RU2074173C1 - Amides, methods of their synthesis and pharmaceutical composition showing property of channel opening for cellular potassium - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: amides of the formula (I):

where: a): E - nitrogen and X - phenylsulfonyl; b): E - group CZ where C - ring carbon atom; Z - hydrogen, cyano-group, halogen, hydroxyl, alkyl or alkoxyl; X - phenylcarbonyl, phenylsulfinyl or phenyl sulfonyl; c): X - cyano-group and Z - phenylsulfonyl; R₂ and R₃ free alkyl or alkyl substituted with fluorine or they together form 3-5-membered cycloalkyl, and pharmcomposition based on amides of the formula (I) and methods of amide synthesis. Method 1. Reagent 1: the corresponding aniline. Reagent 2: the corresponding acid. Method 2. Reagent 1: amide of the formula (I) containing hydroxyl-protected group. Reaction condition: protective group removing. Method 3. Reagent 1: amide of the formula (I) where X - phenyl sulfide. Reagent 2: oxidizing agent. Synthesized compounds can be used in medicine. EFFECT: improved method of synthesis. 6 cl, 2 tbl

Description

 The invention relates to compounds useful as means for opening channels of cellular potassium in mammals, such as humans. More specifically, the invention relates to certain substituted amides useful in the treatment of mammalian urinary incontinence. Since the compounds of the invention function as channel openers for cellular potassium, they can also be useful in the treatment of conditions and diseases in which a drug and its potassium channel opening action are desirable or known to produce a beneficial effect.

 Such conditions or diseases include hypertension, asthma, peripheral blood vessel disease, right ventricular heart failure, congestive heart failure, tonsillitis, coronary heart disease, renal colic, kidney stone disorders, irritable bowel syndrome, some forms of male pattern baldness, premature birth, impotence and peptic ulcer.

 Treatment using a compound of the invention may be curative or therapeutic, as with the administration of the compound at the onset or with the progression of urinary incontinence in a patient. Treatment may also be prophylactic or prophylactic with the administration of a compound in anticipation that urinary incontinence may develop, for example, in a patient who has suffered from urinary incontinence in the past.

 It is known that bladder tissue is excitable and that urinary incontinence can be caused by uncontrolled or unstable bladder contractions. It is further known that when performing the function of opening potassium channels, compounds opening potassium channels act as smooth muscle relaxants. Without going deep into issues of the theory of the phenomenon, we believe that the compounds according to the invention act when opening potassium channels in the cells of the bladder and at the same time relax the tissues of the smooth muscle of the bladder, preventing or attenuating the intensity of uncontrolled contractions of the bladder, which can cause urinary incontinence.

This invention provides an amide of formula I (the formula is presented together with the other formulas mentioned in the description, the Roman numeral on the pages following the description of the examples), in which:
E is selected from nitrogen or CZ, where C is ring carbon and Z is a substituent as defined below, if E is CZ, then X and Z are selected from the group consisting of:
(A) X is ArY, where Y is a linking group selected from carbonyl, sulfinyl and sulfonyl, and Ar is selected from the group consisting of:
phenyl substituted with 0-2 substituents selected from halo, hydroxy, cyano, (C ₁ -C ₄ ) -alkyl and (C ₁ -C ₄ ) -alkoxy provided that the 4-position of said phenyl can only be replaced by an atom fluorine and that said phenyl cannot be 3,5-disubstituted;
a six-membered heteroaryl ring containing 1-2 nitrogen atoms as the only heteroatoms;
a five-membered heteroaryl ring containing 1-2 heteroatoms selected from nitrogen, oxygen and sulfur, provided that Ar is not 3-chlorophenyl, 3-bromophenyl, 3-iodophenyl, 3- (C ₁ -C ₄ ) -alkylphenyl or 4 -pyridyl, if Y is carbonyl, and that Ar is not 5-pyrimidinyl, if Y is sulfonyl or carbonyl, and Z is selected from hydrogen, cyano, halo, hydroxy, (C ₁ -C ₄ ) -alkyl and (C ₁ - C ₄ ) alkoxy;
(B) X is cyano, and Z is selected from the group consisting of phenylthio, phenylthionyl and phenylsulfonyl, the phenyl rings of which are substituted with 0-2 substituents selected from halo, hydroxy, cyano, nitro, (C ₁ -C ₄ ) -alkyl and ( C ₁ -C ₄ ) alkoxy;
if E is nitrogen, then X is independently selected from any value presented for X in paragraph (A);
R ² and R ^{3 are} independently selected from the group consisting of (C ₁ -C ₃ ) -alkyl substituted with 0 to 2 and + 1 groups selected from fluorine and chlorine atoms, in which is the number of carbon atoms in said (C ₁ -C ₃ ) -alkyl, provided that R ² and R ³ are not both methyl; or
together with the carbon atom to which both of R ² and R ^{3 are} attached, form a 3-5-membered cycloalkyl ring optionally substituted with from 0 to 2m-2 fluorine atoms, in which m is the number of carbon atoms in said ring;
and pharmaceutically acceptable, in vivo hydrolysing esters of said amide;
and pharmaceutically acceptable salts of said amides and esters.

 The invention further provides a method of treating urinary incontinence, comprising administering to the mammal (including humans), if necessary, such an effective amount of an amide of formula I as defined above, or a pharmaceutically acceptable amide salt, or a pharmaceutically acceptable in vivo hydrolyzable amide ester and a pharmaceutically acceptable diluent or carrier .

 The invention further provides a pharmaceutical composition suitable for the treatment of urinary incontinence, comprising an amide of the formula I as defined above, or a pharmaceutically acceptable in vivo hydrolyzable ester, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

 In this description, the terms “alkyl” and “alkoxy” include straight and branched chain radicals, but it should be borne in mind that references to individual radicals such as “propyl” or “propoxy” refer only to straight chain radicals (“normal” radical), branched chain isomers such as "isopropyl" or "isopropoxy" are specifically referred to.

 The term "halo" includes an atom of fluorine, chlorine, bromine and iodine, unless otherwise specified.

 Specialists in this field should be aware that some compounds of formula I contain an asymmetrically substituted carbon and / or sulfur atom; and, therefore, can exist and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism.

 It should be borne in mind that the invention encompasses any racemic, optically active, polymorphic or stereoisomeric form, or mixtures thereof, if the form has properties useful in the treatment of urinary incontinence, and that it is widely known in the art how to obtain optically active forms (e.g., resolution of racemic forms by recrystallization methods, synthesis from optically active starting materials, chiral synthesis or chromatographic separation using a chiral stationary phase), and how to determine the efficiency of cheniya urinary incontinence by standard tests described later.

 Specific values for Ar as phenyl substituted with 0-2 substituents include phenyl, 2- and 3-halophenyl, 4-fluorophenyl, 2- and 3-hydroxyphenyl, 2- and 3-cyanophenyl, 2- and 3-methylphenyl, 2 - and 3-ethylphenyl, 2- and 3-propylphenyl, 2- and 3-methoxyphenyl, 2- and 3-ethoxyphenyl, 2- and 3-propoxyphenyl, 2,5-difluorophenyl and 2,3-difluorophenyl.

 Specific values for Ar as a six-membered heteroaryl ring containing 1-2 nitrogen atoms include 2,3- and 4-pyridyl, 2-pyrazinyl, 2- and 4-pyrimidinyl, and 3- and 4-pyridazinyl.

 Specific values for Ar as a five-membered heteroaryl ring containing 1-2 heteroatoms selected from nitrogen, oxygen and sulfur include 3-, 4- and 5-isothiazolyl, 2-, 4- and 5-oxazolyl, 2-, 4- and 5-thiazolyl, 2- and 3-furyl and 2- and 3-thienyl.

