SELECTIVE N-SULFONYLATION OF 2-AMINO
TRIFLUOROALKYL SUBSTITUTED ALCOHOLS
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 j8-amyloid production.
What is needed in the art are alternate processes for preparing sulfonamide
compounds useful for inhibiting /S-amyloid production.
SUMMARY OF THE INVENTION
In one aspect, processes for preparing sulfonamide trifluoroalkyl substituted
alcohols are provided.

In a further aspect, processes for preparing sulfonamide tnfhioroaucyl
substituted alcohols of the following structure are provided:
In another aspect, processes for preparing sulfonamide trifluoroalkyl
substituted alcohols of the following structures are provided:


la yet another aspect, a process is provided for preparing 5-chloro-[N-(1S)-
33,3-trifluoro-l-(hydroxyraethyl)-2-(trifluoromethyl)propyl]tbiophene-2-
sulfonamide.
In still a further aspect, a process is provided for preparing 4-chloro-[N-(lS)-
33,3-trifluoro-l-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide.
Other aspects and advantages of the invention will be readily apparent from
the following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Processes are provided for preparing sulfonamide substituted compounds.
Desirably, the processes are for preparing trifluoroalkyl-containing heterocyclic or
phenyl sulfonamide compounds. A route to trifluoroalkyl-containing heterocyclic or
phenyl sulfonamide compounds is therefore provided from the corresponding
trifiuoroalkyl aminoalcohol and sulfonyl chloride via only 1 step. This process also
avoids the need for any protection and deprotection steps.
In one embodiment, the following trifluoroalkyl-containing heterocyclic or
phenyl sulfonamide compounds are prepared.

wherein, R1 and R2 are independently selected from among H, C1 to C6 alkyl,
substituted C1 to C6 alkyl, CF3, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6
alkynyl, and substituted C2 to C6 alkynyl; R3 is selected from among H, C1 to C6 alkyl
and substituted C1 to C6 alkyl; R4 is selected from among (CF3)nalkyl,
(CF3)n(substituted alkyl), (CF3)nalkyl phenyl, (CT3)nalkyl(substituted phenyl), and
(F)ncycloalkyl; n is 1 to 3; 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; R8, R9, R10, R11, and R12 are independently
selected from among H, halogen, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, NO2,
C1 to C6 alkyl, and substituted C1 to C6 alkyl; or R8 and R9; R9 and R10; Rl l 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) may be substituted by 1 to 3
substituents including C1 to C6 alkyl or substituted C1 to C6 alkyl; or a
phannaceutically acceptable salt, hydrate, or prodrug thereof.
In one embodiment, R1 - R3 are H or C1-C6 alkyl. In one example, R1-R3 are
H. In another example, R1 and R2 are CH3 and R3 is H. In a further example, R1 is
CH3 and R2 and R3 are H.

R4 is (CF3)2CH. In another example, R is In a further example, R4 is
(CH2CF3)2CH. In still another example, R4 is CF3CH2(CH3)CH. In yet another
example, R4 is (F)2cycloalkyl.
In a further embodiment, R5 is halogen.
In another embodiment, the following trifluoroalkyl-containing heterocyclic or
phenyl sulfonamide compounds are provided, where R1-R5, R8-R12, W, X, Y, and Z
are defined above.

The point of attachment of the W-X-Y-Z-C heterocyclic nng 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 example, the compounds are thiophenesulfonamides, and more
desirably 5-halo thiophene sulfonamides, and most desirably 5-halo thiophene
sulfonamides with -branches in the side chain of a primary alcohol.
In another example, the compounds 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 a further example, the compounds 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 example, the sulfonamide trifiuoroalkyl substituted alcohol is 5-
Chloro-N-[(lS)-3,3,3-trifluoro-I-(hydroxymethyl)-2-
(trifluorcmemyl)propyl]thiophene-2-sulfonamide or 4-Chloro-N-[(lS)-3,3,3-trifluoro-
l-(hydroxymemyl)-2-(trifluoromethyl)propyl]benzenesulfonamide.
In yet another example, R1 to R3 are H, R4 is (CF3)2CH, desirably of S-
stereochemistry, R5 is halogen, and W=C, X=S, Y=CH, Z=CH with the sulfonamide
attached to C-2 of the thiophene ring.
In a further example, R1 to R3 are H, R5 is halogen, W=C, X=S, Y=CH, Z=CH
with the sulfonamide attached to C-2 of the thiophene ring and R4 is of the structure:

