MX2008010608A - Methods for preparing sulfonamide substituted alcohols and intermediates thereof - Google Patents

Abstract

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.

Description

METHODS FOR THE PREPARATION OF SUBSTITUTE SULFONAMIDE ALCOHOLS AND THESE INTERMEDIARIES BACKGROUND OF THE INVENTION This invention relates to inhibitors of amyloid beta 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 the elderly. The main pathological lesions of AD found in the brain consist of extracellular deposits of beta amyloid protein in the form of plates 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 related to cognitive decline. Recent studies have shown that the aggregated amyloid beta is toxic to neurons in cell culture, suggesting even more a causative role for beta amyloid in AD. Heterocyclic and phenylsulfonamide compounds, especially heterocyclic sulfonamide compounds containing fluoro and trifluoroalkyl have been shown to be useful in inhibiting 3-amyloid production. What is needed in the art are alternative methods for preparing sulfonamide compounds, which are useful for inhibiting the production of -amyloid and their intermediaries.

BRIEF DESCRIPTION OF THE INVENTION In one aspect, methods are provided for preparing alcohols or amino salts thereof. In another aspect methods are provided for preparing substituted sulfonamide alcohols. 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 described herein provide routes for substituted sulfonamide alcohols. The methods also provide novel steps to prepare intermediates thereof, including aminoalcohols.

A. Methods for preparing amino alcohols A method for preparing an amino alcohol, or salt thereof, from an amino ester is described. See scheme 1, wherein R, R2, R3 and R4 are defined below.

SCHEME 1 In one embodiment, the aminoalcohol is of structure: H wherein R2 is a protecting group; R3 is selected from hydrogen, lower alkyl and substituted lower alkyl; R 4 is selected from (CF 3) n alkyl, (CF 3) n (substituted alkyl), (CF 3) nalkylphenyl, (CF 3) nalkyl (substituted phenyl) and (F) n Cycloalkyl; and n is 1 to 3. Preferably R2 is 1-methylbenzyl. The term "protecting group" as used herein refers to groups that protect a functional amino group. Preferably, the protecting group can be removed by deprotection under conditions known to those skilled in the art. A variety of protecting groups are known in the art and include those set forth in their Green et al., "Protective Groups in Organic Synthesis," 3rd Edition, John Wiley & Sons Inc, June, 1999, which are incorporated herein by reference herein. More preferably, the protecting group is an optionally substituted alkyl, cycloalkyl or carbonyl. Even more preferably, the protecting group is 1-methylbenzyl, benzyl, t-butyloxycarbonyl (BOC), or acetyl, among others. Plus preferably the protecting group is 1-methylbenzyl. In a further embodiment, the aminoalcohol has the following structure: ph R4 R3 wherein R3 is selected from hydrogen, lower alkyl and substituted lower alkyl; R 4 is selected from (CF 3) n alkyl, (CF 3) n (substituted alkyl), (CF 3) nalkylphenyl, (CF 3) nalkyl (substituted phenyl) and (F) n cycloalkyl; and n is 1 to 3. In one example, R4 is (CF3) alkyl such as CF3CH2) CH (CH3) CH2CF3, CH (CH2CF3) 2, CH (CH3) CF3 or CH (CF3) 2. In another example, R4 is (F) n Cycloalkyl, preferably (F) 2 cycloalkyl, more preferably (F) 2-cyclohexane and bicyclo [3.1. Ojhexane, and more desirably 4,4-difluoro-cyclohexane and 4,4-diflurobicyclo [3.1 .0 ] -3hexane. In one embodiment, the aminoalcohol is:H In a further embodiment, the aminoalcohol is (2S) -4,4,4-trifluoro-2-. { [(1 R) -1-phenylethyl] amino} -3- (trifluoromethyl) butan-1 -ol: Alternatively, an aminoalcohol salt of the following can be prepared from the aminoesters noted above.