Specific values for Z as (C ₁ -C ₄ ) -alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

Specific values for Z as (C ₁ -C ₄ ) alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

 Specific values for Z as phenylthio substituted with 0-2 substituents include phenylthio, 2-, 3- and 4-halophenylthio, 2-, 3- and 4-oxophenylthio, 2-, 3- and 4-cyanophenylthio, 2-, 3- and 4-methylphenylthio, 2-, 3- and 4-ethylphenylthio, 2-, 3- and 4-propylphenylthio, 2-, 3- and 4-methoxyphenylthio, 2-, 3- and 4-ethoxyphenylthio, 2-, 3- and 4-propoxyphenylthio, 2,4-difluorophenylthio and 2,3-difluorophenylthio.

 Specific values for Z as phenylthionyl substituted with 0-2 substituents include phenylthionyl, 2-, 3- and 4-halophenylthionyl, 2-, 3- and 4-hydroxyphenylthionyl, 2-, 3- and 4-cyanophenylthio, 2-, 3 - and 4-methylphenylthionyl, 2-, 3- and 4-ethylphenylthionyl, 2-, 3- and 4-propylphenylthionyl, 2-, 3- and 4-methoxyphenylthionyl, 2-, 3- and 4-ethoxyphenylthionyl. 2-, 3- and 4-propoxyphenylthionyl, 2,4-difluorophenylthionyl and 2,3-difluorophenylthionyl.

 Specific values for Z as phenylsulfonyl substituted with 0-2 substituents include 2-, 3- and 4-halophenylsulfonyl, 2-, 3- and 4-hydroxyphenylsulfonyl, 2-, 3- and 4-cyanophenylsulfonyl, 2-, 3- and 4-methylphenylsulfonyl, 2-, 3- and 4-ethylphenylsulfonyl, 2-, 3- and 4-propylphenylsulfonyl, 2-, 3- and 4-methoxyphenylsulfonyl, 2-, 3- and 4-ethoxyphenylsulfonyl, 2-, 3- and 4-propoxyphenylsulfonyl, 2,4-difluorophenylsulfonyl and 2,3-difluorophenylsulfonyl.

Specific values for R ² and R ³ as (C ₁ -C ₃ ) -alkyl substituted with 0 to 2k + 1 groups selected from fluorine and chlorine atoms include methyl, ethyl, propyl, isopropyl, chloromethyl, dichloromethyl, chlorodifluoromethyl, trichloromethyl, 1-chloroethyl, 1,1-dichloroethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 1,2-dichloroethyl, 1,1,2-trichloroethyl. 1,2,2-trichloroethyl, 1,1,2,2-tetrachlorethyl, 1,2,2,2-tetrachlorethyl, 1,1,2,2,2-pentachloroethyl, 1-chloropropyl, 1,1-dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 1,1,2-trifluoroethyl, 1, 2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, 1,2,2,2-tetrafluoroethyl, 1,1,2,2,2-pentafluoroethyl, 1-fluoropropyl and 1,1-difluoropropyl.

Specific values for a 3-5-membered cycloalkyl ring substituted with 0 to 2m-2 fluorine atoms, which can be formed by the radicals R ² and R ³ together with the carbon atom, and to which R ² and R ^{3 are} attached, include cyclopropyl, cyclobutyl, cyclopentyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, 2,2,3-trifluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,3-difluorocyclobutyl, 2,4-difluorocyclobutyl, 2,2-difluorocyclobutyl, 2,3,4-trifluorocyclobutyl, 2,3,3-trifluorocyclobutyl, 2,2,3-trifluorocyclobutyl, 2,2,4-trifluorocyclo butyl, 2,2,3,4-tetrafluorocyclobutyl, 2,3,3,4-tetrafluorocyclobutyl, 2,2,3,3-tetrafluorocyclobutyl, 2,2,4,4-tetrafluorocyclobutyl, 2,2,3,3, 4-pentafluorocyclobutyl, 2,2,3,4,4-pentafluorocyclobutyl, hexafluorocyclobutyl, 2-fluorocyclopentyl, 3-fluorocyclopentyl, 2,2-difluorocyclopetyl, 2,3-difluorocyclopentyl, 2,4-difluorocyclopentyl, 2,5-difluorocyclopentyl, 3,3-difluorocyclopentyl, 2,2,3-trifluorocyclopentyl, 2,2,4-trifluorocyclopentyl, 2,2,5-trifluorocyclopentyl, 2,3,3-trifluorocyclopentyl, 3,3,4-trifluorocyclopentyl, 2,4, 4-trifluorocyclopentyl, 2,2,3,3-tetrafluorocyclopentyl, 2,2,4,4-tetrafluorocyclopentyl, 2,2,5,5-tetrafluoro cyclopentyl, 3,3,4,4-tetrafluorocyclopentyl, 2,2,3,4-tetrafluorocyclopentyl, 2,2,3,5-tetrafluorocyclopentyl, 2,2,4,5-tetrafluorocyclopentyl, 2,3,3,4- tetrafluorocyclopentyl, 2,3,3,5-tetrafluorocyclopentyl, 3,3,4,5-tetrafluorocyclopentyl, 2,3,4,5-tetrafluorocyclopentyl, 2,2,3,3,4-pentafluorocyclopentyl, 2,2,3, 3,5-pentafluorocyclopentyl, 2,2,3,4,4-pentafluorocyclopentyl, 2,2,3,5,5-pentafluorocyclopentyl, 2,2,3,4,5-pentafluorocyclopentyl, 2,3,3,4, 4-pentafluorocyclopentyl, 2,3,3,5,5-pentafluorocyclopentyl, 2,3,3,4,5-pentafluorocyclopentyl, 2,2,3,3,4,4-hexafluorocyclopentyl, 2,2,3,3, 5,5-hexafluorocyclopentyl, 2,2,3,3,4,5-hexafluorocyclopentyl 2,3,3,4,4,5-hexafluorocyclopentyl, 2,3,3,4,4,5-hexafluorocyclopentyl, 2,2,3,4,4,5-hexafluorocyclopentyl, 2,2,3,3 4,4,5-heptafluorocyclopentyl, 2,2,3,3,4,5,5-heptafluorocyclopentyl and oxafluorocyclopentyl.

 A more specific value for E is CZ, where Z is selected from the more specific values defined below.

 More specific values for Ar as phenyl substituted with 0-2 substituents are those values of phenyl substituted with 0- one substituent that include phenyl, 2-, 3- and 4-fluorophenyl, 2- and 3-chlorophenyl, 2- and 3 -cyanophenyl, 2- and 3-hydroxyphenyl, 2- and 3-methoxyphenyl and 2- and 3-methylphenyl.

 More specific values for Ar as a six-membered heteroaryl ring containing 1 to 2 nitrogen atoms are 2-, 3- and 4-pyridyl and 2- and 4-pyrimidyl.

 More specific values for Ar as a five-membered heteroaryl ring containing 1-2 heteroatoms are 3- and 4-isothiazolyl, 2- and 4-oxazolyl, 2- and 4-thiazolyl, 2- and 3-furyl and 2- and 3- thienyl.

More specific values for Z as (C ₁ -C ₄ ) -alkyl are (C ₁ -C ₂ ) -alkyl, including methyl and ethyl.

More specific values for Z as (C ₁ -C ₄ ) alkoxy are (C ₁ -C ₂ ) alkoxy values including methoxy and ethoxy.

 More specific values for Z as phenylthio substituted with 0-2 substituents are phenylthio substituted with 0-1 substituent, including phenylthio, 2-, 3- and 4-fluorophenylthio, 2-, 3- and 4-chlorophenylthio, 2-, 3- and 4-cyanophenylthio, 2-, 3- and 4-hydroxyphenylthio, 2-, 3- and 4-methoxyphenylthio and 2-, 3- and 4-methylphenylthio.

