as defined above.
In said process of making the compound of formula IV, or the enantiomer of
said
compound, preferred substituents for R', Rz, R4 and X are as stated above for
said process of
making the compound of formula V. In another preferred embodiment, the
compounds of
formula II and III are treated with a titanium(IV) halide; followed by a
tertiary diamine base;
then a donor iigand selected from 1-methyl-2-pyrrolidinone, dimethylformamide,
1,3-dimethyl-
3,4,5,6-tetrahydro-2(1 H)-pyrimidinone, triethylphosphate, and 2,2'-dipyridyl;
and finally a
protic quench. Most preferably, the compound of formula II is 2-bromo-4-
fluorobenzaldehyde, the compound of formula III is (R)-4-benzyl-3-[3-phenyl-
propionyl]-
oxazolidin-2-one, the titanium (IV)halide is titanium tetrachloride, the
tertiary diamine base is
N,N,N;N'-tetramethlethylenediamine, the donor ligand is 1-methyl-2-
pyrrolidinone, and the
protic quench is aqueous ammonium chloride.
In a further aspect of the invention, the compound of formula III, or the
enantiomer of
said compound, wherein R' and R4 are as defined above, is prepared by treating
a compound
of the formula
O
~Y
R'
I
wherein R' is as defined above, and Y is halo or OH, with a compound of the
formula
O
N'
~O
R/~4
la
wherein R4 is as defined above, in the presence of a tertiary amine base and a
catalytic additive.
In said process of making the compound of formula III, or the enantiomer of
said
compound of formula la in the preparation of the enantiomer of the compound of
formula III
preferred substituents for R' and R4 are as stated above for said process of
making the
compound of formula IV. In another preferred embodiment, the compounds of
formula II and
III are treated with a tertiary amine base selected from triethylamine and
diethylisopropylamine; and the catalytic additive selected from
dimethylaminopyridine and N-
methylimidazole. Most preferably, the compound of formula I is 3-phenyl-
propionyl chloride,
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the compound of formula la is (R)-4-benzyl-oxazolidin-2-one, Ri is benzyl, Y
is CI, the tertiary
amine base is triethylamine; and the catalytic additive is
dimethylaminopyridine.
In a further aspect of the invention, the compound of formula VIII, wherein R3
is as
defined above, is prepared by reacting a compound of formula XII having the
structure:
XII
wherein R3 is as defined above, with a metal amide in the presence of a
trialkylborate.
In said process of preparing the compound of formula VIII, preferred
substituents for R3 is as
stated above for said process of preparing a compound of formula XI; the metal
amide is
selected from lithium diisopropylamide or lithium 2,2,6,6-
tetramethylpiperidine; and the
trialkylborate is selected from triisopropylborate, triethylborate and
trimethylborate. Most
preferably, said compound of formula XII is (isopropoxycarbonyl)-3-
trifluoromethyl-benzene,
the metal amide is lithium diisopropylamide and the trialkylborate is
triisopropylborate.
In a further aspect of the invention, the compound of formula XII, wherein R3
is as
defined above, is prepared by treating a compound of the formula XIII having
the structure:
O
Y
R3
xltl
wherein R3 is as defined above and Y is OH or halo, with isopropyl alcohol and
a
thionyl halide. Substituents for R3 are as stated above for said process of
making a compound
of formula XI. Preferably, said esterification is effected using thionyl
chloride or bromide.
Most preferably, said compound of formula XIII is 3-trifluoromethyl-benzoyl
chloride.
In accordance with the present invention, chiral auxiliary Ila is acylated in
the first
step of the pathway shown in Scheme 1 with an acylchloride of formula 1 in the
presence of a
tertiary amine base. The base may be triethylamine or diethylisopropylamine,
and is
preferably triethylamine. The reaction is favorably carried out in the
presence of an additive
such as dimethylaminopyridine or N-methyl imidazole, which is preferably
dimethylaminopyridine, in a solvent such as dichloromethane or 1,2-
dichloroethane,
preferably dichforomethane, at a temperature between -20 °C and 40
°C, preferably about
room temperature to afford a compound of formula III.