HCI wherein R3 is selected from hydrogen, lower alkyl and substituted lower 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; and n is 1 to 3. In another embodiment, the aminoalcohol salt is: In a further embodiment, the aminoalcohol salt is: The amino alcohols are prepared by reducing the amino ester. The reduction is carried out by adding the amino ester 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 amino ester to an alcohol functional group. A person skilled in the art will be able to select a suitable reducing agent for reduction. Suitable reducing agents include hydride reducing agents such as, without restriction, sodium borohydride (NaBH4), lithium aluminum hydride (LAH), lithium borohydride, diisobutylaluminum hydride (DIBAL-H), bis-methoxyethoxyaluminum hydride and sodium, hydride of bis (2-methoxyethoxy) aluminum and sodium (red-A1), k-selectride, among others, including those established in "Comprehensive Organic Transformations", RC Larock, CVH Publishers, Inc., New Cork, NY, 1989, which is incorporated herein by reference herein. Preferably, the reducing hustle 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 used during the reduction. Preferably, the non-reactive solvent used during the reduction includes toluene, tetrahydrofuran (THF), hexanes, heptane, dichloromethane, cyclohexane, among others. The inventors have discovered that when the amino ester is added to the reducing agent, ie DIBAL-H, the production of aminoalcohol is greater than if the reducing agent were added to the amino ester. Typically, the Amino alcohol is prepared in a yield 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 the embodiment, the amino alcohol is prepared in a production of about 90 to about 95%. The temperature used during the reduction is greater than -60C. In one embodiment, the reduction to the aminoalcohol is carried out at about -60 ° to about 10 ° C. In another embodiment, the reduction is performed around -20 to about -10 ° C. In a further embodiment, the reduction is performed at about -8 to 1 ° C. In even another mode, the reduction takes place at around -10 ° C. The reduction to the aminoalcohol is subsequently extinguished using a protic solvent. By the term "protic solvent" is meant a solvent that contains a source of hydrogen (H +) that can be released into 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 restriction, strong and weak acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trihaloacetic acid, hydrogen bromide, maleic acids, sulfonic acids, propionic acids, acids tartarics, lactic acids, camphoric acids, aspartic acids, citronellic acids, BCI3, ethanolic acids, hydrogen sulfide, methanesulfonic acid, trifluoroacetic acid, among others. In still another embodiment, the protic solvent is a mixture of solvents containing hydrogen atoms that can be released into the solution. A number of amino esters can be reduced and can be determined by one skilled in the art using techniques and knowledge in the art and in the example specification. Preferably, the amino ester contain one or more chiral carbon centers. More preferably, the amino ester is a protected amino ester. More preferably, the amino ester is an N-protected amino ester. In one embodiment, the amino ester has the following structure: wherein R1 is alkyl or benzyl; R2 is a protecting group; R3 is selected from hydrogen, lower alkyl and substituted lower alkyl; R 4 is selected from (CF 3) nalkyl, (CF 3) n (substituted alkyl), (CF 3) n alkylphenyl (CF 3) nalkyl (substituted phenyl), and (F) n-cycloalkyl; and n is 1 to 3. In another embodiment, the amino ester has the following structure, wherein R1, R3, and R4 are defined as above: In a further embodiment, the amino ester has the following structure wherein R1, R3, and R4 are defined above: In even another embodiment, the amino ester is: In even an additional embodiment the amino ester is: In one example, there is provided a method for preparing an aminoalcohol or salt thereof, from an amino ester including reducing the amino ester by adding the amino ester to diisobutylaluminum hydride at about -60 ° to about -10 ° C. In another example, the method for preparing an amino alcohol of the structure is provided: wherein an amino ester of the following structure is reduced by adding the amino ester to diisobutylaluminum hydride at about -60 ° to about -10 ° C.

B. Methods for Preparing Substituted Sulfonamide Alcohols Methods for preparing substituted sulfonamide alcohols are also provided. In one embodiment, the substituted sulfonamide alcohol is substituted with one or more trifluoroalkyl groups. In another embodiment, the substituted sulfonamide alcohol is a substituted heterocyclic sulfonamide alcohol or substituted sulfonamide alcohol is a heterocyclic substituted sulfonamide alcohol or substituted phenylisulfonamide alcohol. See scheme 2. In one embodiment, the substituted sulfonamide alcohol is of the structure: wherein R3 is selected from H, lower alkyl and substituted lower alkyl; R 4 is selected from (CF 3) nalkyl, (CF 3) n (substituted alkyl), (CF 3) nalkyl, (CF 3) nalkyl (substituted phenyl), and (F) n-cycloalkyl; n is 1 to 3; R5 is selected from 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 C, CR6 and N, wherein at least one of W, Y or Z is C; X is selected from O, S, S02, and NR7; R6 is selected from H, halogen, Ci to C6 alkyl and substituted Ci to C6 alkyl; and R7 is selected from H, Ci to C6 alkyl and C3 to C8 cycloalkyl.

