METHODS FOR PREPARING SULFONAMIDE SUBSTITUTED
ALCOHOLS AND INTERMEDIATES THEREOF
BACKGROUND OF THE INVENTION
This invention relates to inhibitors of beta amyloid production, which have utility
in the treatment of Alzheimer's disease.
Alzheimer's Disease (AD) is the most common form of dementia (loss of
memory) in the elderly. The main pathological lesions of AD found in the brain consist
of extracellular deposits of beta amyloid protein in the form of plaques and angiopathy
and intracellular neurofibrillary tangles of aggregated hyperphosphorylated tau protein.
Recent evidence has revealed that elevated beta amyloid levels in the brain not only
precede tau pathology but also correlate with cognitive decline. Further suggesting a
causative role for beta amyloid in AD, recent studies have shown that aggregated beta
amyloid is toxic to neurons in cell culture.
Heterocyclic- and phenyl-sulfonamide compounds, specifically fluoro- and
trifluoroalkyl-containing heterocyclic sulfonamide compounds, have been shown to be
useful for inhibiting -amyloid production..
What is needed in the art are alternate processes for preparing sulfonamide
compounds, which are useful for inhibiting -amyloid production, and the intermediates
thereof.
SUMMARY OF THE INVENTION
In one aspect, methods for preparing amino alcohols or salts thereof are provided.
In another aspect, methods for preparing sulfonamide substituted alcohols are
provided.
Other aspects and advantages of the invention will be readily apparent from the
following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION
The methods describe herein provide routes to sulfonamide substituted alcohols.
The methods also provide novel steps for preparing the intermediates thereof, including
ammo alcohols.
A. Methods of Preparing Amino Alcohols
A method for preparing an amino alcohol, or salt thereof, from an aminoester is
described. See, Scheme 1, wherein R1, R2, R3 and R4 are defined below.

wherein, R2 is a protecting group; R3 is selected from among hydrogen, lower alkyl and
substituted lower alkyl; R4 is selected from among (CF3)nalkyl, (CF3)n(substituted alkyl),
(CF3)nalkylphenyl, (CF3)nalkyl(substituted phenyl), and (F)ncycloalkyl; and n is 1 to 3.
Desirably, R2 is 1-methylbenzyl.
The term "protecting group" as used herein refers to a group that protects an
amino functional group. Desirably, the protecting group may be removed by
deprotection under conditions known to those of skill in the art. A variety of protecting
groups are known in the art and include those set forth in Green et al., "Protective Groups
in Organic Synthesis", 3rd Edition, John Wiley & Sons Inc, June, 1999, which is hereby
incorporated by reference herein. More desirably, the protecting group is an optionally
substituted alkyl, cycloalkyl, or carbonyl. Even more desirably, the protecting group is 1-
methylbenzyl, benzyl, t-butyloxycarbonyl (BOC), or acetyl, among others. Most
desirably, the protecting group is 1-methylbenzyl.

In a further embodiment, the amino alcohol is of the following structure:

wherein, R3 is selected from among hydrogen, lower alkyl and substituted lower alkyl; R4
is selected from among (CF3)nalkyl, (CF3)n(substituted alkyl), (CF3)nalkylphenyl,
(CF3)nalkyl(substituted phenyl), and (F)nycloalkyl; and n is 1 to 3.
In one example, R4 is (CF3)nalkyl such as CF3CH2, CH(CH3)CH2CF3,
CH(CH2CF3)2, CH(GH3)CF3, or CH(CF3)2. In another example, R4 is (F)ncycloalkyl,
desirably (F)2cycloalkyl, more desirably (F)2cyclohexane and bicyclo[3.1.0]hexane, and
most desirably 4,4-difluoro-cyclohexane and 4,4-difluorobicyclo[3.1.0]-3-hexane.
In one embodiment, the amino alcohol is:

In a further embodiment, the amino alcohol is (2S)-4,4,4-trifluoro-2-{[(lR)-l-
phenylethyl]amino}-3-(trifluoromethyl)butan-l-ol:

Alternatively, an amino alcohol salt of the following structure can be prepared
from the aminoesters noted above.
wherein, R3 is selected from among hydrogen, lower alkyl and substituted lower alkyl;
R4 is selected from among (CF3)nalkyl, (CF3)n(substituted alkyl), (CF3)nalkylphenyl,
(CF3)nalkYl(substituted phenyl), and (F)ncycloalkyl; and n is 1 to 3.
In another embodiment, the amino alcohol salt is:


The amino alcohols are prepared by reducing the aminoester. The reduction is
performed by adding the aminoester to a reducing agent. The term "reducing agent" as
used herein refers to a compound or complex that converts the ester functional group of
the aminoester to an alcohol functional group. One of skill in the art would readily be
able to select a suitable reducing agent for the reduction. Suitable reducing agents
include hydride reducing agents including, without limitation, sodium borohydride
(NaBEH4), lithium aluminum hydride (LAH), lithium borohydride, diisobutylaluminum
hydride (DIBAL-H), sodium bis-methoxy ethoxy aluminum hydride, sodium bis(2-
methoxyethoxy)aluminum hydride (red-A1), k-selectride, among others, including those
set forth in "Comprehensive Organic Transformations", R. C. Larock, VCH Publishers,
Inc., New York, NY, 1989, which is hereby incorporated by reference herein. Desirably,
the reducing agent is DIBAL-H.
The reduction is typically performed using a non-reactive solvent. The term
"non-reactive solvent" as used herein refers to a solvent that does not react with any of
the reagents utilized during the reduction. Desirably, the non-reactive solvent utilized
during the reduction includes toluene, tetrahydrofuran (THF), hexanes, heptane,
dichloromethane, cyclohexane, among others.
The inventors have found that when the aminoester is added to the reducing agent,
i.e., DIBAL-H, the yield of amino alcohol is higher than if the reducing agent is added to
the aminoester. Typically, the amino alcohol is prepared in a yield of greater than about
90%, greater than about 91%, greater than about 92%, greater than about 93%, greater

