MX2008010607A - Selective n-sulfonylation of 2-amino trifluoroalkyl substituted alcohols - Google Patents

Abstract

Processes for the preparation of trifluoroalkyl substituted N-(2-hydroxyalkyl) heteroarene- and benzenesulphonamide 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).

Description

SELECTIVE N-SULFONILATION OF SUBSTITUTE 2-AMINO TRIFLUOROALKYL 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 (memory loss) in elderly people. The main pathological lesions of AD found in the brain consist of intracellular beta-amyloid protein deposits in the form of plaques and angiopathy and intracellular neurofibrillary tangles of aggregated hyperphosphorylated tau protein. Recent evidence has revealed that elevated levels of amyloid beta in the brain not only precede tau pathology but are also correlated 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 compounds and phenylsulfonamide, specifically heterocyclic sulfonamide compounds containing fluoro- and trifluoroalkyl, have been shown to be useful in inhibiting β-amyloid production What is needed in the art are alternative methods for preparing sulfonamide compounds useful for inhibiting β-amyloid production.

BRIEF DESCRIPTION OF THE INVENTION In one aspect, processes are provided for preparing substituted trifluoroalkyl sulfonamide alcohols. In another aspect, processes for preparing substituted trifluoroalkyl sulfonamide alcohols of the following structures are provided: Formula I Formula II In a further aspect, procedures are provided for preparing substituted trifluoroalkyl sulfonamide alcohols of the following structure: In yet another aspect, a process for preparing 5-chloro- [N- (1S) -3,3,3-trifluoro-1- (hydroxymethyl) -2- (trifluoromethyl) propyl] thiophen-2-sulfonamide is provided. In a further aspect, a process for preparing 4-chloro- [N- (1S) -3,3,3-trifluoro-1- (hydroxymethyl) -2- (trifluoromethyl) propyl] benzenesulfonamide is 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 Procedures are provided for preparing substituted sulfonamide compounds. Desirably, the processes are for the preparation of heterocyclic or phenylisulfonamide compounds containing trifluoroalkyl. Therefore, a pathway is provided for the heterocyclic or phenylisulfonamide compounds containing trifluoroalkyl from the corresponding trifluoroalkyl aminoalcohol and sulfonyl chloride only through one step. This procedure also avoids the need for any step of protection and deprotection. In one embodiment, the following heterocyclic or phenylisulfonamide compounds containing trifluoroalkyl are prepared. wherein R1 and R2 are independently selected from H, Ci to Ce alkyl, substituted Ci to C6 alkyl, CF3, C2 to C6 alkenyl, substituted C2 to C alkenyl, C2 alkynyl to Ce and C2 alkynyl a C replaced; R3 is selected from H, C1 to C6 alkyl and substituted C1 to C6 alkyl; R 4 is selected from (CF 3) nalkyl, (CF 3) n (substituted alkyl), (CF 3) nalkylphenyl, (CF 3) nalkyl (substituted phenyl), and (F) n-cycloalkyl; n is 1 to 3; R5 is selected from H, halogen, and CF3; W, Y and Z are independently selected from C, CR6 and N, wherein at least one of W, Y or Z is C; X is selected from O, S, SO2 and NR7; R6 is selected from H, halogen, C1 to C6 alkyl, and substituted C1 to C6 alkyl; R7 is selected from H, Ci to C6 alkyl, and C3 to C8 cycloalkyl; R8, R9, R10, R11, and R12 are independently selected from H, halogen, C1 to C alkoxy, substituted C1 to C6 alkoxy, NO2, C1 to C6 alkyl, and substituted d to C6 alkyl; or R8 and R9; R9 and R10; R1 and R12; or R10 and R are fused to form (i) a saturated carbon-based ring containing 3 to 8 carbon atoms; (ii) an unsaturated ring based on carbon containing 3 to 8 carbon atoms; or (iii) a heterocyclic ring containing 1 to 3 heteroatoms selected from O, N, and S in the basic structure of the ring; wherein the rings (i) to (iii) can be substituted with 1 to 3 substituents including C1 to C6 alkyl or alkyl of Ci to C6 substituted; or a pharmaceutically acceptable salt, hydrate or prodrug thereof. In one embodiment, R1-R3 are H or 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, R is CH3 and R2 and R3 are H. In another embodiment, R4 is (CF3) nalkyl or (F) n-cycloalkyl. In one example, R4 is (CF3) nCH. In another example, R4 is ^^? ^^. In a further example, R4 is (CH2CF3) 2CH. In yet another example, R 4 is CF 3 CH 2 (CH 3) CH. In another example, R 4 is (F) 2 cycloalkyl. In a further embodiment, R5 is halogen. In another embodiment, the following heterocyclic or phenylsulfonamide compounds containing trifluoroalkyl are provided, wherein R1-R5; R8-R12, W, X, Y, and Z are defined above.