SCHEME 2 me diastereomeric zcla 1 diastereomer agent -60 ° c to -10 ° c reducer The point of attachment of the heterocyclic ring W-X-Y-Z-C to the SO2 group is not a limitation. The ring can be attached to the S02 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 more preferably 5-halo thiophenesulfonamides with β-branches in the side chain of a primary alcohol. In a further embodiment, the substituted sulfonamide alcohol is: In other Preparations are furonsulfonamides. Thus, the compounds have a structure in which X is O. In a desirable embodiment, the furansulfonamides are characterized by branching? of a primary alcohol. In even 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 substituted alcohol of trifluoroalkyl sulfonamide is 5-chloro-N - [(1 S) -3,3,3-trifluoro-1- (hydroxymethyl) -2- (trifluoromethyl) propyl] thiophene-2-sulfonamide or 4-chloro-N - [( 1 S) -3,3,3-trfluoro-1- (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 even a further example, R3 is H, R4 is (F) 2-cycloalkyl, 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 yet another example the substituted sulfonamide alcohol is: even an additional example, the substituted sulfonamide alcohol is: another embodiment, the substituted sulfonamide alcohol has the structure: wherein R3 is selected from H, lower alkyl and substituted lower alkyl; R 4 is selected from (CF 3) nalkyl, (CF 3) n (substituted alkyl), (CF 3) nalkylphenyl and (CF 3) nalkyl (substituted phenyl), and (F) n-cycloalkyl; n is 1 to 3; R8, R9, R10, R11 and R12 are independently selected from H, halogen, Ci to C6 alkyl, substituted Ci to C6 alkyl, Ci to C6 alkoxy, substituted Ci to C6 alkoxy and NO2; or R8 and R9; R9 and R10; R1 and R12; or R10 and R1 are fused to form (i) a saturated ring with a carbon base containing from 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 O, N and S in the ring structure; wherein rings (i) to (iii) are optionally substituted by 1 to 3 substituents including Ci to C6 alkyl or substituted Ci to C6 alkyl. In one example, the substituted sulfonamide alcohol is: The methods here include isolating a diastereomer of an N-protected amino ester by reacting a diastereomeric mixture of N-protected amino esters with a protic acid to form the salt of corresponding N-protected amino ester. The desired diastereomer of the salt Amino ester 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 used to convert aminoalcohols to the corresponding salt and include, without Restriction, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, among others. The individual diastereomeric N-protected amino ester salt desired is precipitated from the solution and then isolated using techniques in the technique such as filtration, decanting, among others. Preferably, the salt of N-protected diastereomeric amino ester is isolated using filtration.

The N-protected amino ester salt can then be used without purification additional or can be purified using techniques known to experts in the technique.

In one embodiment, the N-protected amino ester salt is from the structure: HCI Wherein R is alkyl or benzyl; R3 is selected from hydrogen, lower alkyl and substituted lower alkyl; R4 is selected from (CF3) nalkyl, (CF3) n (substituted alkyl), (CF3) nalkylphenyl and (CF3) nalkyl (substituted phenyl), and (F) n Cycloalkyl; and n is 1 to 3. In another embodiment, the N-protected amino ester salt is: HCI The N-protected amino ester salt is then treated with a base to form the corresponding N-protected amino ester of the individual diastereomer. The term "base" as used herein refers to a chemical compound that is capable of accepting protons. Therefore, the base term includes, without restriction, hydroxides such as potassium, lithium or sodium hydroxide, alkoxides, hydrides, amines, among others and includes those described in US patent application A. Publication No.US-2005/02729323 , which is incorporated herein by reference. The N-protected amino ester is then reduced to the N-protected amino alcohol by adding the N-protected amino ester to DIBAL-H as described above. The reduction is then quenched with a protic solvent as described above to form the N-protected aminoalcohol. The N-protected amino alcohol is then converted to the N-protected aminoalcohol salt by reacting the N-protected amino alcohol with a protic acid as described above.