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The second step of the preparative method is a diastereoselective aldol
reaction
(Scheme 1 ). Acylated chiral auxiliary III is treated with a titanium(IV)
halide, preferably
titanium tetrachloride, in an aprotic solvent such as dichloromethane, 1,2-
dichloroethane, or
toluene, preferably dichloromethane, at a temperature of about -80 to
0°C, preferably -60 to -
50°C, followed by treatment with a tertiary diamine base, such as
N,N,N;N=
tetramethlethyfenediamine, preferably, at a temperature of about -80 to
0°C, preferably -65 to
-50°C. This is followed by treatment with a donor ligand, such as 1-
methyl-2-pyrrolidinone,
dimethylformamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone,
triethylphosphate, or
2,2'-dipyridyl, preferably 1-methyl-2-pyrrolidinone, at a temperature of about
-80 to 0°C,
preferably -65 to -50°C. This mixture is treated with substituted
benzaldehyde II at a
temperature of about -80 to 0°C, preferably -65 to -50°C, over a
period of about 2 hours, and
allowed to warm to a temperature of 0 to 30°C, preferably 15°C,
over a period of about one to
24 hours, preferably about 4 hours. This mixture is treated with aprotic
quench, preferably
aqueous ammonium chloride, at a temperature of 0 to 30°C, preferably
15°C, to yield alcohol
IV. Where treatment with a donor ligand is done, the alcohol IV is, in some
cases, provided
as a crystalline solvate with the donor ligand. Stirring the quenched reaction
mixture with a
solid support such as CeliteT"' for a period of about 12 hours at a
temperature of about 20°C
improves the filtration of the reaction mixture for removal of titanium
byproducts.
The third step shown in Scheme 1 is the hydrolysis of the chiral aldol product
IV to
regenerate the chiral auxiliary Ila. Compound IV is treated with lithium
hydroxide and
aqueous hydrogen peroxide, or lithium hydroperoxide, preferably a mixture of
lithium
hydroxide and aqueous hydrogen peroxide, in a solvent such as tetrahydrofuran,
diisopropyl
ether or tent-butyl methyl ether, preferably tetrahydrofuran, at a temperature
between 0°C and
40°C, preferably about room temperature, for a period between 5 and 48
hours, preferably
about 15 hours. The reaction mixture is treated with a reducing agent such as
sodium sulfite
or sodium thiosulfate, preferably sodium sulfite, followed by treatment with
an amine such as
benzylamine, dicyclohexylamine, 2-methylbenzylamine, preferably benzylamine,
afford the
salt V. Compound Ila can be recovered from the mother liquor and purified by
extraction and
crystallization. In the present invention, hydrolysis of IV serves to cleave
the chiral auxiliary
whereas the process of the prior art method used a reductive cleavage to
provide compound
VI. Among the several advantages to the present process, the recovery of the
auxiliary Ila is
very high and also much simpler because compound XIV (as the free acid) can be
crystallized
as a salt (V) while auxiliary Ila does not form a salt under the conditions
used. Compounds V
and Ila can be separated by a simple crystallization. In one embodiment, the
formation of the
benzylamine salt (V) is high yielding. The use of a chiral amine allows for
enantioenrichment
of compound XIV. Therefore, if a compound such as XIV is obtained in a low
enantiomeric
excess, the use of a chiral amine such as XV will provide a final product XVI
of higher
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enantiomeric excess (Scheme 4). This was not possible by previous approaches
where
compound VI was generated directly since it did not allow for salt formation.