The point of attachment of the heterocyclic ring W-X-Y-Z-C with the group S02 is not a limitation. The ring may be attached to the SO2 group through a carbon atom or a nitrogen atom. In one example, the compounds are thiophenesulfonamides, and more conveniently 5-halothiofensulfonamides, and in particular 5- halotiofensulfonamidas with ß 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 a desirable embodiment, the furansulfonamides are characterized by β-branching in the side chain of a primary alcohol. In a further example, the compounds are pyrazolesulfonamides. In this way, the compound has a structure in which X is N7, W is N and Z and Y are C or CR6, with the proviso that at least one of Y or Z has to be C. In another example, the substituted trifluoroalkyl sulfonamide alcohol is 5-chloro-N - [(1S) -3,3,3-trifluoro-1- (hydroxymethyl) -2- (trifluoromethyl) propyl] thiophen-2-sulfonamide or 4-chloro- N - [(1 S) -3,3,3-trifluoro-1- (hydroxymethyl) -2- (trifluoromethyl) propyl] benzenesulfonamide. Even in another example, R1 to R3 are H, R4 is (CF3) 2CH, conveniently 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 R 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. Even in 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 another example, R a R 3 is H, R 4 is (F) 2 cycloalkyl, R 5 is halogen, and W = C, X = S, Y = CH, Z = CH, with the sulfonamide attached to C-2 in the ring triofen The processes for forming the substituted sulfonamide trifluoroalkyl alcohols therefore include reacting a substituted trifluoroalkyl amino alcohol and a sulfonyl halide in a base / solvent system. See Scheme 1. In one embodiment, the process includes reacting a substituted trifluoroalkyl amino alcohol, a sulfonyl chloride, and a base / solvent system. The inventors have discovered that by using specific base / solvent systems, higher yields of the sulfonamide product are obtained. The base / solvent systems include 4-methylmorpholine / isopropyl acetate; Hünig base / tetrahydrofuran; 4-methylmorpholine / acetonitrile; 4-methylmorpholine / propionitrile; and 4-methylmorpholine / toluene.

SCHEME 1 Desirably, the process is carried out at a temperature of about -10 to about 80 ° C. Most conveniently, the process is carried out at a temperature of from about 0 to about 45 ° C. The substituted sulfonamide trifluoroalkyl alcohols can therefore be isolated from the solvent / base system in high yields. In a modality, the substituted sulfonamide trifluoroalkyl alcohols are isolated by carrying out a solvent exchange. By doing this, highly pure substituted trifluoroalkyl sulfonamide alcohols are isolated. In an advisable manner, the solvent used in the solvent / base system is exchanged for an antisolvent. Most conveniently, the solvent used in the solvent / base system is slowly exchanged for an antisolvent.