In another example, R1 to R3 are H, R4 is (CH2CF3)2CH, R5 is halogen, and
W=C, X==S, Y=CH, Z==CH with the sulfonamide attached to C-2 of the thiophene
ring.
In a further example, R1 and R2 are CH3, R3 is H, R4 is CF3CH2(CH3)CH, R5 is
halogen, and W=C, X=S, Y=CH, Z=CH with the sulfonamide attached to C-2 of the
thiophene ring.
In still another example, R1 is CH3, R2 is H, R3 is H, R4 is (CF3)2CH, R5 is
halogen, and W=C, X=S, Y=CH, Z=CH with the sulfonamide attached to C-2 of the
thiophene ring.

In yet a further example, R1 to R3 are H, R4 is (F)2cycloalkyl, R5 is halogen,
and W=C, X=S, Y=CH, Z=CH with the sulfonamide attached to C-2 of the thiophene
ring.
The processes to form the sulfonamide triftuoroalkyl substituted alcohols
thereby includes reacting a trifluoroalkyl substituted amino alcohol and a sulfonyl
halide, in abase/solvent system. See, Scheme 1. In one embodiment, the process
includes reacting a trifluoroalkyl substituted amino alcohol, a sulfonyl chloride, and a
base/solvent system. The inventors have found mat by using specific base/solvent
systems, higher yields of the sulfbnamide product are obtained. The base/solvent
systems include 4-methyl morpholine/isopropyl acetate; Hunig's
base/tetrahydrofuran; 4-methyl morpholine/acetonitrile; 4-methyl
morpnoline/propionitrile; and 4-methyl morpholine/toluene.

Desirably, the process is performed at a temperature of about -10 to about
80°C. More desirably, the process is performed at a temperature of about 0 to about
45 °C.
The sulfonamide trifluoroalkyl substituted alcohols can thereby be isolated
from the solvent/base system in high yields. In one embodiment, the sulfonamide
trifluoroalkyl substituted alcohols are isolated by performing a solvent exchange. By
doing so, highly pure sulfonamide trifluoroalkyl substituted alcohols are isolated.
Desirably, the solvent utilized in the solvent/base system is exchanged for an anti-
solvent. More desirably, the solvent utilized in the solvent/base system is slowly
exchanged for an anti-solvent.

A variety of anti-solvents can be utilized to isolate highly pure sulforiamide
trifluoroalkyl substituted alcohols and include heptane or an anti-solvent that has a
polarity similar to heptane such as hexanes or cyclohexane. Desirably, the anti-
solvent is heptane. One of skill in the art would readily be able to select a suitable
anti-solvent for use in processes by using knowledge of skill in the art and the
teachings provided herein.
In one embodiment, the trifluoroalkyl substituted amino alcohol is of the
structure:

where R1-R4 are defined above. In another embodiment, the trifluoroalkyl substituted
amino alcohol utilized is of the structure:

In one example, R4 is (CF3)nalkyl such as CF3CH2, CH(CH3,)CH2CF3,
CH(CH2CF3)2, CH(CF3)CH3, 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 a further example, the trifluoroalkyl substituted amino alcohol is a salt of (2S)-2-
amino-4,4,4-trifluoro-3-(trifluoromethyl)butan-l-ol. In yet another embodiment, the
trifluoroalkyl substituted amino alcohol is a (2S)-2-amino-4,4,4-trifluoro-3-
(trifluoromethyl)butan-l-ol hydrochloride salt
The sulfonyl chloride reacts with the trifluoroalkyl substituted alcohol. In one
embodiment, the sulfonyl chloride is of the following structure, where R5, W, X, Y,
and Z are defined above. Desirably, R5 is chloride.