The fourth step in Scheme 1 is the reduction of a carboxylic acid. Compound V
is
treated with a reducing agent such as sodium borohydride in the presence of
boron trifluoride
diethyl ether complex or boron trifluoride tetrahydrofuran complex, borane
tetrahydrofuran
complex, or borane dimethyl sulfide complex, at a temperature between
0°C and reflux,
preferably 35-40°C, for a period between 10 and 48 hours, preferably
about 29 hours. The
reaction is treated with an aqueous acid such as citric acid, to provide an
alcohol of formula
VI.
The fifth step in Scheme 1 is an intramolecular aromatic substitution whereby
the
primary hydroxyl in diol VI displaces ortho fluorine to generate the chromanol
ring system of
VII. Diol VI is treated with a base, such as potassium tent-butoxide, sodium
bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or cesium
carbonate, preferably
potassium tert-butoxide, in an aprotic solvent such as THF, or 1-methyl-2-
pyrrolidinone,
preferably THF, at a temperature of between ambient temperature and
130°C, preferably
about 70°C, for a period of 30 minutes to 12 hours, typically about one
hours, giving
chromanol VII.
Illustrated in Scheme 2 are methods to prepare the desired isopropyl ester
starting
material for the subsequent step, i.e., the formation of a boronic acid. In
the second step of
Scheme 2, isopropyl ester XII is treated with a metal amide base such as
lithium
diisopropylamide or lithium 2,2,6,6-tetramethylpiperidine preferably lithium
diisopropylamide,
in the presence of a trialkylborate such as triisopropylborate,
triethylborate, or trimethylborate,
preferably triisopropylborate, in an ethereal solvent such as tetrahydrofuran,
diisopropyl ether,
or methyl tert-butyl ether, preferably tetrahydrofuran, over a temperature
range of about -40°C
to room temperature, preferably at about 0°C. After a period of 10
minutes to 5 hours,
typically about 1 hour, the reaction is quenched with aqueous acid giving
boronic acid VIII.
The third step in Scheme 2 is the formation of the diethanolamine complex XI
of the
boronic acid (VIII). This complex formation serves to facilitate the handling
of boronic acid
VIII before proceeding to the second step of Scheme 3, wherein the boronic
acid VIII is
reacted with diethanolamine in a solvent such as isopropanol, ethanol,
methanol, hexanes,
toluene, or a combination of the foregoing solvents, preferably isopropanol
with hexanes, at a
temperature within the range of 0°C to reflux temperature, preferably
ambient temperature, for
a period of 15 minutes to 10 hours, preferably 10 hours, to provide the
diethanolamine
complex XI.
The first step in Scheme 3 is the hydrolysis of the diethanolamine complex XI
to
boronic acid VIII according to methods known to those skilled in the art. Such
methods
include the use of aqueous acid, such as hydrochloric acid in a solvent such
as
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tetrahydrofuran, toluene, tert-butyl methyl ether, diisopropyl ether, or a
mixture of the
foregoing solvents, preferably a mixture of tetrahydrofuran and toluene, at a
temperature
between 1°C and 60°C, preferably ambient temperature, for a
period of 1 to 12 hours,
preferably about 3.5 hours. After generation from XI, compound VIII can either
be carried on
in situ or isolated as a solid prior to the coupling with VII in step 2.
Compound X is isolated as
a solid by displacing the THF solvent with hexanes or some other non-polar
solvent. The use
of the isopropyl ester allows for the crystallization of compound IX.
The second step 2 in Scheme 3 is a Suzuki coupling between boronic acid VIII
and
chromanol VII to form the biaryl bound of IX. To carry out this process, a
mixture is prepared
containing boronic acid VIII, chromanol VII, a palladium catalyst, such as
dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate,
optionally in the presence
of triphenylphosphine, preferably
dichlorobis(triphenylphosphine)palladium(II), a base, such
as sodium carbonate, sodium bicarbonate, cesium carbonate, tripotassium
phosphate, or
sodium hydroxide, preferably sodium carbonate, and a solvent such as toluene,
ethanol,
dimethoxyethane, tetrahydrofuran, or a mixture of the foregoing solvents,
optionally
containing water, preferably a mixture of toluene and tetrahydrofuran
containing water, at a
temperature of between ambient temperature and reflux temperature, preferably
about 80°C,
for a period of about 10 minutes to about 6 hours, preferably 2-3 hours, to
provide biaryl ester
IX.