A variety of antisolvents can be used to isolate highly pure substituted trifluoroalkyl sulfonamide alcohols and include heptane or an antisolvent having a heptane-like polarity such as hexanes or cyclohexane. In an advisable manner, the antisolvent is heptane. One skilled in the art will readily be able to select an antisolvent suitable for use in the processes by utilizing the knowledge of the skill in the art and the teachings provided herein. In one embodiment, the substituted trifluoroalkyl amino alcohol is of the structure: where F -R4 are defined above. In another embodiment, the substituted trifluoroalkyl amino alcohol used 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) n Cycloalkyl, conveniently (F) 2-cycloalkyl, in an advisable manner (F) 2-cyclohexane and bicyclo [3.1.0] hexane, and particularly 4,4-difluoro-cyclohexane and 4,4-difluorobicyclo [3.1.0] -3-hexane. In a further example, the substituted trifluoroalkyl amino alcohol is a salt of (2S) -2- amino-4,4,4-trifluoro-3- (trifluoromethyl) butan-1-ol. In yet another embodiment, the substituted trifluoroalkyl amino alcohol is a hydrochloride salt of (2S) -2-amino-4,4,4-trifluoro-3- (trifluoromethyl) butan-1-ol. The sulfonyl chloride reacts with the substituted trifluoroalkyl alcohol. In one embodiment, the sulfonyl chloride is of the following structure, wherein R5, W, X, Y, and Z are defined above. Conveniently, R5 is chloride.

In one embodiment, the sulfonyl chloride is of the structure, wherein R5 is defined above: i Suphonyl chloride can also be of the structure where R8-R12 are defined above: In another embodiment, the sulfonyl chloride has the following structure, wherein R1 is defined above and is in any position in the benzene ring including the ortho, meta and para positions. Desirably, R11 is halogen, nitro, Ci to CQ alkyl, or Ci to C6 alkoxy. Conveniently, R 11 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 can therefore give rise to optical isomers and diastereomers. Although shown irrespective of the stereochemistry, when the compounds contain one or more chiral centers, at least the chiral center of the β-amino alcohol has S-stereochemistry. Conveniently, the chiral centers include the carbon atom to which they are attached. N atom, R3 and R4 (the carbon atom a), the carbon atom to which OH, R1, and R2 are attached (the carbon atom β), or a combination thereof. Most conveniently, the carbon atom a is chiral. Particularly, the carbon atom a is chiral and of S stereochemistry. In this manner, the compounds include said optical isomers and diastereomers; as well as the racemic and resolved stereoisomers, enantiomerically pure; as well as other mixtures of the stereoisomers R and S, and pharmaceutically acceptable salts, hydrates and prodrugs thereof.

The term "alkyl" is used herein to refer to straight and branched chain saturated aliphatic hydrocarbon groups having one to ten carbon atoms (eg, Ci, C2, C3, C4) C5, C6, C7, Ce, C9 or C10), such as one to eight carbon atoms (eg, C2, C3, C4, C5, C6, C7, or C8), one to six carbon atoms (eg, C2, C3, C4, C5) , or Ce), or one to four carbon atoms (eg, C1, C2, C3, or C4). The term "lower alkyl" refers to straight and branched chain saturated aliphatic hydrocarbon groups having one to six carbon atoms (eg, Ci, C2, C3, C4, C5, or Ce), conveniently one to four carbon atoms. carbon (for example, C ^ C2, C3, or C). The term "alkenyl" refers to straight and branched chain alkyl groups with at least one carbon-carbon double bond and two to eight carbon atoms (eg, C2, C3, C4, C5, C6, C7, or C8) , two to six carbon atoms (eg, C2, C3, C4, C5, or C6), or two to four carbon atoms (eg, C2, C3, or C4). The term "alkynyl" refers to straight and branched chain alkyl groups with at least one carbon-carbon triple bond and two to eight carbon atoms (eg, C2, C3, C4) C5, C6, C7, or Cs) , two to six carbon atoms (eg, C2, C3, C4, C5, or C6), or two to four carbon atoms (eg, C2, C3, or C4). The terms "substituted alkyl", "substituted alkenyl" and "substituted alkynyl" refer to alkyl, alkenyl and alkynyl groups as just described having one to three substituents including halogen, CN, OH, NO2, amino, aryl, substituted aryl, heterocyclic, heterocyclic substituted, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio. In one example, the substituent is selected from halogen, CN, OH, NO2, amino, aryl, heterocyclic, heteroaryl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio. In another example, the substituent is selected from halogen, CN, OH, NO2, amino, aryl, heterocyclic, heteroaryl, and alkoxy. These substituents can be attached to any carbon of an alkyl, alkenyl or alkynyl group provided that the bond constitutes a stable chemical moiety. The term "cycloalkyl" is used herein to describe a saturated carbon-based ring having more than 3 carbon atoms and forming a stable ring. The term "cycloalkyl" may include groups wherein two or more cycloalkyl groups have been fused to form a stable multicyclic ring. Conveniently, cycloalkyl refers to a ring having from about 4 to about 9 carbon atoms, and more conveniently, about 6 carbon atoms. The term "substituted cycloalkyl" is used herein to refer to a cycloalkyl group as just described and having one to five substituents including, without limit, 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. In an example, the substituents are selected from halogen, CN, OH, NO2, amino, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio, heterocyclic, heteroaryl, and aminoalkyl. In another example, the substituents are selected from halogen, CN, OH, NO2, 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, preferably aromatic rings, fused or linked so that at least a portion of the rings fused or linked forms the aromatic conjugate system. Aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl, and indane. In an advisable manner, an aryl group has six to fourteen carbon atoms. The term "substituted aryl" refers to aryl as it has been newly defined to have one to four substituents including halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy , alkylamino and arylthio. In one example, the substituent may be selected from halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio. In another example, the substituent can be selected from halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy.