The N-protected aminoalcohol salt is then hydrogenated to form the unprotected aminoalcohol salt. One skilled in the art would be able to readily select a suitable hydrogenation agent for use in hydrogenation. Preferably, hydrogen is used in the presence of a catalyst. Catalysts that are useful in hydrogenation include those stated in Larock et al. cited above, which is incorporated herein by reference. Preferably, the hydrogenation is carried out using Pd / C. The unprotected aminoalcohol salt is sulfonylated using a sulfonyl chloride to form a substituted sulfonamide alcohol. In one embodiment, the sulfonamide chloride is of the structure: Wherein 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, Ci to C6 alkyl and substituted C to i to C6 alkyl; R7 is selected from H, Ci to C6 alkyl and C3 to C8 cycloalkyl. In another embodiment, the sulfonyl chloride is: In even an additional embodiment, the sulfonyl chloride is of the structure: wherein R8; R9 and R10; R1 1 and R 2 are independently selected from H, halogen, Ci to C6 alkyl, substituted Ci to C6 alkyl, Ci to C6 alkoxy, substituted d to C6 alkoxy and N02; or R8 and R9; R9 and R10; R1 and R12; or R10 and R1 1 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 O, N and S in the ring structure; wherein the rings (i) to (iii) are optionally substituted by 1 to 3 substituents including C 1 to C 6 alkyl or substituted Ci to C 6 alkyl. Preferably, the sulfonylation is carried out in the absence of protection and deprotection steps. More preferably, the sulfonylation is carried out in the absence of any silylation or desilylation step as described in U.S. Patent Application Publication No. US-2004/0198778 A1, which is incorporated herein by reference. Typically, the sulfonylation is performed using a base / solvent system using 4-methyl morpholine / isopropyium acetate, Hünig / tetrahydrofuran base, 4-methyl morpholine / acetonitrile, 4-methyl morpholine / propionitrile, and 4-methyl morpholine / toluene using the procedure described in U.S. Provisional Patent Application No. 60 / 774,300, which is incorporated herein by reference. The substituted sulfonamide alcohol is optionally purified using techniques known to those skilled in the art. Preferably, the purification is carried out 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. Although shown irrespective of the stereochemistry, when the compounds contain one or more chiral centers, at least the chiral center of -aminoalcohol is S-stereochemistry. Preferably, the chiral centers include the carbon atom to which the N atom is attached, R3, and R4 (the a-carbon atom). More preferably, the α-carbon atom is chiral. More preferably the α-carbon atom is chiral and of S stereochemistry. Thus, the compounds include such 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, as well as 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, Ce, C7, C8> C9) or C10), as one to eight carbon atoms (e.g., Ci, C2, C3, C4, C5, C6, C7, or C8), one to six carbon atoms (e.g., Ci, C2 > C3, C4) C5, or C6), or one to four carbon atoms (eg, Ci, 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 d, C2, C3, C, C5, or C6), preferably one to four carbon atoms (for example Ci, C2, C3, or C4). 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 (for example C2), C3) C4, C5, C6, C, or Cs), two to six carbon atoms (for example C2, C3, C, C5, or Ce), or two to four carbon atoms (for example 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 (eg C2, C3, C4, C5, C6, C, or C8) , two to six carbon atoms (for example C2, C3, C4, C5, or C6), or two to four carbon atoms (for example C2, C3, or C).