The third step in Scheme 3 is an ester hydrolysis. Ester IX is treated with
aqueous
hydroxide base, such as aqueous lithium hydroxide, in a solvent, such as
isopropyl alcohol, at
a temperature between 40°C and reflux temperature, preferably about
80°C, for a period of
about one to about 24 hours, preferably about 6 hours. The reaction mixture is
cooled to
ambient temperature and partitioned between aqueous base and an organic
solvent, such as
a mixture of hexane and isopropyl ether. The aqueous solution is acidified,
and the final
compound X is extracted into an organic solvent such as toluene. This method
of extracting
compound X with organic solvents removes neutral. In a preferred embodiment of
the
invention, lithium hydroxide is used in the hydrolysis of IX to X.
The process shown in a preferred embodiment in Scheme 4 is diastereomeric salt
formation. between carboxylic acid XIV and a chiral amine. A chiral amine,
such as R-a
methylbenzylamine, may be added to a solution of XIV in an organic solvent at
room
temperature. After a solid forms, the diastereomeric salt is isolated by
filtration, or by other
techniques well known in the art. Other solvent combinations, resolving
agents, and
temperature ranges would also be apparent to those skilled in the art. The use
of chiral
amines results in enantioenrichment of one antipode of intermediate Va, e.g.,
XIV. In
addition, due to preferential reaction with one antipode of the amine, use of
a racemic amine
also permits enantioselection by preferential crystallization. Thus, (R)-a-
methylbenzylamine
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forms a crystalline solid with XIV, but under similar conditions the (S)-
antipode of the chiral
amine does not.
The compounds prepared by the processes of the invention can be administered
to
humans for the treatment of LTB4 induced illnesses, including inflammatory
disorders, such
as rheumatoid arthritis, osteoarthritis and inflammatory bowel disease,
psoriasis, eczema,
erythma, pruritis, acne, stroke, graft rejection, autoimmune diseases, and
asthma, by various
routes including orally, parenteraily and topically, and through the use of
suppositories and
enemas. On oral administration, dosage levels of about 0.5 to 1000 mg/day,
advantageously
about 5-500 mg/day may be given in a single dose or up to three divided doses.
For
intravenous administration, dosage levels are about 0.1-500 mg/day,
advantageously about
1.0-100 mg/day. Intravenous administration can include a continuous drip.
Variations will
necessarily occur depending on the age, weight and condition of the subject
being treated
and the particular route of administration chosen as will be known to those
skilled in the art.
The compounds prepared by the processes of the invention may be administered
alone, but will generally be administered in admixture with a pharmaceutical
carrier selected
with regard to the intended route of administration and standard
pharmaceutical practice. For
example, they can be administered orally in the form of tablets containing
such excipients as
starch or lactose, or in capsules either alone or in admixture with
excipients, or in the form of
elixirs or suspensions containing flavoring or coloring agents. They can be
injected
parenterally, for example, intramuscularly, intravenously or subcutaneously.
For parenteral
administration, they are best used in the form of a sterile aqueous solution
which can contain
other solutes, for example, enough salt or glucose to make the solution
isotonic.
The LTB4 activity of the compounds prepared by the processes of the invention
may
be determined by comparing the ability of the compounds of the invention to
compete with
radiolabelled LTB4 for specific LTB4 receptor sites on guinea pig spleen
membranes. Guinea
pig spleen membranes were prepared as described by Chang et al. (J.