The term "heterocycle" or "heterocyclic" as used herein, may be used interchangeably to refer to a saturated heterocyclic, monocyclic, or multicyclic ring of 3 to 9 elements, saturated 0 partially unsaturated. The heterocyclic ring has in its basic structure carbon atoms and one or more heteroatoms which include nitrogen, oxygen and sulfur atoms. In one embodiment, the heterocyclic ring contains 1 to about 4 heteroatoms in the basic structure of the ring. When the heterocyclic ring contains nitrogen or sulfur atoms in the basic structure 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 with 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 that the resulting heterocyclic ring structure is chemically stable. In a modality, 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 rings containing heteroatoms, fused rings containing heteroatoms, and combinations thereof. Examples of heterocyclic groups include, without limit, tetrahydrofuranyl, piperidinyl, 2-oxopiperidinyl, pyrrolidinyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, pyranyl, pyronyl, dioxinyl, piperazinyl, dithiolyl, oxathiolyl, dioxazolyl, oxathiazolyl, oxazinyl, oxathiazinyl, benzopyranyl, benzoxanzinyl and xanthenyl. The term "heteroaryl" as used herein refers to a stable ring containing monocyclic or multicyclic aromatic hero atoms of 5 to 14 elements. The heteroaryl ring has in its basic structure carbon atoms and one or more heteroatoms which include nitrogen, oxygen and sulfur atoms. In one embodiment, the heteroaryl ring contains 1 to about 4 heteroatoms in the basic structure of the ring. When the heteroaryl ring contains nitrogen or sulfur atoms in the basic structure 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 that the resulting 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 rings containing heteroatoms, fused rings containing heteroatoms, and combinations thereof. Examples of heteroaryl groups include, without limit, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, azepinyl, thienyl, dithiolyl, oxathiolyl, oxazolium, thiazolyl, oxadiazolyl, oxatriazolyl, oxepinyl, thiepinyl, diazepinyl, benzofuranyl, thionaptene, indolyl, benzazolyl, purindinyl, pyranopyrrolyl, isoindazolyl, indoxazinyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzodiazonyl, naptilridinyl, benzothienyl, pyridopyridinyl, acridinyl, carbazolyl, and purinyl. 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 , perfluoroalkyl of C1 to C3, perfluoroalkoxy of C1 to C3, alkoxy, aryloxy, alkyloxy including -O- (C1 to C10 alkyl) or -O- (substituted alkyl C1 to Cio), alkylcarbonyl including -CO- (alkyl C10) or -CO- (substituted alkyl C1 to do), alkylcarboxy including -COO- (alkyl of C10) or -COO- (substituted alkyl of C10), -C (NH2) = N-OH, -SO2- (alkyl) C1 to Cio), -SO2- (substituted alkyl C1 to do), -O-CH2-aryl, alkylamino, arylthio, aryl, or heteroaryl, groups which may be optionally substituted. In one example, the substituents may be selected from halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl of C1 to C3, perfluoroalkoxy of C1 to C3, alkoxy, aryloxy, alkyloxy including -O- ( alkyl given) or -O- (substituted alkyl C1 to C10), alkylcarbonyl including -CO- (C1 to C0 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- (C0 alkyl), -SO2- (C1 to C10 substituted alkyl), - O-CH2- aryl, alkylamino, arylthio, aryl, or heteroaryl. In another example, the substituents can be selected from halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl of C1 to C3, perfluoroalkoxy of C1 to C3, alkoxy, aryl, or heteroaryl. A heterocycle or substituted heteroaryl group may have 1, 2, 3, or 4 substituents. The term "alkoxy" is used herein to refer to the group OR, wherein R is alkyl or substituted alkyl. The term "lower alkoxy" refers to alkoxy groups having one to six carbon atoms. The term "aryloxy" is used herein to refer to the group OR, wherein R is aryl or substituted aryl. The term "arylthio" is used herein to refer to the SR group, wherein R is aryl or substituted aryl. The term "alkylcarbonyl" is used herein to refer to the RCO group, wherein R is alkyl or substituted alkyl. The term "alkyl carboxy" is used herein to refer to the group COOR, wherein R is alkyl or substituted alkyl. The term "aminoalkyl" refers to secondary and tertiary amines wherein the alkyl or substituted alkyl groups contain one to eight carbon atoms, which may be the same or different and the point of attachment is at the nitrogen atom. The term "halogen" refers to Cl, Br, F or I. The pharmaceutically acceptable salts can be formed from organic and inorganic acids including, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids. Alkali metal salts including, for example, sodium, lithium, or potassium, and organic bases, such as ammonium, mono-, di-, and trimethylammonium salts, may also be formed from inorganic bases, conveniently -, di- and triethylammonium, mono-, di- and tripropylammonium (iso and normal), ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium, benzylammonium, dibenzylammonium, piperidinium, morpholinium, pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium, 1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butylpiperidinium, 2-methylpiperidinium, 1-ethyl-2-methylpiperidinium, mono-, di- and triethanolammonium, ethyl diethanolammonium, n-butylmonoethanolammonium, tris (hydroxymethyl) methylammonium, phenylmonoethanolammonium, and the like. The physiologically acceptable alkali salts and alkaline earth metal salts may include, without limitation, sodium, potassium, calcium and magnesium salts in the form of asters, and carbamates. These salts, as well as other compounds, may be in the form of esters, carbamates and other conventional forms of "pro-drug", which, when administered in such form, are converted to the active portion in vivo. In one embodiment, prodrugs are esters. In another embodiment, the prodrugs are carbamates. See, for example, 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 & amp;; Sons (1996).