than about 94%, or greater than about 95%. In one embodiment, the amino alcohol is
prepared in a yield of about 90 to about 95%.
The temperature utilized during the reduction is higher than about -60°C. In one
embodiment, the reduction to the amino alcohol is performed at about -60° to about -
10°C. In another embodiment, the reduction is performed at about-20 to about-10°C. In
a further embodiment, the reduction is performed at about -8 to -11°C. In yet another
embodiment, the reduction is performed at about -10°C.
The reduction to the amino alcohol is later quenched using a protic solvent. By
the term "protic solvent" is meant a solvent that contains a hydrogen source (H+) that can
be released in a solution. Typically, the hydrogen source is attached to an oxygen atom
of the protic solvent. In one embodiment, the protic solvent contains a hydroxyl group.
In another embodiment, the protic solvent is an alcohol, such as ethanol. In a further
embodiment, the protic solvent is a protic acid. The term "protic acid" as used herein
includes, without limitation, strong and weak acids such as hydrochloric acid, sulfuric
acid, phosphoric acid, acetic acid, trihaloacetic acid, hydrogen bromide, maleic acids,
sulfonic acids, propionic acids, tartaric acids, lactic acids, camphoric acids, aspartic acids,
citronellic acids, BCl3, ethanolic acids, hydrogen sulfide, methanesulfonic acid,
trifluoroacetic acid, among others. In yet another embodiment, the protic solvent is a
mixture of solvents that contain hydrogen atoms that can be released in solution.
A number of aminoesters can be reduced and can be determined by one of skill in
the art utilizing techniques and knowledge in the art and in the instant specification.
Desirably, the aminoester contains one or more chiral carbon centers. More desirably,
the aminoester is a protected aminoester. Most desirably, the aminoester is an N-
protected aminoester. In one embodiment, the aminoester is of the following structure:

wherein, R1 is alkyl or benzyl; R2 is a protecting group; R3 is selected from among
hydrogen, lower alkyl and substituted lower alkyl; R4 is selected from among (CF3)nalkyl,

(CF3)n(substituted alkyl), (CF3)nalkylphenyl, (CF3)nalkyl(substituted phenyl), and
(F)ncycloalkyl; and n is 1 to 3.
In another embodiment, the aminoester is of the following structure, wherein R1,
R3, and R4 are defined above:
In a further embodiment, the aminoester is of the following structure, wherein R1,
R3; and R4 ate defined above:
In still another embodiment, the aminoester is:

In yet a further embodiment, the aminoester is:

In one example, a method is provided for preparing an amino alcohol, or salt
thereof, from an aminoester including reducing the aminoester by adding the aminoester
to diisobutylaluminum hydride at about -60° to about -10°C.
In another example, a method is provided for preparing an amino alcohol of the
structure:

wherein, an aminoester of the following structure is reduced by adding the
aminoester to diisobutylaluminum hydride at about -60° to about -10°C.

B. Methods for Preparing Sulfonamide Substituted Alcohols
Also provided are methods for preparing sulfonamide substituted alcohols. In one
embodiment, the sulfonamide substituted alcohol is substituted with one or more
trifluoroalkyl groups. In another embodiment, the sulfonamide substituted alcohol is a
heterocyclic sulfonamide substituted alcohol or phenylsulfonamide substituted alcohol.
See, Scheme 2.
In one embodiment, the sulfonamide substituted alcohol is of the structure:

wherein, R3 is selected from among H, lower alkyl and substituted lower alkyl; R4 is
selected from among (CF3)nalkyl, (CF3)n(substituted alkyl), (CF3)nalkyl phenyl,
(CF3)nalkyl(substituted phenyl), and (F)ncycloalkyl; n is 1 to 3; R5 is selected from among
H, halogen, CF3, diene fused to Y when Y is C, and substituted diene fused to Y when Y
is C; W, Y and Z are independently selected from among C, CR6 and N, wherein at least
one of W, Y or Z is C; X is selected from among O, S, SO2, and NR7; R6 is selected from
among H, halogen, C1 to C6 alkyl, and substituted C1 to C6 alkyl; and R7 is selected from
among H, C1 to C6 alkyl, and C3 to C8 cycloalkyl.


The point of attachment of the W-X-Y-Z-C heterocyclic ring to the SO2 group is
not a limitation. The ring may be attached to the SO2 group through a carbon-atom or
nitrogen-atom.
In one embodiment, the compounds prepared as described herein are
thiophenesulfonamides, more desirably 5-halo thiophenesulfonamides, and most
desirably 5-halo thiophene sulfonamides with -branches in the side chain of a primary
alcohol.
In a further embodiment, the substituted sulfonamide substituted alcohol is:

In another embodiment, the compounds prepared are furansulfonamides. Thus,
the compounds have a structure in which X is O. In one desirable embodiment, the
furansulfonamides are characterized by -branches in the side chain of a primary alcohol.