Pharmacology and
Experimental Therapeutics 232: 80, 1985). The 3H-LTB4 binding assay was
performed in 150
p1 containing 50 mM Tris pH 7.3, 10 mM MgCl<sub>2</sub>, 9% Methanol, 0.7 nM 3H-LTB4
(NEN,
approximately 200 Ci/mmol) and 0.33 mg/ml guinea pig spleen membranes.
Unlabeled LTB4
was added at a concentration 5 pM to determine non-specific binding.
Experimental
compounds were added at varying concentrations to evaluate their effects on 3H-
LTB4
binding. The reactions were incubated at 4° C for 30 minutes. Membrane
bound 3H-LTB4 was
collected by filtration through glass fiber filters and the amount bound was
determined by
scintillation counting. The IC50 value for an experimental compound is the
concentration at
which 50% of specific 3H-LTB4 binding is inhibited.
The present invention is illustrated by the following examples, but is not
limited to the
details thereof.
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EXAMPLE 1
(R)-4-Benzyl-3-(3-phe~l-oropionyll-oxazolidin-2-one (3)
To a solution of (R)-4-benzyl-2-oxazolidinone (30.0g, 017 mol) in a mixture of
methylene chloride (250 mL), triethyl amine (47.5 mL, 0.34 mol) and 4-
dimethylamino pyridine
(4.15 g, 0.0034 mol) was added a solution of dihydrocinnamoyl chloride (28.1
mL, (0.19 rriol)
in methylene chloride (150 mL) while maintaining the temperature at
approximately ambient
(max 30 °C). The reaction was then stirred at ambient temperature for 2
hours and quenched
into water (250 mL). The methylene chloride layer was separated and washed
with 1 N HC1
(150 mL) and then aqueous sodium bicarbonate (100 mL). The methylene chloride
was then
removed by distillation until a volume of approximately 65 mL remained.
Tetrahydrofuran
(150 mL total) was added and the distillation continued until methylene
chloride was
completely displaced and the volume had returned to approximately 65 mL. Then
hexane
(120 mL) was added and the mixture stirred and the solids filtered and dried
to yield 48.25 g
(92.3%) of product as an off-white solid which was characterized by high
performance liquid
chromatography to be of high purity and identical to samples of the same
compound prepared
by other routes.
EXAMPLE 2
f4R-f3(2R.3R)11-4-benzyl-3-f2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy_-
prooionyll-oxazolidin-2-one (5)
To a solution of (R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one (100 g,
0.32
mol) in methylene chloride (1000 mL) at -50°C to -60°C was added
a 1 M solution of titanium
tetrachloride in methylene chloride (390 mL, 0.39 mol). Then while maintaining
-50°C to -
55°C, tetramethyl ethylene diamine (148 mL, 0.98 mol) was added,
followed by methylene
chloride (100 mL) and N-methyl pyrrolidinone (62 mL, 0.65 mol). To this
mixture at -50°C to -
65°C was added a solution of 2-bromo-4-fluorobenzaldehyde (62.5 g, 0.31
mol) in methylene
chloride (250 mL) over approximately 2 hours. The reaction was then warmed to
approximately 15°C and diluted with a solution of ammonium chloride (80
g, 1.48 mol) in
water (500 mL). The resulting precipitate of titanium dioxide was filtered and
the methylene
solution was determined by HPLC and shown to contain 92% product which was
held in
solution for the next step.
EXAMPLE 3
(2R,3~-Benzylammonium-2-benz~-3-(4-bromo-2-fluoro-phenyl)-3-hydroxv-propionic
acid (6) and Recovery of (R)-4-Benzyl-2-oxazolidinone (2)
To a solution of [4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-
phenyl)-3
hydroxy-propionyl]-oxazolidin-2-one (21.36 g, 41.7 mmol) in 115 mL THF at
ambient
temperature was added a solution of lithium hydroperoxide (formed by mixing in
order 115 mL
water, 8.1 g (83.4 mmol) 35% hydrogen peroxide and 2.63 g(62.6 mmol) of
lithium hydroxide
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monohydrate). The mixture was stirred at ambient conditions for approximately
15 hours.