In one embodiment, a process for preparing 5-chloro-N - [(1 S) -3,3,3-trifluoro-1- (hydroxymethyl) -2- (trifluoromethyl) propyl] thiophen-2-sulfonamide is provided and includes react (2S) -2-amino-4,4,4-trifluoro-3- (trifluoromethyl) butan-1-ol, 5-chlorothiophen-2-sulfonyl chloride, and 4-methylmorpholine in isopropyl acetate. See, Scheme 2.

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

SCHEME 3 The following examples are only illustrative and are intended to be a limitation for the present invention.

EXAMPLES EXAMPLE 1 Preparation of 5-chloro-N-rf 1 S) -3,3,3-trifluoro-1- (hydroxymethyl) -2- (trifluoromethyl) propylthiophene-2-sulfonamide To a suspension of (2S) -2-amino-4,4,4-tri-fluoro-3- (trifluoromethyl) butan-1-ol (2 g, 8.1 mmol) in isopropyl acetate (10 mL) was added 4-methylmorpholine (2.7 mL, 24.6 mmol). The mixture was stirred at 20-25 ° C for 5 to 10 minutes and then 5-chlorothiophen-2-sulfonyl chloride (2.0 g, 9.2 mmol) was added. The reaction mixture was stirred at 20-25 ° 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 (approximately 10 mL). The mixture was reduced in volume to about half by distillation under atmospheric conditions. While the solution remained between 80 and 90 ° C, heptane (10 mL) was added for 5 to 10 minutes. During the addition of heptane a solid began to form. After the addition, the mixture was cooled between 20 and 25 ° C, the solution was stirred for 1 to 2 hours, and then further cooled between 5 and 10 ° C for 1 hour. The solid was collected by filtration, washed with heptane (5 mL) and dried in oven to give 2.15 g (67%) of an off-white solid. 98% purity area HPLC and > 99% chiral purity through HPLC.