More specific values for Z as phenylthionyl substituted with 0-2 substituents are those values of phenylthionyl substituted with 0-1 substituent, including phenylthionyl, 2-, 3- and 4-fluorophenylthionyl, 2-, 3- and 4-chlorophenylthionyl, 2- , 3- and 4-cyclophenylthionyl, 2-, 3- and 4-hydroxyphenylthionyl, 2-, 3- and 4-methoxyphenylthionyl and 2-, 3- and 4-methylphenylthionyl,
More specific values for Z as phenylsulfonyl substituted with 0-2 substituents are those values of phenylsulfonyl substituted with 0-1 substituents, including phenylsulfonyl, 2-, 3- and 4-fluorophenylsulfonyl, 2-, 3- and 4-chlorophenylsulfonyl, 2- , 3- and 4-cyanophenylsulfonyl, 2-, 3- and 4-hydroxyphenylsulfonyl, 2-, 3- and 4-methoxyphenylsulfonyl and 2-, 3- and 4-methylphenylsulfonyl.

More specific values for R ² and R ³ as (C ₁ -C ₃ ) -alkyl substituted with from 0 to 2k + 1 groups selected from chlorine and fluorine atoms are only those fluorine substituted groups, including fluoromethyl, difluoromethyl, trifluoromethyl, 1 -fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 1,1,2-difluoroethyl, 1,1,2-trifluoroethyl, 1 , 2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, 1,2,2,2-tetrafluoroethyl and 1,1,2,2,2-pentafluoroethyl.

The particular amide has the formula Id in which:
X and Z are selected from the group including:
(A) X is ArY, where Y is a linking group selected from carbonyl, sulfonyl and thionyl, and Ar is selected from the group consisting of phenyl, 2-, 3- and 4-fluorophenyl, 2- and 3-chlorophenyl, 2- and 3-cyanophenyl, 2- and 3-hydroxyphenyl, 2- and 3-methoxyphenyl, 2- and 3-methylphenyl, 2,3- and 4-pyridyl, 2- and 4-pyrimidinyl, 3- and 4-isothiazolyl, 2- and 4-oxazolyl, 2- and 4-thiazolyl, 2- and 3-furyl and 2- and 3-thienyl;
Z is selected from hydrogen, cyano, halo, hydroxy, (C ₁ -C ₂ alkyl and (C ₁ -C ₂ ) alkoxy;
(B) X is CN, Z is phenylsulfonyl;
R ² and R ^{3 are} independently selected from the group consisting of (C ₁ -C ₃ ) -alkyl substituted with 0 to 2k + 1 fluorine atoms, where k is the number of carbon atoms in the (C ₁ -C ₃ ) -alkyl with the proviso that R ² and R ^{3 are} both not methyl;
and pharmaceutically acceptable in vivo hydrolysable esters of said amide and
pharmaceutically acceptable salts of said amides and esters.

A preferred amide has the formula Id in which X is ArY and where:
Ar, Y, and Z are selected from the group consisting of:
(i) Y is sulfonyl, Z is hydrogen, and Ar is selected from the group consisting of:
phenyl substituted with 0-1 a substituent selected from phenyl, 2-, 3- and 4-fluorophenyl, 2- and 3-chlorophenyl, 2- and 3-methoxyphenyl, 2- and 3-cyanophenyl, 2- and 3-hydroxyphenyl and 2- and 3-methylphenyl;
six-membered heteroaryl rings selected from 2-, 3- and 4-pyridine and 2-pyrimidinyl;
five-membered heteroaryl rings selected from 2-thienyl and 2-thiazolyl;
(ii) Y is sulfonyl, Ar is phenyl or 4-pyridyl and Z is selected from the group consisting of cyano, fluoro, hydroxy, methoxy and methyl, and
(iii) Y is carbonyl, Z is hydrogen, and Ar is selected from the group consisting of phenyl and 2-pyridyl, and
R ² and R ^{3 are} independently selected from the group consisting of:
(i) R ² is trifluoromethyl and R ^{3 is} selected from the group consisting of methyl, ethyl and trifluoromethyl, and
(ii) R ² is difluoromethyl and R ³ is difluoromethyl, and
pharmaceutically acceptable in vivo hydrolysable esters of said amide, and
pharmaceutically acceptable salts of amide and esters.

 Where applicable, the S configuration is typically the preferred stereochemistry of the compounds of the invention.

Particularly preferred amides include the following compounds:
N- (4- (4-pyridylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide,
S - (-) - N- (4- (4-pyridylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide,
N- (4- (phenylcarbonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methyl-propanamide,
S - (-) - N- (4-phenylcarbonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide,
N- (4- (4-pyridylsulfonyl) phenyl) -3,3-difluoro-2-hydroxy-2-difluoromethylpropanamide,
N- (4- (phenylcarbonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-trifluoromethylmethylpropanamide,
N- (4- (4pyridylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-trifluoromethylpropanamide and
N- (3-hydroxy-4- (4-pyridylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

 The above compounds are preferred because of their selectivity to the bladder, they do not have a significant effect on the cardiovascular system, as shown by blood pressure measurements in an in vivo test that predicts the selectivity mentioned in the description.

Amides of formula I can be prepared by methods that include processes known in the art of chemistry and the preparation of structural analogs of the compounds. Such processes for the preparation of an amide of the formula I as defined above represent further features of the invention and are shown in the following processes in which the meanings of the radicals are given above, unless otherwise specified. Such a process can be carried out, in general, as follows:
(a) reacting an aniline of formula II with an acid of formula III, wherein G is an oxy group. The reaction can be carried out in a suitable solvent and in the presence of a suitable coupling reagent. Combining suitable reagents are commonly known in the art as standard peptide coupling reagents, and as such thionyl chloride (Morris et al. J. Med. Chem. 34, 447 (1991), carbonyldiimidazole (CDI) and dicyclohexylcarbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine (DMAP) or 4-pyrrolidinopyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide.The reaction of the compound can be carried out at (-40) (40) ^° C;
(b) deprotecting a protected amide having the formula IV, wherein PG is a suitable protecting group, such as a benzyl group.

Examples of suitable reagents for use in cleaving the ether portion of the molecule to form an oxy group include (I) hydrogen in the presence of a palladium-carbon catalyst, i.e. hydrogenolysis; (2) hydrogen bromide or hydrogen iodide; (3) trimethylsilyl iodide; and (4) alkyl sulfides or alkyl phosphides. The reaction can be carried out in a suitable solvent, such as ethanol, methanol, acetonitrile or dimethyl sulfoxide at (-40) to (100) ^o C.

(c) in a compound of formula I, wherein X is substituted or unsubstituted phenylthionyl or phenylsulfonyl, oxidizing the corresponding substituted or unsubstituted phenylsulfide. Suitable oxidizing agents include potassium permanganate, oxone, sodium periodate and hydrogen peroxide. The reaction can be carried out in a suitable solvent, such as diethyl ether, methanol, ethanol, water, acetic acid and mixtures of two or more of these solvents. The reaction can be carried out at (-40) (70) ^o C.

(d) reacting an amide of formula V with a sufficiently strong base (i.e., for example, lithium dialkylamide such as lithium diisopropylamide) to produce an amide dianion followed by reacting the dianion thus obtained with oxygen in the presence of a reducing agent (e.g., such as triphenylphosphine ) to give the corresponding compound of formula I. The reaction sequence can be carried out at (-100) (-20) ^o C in a suitable solvent, such as tetrahydrofuran or diethyl ether.