In still a further embodiment, the compounds described herein are pyrazole
sulfonamides. Thus, the compound has a structure in which X is NR7, W is N and Z and
Y are C or CR6, with the proviso that at least one of Y or Z must be C.
In another embodiment, the sulfonamide trifluoroalkyl substituted alcohol is 5-
Chloro-N-[(lS)-3,3,3-trifluoro-l-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-
2-sulfonamide or 4-Chloro-N-[(lS)-3,3,3-trifluoro-l-(hydroxymethyl)-2-
(trifluoromethyl)propyl]benzenesulfonamide.
In one example, R3 is H, R4 is (CF3)2CH, desirably of S-stereochemistry, R5 is
halogen, W is C, X is S, Y is CH, and Z is CH with the sulfonamide attached to C-2 of
the thiophene ring.
In another example, R3 is H, R4 is (CH2CF3)2CH, R5 is halogen, W is C, X is S, Y
is CH, and Z is CH with the sulfonamide attached to C-2 of the thiophene ring.
In yet a further example, R3 is H, R4 is (F)2cycloalkyl, R5 is halogen, W is C, X is
S, Y is CH, Z is CH with the sulfonamide attached to C-2 of the thiophene ring.
In still another example, the substituted sulfonamide substituted alcohol is:


wherein, R3 is selected from among H, lower alkyl and substituted lower alkyl; R4 is
selected from among (CF3)nalkyl, (CF3)n(substituted alkyl), (CF3)nalkyl phenyl,
(CF3)nalkyl(substituted phenyl), and (F)nCycloalkyl; n is 1 to 3; R8, R9, R10, R11, and R12
are independently selected from among H, halogen, C1 to C6 alkyl, substituted C1 to C6
alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, and NO2; or R8 and R9; R9 and R10;
R11 and R12; or R10 and R11 are fused to form (i) a carbon-based saturated ring containing
3 to 8 carbon atoms; (ii) a carbon-based unsaturated ring containing 3 to 8 carbon atoms;
or (iii) a heterocyclic ring containing 1 to 3 heteroatoms selected from among O, N, and S
in the backbone of the ring; wherein rings (i) to (iii) are optionally substituted by 1 to 3
substituents including C1 to C6 alkyl or substituted C1 to C6 alkyl.
In one example, the substituted sulfonamide substituted alcohol is:

The methods thereby include isolating one diastereomer of an N-protected
aminoester by reacting a diastereomeric mixture of N-protected aminoesters with a protic
acid to form the corresponding N-protected aminoester salt The desired diastereomer of
the aminoester salt is typically isolated by treating the diastereomeric mixture with a
protic acid to form salts of the N-protected aminoesters. The term "protic acid" as used
herein refers to any acid that donates a hydrogen atom (H+). A variety of protic acids can
be utilized to convert the amino alcohols to the corresponding salt and include, without
limitation, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, among others.
The desired single diastereomeric N-protected aminoester salt precipitates from the
solution and is then isolated using techniques in the art such as filtration, decanting,
among others. Desirably, the single diastereomeric N-protected aminoester salt is
isolated using filtration. The N-protected aminoester salt can then be utilized without
further purification or can be purified using techniques known to those of skill in the art.
In one embodiment, the N-protected aminoester salt is of the structure:


wherein, R1 is alkyl or benzyl; R3 is selected from among hydrogen, lower alkyl and
substituted lower alkyl; R4 is selected from among (CF3)nalkyl, (CF3)n(substituted alkyl),
(CF3)nalkylphenyl, (CF3)nalkyl(substituted phenyl), and (F)ncycloalkyl; and n is 1 to 3.
In another embodiment, the N-protected aminoester salt is:

The N-protected aminoester salt is then treated with a base to form the
corresponding N-protected aminoester of the single diastereomer. The term based as
used herein refers to a chemical compound that is capable of accepting protons.
Therefore, the term base includes, without limitation, hydroxides such as potassium,
lithium or sodium hydroxide, alkoxides, hydrides, amines, among others and including
those described in US Patent Application Publication No. US-2005/0272932, which is
hereby incorporated by reference.
The N-protected aminoester is then reduced to the N-protected amino alcohol by
adding the N-protected aminoester to DIBAL-H as described above. The reduction is
then quenched with a protic solvent as described above to form the N-protected amino
alcohol.
The N-protected amino alcohol is then converted to the corresponding N-
protected amino alcohol salt by reacting the N-protected amino alcohol with a protic acid
as described above.
The N-protected amino alcohol salt is then hydrogenated to form the unprotected
amino alcohol salt. One of skill in the art would readily be able to select a suitable
hydrogenating agent for use in the hydrogenation. Desirably, hydrogen is utilized in the
presence of a catalyst. Catalysts that are useful in the hydrogenation include those recited

in Larock et al. cited above, which is hereby incorporated by reference. Desirably, the
hydrogenation is performed using Pd/C.
The unprotected amino alcohol salt is then sulfonylated using a sulfonyl chloride
to form a sulfonamide substituted alcohol. In one embodiment, the sulfonyl chloride is of
the structure:
wherein, R5 is selected from among H, halogen, and CF3; W, Y and Z are independently
selected from among C, CR6 and N, wherein at least one of W, Y or Z is C; X is selected
from among O, S, SO2, and NR7; R6 is selected from among H, halogen, C1 to C6 alkyl,
and substituted C1 to C6 alkyl; R7 is selected from among H, C1 to C6 alkyl, and C3 to C8
cycloalkyl.
In another embodiment, the sulfonyl chloride is:

In still a further embodiment, the sulfonyl chloride is of the structure:

wherein, R8, R9, R10, R11, and R12 are independently selected from among H, halogen, C1
to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, and
NO2; or R8 and R9; R9 and R10; R11 and R12; or R10 and R11 are fused to form: (i) a
carbon-based saturated ring containing 3 to 8 carbon atoms; (ii) a carbon-based
unsaturated ring containing 3 to 8 carbon atoms; or (iii) a heterocyclic ring containing 1
to 3 heteroatoms selected from among O, N, and S in the backbone of the ring; wherein
rings (i) to (iii) are optionally substituted by 1 to 3 substituents including C1 to C6 alkyl or
substituted C1 to C6 alkyl.