In one embodiment, tne sulionyi chloride is of me structure, where R5 is
defined above:

In another embodiment, the sulfonyl chloride is of the following structure,
where R1' is defined above and is at any position on the benzene ring including the
ortho, meta, and para positions. Desirably, Ru is halogen, nitto, C1 to C6 alkyl, or C1
to C6 alkoxy. More desirably, R11 is chloride, nitro, methyl, or methoxy.

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), the carbon atom to which the OH, R1, and R2 are attached (the  carbon
atom), or a combination thereof. More desirably, the -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, Cs, C6, C7, or C8), one to six carbon atoms (e.g., C1, C2, C3, C4, C4, or C6), or one
to four carbon atoms (e.g., C1,, C2, C3, or G4). The term "lower a alkyl refers to
straight- and branched-chain saturated aliphatic hydrocarbon groups having one to six
carbon atoms (e.g., C1 C2, C3, C4, C5, or C6), desirably one to four carbon atoms (e.g.,
C1, C2, C3, or C4). The term "alkenyl" refers to both straight- and branched-chain
aikyl groups -with at least one carbon-carbon double bond and two to eight carbon
atoms (e.g., C2, C3, C4, C3, 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 terra "aikynyl" 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 Cg), 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 tetms "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, amino, aryl, substituted aryl,
heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, alkoxy,
substituted alkoxy, aryloxy, substituted aryloxy, alkylcarbonyl, alkylcaxboxy,
alkylamino, and arylthio. In one example, the substinjent is selected from among
halogen, CN, OH, NO2, amino, aryl, heterocyclic, heteroaryl, alkoxy, aryloxy,
alkylcarbonyl, alkylcarboxy, alkylamino, and aryltbio. to another example, the
substituent is selected from among halogen, CN, OH, NO2, amino, aryl, hetetocyclic,
heteroaryl, and alkoxy. 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,
aikylamino, substituted alkylaniino, arylthio, heterocyclic, substituted heterocyclic,
heteroaryl, substituted heteroaryl, aminoalkyl, and substituted aminoalkyl. In one
example, the substituenls are selected from among halogen, CN, OH, NO2, amino,
alkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, aikylamino,
arylthio, heterocyclic,, heteroaryl, and aminoalkyl. In another example, the
substituents are selected from among halogen, CN, OH, NQ2, amino, alkyl, alkenyl,
alkynyl, alkoxy, heterocyclic, and heteroaryl.
The term "aryl" is used herein to refer to a carbocyclic aromatic system, which
may be a single ring, or multiple carbocyclic rings, desirably aromatic rings, fused or
linked together 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,
an aryl group has six to fourteen 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,
aikylamino, and arylthio. In one example, the substituent may be selected from
among halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy,
aryloxy, alkylcarbonyl, alkylcarboxy, alkylaraino, and arylthio. In another example,
the substituent may be selected from among halogen, CN, OH, NO2, amino, alkyl,
cycloalkyl, alkenyl, alkynyl, and alkoxy.
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 hi the backbone of Che 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, oxathiolyL, dioxazolyl, oxathiazolyl, oxazinyl, oxathiazinyl, benzopyranyl,
benzoxazinyl and xanthenyl.
The term "heteroaryi" as used herein refers to a stable, aromatic 5- to 14-
membered monocyclic or multicyclic heteroatom-containing ring. The heteroaryi ring
has in its backbone carbon atoms and one or more heteroatoms including nitrogen,
oxygen, and sulfur atoms, in one embodiment, the heteroaryi ring contains 1 to about
4 heteroatoms in the backbone of the ring. When the heteroaryi ring contains nitrogen
or sulfur atoms in the backbone of the ring, the nitrogen or sulfur atoms can be
oxidized. The term "heteroaryi" also refers to multicyclic rings in which a heteroaryi
ring is fused to an aryl ring. The heteroaryi 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 heteroaryi ring includes multicyclic
systems having 1 to 5 rings.
A variety of heteroaryi 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 heteroaryi groups include, without limitation,
furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, triazinyl, azepinyl, thienyl, dithiolyl, oxathiolyl, oxazolyl, thiazolyl,
oxadiazolyl, oxatriazolyl, oxepinyl, thiepinyl, diazepinyl, benzofuranyl, thionapthene,
indolyl, benzazolyl, purindinyl,pyranopyrrolyl, isoindazolyl, indoxazinyl,
benzoxazolyl, quinolinyl, isoquinolinyl, benzodiazonyl, napthyhidinyl, benzotbienyl,
pyridopyridinyl, acridinyl, carbazolyl, and purinyl rings.