(e) in a compound of formula Id, where X is substituted or unsubstituted phenylsulfonyl, by reacting a corresponding substituted or unsubstituted compound of formula VI, where the value corresponding to X is unsubstituted or substituted phenylsulfonyl, and Hal indicates a halogen substituent (e.g., the corresponding chloride) with the corresponding dianion of an alkali metal amide having the formula VII, wherein A is an alkali metal such as sodium or lithium. The reaction can be carried out at (-40) - (100) ^o C and in a suitable solvent, such as dimethylformamide, dimethyl sulfoxide or tetrahydrofuran;
(f) reacting a compound (alkyl ester) of formula VIII, where R ⁴ is a (C ₁ -C ₄ ) -alkyl group (e.g. methyl, ethyl or propyl) with a (C ₂ -C ₃ ) magnesium alkyl halide (e.g. Grignard reagent). The reaction, i.e., the addition of the Grignard reagent to the ester, can be carried out at (-100) (20) ^° C in a suitable solvent such as tetrahydrofuran or diethyl ether, higher alkyl esters can be used, but they do not give particular advantages ;
(g) if X is substituted or unsubstituted benzoyl (in Formula I), by reacting the corresponding compound of Formula IXa with suitably substituted or unsubstituted triphenylaluminum or triphenyltin or carbon monoxide in the presence of a suitable catalyst such as bis (triphenylphosphine) palladium chloride (II) . The reaction can be carried out at (-20) - (100) ^o C in a suitable solvent, such as benzene, toluene, tetrahydrofuran or diethyl ether;
(h) if X is a substituted or unsubstituted benzoyl, oxidizing the compound of formula IXb to the corresponding compound of formula I, where X is the corresponding substituted or unsubstituted part of benzoyl, oxidizing agents such as bromine and pyridinium dichromate and solvents such as, respectively, can be used. methanol and dichloromethane.

 If it is impossible to get on the market, then some of the necessary starting materials for carrying out the processes described above can be obtained by methods selected among standard methods of organic chemistry, methods that are analogs of the synthesis of known structurally similar compounds, or methods similar to the processes described above, or methods described in the examples.

 In the following discussion, Ar refers to an unsubstituted or substituted phenyl group or heterocyclic radical, as previously defined.

In general, compounds of formulas IV, V, VIII, IXa and IXb can be prepared by a method similar to that described in process (a) above to obtain an amide of formula I, i.e. a combination of the corresponding aniline with the corresponding acid. Thus, in order to obtain a protected amide of formula IV, the corresponding aniline of formula II can be combined with an acid of formula III, where the group corresponding to G is OPG. The protected acid can be prepared in a conventional manner, for example, (i) by esterification of an acid of formula III, where Q is an oxy group, by a conventional esterification process, such as the reaction of a lower alcohol (eg, methanol) in the presence of an acid catalyst (eg, sulfuric acid);
(ii) reacting the ester thus obtained with a reagent that provides a PG protecting group, such as benzoyl chloride (to obtain a benzyl protecting group) or any of the conventionally known and used silylating reagents (such as 2-trimethylsilyl ethoxymethyl chloride, SEM, in the presence of a suitable base such as sodium hydroxide or triethylamine, optionally in the presence of a catalyst such as dimethylaminopyridine), and (iii) cleavage of the ester group under mild alkaline conditions (i.e., applying a base such as potassium carbonate) to give the desired protected acid.

 As a further example, a compound of formula IXa can be prepared by reacting an acid of formula III, where G is an oxy group, with an aniline of formula II, where the group corresponding to X is an iodine atom and E is CH. It should be borne in mind that compounds having the other formulas indicated above can be obtained in a similar manner using suitable appropriate starting materials.

Aniline of formula XI, where n = 0, 1 or 2 (i.e., aniline of formula II, where X is ArS, ArSO or ArSO ₂ ) can be obtained by reducing the corresponding nitro compound of formula XII with a suitable reducing agent, as is known in the art (A Cowetin, Jlelv, Chim. Acta, 1046. 66, (1983) and H. Jilman et al. J. Amer. Chem. Soc. 09. 2053. (1947).

Suitable reducing agents include tin (II) chloride dihydrate in ethanol, and the reduction is carried out at a temperature of from 20 ^{° C.} to a reflux temperature; iron in the water-ethanol mixture and the reduction is carried out at a temperature from Celsius to reflux temperature, and aniline can be obtained by catalytic hydrogenation using a palladium or platinum catalyst, carried out at 20-50 ^o C.

 Aniline of formula XI, in which n = 2, can also be obtained by acid hydrolysis (aqueous mixture of hydrochloric acid and ethanol at reflux temperature) of acetanilide of formula XIII to obtain the corresponding aniline.

The nitro compound of formula XII in which n = 1 or 2 can be obtained by oxidation of the corresponding compound of formula XII, where n = 0 (i.e., the corresponding sulfide), thereby obtaining the corresponding compound of formula XII in which n = 1 or 2. Suitable reagents for preparing a compound in which n = 1 are sodium periodate in a suitable solvent, such as methanol or dioxane, at 20-80 ^° C; bromine and potassium carbonate in a mixture of water and methylene chloride at room temperature and 30% hydrogen peroxide in acetic acid at room temperature. Suitable reagents for preparing the compound in which n = 2 are potassium permanganate in a mixture of acetic acid water at 70 ^° C; oxone in aqueous methanol at room temperature and meta-chloroperbenzoic acid in methylene chloride at a temperature of from 0 ^o C to reflux temperature.

The nitro compound of formula XII in which n = 0 or 2 can also be prepared by reacting the corresponding alkali metal acid salt of the formula ArSO _n Am, where Am is an alkali metal such as sodium, lithium or potassium, with a halide of the formula XIV in which Hal means a halide substituent (such as a chlorine atom). The reaction is carried out in solvents such as aqueous ethanol, dimethylformamide or dimethylacetamide at 20-155 ^o C.

The nitro compound of formula XII in which n = 0 or 2 can also be obtained by reacting the corresponding compound of formula ArHal, where Hal is halogen (e.g. 2-chloro-5-nitropyridine) with the corresponding salt of formula XY (n = 0 or 2), where Am is an alkali metal such as sodium, lithium or potassium. The reaction is carried out in solvents, such as a mixture of ethanol-water, dimethylformamide or dimethylacetamide at 20-155 ^o C.

 Aniline of formula XVI can be prepared by reacting the corresponding acid of the formula ArCOOH or the corresponding anhydride of the formula ArCOO-O-COAr with aniline in the presence of polyphosphoric acid (B. Staskum. J. Org. Chem. 29. 2856 (1964) and A. Denton et al. J. Chem. Soc. 4741 (1963).

 It should be noted that most of the starting materials for the synthesis, as described above, are commercially available and / or widely covered in the scientific literature.

 In cases where the compounds of formula I (or Id) are sufficiently basic or acidic to form stable acid or base salts, administration of the compound in salt form may be suitable and pharmaceutically acceptable salts may be prepared by conventional methods, such as those described below. Examples of pharmaceutically acceptable salts are acid addition salts formed with acids that form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, tartrate, citrate, succinate, benzoate, ascorbate, α-ketoglutarate and a-glycerophosphate. Suitable inorganic salts can also be formed, such as sulfate, nitrate and hydrochloride. Pharmaceutically acceptable salts may be prepared using standard methods well known in the art. For example, by reacting a sufficiently basic compound of formula I (or an ester thereof) with a suitable acid giving a physiologically acceptable anion. It is also possible with most compounds of the invention to produce the corresponding salt of an alkali metal (e.g. sodium, potassium or lithium) and an alkaline earth metal (e.g. calcium) by treating an amide of formula I (and in some cases an ester) with one equivalent of alkali metal hydroxide or alkali - a ground metal or an alcoholate (for example, ethylate or methylate) in an aqueous medium followed by traditional cleaning methods.