Desirably, the sulfonylation is performed in the absence of protection and
deprotection steps. More desirably, the sulfonylation is performed in the absence of any
silylation or desilylation steps as described in US Patent Application Publication No. US-
2004/0198778 Al, which is hereby incorporated by reference.
Typically, the sulfonylation is performed using abase/solvent system including 4-
methyl morpholine/isopropyl acetate, Hünig's base/tetrahydrofuran, 4-methyl
morpholine/acetonitrile, 4-methyl morpholine/propionitrile, and 4-methyl
morpholine/toluene using the procedure described in US Provisional Patent Application
No. 60/774, 300, which is hereby incorporated by reference.
The sulfonamide substituted alcohol is then optionally purified using techniques
known to those of skill in the art Desirably, the purification is performed in the absence
of chromatography, including the use of silica gel chromatography.
The compounds may contain one or more asymmetric carbon atoms and some of
the compounds may contain one or more asymmetric (chiral) centers and may thus give
rise to optical isomers and diastereomers. While shown without respect to
stereochemistry, when the compounds contain one or more chiral centers, at least the
chiral center of the -amino alcohol is of S-stereochemistry. Desirably, the chiral centers
include the carbon atom to which the N-atom, R3, and R4 are attached (the -carbon
atom). More desirably, the os-carbon atom is chiral. Most desirably, the -carbon atom is
chiral and is of S-stereochemistry. Thus, the compounds include such optical isomers
and diastereomers; as well as the racemic and resolved, enantiomerically pure
stereoisomers; as well as other mixtures of the R and S stereoisomers, and
pharmaceutically acceptable salts, hydrates, and prodrugs thereof.
The term "alkyl" is used herein to refer to both straight- and branched-chain
saturated aliphatic hydrocarbon groups having one to ten carbon atoms (e.g., C1, C2, C3,
C4, C5, C6, C7, C8, C9, or C10), such as one to eight carbon atoms (e.g., C1, C2, C3,
C4, C5, C6, C7, C8), one to six carbon atoms (e.g., C1, C2, C3, C4, C5, C6), or one to four
carbon atoms (e.g., C1, C2, C3, C4). The term "lower alkyl" refers to straight- and
branched-chain saturated aliphatic hydrocarbon groups having one to six carbon atoms

(e.g., C1, C2, C3, C4, C5, C6), desirably one to four carbon atoms (e.g., C1, C2, C3, or
C4). The term "alkenyl" refers to both straight- and branched-chain alkyl groups with at
least one carbon-carbon double bond and two to eight carbon atoms (e.g., C2, C3, C4, C5,
C6, C7, or C8), two to six carbon atoms (e.g., C2, C3, C4, C5, or C6), or two to four carbon
atoms (e.g., C2, C3, or C4). The term "alkynyl" refers to both straight- and branched-
chain alkyl groups with at least one carbon-carbon triple bond and two to eight carbon
atoms (e.g., C2, C3, C4, C5, C6, C7, or C8), two to six carbon atoms (e.g., C2, C3, C4, C5, or
C6), or two to four carbon atoms (e.g., C2, C3, or C4).
The terms "substituted alkyl", "substituted alkenyl", and "substituted alkynyl"
refer to alkyl, alkenyl, and alkynyl groups as just described having from one to three
substituents including halogen, CN, OH, NO2, ammo, aryl, substituted aryl, heterocyclic,
substituted heterocyclic, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy,
aryloxy, substituted aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio.
These substituents may be attached to any carbon of an alkyl, alkenyl, or alkynyl group
provided that the attachment constitutes a stable chemical moiety.
The term "cycloalkyl" is used herein to describe a carbon-based saturated ring
having more than 3 carbon-atoms and which forms a stable ring. The term cycloalkyl can
include groups where two or more cycloalkyl groups have been fused to form a stable
multicyclic ring. Desirably, cycloalkyl refers to a ring having about 4 to about 9 carbon
atoms, and more desirably about 6 carbon atoms.
The term "substituted cycloalkyl" is used herein to refer to a cycloalkyl group as
just described and having from one to five substituents including, without limitation,
halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino,
substituted alkylamino, arylthio, heterocyclic, substituted heterocyclic, heteroaryl,
substituted heteroaryl, aminoalkyl, and substituted aminoalkyl.
The term "aryl" is used herein to refer to a carbocyclic aromatic system, which
may be a single ring, or multiple aromatic rings fused or linked together as such that at
least one part of the fused or linked rings forms the conjugated aromatic system. The aryl

groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl,
tetrahydronaphthyl, phenanthryl, and indane. Desirably, aryl refers to a carbocyclic
aromatic system having about 6 to about 14 carbon atoms.
The term "substituted aryl" refers to aryl as just defined having one to four
substituents including halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl,
alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and
arylthio.
The term "heterocycle" or "heterocyclic" as used herein can be used
interchangeably to refer to a stable, saturated or partially unsaturated 3- to 9-membered
monocyclic or multicyclic heterocyclic ring. The heterocyclic ring has in its backbone
carbon atoms and one or more heteroatoms including nitrogen, oxygen, and sulfur atoms.
In one embodiment, the heterocyclic ring contains 1 to about 4 heteroatoms in the
backbone of the ring. When the heterocyclic ring contains nitrogen or sulfur atoms in the
backbone of the ring, the nitrogen or sulfur atoms can be oxidized. The term
"heterocycle" or "heterocyclic" also refers to multicyclic rings in which a heterocyclic
ring is fused to an aryl ring of about 6 to about 14 carbon atoms. The heterocyclic ring
can be attached to the aryl ring through a heteroatom or carbon atom provided the
resultant heterocyclic ring structure is chemically stable. In one embodiment, the
heterocyclic ring includes multicyclic systems having 1 to 5 rings.
A variety of heterocyclic groups are known in the art and include, without
limitation, oxygen-containing rings, nitrogen-containing rings, sulfur-containing rings,
mixed heteroatom-containing rings, fused heteroatom containing rings, and combinations
thereof. Examples of heterocyclic groups include, without limitation, tetrahydrofuranyl,
piperidinyl, 2-oxopiperidinyl, pyrrolidinyl, morpholinyl, thiamorpholinyl,
thiamorpholinyl sulfoxide, pyranyl, pyronyl, dioxinyl, piperazinyl, dithiolyl, oxatbiolyl,
dioxazolyl, oxathiazolyl, oxazinyl, oxathiazinyl, benzopyranyl, benzoxazinyl and
xanthenyl.
The term "heteroaryl" as used herein refers to a stable, aromatic 5- to 14-
membered monocyclic or multicyclic heteroatom-containing ring. The heteroaryl ring

has in its backbone carbon atoms and one or more heteroatoms including nitrogen,
oxygen, and sulfur atoms. In one embodiment, the heteroaryl ring contains 1 to about 4
heteroatoms in the backbone of the ring. When the heteroaryl ring contains nitrogen or
sulfur atoms in the backbone of the ring, the nitrogen or sulfur atoms can be oxidized.
The term "heteroaryl" also refers to multicyclic rings in which a heteroaryl ring is fused
to an aryl ring. The heteroaryl ring can be attached to the aryl ring through a heteroatom
or carbon atom provided the resultant heterocyclic ring structure is chemically stable. In
one embodiment, the heteroaryl ring includes multicyclic systems having 1 to 5 rings.
A variety of heteroaryl groups are known in the art and include, without
limitation, oxygen-containing rings, nitrogen-containing rings, sulfur-containing rings,
mixed heteroatom-containing rings, fused heteroatom containing rings, and combinations
thereof. Examples of heteroaryl groups include, without limitation, furyl, pyrrolyl,
pyrazolyl, imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyi,
azepinyl, thienyl, dithiolyl, oxathiolyl, oxazolyl, thiazolyl, oxadiazolyl, oxatriazolyl,
oxepinyl, thiepinyl, diazepinyl, benzofuranyl, thionapthene, indolyl, benzazolyl,
purindinyl, pyranopyrrolyl, isoindazolyl, indoxazinyl, benzoxazolyl, quinolinyl,
isoquinolinyl, benzodiazonyl, napthylridinyl, benzotbienyl, pyridopyridinyl, acridinyl,
carbazolyl, and purinyl rings.
The term "substituted heterocycle" and "substituted heteroaryl" as used herein
refers to a heterocyclic or heteroaryl group having one or more substituents including
halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, C1 to C3
perfluoroalkyl, C1 to C3 perfluoroalkoxy, alkoxy, aryloxy, alkyloxy including -O-(C1 to
C10 alkyl) or-O-(C1 to C10 substituted alkyl), alkylcarbonyl including -CO-(C1 to C10
alkyl) or -CO-(C1 to C10 substituted alkyl), alkylcarboxy including -COO-(C1 to C10
alkyl) or -COO-(C1 to C10 substituted alkyl), -C(NH2)=N-OH,, -SO2-(C1 to C10 alkyl), -
SO2-(C1 to C10 substituted alkyl), -O-CH2-aryl, alkylamino, arylthio, aryl, substituted
aryl, heteroaryl, or substituted heteroaryl which groups may be optionally substituted. A
substituted heterocycle or heteroaryl group may have 1, 2, 3, or 4 substituents.

The term "alkoxy" is used herein to refer to the OR group, where R is alkyl or
substituted alkyl. The term "lower alkoxy" refers alkoxy groups having one to six carbon
atoms.
The term "aryloxy" is used herein to refer to the OR group, where R is aryl or
substituted aryl.
The term "arylthio" is used herein to refer to the SR group, where R is aryl or
substituted aryl.
The term "alkylcarbonyr is used herein to refer to the RCO group, where R is
alkyl or substituted alkyl.
The term "alkylcarboxy" is used herein to refer to the COOR group, where R is
alkyl or substituted alkyl.
The term "aminoalkyl" refers to both secondary and tertiary amines wherein the
alkyl or substituted alkyl groups, containing one to eight carbon atoms, may be either the
same or different, and the point of attachment is on the nitrogen atom.
The term "halogen" refers to Cl, Br, F, or I.
Phannaceutically acceptable salts can be formed from organic and inorganic acids
including, e.g., acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic,
mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,
methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfbnic, camphorsulfonic,
and similarly known acceptable acids. Salts may also be formed from inorganic bases,
desirably alkali metal salts including, e.g., sodium, lithium, or potassium, and organic
bases, such as ammonium salts, mono-, di-, and trimethylammonium, mono-, di- and
triethylammonium, mono-, di- and tripropylammonium (iso and normal), ethyl-
dimethylammonium, benzyldimethylammonium, cyclohexylamrnoniurn, benzyl-
ammonium, dibenzylammonium, piperidinium, morpholinium, pyrrolidinium,
piperazinium, 1-methylpiperidinium, 4-ethyhnorpholinium, 1-isopropylpyrrolidinium,
1,4-dimethylpiperazinium, 1-n-butyl piperidinium, 2-methylpiperidinium, l-ethyl-2-
methylpiperidinium, mono-, di- and triethanolammonium, ethyl diethanolammonium, n-