EXAMPLE 2 Preparation of 4-C gold N - [(1S) -3,3,3-trifluoro-1- (hydroxymethin-2- (trifluoromethyl) propylenebenzene sulfonamide To a suspension of (2S) -2-amino-4, 4,4-trifluoro-3- (trifluoromethyl) butan--ol (5 g, 20.2 mmol) in isopropyl acetate (50 mL), 4-methylmorpholine (5 mL, 45.5 mmol) was added. The mixture was stirred between 20 and 25 ° C for 5 to 10 minutes and then 4-chlorobenzenesulfonyl chloride (4.5 g, 21.3 mmol) was added. The reaction mixture was stirred at 20-25 ° 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% NaHCO3 (25 mL) and 10% NaCl (25 mL), and added heptane (50 ml_) to the isopropyl acetate layer (approximately 50 ml_). The mixture was reduced in volume to about half by distillation at atmospheric conditions. While the solution remained between 80 and 90 ° C, heptane (50 mL) was added for 5 to 10 minutes. During the addition of heptane a solid began to form. After the addition, the mixture was cooled between 20 and 25 ° C, the solution was stirred for 1 to 2 hours, and then further cooled between 5 and 10 ° C for 1 hour. The solid was collected by filtration, washed with heptane (15 mL) and dried in oven to give 6.44 g (83%) of an off-white solid. 98% purity area HPLC. All publications cited in this specification are incorporated herein by reference. Although 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. Said modifications are intended to be within the scope of the appended claims.

Claims (23)