 In vivo hydrolysable esters of the compounds of the invention can be prepared by reaction with a pharmaceutically acceptable carboxylic acid or an activated derivative thereof. For example, the combination may be carried out by treating the starting amide of formula I with a suitable acid chloride (e.g. acetyl chloride, propionyl chloride or benzoyl chloride) or acid anhydride (e.g. acetic anhydride, propionic anhydride or benzoic acid anhydride) in the presence of a suitable base such as triethylamine. It will be appreciated that other suitable carboxylic acids (including their activated derivatives) for the formation of in vivo hydrolyzable esters are known in the art and that they are also included in the scope of the invention. Catalysts such as 4-dimethylaminopyridine may also be useful.

 When used for the treatment of urinary incontinence, a compound of formula I is usually administered as a suitable pharmaceutical composition, which includes a compound of formula I, as previously defined, together with a pharmaceutically acceptable diluent or carrier, and the composition is intended for a particular route of administration.

 Such compositions are further features of the invention. They can be obtained using traditional methods and fillers, and binders, and can be in various dosage forms. For example, they can be in the form of tablets, capsules, solutions or suspensions for oral administration, suppositories for administration through the rectum, in the form of sterile solutions or suspensions for intravenous, intravesical (i.e. directly into the bladder), subcutaneous or intramuscular injection or injection, or in the form of an adhesive patch for transdermal administration.

 The dose of the compound of formula I to be administered will inevitably vary in accordance with principles well known in the art, taking into account the route of administration, the severity of the disease, the weight and age of the patient. In general, a compound of formula I is administered to warm-blooded animals (such as humans) in such a way as to achieve an effective oral dose, with a typical daily dose of 50-500 mg. For the specific compounds mentioned above that are preferred, due to their selectivity to the bladder, an effective oral dose may be from a total daily dose of 50 mg to a dose of 200 mg. No adverse effects were observed in laboratory animals after administration of the compounds of the invention at multiple times the minimum effective doses in the animal experiments described below.

 It should be appreciated that the compound of formula I can be administered in conjunction with other therapeutic or prophylactic agents and / or medications that are compatible with it.

The effects of the compounds of formula I as smooth muscle relaxants useful as therapeutic agents for the treatment of urinary incontinence can be shown using suitably designed in vitro tests, such as the experiment described below. The compounds of the invention typically show an IC ₅₀ at 30 μmol or less in the experiment. IR ₅₀ is a well-known term and refers to the concentration of the test compound that causes a 50% reduction in in vitro reduction of bladder tissue as described in a subsequent test.

Hartley male albino guinea pigs (weighing 450-500 g) were euthanized by displacement of the cervical vertebrae. The lower abdomen was opened, and the bladder was localized. The fixed bladder was cleaned of the surrounding connective and adipose tissue. Two nerves of the renal pelvis on the central surface of the bladder were cut off, then the body of the bladder was removed by inflating the ureters. The bladder was washed in Krebs-Jlenseleit buffer solution (composition, mmol): NaCl 118.0; KCl 4.7; MgSO ₄ 1,2; KH ₂ PO ₄ 1.2; CaCl ₂ 2.5; NaHCO ₃ 25.0 and D-glucose 11.1) and then placed on buffer-soaked gauze in a Petri dish. The vault of the bubble was cut off and removed.

 A mid-ventral longitudinal incision was made with scissors and the bubble was laid flat on gauze. Strips were cut from the edge of the dome and the edge of the base and removed. The remaining shortened middle section was cut into two wide (horizontal) strips of approximately 2.0 mm wide. These two strips were cut in half in the mid-dorsal portion to obtain four strips of similar sizes. Each strip thus contained both the dorsal and ventral parts of the bladder.

 Each individual strip was tied at one end directly to the glass support rod, and black woven silk suture 4-0 was tied to the other end. Glass rods were placed in 20 mm tissue baths, and the ends of the suture were attached to a dynamometric electromechanical sensor (Grass model FTO3).

Tissues were washed in Krebs-Jlenseleit buffer solution. The washing solution was heated to 37 ^° C. and aerated with 5% CO ₂ and 95% O ₂ with vigorous bubbling. The solution should have a pH value close to 7.4.

 The sensors were connected to a polygraph (Jrass model 7E) and connected to a signal processor system for receiving, transmitting and processing data (Biowindow Data Aoquisition Saftware) (executed on the OS / 2 microsoft with a personal computer compatible with IBM).

 The polygraph was calibrated at 5 mW / cm, and the calibration was checked for linearity at a load of 5 and 0.5 g.

 Tissue was incubated in buffer for 15 min without pre-loading, then for 30 min with applied loading. The pre-applied loading was 2 g, which weakened to approximately 1.0 g. The fabric was washed at 15-minute intervals, setting the loading to 2.0 g, as before washing. After this 45-min equilibrium period, an initial dose of 15 mmol of potassium chloride was introduced (total concentration in the bath). The tissue was washed after 10 minutes and washed two more times at 15 minute intervals with a loading of 2 g set before each washing.

 When the tissue relaxed to a steady state, 15 mmol KCl was added again after the final wash. When the tissue reaches a steady state, basic data appears in the Biowindow Data Aoquisition System. This is achieved by averaging data for 5 min collected at 32 Hz. After obtaining a zero reference, the experimental compounds are dosed cumulatively in semilogarithmic increment units. The contact time for each dose is 10 minutes, of which the last 5 minutes are the time period when data characterizing the tissue response to the dose are obtained. If 30 μmol of the test compound does not eliminate the shift in mechanical activity, then 30 μmol of cromacalim is added to cause a maximum reaction. The action of the compounds is expressed as a percentage of the maximum relaxation of loading due to the agonist.

Typical IR ₅₀ values in the test described above are 1.27 ± 0.31 μmol for the connection along the perimeter 1 and 5.14 ± 1.89 μmol for the connection in example 2.

 It should be borne in mind that the effectiveness of the compounds according to the invention can be demonstrated by standard in vivo assays. The following is a description of such a standard test, which is used to evaluate test compounds for their ability and smooth muscle relaxation.

 Male Wistar rats. Weighing 450-550 g, 20 mg / kg of Nembutal was anesthetized intraperitoneally and 80 mg / kg of Ketamine intraperitoneally. A cannula was inserted into the trachea to prevent airway blockage. Body temperature was maintained using a heating pad. Arterial blood pressure and heart rate were measured with a pressure transducer connected to a polyethylene tube (PE 50) inserted into the right carotid artery. A cannula was inserted into the first jugular vein for medication. The bladder was exposed by dissection along the midline of the abdominal cavity and freed from the contents by light pressure by hand. A catheter (50 PE) was inserted through the top of the bladder by about 3-4 mm into its lumen and ligated with suture material (4-0 shel) to prevent leakage.

 A bladder catheter was attached to a pressure sensor to measure bladder pressure. Then the bladder was placed back into the abdominal cavity and the incision was sutured with the exception of the catheter insertion bridge into the cavity. The bladder was equilibrated in approximately 15 minutes.

 After the equilibrium period, the rats were injected with physiological saline directly into the bladder at a rate of 0.05 ml / min for the entire duration of the experiment. Bladder pressure was recorded on a monitor to determine the onset of bladder contractions. After the start of contractions, the animal was allowed to stabilize its own rhythm of contractions approximately 30-45 minutes before drug administration.