Residual peroxides were destroyed by addition of 2.62 g sodium sulfite and 70
mL ethyl
acetate, followed by 15 mL concentrated hydrochloric acid. The organic (top)
layer was
separated and partially concentrated by distillation. Ethyl acetate was added
and the
distillation continued to remove residual water. Benzylamine (5.04 g, 45.9
mmol) was added
and the mixture was stirred and then filtered. The solids were dried to give
18.7 g (97% yield)
of 6, (2R,3R)-benzylammonium-2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-
propionic
acid.
(R)-4-Benzyl-2-oxazolidinone, the chiral auxiliary (2), was recovered for
potential
recycle from the filtrate by washing the organic solution successively with 1
N NaOH (15 mL)
and 1 N HCI (15 mL) and concentrating the organic layer to about 20 mL
followed by addition
of hexanes (50 mL). The mixture was concentrated again to about 20 mL volume,
hexanes
(50 mL) were again added and the mixture concentrated to about 20 mL
diisopropyl ether
(18.5 mL) was added, followed by isopropanol (3.7 mL) and the resulting slurry
was
granulated, filtered and dried to give 5.48 g (74% yield) of compound (R)-4-
benzyl-2-
oxazolidinone (2).
EXAMPLE 4
(1 R.2S)-2-Benzyl-1-(4-bromo-2-fluoro-ahenyl)-propane-1 3-diol (7)
To a slurry of (2R,3R)-benzylammonium-2-benzyl-3-(4-bromo-2~fluoro-phenyl)-3
hydroxy-propionic acid (50.0 g, 108 mmol) and sodium borohydride (7.14 g,
184.9mmol) in
tetrahydrofuran (250 mL) at ambient temperature was added boron trifluoride
tetrahydrofuran
complex (27.2 mL, 246.5 mmol). The reaction was stirred at 35-40 °C for
29 hours followed
by addition of a 40% aqueous solution of citric acid (250 mL). The mixture was
stirred two
hours at 58°C, cooled to ambient temperature and extracted by adding
methyl t-butyl ether
(250 mL) and sodium chloride (20 g). The organic layer was separated and
washed with a
1:1 mixture of saturated brine solution and water, followed by washes with
water and
saturated sodium bicarbonate until the pH was about 5Ø The organic layer was
filtered
through CeliteT"" and concentrated to a yellow oil which crystallized on
standing and weighed
37.87 g (103% of theory). 'H NMR of the product was identical to that prepared
by calcium
borohydride reduction of [4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-
fluoro-phenyl)-3-
hydroxy-propionyl]-oxazolidin-2-one (7).
EXAMPLE 5
(3S.4R)-3-Benzyl-7-bromo-chroman-4-of (8)
A mixture of (1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol (7)
(33.92 g, 100 mmol) in dry tetrahydrofuran (200 mL) was cooled to 5°C
and potassium t
butoxide (27.76 g, 235 mmol) was added. The reaction was heated to reflux for
1 hour,
cooled to 15°C and diluted with water (80 mL). The organic layer was
separated and washed
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with a solution of saturated sodium bicarbonate (80 mL) and then filtered
through CeliteT"'.
The tetrahydrofuran was exchanged with diisopropyl ether by distillation under
vacuum. The
resultant slurry was cooled, granulated, filtered and dried to yield 26.0 g
(81.5%) of (3S,4R)-3
benzyl-7-bromo-chroman-4-of (8) which was identical by'H NMR and HPLC to an
authentic
sample.
EXAMPLE 6
Preparation of IX, the isohropyl ester from the corresponding Carboxylic Acid
Method A, or the Corresponding Acid Chloride (4-trifluorometh I benzoyl
chloride) Methods
B1-B2
Starting from 4-trifluoromethyl benzoic acid (commercially available):
A) Preparation of IX directly from 4-trifluoromethyl benzoic acid.