1. NOVELTY OF THE INVENTION
2. CLAIMS process for preparing a substituted trifluoroalkyl sulfonamide alcohol of the structure: wherein R1 and R2 are independently selected from H, Ci to C6 alkyl, substituted Ci to C6 alkyl, CF3, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl and C2 alkynyl to C6 substituted; R 3 is selected from H, C 1 to C 6 alkyl and C 1 to C 6 alkyl substituted; R 4 is selected from (CF 3) nalkyl, (CF 3) n (substituted alkyl), (CF 3) nalkylphenyl, (CF 3) nalkyl (substituted phenyl), and (F) n-cycloalkyl; n is 1 to 3; R5 is selected from H, halogen, and CF3; W, Y and Z are independently selected from C, CR6 and N, wherein at least one of W, Y or Z is C; X is selected from O, S, SO2 and NR7; R6 is selected from H, halogen, C1 to C6 alkyl, and substituted C1 to C6 alkyl; R7 is selected from H, alkyl from d to Ce, and cycloalkyl from C3 to C8; R8, R9, R10, R11, and R12 are independently selected from H, halogen, C1 to C6 alkyl, C- alkyl? a C6 substituted, C1 to C6 alkoxy, substituted C ^ to C6 alkoxy, and NO2; or R8 and R9; R9 and R10; R 1 and R 12; or R10 and R1 are fuse to form: (i) a saturated ring based on carbon containing 3 to 8 carbon atoms; (I) an unsaturated ring based on carbon 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 basic structure of the ring; wherein rings (i) to (iii) are optionally substituted with 1 to 3 substituents comprising Ci to C6 alkyl or C- alkyl? a C replaced; or a pharmaceutically acceptable salt, hydrate or prodrug thereof; said process comprises reacting a substituted trifluoroalkyl amino alcohol, a sulfonyl chloride, and a base / solvent system selected from the group consisting of (a) 4-methylmorpholine / isopropyl acetate; (b) Hünig / tetrahydrofuran base; (c) 4-methylmorpholine / acetonitrile; (d) 4-methylmorpholine / propionitrile; and 4-methylmorpholine / toluene. 2. The process according to claim 1, further characterized in that said substituted trifluoroalkyl sulfonamide alcohol is of the structure:
3. 3. - The method according to claim 1 or 2, further characterized in that said sulfonyl chloride is of the structure:
4. 4. - The method according to claim 3, further characterized in that R5 is chloro.
5. 5. The process according to claim 1, further characterized in that said substituted trifluoroalkyl sulfonamide alcohol is of the structure:
6. 6. - The method according to claim 1 or 5, further characterized in that said sulfonyl chloride is of the structure: wherein R11 is chloro, nitro, methyl or methoxy.
7. 7. The process according to claim 6, further characterized in that said sulfonyl chloride is of the structure:
8. 8. - The method according to claim 1, further characterized in that said substituted trifluoroalkyl amino alcohol is of the structure:
9. 9. The process according to any of claims 1 to 8, further characterized in that said substituted trifluoroalkyl amino alcohol is of the structure:
10. 10. - The method according to any of claims 1 to 9, further characterized in that R4 is CH (CH3) CF3.
11. 11. The process according to any of claims 1 to 9, further characterized in that said substituted trifluoroalkyl amino alcohol is (2S) -2-amino-4,4,4-trifluoro-3- (trifluoromethyl) butan-1- ol.
12. 12. The process according to claim 11, further characterized in that said substituted trifluoroalkyl sulfonamide alcohol is 5-chloro-N - [(1S) -3,3,3-trifluoro-1- (hydroxymethyl) -2- (trifluoromethyl) ) propyl] thiophen-2-sulfonamide.
13. 13. The process according to claim 11, further characterized in that said substituted trifluoroalkyl sulfonamide alcohol is 4-Chloro-N - [(1S) -3,3,3-trifluoro-1- (hydroxymethyl) -2- (trifluoromethyl) propyl ] benzenesulfonamide.
14. 14. The process according to any of claims 1 to 13, further characterized in that said base / solvent system is isopropyl acetate and 4-methylmorpholine.
15. 15. The process according to any of claims 1 to 13, further characterized in that said base / solvent system is tetrahydrofuran and Hünig base.
16. 16. - The method according to any of claims 1 to 13, further characterized in that said base / solvent system is acetonitrile and 4-methylmorpholine.
17. 17. - The method according to any of claims 1 to 13, further characterized in that said base / solvent system is propionitrile and 4-methylmorpholine.
18. 18. - The method according to any of claims 1 to 13, further characterized in that said base / solvent system is toluene and 4-methylmorpholine.
19. 19. The process according to any of claims 1 to 18, further characterized in that it additionally comprises isolating said substituted trifluoroalkyl sulfonamide alcohol by conducting a solvent exchange with heptane.
20. 20. - A process for preparing 5-chloro- [N- (1S) -3,3,3-trifluoro-1- (hydroxymethyl) -2- (trifluoromethyl) propyl] thiophene-2-sulfonamide, which comprises reacting ( 2S) -2-amino-4,4,4-trifluoro-3- (trifluoromethyl) butan-1-ol, 5-chlorothiophen-2-sulfonyl chloride, and 4-methylmorpholine in isopropyl acetate.
21. 21. The process according to claim 20, further characterized in that it additionally comprises isolating said 5-chloro- [N- (1S) -3,3,3-trifluoro-1- (hydroxymethyl) -2- (trifluoromethyl) propyl. ] thiophen-2-sulfonamide by exchanging said isopropyl acetate with heptane.
22. 22. A process for preparing 4-chloro-N - [(1S) -3,3,3-trifluoro-1- (hydroxymethyl) -2- (trifluoromethyl) propyl] benzenesulfonamide, which comprises reacting (2S) -2-amino-4,4,4-trifluoro-3- (trifluoromethyl) butan-1-ol, 4-chlorobenzene-2-sulfonyl chloride, and 4-methylmorpholine in isopropyl acetate.
23. 23. - The method according to claim 22, further characterized in that it additionally comprises isolating said 4-chloro-N - [(1S) -3,3,3-trifluoro-1- (hydroxymethyl) -2- (trifluoromethyl) propyl ] benzenesulfonamide by exchanging said isopropyl acetate with heptane.