butylmonoethanolammonium, tris(hydroxymethyl)methylammonium, phenylmono-
ethanolammonium, and the like.
Physiologically acceptable alkali salts and alkaline earth metal salts can include,
without limitation, sodium, potassium, calcium and magnesium salts in the form of esters,
and carbamates.
These salts, as well as other compounds, can be in the form of esters, carbamates
and other conventional "pro-drug" forms, which, when administered in such form,
convert to the active moiety in vivo. In one embodiment, the prodrugs are esters. In
another embodiment, the prodrugs are carbamates. See, e.g., B. Testa and J. Caldwell,
"Prodrugs Revisited: The "Ad Hoc" Approach as a Complement to Ligand Design",
Medicinal Research Reviews, 16(3):233-241, ed., John Wiley & Sons (1996).
In one example, a method is provided for preparing a sulfonamide substituted
alcohol, including isolating one diastereomer of a N-protected aminoester by reacting a
mixture of diastereomers of a N-protected aminoester with a protic acid to form a N-
protected aminoester salt; neutralizing the N-protected aminoester salt with a base to
form a N-protected aminoester; reducing the N-protected aminoester by adding the N-
protected aminoester to a reducing agent at -60°C to about -10°C; quenching the
reduction with a protic solvent; reacting the N-protected amino alcohol with a protic acid
to form a N-protected amino alcohol salt; hydrogenating the N-protected amino alcohol
salt to form an unprotected amino alcohol salt; and sulfonylating the unprotected amino
alcohol with a sulfonyl chloride in the presence of a base/solvent system. See, Scheme 3.


In another example, a method is provided for preparing a sulfonamide substituted
alcohol, including isolating one diastereomer of a N-protected aminoester by reacting a
mixture of diastereomers of a N-protected aminoester with a protic acid to form aN-
protected aminoester salt; neutralizing the N-protected aminoester salt with a base to
form a N-protected aminoester; reducing the N-protected aminoester by adding the N-
protected aminoester to diisobutylaluminum hydride at -60°C to about -10°C; quenching
the reduction with a protic solvent; reacting the N-protected amino alcohol with a protic
acid to form a N-protected amino alcohol salt; hydrogenating the N-protected amino
alcohol salt to form an unprotected amino alcohol salt; and sulfonylating the unprotected
amino alcohol with a sulfonyl chloride in the presence of a base/solvent system.
In a further example, a method is provided for preparing a sulfonamide
substituted alcohol, including isolating one diastereomer of a N-protected aminoester by
reacting a mixture of diastereomers of a N-protected aminoester with a protic acid to
form a N-protected aminoester salt; neutralizing the N-protected aminoester salt with a

base to form a N-protected aminoester; reducing the N-protected aminoester by adding
the N-protected aminoester to diisobutylaluminum hydride at -60°C to about -10°C;
quenching the reduction with a protic solvent; reacting the N-protected amino alcohol
with a protic acid to form a N-protected amino alcohol salt; hydrogenating the N-
protected amino alcohol salt to form an unprotected amino alcohol salt; and sulfonylating
the unprotected amino alcohol with a sulfonyl chloride in the presence of a base/solvent
system selected from among 4-methyl morpholine/isopropyl acetate, Hünig's
base/tetrahydrofuran, 4-methyl morpholine/acetonitrile, 4-methyl
morpholine/propionitrile, and 4-methyl morpholine/toluene.
In yet another example, a method is provided for preparing a sulfonamide
substituted alcohol, including isolating one diastereomer of a N-protected aminoester by
reacting a mixture of diastereomers of a N-protected aminoester with a protic acid to
form a N-protected aminoester salt; neutralizing the N-protected aminoester salt with a
base to form a N-protected aminoester; reducing the N-protected aminoester by adding
the N-protected aminoester to diisobutylaluminum hydride at -60°C to about -10°C;
quenching the reduction with a protic solvent; reacting the N-protected amino alcohol
with a protic acid to form a N-protected amino alcohol salt; hydrogenating the N-
protected amino alcohol salt to form an unprotected amino alcohol salt; and sulfonylating
the unprotected amino alcohol with a sulfonyl chloride in the presence of a base/solvent
system, wherein the sulfonylation is performed in the absence of protection and
deprotection steps.
In still a further example, a method is provided for preparing a sulfonamide
substituted alcohol, including isolating one diastereomer of a N-protected aminoester by
reacting a mixture of diastereomers of a N-protected aminoester with a protic acid to
form a N-protected aminoester salt; neutralizing the N-protected aminoester salt with a
base to form a N-protected aminoester, reducing the N-protected aminoester by adding
the N-protected aminoester to diisobutylaluminum hydride at -60°C to about -10°C;
quenching the reduction with a protic solvent; reacting the N-protected amino alcohol
with a protic acid to form a N-protected amino alcohol salt; hydrogenating the N-