To a clean dry nitrogen purged 500 mL round bottom flask, was charged 67 mL of
isopropanol, followed by 6.7 g of 4-trifluoromethyl benzoic acid. The mixture
was agitated for
5 minutes and, maintaining the reaction at a temperature of less than
30°C, 6.3 g thionyl
chloride was charged. After the addition was complete, the reaction was heated
to reflux and
stirred for 10 hrs, or until completed (<4% carboxylic acid) by LC. The
reaction was then
cooled to <25°C and 40 mL hexanes added. To this organic mixture, was
added a solution of
sodium bicarbonate (5.4 g NaHC03 to 81 mL water) and the resulting quench
solution stirred
at <25°C fob 1 hr. The lower aqueous layer was removed and discarded.
The organic layer
was washed a second time with an aqueous solution of sodium bicarbonate (5.4 g
NaHC03 to
81 mL water). The lower aqueous layer was removed and discarded. The organic
layer was
concentrated to an oil under reduced pressure. To the resulting oil was added
25 mL
hexanes, and the solution concentrated again to an oil to effect removal of
residual IPA. The
oil form of IX was typically isolated in 95% yield />99% potency and was used
directly in the
next processing step.
B1) Preparation of 4-trifluoromethyl benzoyl chloride from 4-trifluoromethyl
benzoic
acid.
To a clean dry nitrogen purged 500 mL round bottom flask, was charged 6.7 g of
from
4-trifluoromethyl benzoic acid, followed by 18 g of thionyl chloride. The
mixture was agitated
for 5 minutes then heated to reflux for 3 hrs or until complete (<2% from 4-
trifluoromethyl
benzoic acid by LC). Thionyl chloride was then removed by distillation under
reduced
pressure. The concentrated oil of 4-trifluoromethyl benzoyl chloride is used
directly in the
ester formation step described below.
B2) Preparation of IX from 4-trifluoromethyl benzoyl chloride.
To a clean dry nitrogen purged 500 mL round bottom flask, was charged 49 mL of
isopropanol, followed by 6.9 g of 4-trifluoromethyl benzoyl chloride. The
mixture was agitated
for 5 minutes then was heated to 50-55°C and stirred for 2 firs, or
until completed (<2%
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carboxylic acid chloride) by LC. The reaction was then cooled to <25°C
and 40 mL hexanes
added. To this organic mixture, was added a solution of sodium bicarbonate
(5.4 g NaHC03
to 81 mL water) and the resulting quench solution stirred at <25°C for
1 hr. The lower
aqueous layer was removed and discarded. The organic layer was washed a second
time
with an aqueous solution of sodium bicarbonate (5.4 g NaHC03 to 81 mL water).
The lower
aqueous layer was removed and discarded. The organic layer was concentrated to
an oil
under reduced pressure. To the resulting oil was added 25 mL hexanes, and the
solution
concentrated again to an oil to effect removal of residual IPA. The oil form
of IX was typically
isolated in 95% yield />99% potency and was used directly in the next
processing step.
EXAMPLE 7
2-f1,3.6.21Dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid isohrowl ester
(11)
A solution of lithium diisopropyl amide was made up by adding hexyl lithium
(100 mL
of a 2.5M solution in hexanes, 0.25 mol) to a solution of diisopropyl amine
(37 mL, 0.26 mol)
in 90 mL tetrahydrofuran at 0°C. The solution was then added over 40
minutes to a solution
of 4-trifluoromethylbenzoic acid isopropyl ester (9) (40 g, 0.17 mol) and
triisopropyl borate (80
g, 0.21 mol) in tetrahydrofuran (200 mL) at 0 °C. The reaction was then
diluted with hexanes
(300 mL) followed by addition of a solution of water (230 mL) and concentrated
hydrochloric
acid (40 mL). The layers were separated and the organic layer was concentrated
in vacuo to
give 10 (an oil). The oil was dissolved in isopropanol (60 mL), followed by
addition of
hexanes (110 mL) and diethanolamine (18.2 g, 0.19 mol). The resulting product,
2-[1,3,6,2]
dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid isopropyl ester (11 ), was
filtered and dried
to give 53.4 g (90% yield).