The terms "substituted alkyl", "substituted alkenyl" and "substituted alkynyl" refer to alkyl, alkenyl and alkynyl groups just as described having from one to three substituents including halogen, CN, OH, NO2, amino, aryl, aryl substituted, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkyl carbonyl, alkyl carboxy, alkylamino and arylthio. 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 ring with a carbon base having more than three 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. Preferably, cycloalkyl refers to a ring having from about 4 to about 9 carbon atoms and more preferably 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 restriction, halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkyl carbonyl, alkyl carboxy, 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 fused or linked aromatic rings such that at least a portion of the fused or linked rings forms the conjugated aromatic system. Aryl groups include, without restriction, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl, and indane. Preferably, aryl refers to an aromatic carbocyclic system having from about 6 to about 14 carbon atoms. The term "substituted aryl" refers to aryl as defined above 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 may be used interchangeably to refer to a saturated or partially saturated multicyclic or monocyclic 3 to 9 membered heterocyclic ring. The heterocyclic ring has in its structure 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 ring structure. When the heterocyclic ring contains nitrogen or sulfur atoms in the ring structure, the nitrogen or sulfur atoms can be oxidized. The term "heterocycle" or "heterocyclic" also refers to multicyclic rings in which a heterocyclic ring is operated at 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 atom carbon as long as the resulting heterocyclic ring structure is chemically stable. In one embodiment, the heterocyclic ring includes multicyclic systems having 1 to 5 rings. It is known in the art from heterocyclic groups and includes, without restriction, oxygen-containing rings, nitrogen-containing rings, sulfur-containing rings, mixed heteroatom-containing rings, rings containing fused heteroatoms, and combinations thereof. Examples of heterocyclic groups include, without restriction, tetrahydofuranyl, piperidinyl, 2-oxopiperidinyl, pyrrolidinyl, morpholinyl, thiamorpholinyl, thiamorpholinyl, sulfoxide, pyranyl, pyronyl, dioxinyl, piperazinyl, dithiolyl, oxathiolyl, dioxazolyl, oxatazolyl, oxazinyl, oxathiazinyl, benzopyranyl, benzoxazinyl and xanthenyl. The term "heteroaryl" as used herein refers to a ring containing heterocyclic heterocyclics or monocyclics of 5 to 14 stable aromatic members. The heteroaryl ring has in its structure carbon atoms and one or more heteroatoms including nitrogen, oxygen and sulfur atoms. In one embodiment, the heteroaryl ring contains one to about 4 heteroatoms in ring structure. When the heteroaryl ring contains nitrogen or sulfur atoms in the ring structure, 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 ring structure resulting heterocyclic 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 restriction, 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 restriction, furyl, pyrrolyl, puriolyl, imidazolyl, triasolyl, pyridyl, pyridazinyl, pyrimidinyl, purzinyl, triazinyl, azepinyl, thienyl, dithiolyl, oxathiolyl, oxazolyl, thiazolyl, oxadiazolyl, oxatriazolyl, oxepinyl, thiepinyl, diazepinyl, benzofuranyl, thionaphthene, indolyl, benzazolyl, puhndinyl, pyranopyrrolyl, isoindazolyl, n-hexazinyl, benzoxazolyl, quinilinyl, isoquinolinyl, benzodiazonyl, naphthylridinyl, benzothienyl, pyridopyridinyl, acridinyl, carbazolyl, and purinyl. 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, perfluoroalkyl, Ci to C3, 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- (substituted alkyl of C to C 0), alkylcarboxy including -COO- (alkyl of da C10) or -COO- (substituted alkyl of da C10), -C (NH2) = N-OH, -SO2 - (C1 to C10 alkyl), -SO2- (substituted C1 to C10 alkyl), -O-CH2-aryl, alkylamino, arylthiol, aryl, substituted aryl, heteroaryl, or substituted heteroaryl whose groups can be optionally substituted. 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 group SR, wherein R is aryl or substituted aryl. The term "alkylcarbonyl" is used herein to refer to the group RCO, wherein R is alkyl or substituted alkyl. The term "alkylcarboxy" is used herein to refer to the group COOR, wherein 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, can be either the same or different, and the point of attachment is at the nitrogen. The term "halogen" refers to Cl, Br, F, or I. Pharmaceutically acceptable salts can be formed from organic and inorganic acids including for example acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic acids. , mandelic, malic, italic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic and similar known acceptable acids. Salts can also be formed from inorganic bases, preferably alkali metal salts including for example sodium, lithium or potassium, and organic bases such as ammonium, mono-, di-, and trimethylammonium, mono-, di and triethylammonium salts, mono -, di- and tripropylammonium (iso and normal), ethyl-dimethylammonium, benzyldimethylammonium, cyclohexylammonium, benzylammonium, dibenzylammonium, piperidinium, morpholino, pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium, 1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butylpiperidinium, 2-methylpiperidinium, 1-ethyl-2-methylpiperidinium, mono-, di- and triethanolammonium, ethyldiethanolammonium, n-butylmonoethanolammonium, tris (hydroxymethyl) methylammonium, phenylmono-ethanolammonium, and the like. Physiologically acceptable alkali salts and alkaline earth metal salts include, without restriction, sodium, potassium, calcium and magnesium salts in the form of esters and carbamates. These salts, as well as other compounds, may be in the form of conventional esters, carbamates and other "prodrugs", 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 carbonates. 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 example, there is provided a method for preparing a substituted sulfonamide alcohol, including isolating a diastereomer of an N-protected amino ester by reacting a mixture of diastereomers of an N-protected amino ester with an aprotic acid to form an N-amino ester salt. protected; neutralizing the N-protected amino ester salt with a base to form an N-protected amino ester; reduce the N-protected amino ester by adding the N-protected amino ester to a reducing agent at -60 ° C at about 10 ° C; extinguish the reduction with a protic solvent; reacting the N-protected amino alcohol with a protic acid to form an N-protected aminoalcohol salt; hydrogenating the N-protected aminoalcohol salt to form an unprotected aminoalcohol salt; and sulfonating the unprotected amino alcohol with a sulfonyl chloride in the presence of a base / solvent system. See diagram 3.