 The test compounds were administered intravenously and the intermittent dose was 3 mg / kg. In this experimental model, the reference drug cromacalim (Smith-Kline-Brecham, Drugs 40 (6), 785-791, 1990) was evaluated, administered intravenously in an amount of 0.05-0.5 mg / kg.

 In the in vivo experiment described above, it was possible to evaluate both the blood pressure and the cystometric activity of the test compound. Blood pressure is measured immediately after injection of the drug and later after 5, 15 and 30 minutes. Urinary contractions leading to urination are caused by a slow continuous infusion of saline directly into the bladder. The average change (in seconds from control) in the duration of the time interval between contractions in about 20 minutes was obtained for each compound.

 Typical results of the examples are given in table. one.

 MVR mean arterial blood pressure. Pressure shown in mmHg and reflects changes from control.

 The time shown in the table. 1, reflects the immediate effect and actions after 5, 15 and 30 minutes after intravenous administration of the compound.

 IC interval between contractions. A change in the contraction interval means a peak response in seconds from the control.

 The following is a description of the in vivo test, which is complementary to the tests described above and can be used to verify whether the test compound is active and whether it shows bladder selectivity without significant effects on the cardiovascular system when administered orally. In this test, the particularly preferred compounds listed above showed activity and selective effect.

 Male Wistar rats (400-500 g) were anesthetized with 50 mg / kg nembutal intraperitoneally. An abdominal region was shaved in each rat, and povidone-iodine mixture was applied to the neck in front and back, and povidone-iodine was applied to the skin. For catheterization of the carotid artery, the left carotid artery was exposed through a small ventral cervical incision. The exposed area was washed with a 2% lidocaine hydrochloride solution to relax the vessel. A catheter filled with 0.9% saline was injected approximately 2.4 cm into the artery, so that its end was in the aortic arch. The peripheral end of the catheter was introduced out onto the back of the neck, filled with heparin (1000 units / ml) and sealed by heat welding. For catheterization of the bladder, catheters were implanted according to the method of Jaksh TL, Drerant Pac, Brent CR.

 Urination in rats. A chronic model for studying bladder function and the effects of anesthesia (Am. J. Physiol, 251 (Requlatory Jntegrative Comp. Physiol. 20): R1177-R1185, 1986). The bubble was removed through resettlement along the midline of the abdomen. The trocar was passed through the abdominal muscle about 1 cm from the upper end of the incision and then advanced subcutaneously to protrude through the skin on the back of the neck. A catheter filled with saline was passed through a trocar.

 A small hole in the dome of the bladder was burned with Acca.-Femp. A catheter was placed in the bladder and fixed with a 4-0 silk ligature. The catheter was rinsed with brine and the open state was observed. The outer end of the catheter was heat welded to prevent urine from flowing out. The abdominal muscles and skin were sutured. Both catheters were threaded through a retainer (Jntech), which was then sutured in the subcutaneous muscle at the point of externalization (exit to the surface). The skin was stitched over the latch. Animals were taken out of anesthesia.

 After 24-48 hours after surgery, each rat was placed in an exchange cage and connected via a clamp to the Jntech elastic guard and hinge system to protect the catheters in the cage. A carotid catheter was attached to a Gould P23XL pressure transducer to measure blood pressure. A bladder catheter was connected to a saline infusion pump and to a pressure transducer via a piping system and a 4-way stopcock. A load-loaded scale with a collection cuvette was placed under the cage to measure urine output.

 The rats were weighed, dosed orally, dosed (a dosing needle was introduced, but the liquid was not pushed out), and infusion of saline through the bladder began at a rate of 0.18 ml / min and continued throughout the experiment. Changes in blood pressure, heart rate, bladder pressure, and urine output were recorded either on a Jrassa polygraph or on a Gold TA 4000 recording system.

 Animals were allowed to balance until urine samples became normal (approximately 45-90 minutes). At this time, a zero reading of each parameter was recorded and the rats were given oral probe nutrition with the appropriate dose of the compound (in 75% PEC 400 vehicle from saline solution) in concentrations so that the volume was 1 ml / kg body weight. The effect of the compounds on the experimental parameters was monitored for 4 hours after administration. Cromacalim (Smithkline-Brecham) was used as a comparative standard (reference).

 The experimental results for both parameters, the interval between the bladder contractions and also the heart rate in rats, were expressed as the mean ± standard error as a percentage of the zero level for each animal that served as its own control. The mean arterial pressure is expressed as the mean value ± the standard error of the change in mmHg from the baseline. Typical values are given in table. 2 for the indicated examples.

 The compounds of the invention are active in one or more of the tests described above. With reference to those (preferred) compounds that were listed above as exhibiting selectivity for the bladder, most compounds from this list were also tested in vivo in a dog model, and all compounds that were tested showed activity and selectivity.

The invention will be further illustrated by the following, non-limiting examples, in which, unless stated otherwise, then:
(i) temperatures are given in degrees Celsius ( ^o C): operations were carried out at room temperature or at ambient temperature, i.e. at 18-25 ^o C;
(ii) the solvent was evaporated using a rotary evaporator under reduced pressure of 600-4000 Pa; 4.5-30 mmHg at a bath temperature of up to 60 ^o C;
(iii) flash chromatography was performed on Merck Kiselgel silica gel (Art 9385) and column chromatography on Merck Kieselgel 60 (Art 7734); (these materials were obtained from E. Merck, Darmstadt, W, Jermany); thin layer chromatography was performed on 0.25 mm CHLF silica gel plates (Art 21521) obtained from Analtech, New-Jork, DE, USA.

(iv) in general, the progress of the reactions was monitored by thin layer chromatography and the reaction times are given for illustration only;
(v) melting points are not corrected, and (d) indicates decomposition; the melting points given in the description are obtained for materials prepared as described; polymorphism can lead to the release of materials with different melting points in some preparations;
(vi) all final products were sufficiently pure by thin layer chromatography and had satisfactory nuclear magnetic resonance (NMR) spectra and elemental analysis data;
(vii) the outputs are for illustrative purposes only;
(viii) reduced pressures are given as absolute pressures in pascals (Pa); other pressures are given as bar readings;
(ix) solvent ratios are given by volume.

 Example 1

 N- (4- (2-fluorophenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3.3,3-trifluoro-2-hydroxy-2-methyl propionic acid ester (1.42 g, 9.0 mmol) in N, N-dimethylformamide (13 ml) cooled to -20 ^° C was quickly added thionyl chloride (1.13 g, 9.5 mmol), and the mixture (a precipitate formed after several minutes) was stirred at (-15) (-5) ^° C for 1 hour. Then 4- (2-fluorophenylsulfonyl) was added in one portion - benzamine (1.51 g, 6.0 mmol) and the mixture was left overnight with stirring at room temperature. The solution was poured into water, the turbid solution was poured from the obtained resin and filtered through a thin layer of celite. The celite layer was washed with methylene chloride, and the solution was added to the resin solution in methylene chloride. The combined methylene chloride solution was dried (magnesium sulfate), filtered and the solvent was removed in vacuo. The resulting resin was treated with hexane (100 ml) and a sufficient amount of methylene chloride (about 100 ml) to obtain a solution. Then, methylene chloride was evaporated in a steam bath at atmospheric pressure until cloudiness appeared. The solution was cooled and scraped off with a spatula until crystal growth began, returned to the steam bath and concentrated with swirling to a final volume of 100 ml. After cooling, the solid was filtered off and the title propanamide (1.92 g, 82%) was obtained as a light brown solid, melting point 124-133 ^° C.