The term "substituted heterocycle" and "substituted heteroaryl" as used herein
refers to a heterocycle 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-CHa-aryl, alkylamino, arylthio, aryl, or
heteroaryl, which groups may be optionally substituted. In one example, the
substituents may be selected from among 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), -SOH(C1 to C10 substituted alkyl), -
O-CH2-aryl, alkylamino, arylthio, aryl, or heteroaryl. In another example, the
substituents maybe selected from among halogen, CN, OH, NO2, arnino, alkyl,
cycloalkyl, alkenyl, alkynyl, C1 to C3 perfluoroalkyl, d to C3 perfluoroalkoxy,
alkoxy, aryl, or heteroaryl. 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 "alkylcarbonyl" is used herein to refer to the RCO group, where R is
alkyl or substituted alkyl.
The term "allsylcarboxy" 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, which may
be either same or different and the point of attachment is on the nitrogen atom.
The term "halogen" refers to C1, Br, F, or L
Pharmaceutically 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, toluenesulfonic,
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 tripropyl-
ammonmm (iso and normal), ethyldimethylammonium, benzyldimethylammonium,
cyclohexylammonium, benzylammonium, dibenzylammonium, piperidinium,
morpholiniura, pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-
emylmorpholinium, l-isopropylpynolidinium, 1,4-dimethylpiperazinium, 1-n-butyl
piperidinium, 2-methylpiperidinium, l-ethyl-2-methylpiperidinium, mono-, di- and
triethanolammonium, ethyl diethanolammonium, n-burylmonoethanolammonium,
tris(hydroxymethyl)methylammonium, phenylmonoetiianolammonium, 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.t 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 embodiment, a process is provided for preparing 5-chloro-N-[(lS)-
3,3,3-tiiauoro-l-(hydroxymemyl)-2-(trifluoromethyl)propyl]miophene-2-sulfonamide
and includes reacting (2S)-2-amino-4,4,4-trifluoro-3-(trifluoromethyl)butan-l-ol:i 5-

chlorothiopheaie-2-sulfonyl chloride, and 4-methylmorpholine in isopropyl acetate.
See, Scheme 2.

In another embodiment, a process is described for preparing 4-chloro-N-[(lS)-
3,3,3 -trifluoro-1 -(hydroxymethyl)-2-(trifluoromethyl)propyl] benzenesulfonamide
and includes reacting (2S)-2-amino-4,4,4-trifluoro-3-(trifluoromethyl)butan-l-ol, 4-
chlorobenzene-2-sulfonyl chloride, and 4-methylmorpholine in isopropyl acetate.
See, Scheme 3.

The following examples are illustrative only and are not intended to be a
limitation on the present invention.
EXAMPLES
Example 1 - Preparation of 5-Chloro-N-[(1S)-3,3,3-trifluoro-1-(hydroxymethyl)-
2-(trifluoro-methyl)propyI]thiophene-2-suifonamide
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), 4-methyl morpholine (2.7 mL, 24.6
mmol) was added. The mixture was stirred at 20 to 25 °C for 5 to 10 minutes and
then 5-chlorothiophene-2-sulfonyl chloride (2.0 g, 9.2 mmol) was added. The
reaction mixture was stirred at 20 to 25 °C for 6 to 18 hours. Water (10 mL) was
added to the reaction mixture and the solid dissolved. The two layers were separated,