protected amino alcohol salt to form an unprotected amino alcohol salt; sulfonylating the
unprotected amino alcohol with a sulfonyl chloride in the presence of a base/solvent
system; and purifying the sulfonamide substituted alcohol, wherein the purification is
performed in the absence of silica gel.
The following examples are illustrative only and are not intended to be a
limitation on the present invention.
EXAMPLES
Example 1 - Preparation of 4,4,4-Trifluoro-2-(1-Phenethylamino)-3-
Trifluoromethylbutan-1-ol
A solution of 50% NaOH (24 g, 0.302 mol) in water (80 mL) was added to a
suspension of ethyl 4,4,4,4',4',4'-hexafluoro-N-[(1R)-l-phenylethyl]-L-valinate
hydrochloride salt aminoester (100 g, 0.254 mol) in water (278 mL) and toluene (1.01 L).
The mixture was stirred for 30 minutes and then the two phases were separated. The
toluene layer was washed with water (2 x 195 mL) and the water was removed by
azeotroping. The toluene solution was distilled under atmospheric pressure until the
vapor temperature reached about 108-110 °C, whereby about 600 mL of toluene
remained in the flask.
A solution of DIBAL-H in toluene (1.5 N, 518 mL, 0.78 mol) was cooled to -10
°C and then the aminoester toluene solution (about 600 mL) was added over about 90
minutes while keeping the reaction mixture at about -8 to -11 °C. The mixture was then
stirred for about 10 minutes. EtOH (29 mL, 0.5 mol) was then added over 10 minutes,
while keeping the reaction temperature below 25 °C.
A solution of concentrated HC1 (93 g) in water (130 mL) was heated to 35-40 °C.
The reaction mixture was then added to this heated HC1 solution over 60 to 90 minutes
while maintaining the temperature below 45 °C. This mixture was then stirred at 40-45
°C for 30 minutes. The two layers were separated and the organic layer was washed with
15% NaCl (700 mL). The organic layer solution was then cooled to -5 °C and then
concentrated HC1 (32 g, 0.33 mol) was added over 15 minutes. This mixture was then

stirred for 6 hours. The salt product from the previous step was then isolated by
filtration, washed with toluene (2 x 200 mL) and dried in a vacuum oven to give 81 g
(90%) of the final product as an off-white solid. 98.9 area% HPLC purity, 98.5%
strength.
Example 2 - Preparation of S-Chloro-N-[(1S)-3,3,3--trifluoro-1-(hydroxymethyl)-2-
(trifluoro-methyl)propyl]thiophene-2-sulfonamide
4-methyl morpholine (2.7 mL, 24.6 mmol) was added to a suspension of (2S)-2-
amino-4,4,4-tri-fluoro-3-(trifluoromethyl)butan-l-ol (2 g, 8.1 mmol) in isopropyl acetate
(10 mL). The mixture was stirred at about 20-25 °C for about 5-10 minutes and then 5-
chlorothiophene-2-sulfonyl chloride (2.0 g, 9.2 mmol) was added. The reaction mixture
was stirred at 20-25 °C for 6-18 hours. Water (10 mL) was then added to the reaction
mixture, whereby the solids dissolved. The two layers were then separated and the
organic layer was washed with a solution of 10% NaHCO3 (10 mL) and 10% NaCl (10
mL). Heptane (10 mL) was added to the isopropyl acetate layer (about 10 mL). The
mixture was then distilled down to about half of its original volume under atmospheric
distillation. While the solution remained at about 80-90 °C, heptane (10 mL) was added
over 5-10 minutes, during which time solids formed. After the addition of heptane, the
mixture was cooled to 20-25 °C, stirred for about 1-2 hours, and then further cooled to
about 5-10 °C for 1 hour. The solid was then collected by filtration, washed with heptane
(5 mL), and oven-dried to give 2.15 g (67%) of the product as an off-white solid. 98
area% HPLC purity and >99% chiral purity by HPLC.
All publications cited in this specification are incorporated herein by reference.
While the invention has been described with reference to particular embodiments, it will
be appreciated that modifications can be made without departing from the spirit of the
invention. Such modifications are intended to fall within the scope of the appended
claims.

WHAT IS CLAIMED IS:
1. A method for preparing an amino alcohol, or salt thereof, from an
aminoester comprising reducing said aminoester by adding said aminoester to a hydride
reducing agent at about -60° to about -10°C.
2. The method according to claim 1, wherein said aminoester is of the
structure:
wherein:
R1 is alkyl or benzyl;
R2 is a protecting group;
R3 is selected from the group consisting of hydrogen, lower alkyl and substituted
lower alkyl;
R4 is selected from the group consisting of (CF3)nalkyl, (CF3)n(substituted alkyl),
(CF3)nalkylphenyl, (CF3)nalkyl(substituted phenyl), and (F)ncycloalkyl;
n is 1 to 3.
3. The method according to claim 2, wherein said amino alcohol is of the
structure:
wherein:
R2-R4 are as defined in claim 2.
4. The method according to claim 3, wherein said amino alcohol salt is of the
structure:

wherein:
R2-R4 are as defined in claim 2.
5. The method according to any one of claims 1 to 4, wherein said protecting
group R2 is a 1-methylbenzyl group.
6. The method according to any one of claims 1 to 5, wherein R3 is H and R4
is-CH(CF3)2.
7. The method according to claim 6, wherein said amino alcohol is:

8. The method according to any one of claims 1 to 7, wherein said hydride
reducing agent is diisobutylaluminum hydride.
9. The method according to any one of claims 1 to 8, further comprising
quenching said reduction with a protic solvent
10. The method according to claim 9, wherein said protic solvent is a protic
acid.
11. The method according to claim 10, wherein said protic acid is
hydrochloric acid or acetic acid.