¹ H NMR spectrum (400 MHz, DMCO-d ₆ ): 1.59 (s, 3H, CH ₃ ); 7.41 (t, 1H, aromatic); 7.51 (t. 1H, aromatic); 7.59 (s. 1H, OH); 7.77 (m, 1H, aromatic); 7.85 (d. 2H, J = 8.7 Hz, aromatic); 7.98-8.06 (m, 3H, aromatic); 10.48 (s. 1H, NH).

 Mass spectrum (Cl, methane): 392 (M + 1).

Elemental analysis for C ₁₆ H ₁₃ F ₄ NO ₄ S
Calculated, C 49.11; H 3.35; 3.58;
Found, C, 49.28; H 3.51; N, 3.66.

 The starting 4- (2-fluorophenylsulfonyl) benzeneamine is described by N (Sharghi and J. Lalesavi, J. Chem. Eng. Data. 8, 276-278, 1963).

 Example 2

 N- (4- (2-methylphenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

To a stirred solution of 3.3,3-trifluoro-2-hydroxy-2-methyl propanoic acid ester (1.42 g, 9.0 mmol) in N, N-dimethylacetamide (13 ml) cooled to -15 ^° C quickly thionyl chloride (1.13 g, 9.5 mmol) was added and the mixture (a precipitate formed after several minutes) was stirred at (-20) (-10) ^° C for 1 hour.

 Then 4- (2-methylphenylsulfonyl) benzeneamine (1.48 g, 6.0 mmol) was added in one portion, washed with 2 ml of N, N-dimethylacetamide and the mixture was left overnight with stirring at room temperature. The solution was poured into water, the turbid solution was poured from the obtained resin and filtered through a celite pad.

 The celite layer was washed with methylene chloride, and the solution was added to the resin solution in methylene chloride. The combined methylene chloride solution was dried (magnesium sulfate), filtered, and the solvent was removed in vacuo.

 The resulting resin was dissolved in several ml of methanol and was added dropwise to 100 ml of rapidly stirred 3 N. hydrochloric acid. The aqueous phase was decanted from the resin, the resin was dissolved in methylene chloride, dried (magnesium sulfate), filtered, and the solvent was removed in vacuo. The residue was dissolved in 125 ml of methylene chloride and heated in a steam bath, slowly adding 100 ml of hexane to replace methylene chloride. Upon reaching a volume of 125 ml, more hexane (about 50 ml) was added to a cloud point. After cooling the mixture overnight, the resulting solid was filtered to obtain a crude product. The material was further mixed with 300 ml of 0.5 N. hydrochloric acid for 45 minutes The aqueous phase was drained and the remaining resin was dissolved in methylene chloride, dried (magnesium sulfate), filtered, and the solvent was removed in vacuo. The product was dissolved in 100 ml of methylene chloride, 50 ml of hexane was added, and the solution was heated in a steam bath to a final volume of 100 ml.

After cooling, the resulting solid was filtered off, dried at 100-120 ^° C and a pressure of 0.1 mm Hg. within 2.5 hours, the desired compound propanamide was obtained, which was indicated in the title of the example, with a yield of 1.78 g (77%) as a light brown solid, melting point 126-128 ^° C.

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 1.58 (s, 3H, CH ₃ ), 2.39 (s. 3H, aryl CH ₃ ), 7.37-8.10 (m, 8H, aromatic), 7.6 (broad, s, 1H, OH), 10.4 (wide singlet, 1H, NH).

 Mass spectrum (Cl, methane): 388 (M + 1).

Elemental analysis for C ₁₇ H ₁₆ F ₃ NO ₄ S
Calculated, C 52.71; H 4.16; N 3.62;
Found, C, 52.64; H 4.16; N, 3.59.

 The starting 4- (2-methylphenylsulfonyl) benzeneamine is described by H. Jilman and H. Smith Broadbent, J. Amer. Chem. Soc. 69, 2053, 1947.

 Example 3

 N- (4- (2-methoxyphenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3.3,3-trifluoro-2-hydroxy-2-methylpropionic acid (1.42 g, 9.0 mmol) in N, N-dimethylacetamide (13 ml) cooled to -15 ^° C was added quickly chloride thionyl (1.13 g, 9.5 mmol), and the mixture (precipitate formed after a few minutes) was stirred at (-15) (-5) ^° C for 1 hour. Then 4- (2-methoxyphenylsulfonyl) benzeneamine was added in one portion. (1.58 g, 6.0 mmol) and the mixture was left overnight with stirring at room temperature. The solution was poured into 300 ml of 0.5 N. hydrochloric acid, the clear supernatant was decanted, the residual resin was dissolved in methylene chloride, dried (magnesium sulfate), filtered, and the solvent was removed in vacuo. The residue was dissolved in 100 ml of methylene chloride, filtered, treated with 50 ml of hexane and briefly heated in a steam bath until crystals began to form. The final volume was adjusted to 200 ml with hexane, the mixture was cooled for 3 hours, the crystals were filtered and washed with hexane. The solid was dissolved in 700 ml of refluxed methylene chloride, and the methylene chloride was evaporated, while 250 ml of hexane was slowly added. The mixture was concentrated to a final volume of 375 ml. After cooling, the solid was filtered and dried at 135-140 ^o C and a vacuum of 0.1 mm RT.article within 40 hours, the desired propanamide 0.1 CH ₂ Cl ₂ (1.41 g, yield 57%) was obtained as a white solid, melting point 211-209 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 1.55 (s, 3H, CH ₃ ), 3.72 (s. 3H, CH ₃ O), 5.73 (s. 0.2 N , CH ₂ Cl ₂ ), 7.11-7.17 (m. 2H, aromatic), 7.53 (s. 1H, OH). 7.61-7.97 (m, 6H, aromatic); 10.36 (s. 1H, NH).

 Mass spectrum (Cl, methane): 404 (M + 1).

Elemental analysis for C ₁₇ H ₁₆ F ₃ NO ₅ S
Calculated, C 49.87; H 3.96; N, 3.40;
Found, C, 49.71; H 3.96; N, 3.35.

 The starting 4- (2-methoxyphenylsulfonyl) benzeneamine was prepared as follows.

 a) 4- (2-methoxyphenylsulfonyl) benzeneamine.

To a stirred suspension of 2-methoxyphenyl-4-nitrophenyl sulfone (12.36 g, 4.2 mmol) and 90 ml of absolute ethanol were added in one portion tin (II) chloride dihydrate (47.4 g, 21 mmol). The mixture was heated to 50 ^° C. when an exothermic reaction caused strong reflux of the solution. The mixture was stirred at room temperature for 30 minutes, poured into ice water and made basic strongly by adding 350 ml of 15% sodium hydroxide. The mixture was extracted with methylene chloride (3 x 275 ml), the extracts were dried (magnesium sulfate), filtered, the solvent was removed in vacuo and a white solid was obtained, which was recrystallized from ethyl acetate-hexane. After cooling, the solid was filtered off and the target benzeneamine (5.38 g, 49%) was obtained as a white solid, melting point 206-208 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 3.75 (s. 3H, OCH ₃ ); 6.10 (s. 2H, H ₂ ); 6.56-6.61 (m, 2H, aromatic); 7.07-7.13 (m, 2H, aromatic); 7.49-7.61 (m, 3H, aromatic); 7.90 (dd, 1H, J = 8.1 and 1.7 Hz, aromatic).

Mass spectrum: (Cl, methane): 264 (M + 1);
Elemental analysis for C ₁₃ H ₁₃ NO ₃ S.

Calculated, C 59.30; H 4.98; N, 5.32;
Found, C 59.28; H 5.04; N, 5.20.

 c) 2-methoxyphenyl-4-nitrophenylsulfone.