the organic layer was washed with 10% NaHCO3 (10 mL) and 10% NaCl (10 mL),
and heptane (10 mL) was added to the isopropyl acetate layer (about 10 mL). The
mixture was reduced in volume by about half by distillation under atmospheric
conditions. While the solution remained at 80 to 90 °C, heptane (10 mL) was added
over 5 to 10 minutes. A solid began to form during heptane addition. After addition,
the mixture was cooled to 20 to 25 °C, the solution was stirred for 1 to 2 hours, and
then further cooled to 5 to 10 °C for 1 hour. The solid was collected by filtration,
washed with heptane (5 mL), and oven-dried to give 2.15 g (67%) of an off-white
solid. 98% area HPLC purity and >99% chiral purity by HPLC.
Example 2 - Preparation of 4-Chloro-N-[(1S)-3,3,3-trrfluoro-1-(hyclroxymethyl)-
2-(trifluoro-methyJ)propyl]benzenesulfonamide
To a suspension of (2S)-2-amino-4,4,4-tri-fluoro-3-(trifluoromethyl)butan-l-ol
(5 g, 20.2 mmol) in isopropyl acetate (50 mL) was added 4-methyl morpholine (5 mL,
45.5 mmol). The mixture was stirred at 20 to 25 °C for 5 tolO minutes and then 4-
chlorobenzenesulfonyl chloride (4.5 g, 21.3 mmol) was added. The reaction mixture
was stirred at 20 to 25 °C for 6 to 18 hours. Water (25 mL) was added to the reaction
mixture and the solid dissolved. The two layers were separated, the organic layer was
washed with 10% NaHCCb (25 mL) and 10% NaCl (25 mL), and heptane (50 mL)
was added to the isopropyl acetate layer (about 50 mL). The mixture was reduced in
volume by about half by distillation at atmospheric conditions. While the solution
remained at 80 to 90 °C, heptane (50 mL) was added over 5 to 10 minutes. A solid
began to form during heptane addition. After addition, the mixture was cooled to 20
to 25 °C, the solution was stirred for 1 to 2 hours, and then further cooled to 5 to 10
°C for 1 hours. The solid was collected by filtration, washed with heptane (15 mL),
and oven-dried to give 6.44 g (83%) of an off-white solid. 98% area HPLC purity.
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 process for preparing a sulfonamide trifluoroalkyl substituted
alcohol of the structure:

wherein:
R1 and R2 are independently selected from the group consisting of H, C1 to C6
alkyl, substituted C1 to C6 alkyl, CF3, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2
to C6alkynyl, and substituted C2 to C6alkynyl;
R3 is selected from the group consisting of H, C1 to C6 alkyl and substituted C1
to C6 alkyl;
R4 is selected from the group consisting of (CF3)alkyl, (CF3)n(substituted
alkyl), (CF3)nalkyl phenyl, (CF3)nalkyl(substituted phenyl), and (F)ncycloalkyl;
n is 1 to 3;
R5 is selected from the group consisting of H, halogen, and CF3;
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 C8
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 Rn 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 rings (i) to (iii) are optionally substituted by 1 to 3 substituents
comprising C1 to C6 alkyl or substituted C1 to C6 alkyl.
or a pharmaceutically acceptable salt, hydrate, or prodrug thereof;
said process comprising reacting a trifluoroalkyl substituted amino alcohol, a
sulfonyl chloride, and a base/solvent system selected from the group consisting of (a)
4-methyl morpholine/isopropyl acetate, (b) Hunig's base/tetrahydrofuran, (c) 4-
methyl morpholine/acetonitrile, (d) 4-methyl morpholine/propionitrile, and (e) 4-
methyl morpholine/toluene.
2. The process according to claim 1, wherein said sulfonamide
trifluoroalkyl substituted alcohol is of the structure:


6. The process according to claims 1 or 5, wherein said sulfonyl chloride
is of the structure:

wherein, R11 is chlorine, nitro, methyl, or methoxy.
7. The process according to claim 6, wherein said sulfonyl chloride is of
the structure:

8. The process according to claim 1, wherein said trifluoroalkyl
substituted amino alcohol is of the structure:

9. The process according to any of claims 1 to 8, wherein said
trifluoroalkyl substituted amino alcohol is of the structure:

10. The process according to any of claims 1 to 9, wherein R is
CH(CH3)CF3.

11. The process according to any of claims 1 to 9, wherein said
trifluoroalkyl substituted amino alcohol is (2S)-2-amino-4,4,4-trifluoro-3-
(trifluoromethyl)butan-l -ol.
12. The process according to claim 11, wherein said sulfonamide
trifluoroalkyl substituted alcohol is 5-Chloro-[N-[(lS)-3,3,3-trifluoro-l-
(hydroxymemyl)-2-(trifluoromethyl)propyl]tbiophene-2-sulfonamide.
13. The process according to claim 11, wherein said sulfonamide
trifluoroalkyl substituted alcohol is 4-Chloro-[N-[(lS)-3,3,3-trifluoro-l-
(hydioxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonarnide.
14. The process according to any of claims 1 to 13, wherein said
base/solvent system is isopropyl acetate and 4-methylmorpholine.
15. The process according to any of claims 1 to 13, wherein said
base/solvent system is tetrahydroniran and Hiinig's base.
16. The process according to any of claims 1 to 13, wherein said
base/solvent system is acetonitrile and 4-methyl morpholine.
17. The process according to any of claims 1 to 13, wherein said
base/solvent system is propionitrile and 4-methyl morpholine.
18. The process according to any of claims 1 to 13, wherein said
base/solvent system is toluene and 4-methyl morpholine..
19. The process according to any of claims 1 to 18, further comprising
isolating said sulfonamide trifluoroalkyl substituted alcohol by performing a solvent
exchange with heptane.

20. A process for preparing 5-chloro-[N-(l S)-3,3,3,-trifluoro-1 -
(hydroxymethyl)-2-(trifluorometiiyl)propyl]thiophene-2-sulfonanide, comprising
reacting (2S)-2-amino-4,4,4-trifluoro-3-(trifluon)mefliyl)butan-l-oI, 5-
chlorothiophene-2-suIfonyl chloride, and 4-methylmorpholine in isopropyl acetate.
21. The process according to claim 20, further comprising isolating said 5-
chloro-[N-(lS)-3,3,3-trifluoro-l-(hydroxymethyl)-2-
(trifluoromethyl)propyl]thiophene-2-sulfonamide by exchanging said isopropyl
acetate with heptane.
22. A process for preparing 4-chloro-[N-(l S)-3,3,3-trifluoro-l -
(hydroxymethyl)-2-(trifluoromethyl)propyl]benzenesulfonamide, comprising reacting
(2S)-2-amino-4,4,4-trifluoro-3-(trifluoromethyl)butan-l -ol, 4-chlorobenzene-2-
sulfonyl chloride, and 4-methylmorpholine in isopropyl acetate.
23. The process according to claim 22, further comprising isolating said 4-
chloro-[N-(lS)-3,3,3-trifluoro-l-(hydroxymethyl)-2-
(trifluoromethyl)propyl]benzenesulfonamide by exchanging said isopropyl acetate
with heptane.

Processes for the preparation of trifluoroalkyl
substituted N-(2-hydroxyalkyl) heteroarene- and benzene-sulphonamide derivatives of formula (I) or formula (II) (wherein the variables are as defined in the claims) are provided which
comprises reacting a trifluoroalkyl substituted amino alcohol, a sulphonyl chloride and a base/solvent system selected from
the group consisting of (a) 4-methylmorpholine/isopropyl
acetate, (b) Hünig's base/tetrahydrofuran, (c) 4-methylmorpholine/acetonitrile, (d) 4-methylmorpholine/propionitrile and (e)
4-methylmorpholin/ftoluene. Formulae (I) and (II).