EXAMPLE 8
2~2-Methyl-ethoxycarbonyl)-5-trifluoromethyl-benzeneboronic acid (10)
To 2-[1,3,6,2] dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid isopropyl
ester (11)
(10.0 Kg, 29.0 mol) in a mixture of tetrahydrofuran (25 L), toluene (25 L) and
water (60 L) was
added concentrated hydrochloric acid (6.5 L) over about 50 minutes. The
mixture was stirred
for 3.5 hours and the layers were separated. To the organic layer was added
hexanes (50 L)
and the mixture was concentrated to about 5 L. The cycle was repeated until GC
analysis of
the reaction mixture showed less than 1 % of tetrahydrofuran and less than 5%
toluene. The
resulting solid was granulated for a minimum of 2 hours and the solid was
filtered and dried to
provide 2-(2-methyl-ethoxycarbonyl)-5-trifluoromethyl-benzeneboronic acid (6.8
Kg, 85%).
EXAMPLE 9
(3S 4R1-2-(3-Benzyl-4-hydroxy-chroman-7yl)-4-trifluoromethyl-benzoic acid
isopropyl
ester (12)
To a solution of (3S,4R)-3-benzyl-7-bromo-chroman-4-o1 (8) (8.40 Kg, 26.4 mot)
in a
mixture of toluene (33.6 L) and tetrahydrofuran (21.0 L) was added sodium
carbonate (5.67
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Kg), water (33.6 L), CIZPd(PPh3)Z (94.25g, 134.3 mmol) and 2-(2-methyl-
ethoxycarbonyl)-5
trifluoromethyl-benzene-boronic acid (8.01 Kg, 29.0 mol). The reaction mixture
was stirred at
80°C for about 2-3 hours, cooled to 40°C, filtered through a pad
of Hyflo SupercelT"" filter aid
and washed with toluene (about 8 L). The layers of the filtrate were separated
and the
organic layer was concentrated to an oil which was used directly in the next
step.
EXAMPLE 10
(3S.4R)-2-(3-Benzyl-4-hydroxy-chroman-7-)rl)-4-trifluoromethyl-benzoic Acid
(13)
To a solution of the crude (3S,4R)-2-(3-Benzyl-4-hydroxy-chroman-7-yl)-4
trifluoromethyl-benzoic acid isopropyl ester (12) (10.5 Kg, 22.3 mol) in
isopropyl alcohol (84 L)
was added water (16.8 L) and lithium hydroxide monohydrate (2.8 Kg, 66 mol).
The reaction
was stirred at 80°C for 6 hours, cooled to 40°C, and water (72
L) and hexanes (52.5 L) were
added. The layers were separated, toluene (52.2 L) was added, and
concenfirated
hydrochloric acid (6 L) was slowly added (pH of the aqueous layer <2). The
aqueous layer
was removed and the organic layer was concentrated to an oil under vacuum at a
temperature below 40°C to afford (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-
7-yl)-4-
trifluoromethyl-benzoic acid (9.0 Kg, 95%).
EXAMPLE 11
(2R.3R)-f R-a-Methylbenzylammoniuml 2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-
hvdroxypropionate (XVI)
To a solution of (2R,3R)-2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-
propionic
acid (12.5g/35.4 mmol) in ethyl acetate (62.5 ml) was added of R-a-
methylbenzylamine (5.0
m1/1.1 eq.) with agitation. After adding ethyl acetate (50 ml) to mobilize,
and granulating a
short while, the precipitate was filtered to afford (2R,3R)-R-a-
methylbenzylammonium 2-
benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionate (13.5g/28.5 mmol, 81
%).