SCHEME 3 diastereomeric mixture DIBAL diastereomeric mixture j-60oC at 10 ° C extinction In another example there is provided a method for preparing a substituted sulfonamide alcohol, including isolating a diastereomer of an N-protected amino ester by reacting a mixture of diastereomers of an N-protected amino ester with a protic acid to form an N-protected amino ester salt.; neutralizing the N-protected amino ester salt with a base to form an N-protected amino ester; reducing the N-protected amino ester by adding the N-protected amino ester to diisobutylaluminum hydride at -60 ° C at about -10 ° C; extinguish the reduction with a protic solvent; reacting the N-protected amino alcohol with a protic acid to form an N-protected aminoalcohol salt; hydrogenating the N-protected aminoalcohol salt to form an unprotected aminoalcohol salt; and sulfonate the aminoalcohol not protected with a sulfonyl chloride in the presence of a base / solvent system. In a further example, there is provided a method for preparing a substituted sulfonamide alcohol, including isolating a diastereomer of an N-protected amino ester by reacting a mixture of diastereomers of an N-protected amino ester with a protic acid to form an amino ester salt N -protected; neutralizing the N-protected amino ester salt with a base to form an N-protected amino ester; reduce the N-protected amino ester by adding the N-protected amino ester to diisobutyl aluminum hydride at -60 ° C at about -10 ° C; extinguish the reduction with a protic solvent; reacting the N-protected amino alcohol with a protic acid to form an N-protected aminoalcohol salt; hydrogenating the N-protected aminoalcohol salt to form an unprotected aminoalcohol salt; and sulfonating the unprotected amino alcohol with a sulfonyl chloride in the presence of a base / solvent system selected from 4-methyl morpholine / isopropyl acetate; Hünig / tetrahydrofuran base, 4-methyl morpholine / acetonityl, 4-methyl morpholine / propionitrile, and 4-methyl morpholine / toluene. In yet another example, there is provided a method for preparing a substituted sulfonamide alcohol, which includes isolating a diastereomer of an N-protected amino ester by reacting a mixture of diastereomers of an N-protected amino ester with a protic acid to form an amino ester salt N-protected; neutralize the N-protected amino ester salt with a base to form an N-protected amino ester; reducing the N-protected amino ester by adding the N-protected amino ester to diisobutylaluminum hydride at -60 ° C at about -10 ° C; extinguish the reduction with a protic solvent; reacting the N-protected amino alcohol with a protic acid to form an N-protected aminoalcohol salt; hydrogenating the N-protected aminoalcohol salt to form an unprotected aminoalcohol salt; and sulfonating the unprotected aminoalcohol with a sulfonyl chloride in the presence of a base / solvent system, wherein the sulfonylation is carried out in the absence of protection and deprotection steps. In even a further example there is provided a method for preparing a substituted sulfonamide alcohol, including isolating a diastereomer of an N-protected amino ester by reacting a mixture of diastereomers of an N-protected amino ester with a protic acid to form an amino ester salt N -protected; neutralizing the N-protected amino ester salt with a base to form an N-protected amino ester; reducing the N-protected amino ester by adding the N-protected amino ester to diisobutylaluminum hydride at -60 ° C at about -10 ° C; extinguish the reduction with a protic solvent; reacting the N-protected amino alcohol with a protic acid to form an N-protected aminoalcohol salt; hydrogenating the N-protected aminoalcohol salt to form an unprotected aminoalcohol salt; sulfonate the unprotected amino alcohol with a sulfonyl chloride in the presence of a base / solvent system; and purifying the substituted sulfonamide alcohol, wherein the purification is carried out in the absence of silica gel.