12. The method according to claim 9, wherein said protic solvent is ethanol.
13. The method according to any one of claims 1 to 12, wherein said reduction
is performed at about -20 to about -10°C.
14. The method according to any one of claims 1 to 13, wherein said amino
alcohol is prepared in a yield of about 90 to about 95%.
15. A method for preparing an amino alcohol of the structure:

wherein said method comprises reducing an aminoester of the following structure
by adding said aminoester to diisobutylaluminum hydride at about -60° to about -10°C

and if desired converting said amino alcohol to a salt thereof.
16. The method according to any one of claims 1 to 15 in which the
aminoester is N-protected by a chiral protecting group, further comprising, prior to
reducing said N-protected aminoester, reacting a mixture of diastereomers of said N-
protected aminoester with a protic acid to form an N-protected aminoester salt; isolating a
single aminoester salt diastereomer, and neutralizing said aminoester salt with a base to
form a single N-protected aminoester diastereomer.
17. The method according to any one of claims 1 to 16 in which the amino
alcohol is N-protected, further comprising hydrogenating said N-protected amino alcohol
salt to form an unprotected amino alcohol salt; and sulfonylating said unprotected amino

alcohol with a sulfonyl chloride in the presence of a base/solvent system to form a
sulfonamide substituted alcohol.
18. A method for preparing a sulfonamide substituted alcohol, comprising:
(a) isolating one diastereomer of a N-protected aminoester by reacting
a mixture of diastereomers of a N-protected aminoester with a protic acid to form a N-
protected aminoester salt;
(b) neutralizing said N-protected aminoester salt with a base to form
an N-protected aminoester;
(c) reducing said N-protected aminoester by adding said N-protected
aminoester to diisobutylaluminum hydride at -60°C to about -10°C;
(d) quenching the reaction of step (c) with a protic solvent;
(e) reacting the N-protected amino alcohol of step (d) with a protic
acid to form a N-protected amino alcohol salt;
(f) hydrogenating said N-protected amino alcohol salt to form an
unprotected amino alcohol salt; and
(g) sulfonylating said unprotected amino alcohol with a sulfonyl
chloride in the presence of a base/solvent system.

19. The method according to claims 17 or 18 wherein said base/solvent
system is selected from the group consisting of 4-methyl morpholine/isopropyl acetate,
Hünig's base/tetrahydrofuran, 4-methyl morpholine/acetonitrile, 4-methyl
morpholine/propionitrile, and 4-methyl morpholine/toluene.
20. The method according to any one of claims 17 to 19 wherein said
sulfonylation is performed in the absence of protection and deprotection steps.
21. The method according to any one of claims 17 to 20 further comprising
purifying said sulfonamide substituted alcohol,

wherein said purification is performed in the absence of silica gel.
22. The method according to any of claims 17 to 21, wherein said sulfonamide
substituted alcohol is substituted with one or more trifluoroalkyl groups.
23. The method according to any of claims 17 to 22, wherein said sulfonamide
substituted alcohol is of the structure:

wherein:
R3 and R4 are as defined in claim 2;
R5 is selected from the group consisting of H, halogen, CF3, diene fused to Y
when Y is C, and substituted diene fused to Y when Y is C;
W, Y and Z are independently selected from the group consisting of C, CR6 and
N, wherein at least one of W, Y or Z is C;
X is selected from the group consisting of O, S, SO2, and NR7;
R6 is selected from the group consisting of H, halogen, C1 to C6 alkyl, and
substituted C1 to C6 alkyl;
R7 is selected from the group consisting of H, C1 to C6 alkyl, and C3 to Cg
cycloalkyl;
R8, R9, R10, R11, and R12 are independently selected from the group consisting of
H, halogen, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to
C6 alkoxy, and NO2; or
R8 and R9; R9 and R10; R11 and R12; or R10 and R11 are fused to form:
(i) a carbon-based saturated ring containing 3 to 8 carbon atoms;
(ii) a carbon-based unsaturated ring containing 3 to 8 carbon atoms; or

(iii) a heterocyclic ring containing 1 to 3 heteroatoms selected from the
group consisting of O, N, and S in the backbone of said ring;
wherein lings (i) to (iii) are optionally substituted by 1 to 3 substituents
comprising C1 to C6 alkyi or substituted C1 to C6 alkyl.
or apharmaceutically acceptable salt, hydrate, or prodrug thereof.
24. The method according to claim 24, wherein said sulfonamide substituted
alcohol is:
25. The method according to claim 24, wherein said sulfonamide substituted
alcohol is:
26. The method according to any of claims 17 to 25, wherein said
hydrogenation is performed with a catalyst.
27. The method according to any of claims 17 to 26, wherein said unprotected
amino alcohol salt is of the structure:
wherein R3 and R4 are as defined in claim 2.
28. The method according to claim 27, wherein said unprotected ammo
alcohol salt is:
29. The method according to any of claims 17 to 28, wherein said sulfonyl
chloride is of the structure:
wherein:
R5, W, Y, Z, X and R8 - R12 are as defined in claim 23.
30. The method according to claim 29, wherein said sulfonyl chloride is:

Processes for preparing amino alcohols or salts thereof and sulfonamide substituted alcohol compounds are provided. Desirably, the sulfonamide substituted alcohol compounds are heterocyclic sulfonamide trifluoroalkyl-substituted alcohol compounds or phenyl sulfonamide trifluoroalkyl-substituted alcohol compounds.