The following examples are illustrative only and are not intended to be a limitation of 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 an amino ester suspension of hydrochloride salt of 4,4,4,4 ', 4', 4'-hexafluoro-N- [ (1 R) -1-phenylethyl] -L-valinate from ethyl (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 azeotropism. The toluene solution was distilled under atmospheric pressure until the vapor temperature reached about 108-100 ° 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 moles) was cooled to -10 ° C and then the toluene and amino ester solution (about 600 mL) was added in about 90 minutes keeping the mixture reaction around -8 to -1 1 ° C. The mixture was then stirred for about 10 minutes. EtOH (29 mL, 0.5 mole) was then added at the 10 minute step, keeping the reaction temperature below 25 ° C.

A solution of concentrated HCl (93 g) in water (130 mL) was heated to 35-40 ° C. The reaction mixture was then added to this HCI solution heated to the passage of 60 to 90 minutes keeping 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 washed at -5 ° C and then concentrated HCI (32 g, 0.33 mol) was added at the passage of 15 minutes. This mixture was then stirred for 6 hours. The salt product from the previous step was isolated by filtration, washed with toluene (2 x 200 mL) and dried in a vacuum oven to generate 81 g (90%) of the phenal product as an off-white solid. Purity HPLC 98.9% area, concentration of 98.5%.

EXAMPLE 2 Preparation of S-chloro-N-fdSVS.S.S-trifluoro-l-hydroxymethiD ^ -trifluoromethyl) propylJthiophene-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-1-ol (2 g, 8.1 mmoles) in isopropyl acetate (0 mL). The mixture was stirred at about 20-25 ° C for about 5-10 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 6-18 hours. Then water (10 mL) was added to the reaction mixture, whereupon solids were dissolved. The two layers then separated and the organic layer was washed with a solution of 10% NaHCO3 (10mL) and 10% NaC1 (10mL). Heptane (10 mL) was added to the isopropyl acetate layer (about 10 mL). The mixture was then distilled to about half of its original volume under atmospheric distillation. While the solution remained at about 80-90 ° C, heptane (10 mL) was added in the course of 5-10 minutes, during which time solids were 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 one hour. The solid was then collected by filtration, washed with heptane (5 mL) and dried in the oven to generate 2.15 g (67%) of the product as an off-white solid. HPLC purity of 98% area and > 99% chiral purity by HPLC. All publications cited in this description are incorporated herein by reference. Although the invention has been described with distinction to particular embodiments, it will be noted that the modifications can be made without departing from the essence of the invention. Such modifications are intended to fall within the scope of the appended claims.

Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A method for preparing an aminoalcohol, or salt thereof, from an amino ester comprising reducing said amino ester by adding said amino ester to a hydride reducing agent at about -60 ° to about -10 ° C- 2.- The method according to claim 1, further characterized in that said amino ester has 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; R 4 is selected from the group consisting of (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. 3. The method according to claim 2, further characterized in that said aminoalcohol is of the structure: H wherein: R2-R4 are as defined in claim 2. 4. The method according to claim further characterized in that said aminoalcohol salt is of the structure H HC I wherein: R2-R4 are as defined in claim 2. 5. The method according to any of claims 1 to 4, further characterized in that said protective group R2 is a 1-methylbenzyl group. 6. - The method according to any of claims 1 to 5, further characterized in that R3 is H and -R4 is -CH (CF3) 2. 7. - The method according to claim 6, further characterized in that said aminoalcohol is: 8. - The method according to any of claims 1 to 7, further characterized in that said hydride reducing agent is diisobutylaluminum hydride. 9. - The method according to any of claims 1 to 8, further characterized in that it also comprises extinguishing said reduction with a protic solvent. 10. - The method according to claim 9, further characterized in that said protic solvent is a protic acid. eleven . - The method according to claim 10, further characterized in that said protic acid is hydrochloric acid or acetic acid. 12. - The method according to claim 9, further characterized in that said protic solvent is ethanol. 13. - The method according to any of claims 1 to 12, further characterized in that said reduction is performed from about -20 to about -10 ° C. 14. - The method according to any of claims 1 to 13, further characterized in that said aminoalcohol is prepared in a yield of about 90 to about 95%. 5.- A method to prepare an aminoalcohol of the structure: wherein said method comprises reducing an amino ester of the following structure by adding said amino ester to diisobutylaluminum hydride of from about -60 ° to about -10 ° C. and if it is desired to convert said aminoalcohol to a salt thereof. 16. - The method according to any of claims 1 to 15, further characterized in that the amino ester is N-protected by a chiral protecting group, which further comprises, before reducing said N-protected amino ester, reacting a mixture of diastereomers of said N-protected amino ester with a protic acid to form an N-protected amino ester salt; isolating a single amino ester salt diastereomer, and neutralizing said amino ester salt with a base to form an individual N-protected amino ester diastereomer. 7. The method according to any of claims 1 to 16, further characterized in that the aminoalcohol is N-protected, further comprising hydrogenating said N-protected aminoalcohol salt to form an unprotected aminoalcohol salt; and sulfonating said unprotected amino alcohol with a sulfonyl chloride in the presence of a base / solvent system to form a substituted sulfonamide alcohol. 18. - A method for preparing a substituted sulfonamide alcohol, comprising: a) isolating a diastereomer of an N-protected amino ester by reacting a mixture of diastereomers of an N-protected amino ester with a protic acid to form an N-protected amino ester salt; b) neutralizing said N-protected amino ester salt with a base to form an N-protected amino ester; c) reducing said N-protected aminoester by adding said N-protected amino ester to the diisobutylaluminum hydride from -60 ° C to about -10 ° C; d) quenching the reaction of step (c) with a protic solvent; e) reacting the N-protected amino alcohol from step (d) with protic acid to form an N-protected aminoalcohol salt; f) hydrogenating said N-protected aminoalcohol salt to form an unprotected aminoalcohol salt; and g) sulfonating said unprotected amino alcohol with a sulfonyl chloride in the presence of a base / solvent system. 19. - The method according to any of claims 17 or 18, further characterized in that said base / solvent system is selected from the group consisting of 4-methylmorpholine / isopropyl acetate, Hünig base / tetrahydrofuran, 4-methylmorpholine / acetonitroyl, 4-methylmorpholine / propionitrile, and 4-methylmorpholine / toluene. 20. The method according to any of claims 17 to 19, further characterized in that said sulfonylation is carried out in the absence of the step of protection and deprotection. method according to any of claims 17 to 20, further characterized in that it comprises purifying said substituted sulfonamide alcohol, wherein said purification is carried out in the absence of silica gel. method according to any of claims 17 to 21, further characterized in that said substituted sulfonamide alcohol is substituted with one or more trifluoroalkyl groups. method according to any of claims 17 to 22, further characterized in that said substituted sulfonamide alcohol has 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 wherein 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, S02 and NR7; R6 is selected from the group consisting of H, halogen, Ci to C6 alkyl and substituted Ci to C6 alkyl; R7 is selected from the group consisting of H, alkyl of d to C6 and cycloalkyl of C3 to C8; R8, R9, R10, R11 and R 12 are independently selected from the group consisting of H, halogen, C 1 to C 6 alkyl, substituted Ci to C 6 alkyl, Ci to C 6 alkoxy, substituted d to C 6 alkoxy and NO 2; or R8 and R9, R9 and R10; R 1 and R 2; or R 0 and R 11 are fused to form: (i) a saturated ring based on carbon 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 the group consisting of O, N, and S in the base structure of said ring; wherein said rings (i) to (iii) are optionally substituted with 1 to 3 substituents comprising Ci to C6 alkyl or substituted Ci to C6 alkyl, or a pharmaceutically acceptable salt, hydrate or prodrug thereof. method according to claim further characterized in that said substituted sulfonamide alcohol is: method according to claim further characterized in that said substituted sulfonamide alcohol is: 26. - The method according to any of claims 17 to 25, further characterized in that said hydrogenation is carried out with a catalyst. 27. - The method according to any of claims 17 to 26, further characterized in that said unprotected aminoalcohol salt has the structure: HCI wherein R3 and R4 are as defined in claim 2. 28.- The method according to claim 27, further characterized in that said unprotected aminoalcohol salt is: HCI 29. - The method according to any of claims 17 to 28, further characterized in that said sulfonyl chloride has the structure: wherein: R °, W, Y, Z, X and R8-R 2 are as defined in claim 23. 30. The method according to claim 29, further characterized in that said sulfonyl chloride is: I