To a stirred solution of 2-methoxyphenyl-4-nitrophenyl sulfide (13.73 g, 5.25 mmol) and acetic acid (800 ml) was quickly added a solution of potassium permanganate (9.97 g, 6.3 mmol) in water (350 ml) . After stirring for 45 minutes, the mixture was poured into water (2.0 L), clarified by the addition of sodium sulfide and the solid was filtered off, dried for several hours at 40 ^° C and a vacuum of 0.1 torr and recrystallized three times from absolute ethanol (300 ml). The yield of the target sulfone was 12.46 g, 81% in the form of white plates, melting point 140-142 ^o C.

¹ H-NMR spectrum (300 MHz, CDCl ₃ ): 3.79 (s, 3H, OCH ₃ ), 6.94 (d, 1H, J = 8.4 Hz, aromatic), 7.16 (t, J = 7.6 Hz, 1H, aromatic), 7.58-7.64 (m 1H, aromatic), 8.13-8.19 (m 3H, aromatic), 8.31-8.35 (m . 2H, aromatic).

 Mass spectrum (Cl, methane): 294 (M + 1).

Elemental analysis for C ₁₃ H ₁₁ NO ₅ S.

Calculated, C 53.24; H 3.78; N, 4.78;
Found, C, 53.23; H 3.79; N, 4.79.

 c) 2-methoxyphenyl-4-nitrophenyl sulfide.

A solution of 4-chloronitrobenzene (11.23 g, 7.13 mmol) in N, N-dimethylformamide (75 ml) was added to the potassium salt of 2-methoxyphenol (prepared by adding 2-methoxythiophenol (10.0 g, 7.13 mmol) to a solution of potassium hydroxide (4.0 g, 7.13 mmol) in methanol, followed by removal of methanol in vacuo and washing with an additional 15 ml of N, N-dimethylformamide After stirring at room temperature, the mixture left overnight was poured into ice water, stirred 1 h, filtered, the collected solid washed with water and dried by standing overnight at 40 ^o C and a vacuum of 1 m N. The pale yellow solid was recrystallized from 85% ethanol (150 ml) and then from hexane (700 ml) to give the title sulfide (13.8 g, 74%) as a pale-yellow needles, melting point 90-92 ^o C.

Spectrum ¹ H-NMR (300 MHz, CDCl ₃ ): 3.82 (s. 3H, OCH ₃ ), 7.01-7.06 (m. 2H, aromatic), 7.10-7.15 (m. 2H, aromatic), 7.25-7.55 (m, 2H, aromatic), 8.02-8.07 (m, 2H, aromatic).

 Mass spectrum (Cl, methane): 262 (M + 1).

Elemental analysis for C ₁₃ H ₁₁ NO ₃ S.

Calculated, C 59.76; H 4.24; N, 5.36;
Found, C 59.95; H 4.25; N, 4.73.

 Example 4

 N- (4-phenylsulfonyl-3-cyanophenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 1.91 g (5.2 mmol) of N- (4-phenylthio-3-cyanophenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide and 150 ml of glacial acetic acid was added a solution of 0, 99 g (6.3 mmol) of potassium permanganate and 100 ml of water in one portion. The mixture was stirred at room temperature for 45 minutes, poured into 400 ml of water, clarified with a small amount of solid sodium bisulfate, and extracted with three 250 ml portions of chloroform. The extracts were dried (magnesium sulfate), filtered, the solvent was removed, and an oil was obtained, which was chromatographed over 300 g of silica gel using ethyl ether (0, 10, 15, and 20%) in methylene chloride as the gradient mobile phase. Subsequently, the material was recrystallized from hexane containing a small amount of ethyl acetate, and 1.57 g (75%) of the desired propanamide was obtained as a white solid, melting point 163-165 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 1.59 (s. 3H, CH ₃ ), 7.66-7.77 (m. 4H, aromatic, OH), 7.99 (d. 2H, J = 7.3 Hz, aromatic), 8.32 (d, 1H, J = 8.6 Hz, aromatic), 8.40-8.43 (m 2H, aromatic), 10.77 (s . 1H, NH).

 Mass spectrum (Cl, methane): 399 (M + 1).

Elemental analysis for C ₁₇ H ₁₃ F ₃ N ₂ O ₄ S.

Calculated, C 51.26; H 3.29; N, 7.03;
Found, C 51.28; H 3.31; N, 7.01.

 The starting N- (4-phenylthio-3-cyanophenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide was prepared as follows.

 a) N- (4-phenylthio-3-cyanophenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3.3,3-trifluoro-2-hydroxy-2-methylpropionic acid (2.16 g, 13.7 mmol) in N, N-dimethylacetamide (20 ml) cooled to -20 ^° C was added quickly chloride thionyl (1.73 g, 14.5 mmol), and the mixture (a precipitate formed after a few minutes) was stirred at (-20) (-10) ^° C for 1 h (4-amino-2-cyanophenyl) phenyl sulfide ( 2.08 g, 9.2 mmol) was then added in one portion and the mixture was left overnight at room temperature with stirring. The solution was poured into 500 ml of water and extracted with two portions of 100 ml of ethyl ether. The oil obtained after removal of ethyl ether was chromatographed on 325 g of silica gel using a gradient of ethyl ether (0, 5, 10, and 20% in methylene chloride). The appropriate fractions were combined, the solvent was removed in vacuo, the residue was left overnight while heating to a temperature of 60 ^o C and a vacuum of 0.1 mm Hg and 5.35 g (93%) of N- (4-phenylthio-3-cyano-phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide were obtained, melting point 124-126 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 1.59 (s. 3H, CH ₃ ), 7.32-7.47 (m. 6H, aromatic), 7.59 (s. 1H, OH), 8.07 (dd. 1H, 8.8 and 2.3 Hz, aromatic), 8.33 (d. 1H, J = 2.3 Hz, aromatic), 10.48 (s. 1H, NH )

 Mass spectrum (Cl, methane): 367 (M + 1).

 b) 4-amino-2-cyanophenyl-phenyl sulfide.

To a stirred suspension of 4-nitro-2-cyanophenyl sulfide (13.3 g, 5.19 mmol) and 100 ml of absolute ethanol was added tin (II) chloride dihydrate (58.6 g, 26 mmol) in one portion. The mixture was heated to 60 ^° C. when the exothermic reaction caused a strong phlegm of the solution. The mixture was stirred at room temperature for 30 minutes, poured into ice water and made basic strongly by adding 350 ml of 15% sodium hydroxide. The mixture was extracted with methylene chloride (4 times 275 ml), the extracts were dried (magnesium sulfate), filtered, the solvent was removed in vacuo and an oil was obtained which was chromatographed over 300 g of silica gel using a gradient of methylene chloride (20, 40, 60, 80, and 100 %) in hexane. The desired fractions were collected, the solvent was removed, and 4-amino-2-cyanophenyl phenyl sulfide (10.62 g, 91%) was obtained as a pale yellow solid, melting point 73-75 ^° C.

¹ H-NMR spectrum (300 MHz, CDCl ₃ ): 4.01 (s, 2H, H), 6.78 (dd. 1H, J = 8.5 and 2.6 Hz, aromatic), 6.95 ( d, 1H, J = 2.6 Hz, aromatic), 7.28-7.29 (m, 5H, aromatic). 7.34 (d, 1H, J = 8.5 Hz, aromatic).

Mass spectrum (Cl, CH ₄ ): 227 (M + 1).

Elemental analysis for C ₁₃ H ₁₀ N ₂ S.

Calculated, C 69.00; H 4.45; N, 12.38;
Found, C, 68.99; H 4.59; N, 12.27.

 c) 4-nitro-2-cyanophenyl sulfide.

4-chloro-3-cyanonitrobenzyl (12.5 g, 6.84 mmol) was added in portions to the N, N-dimethylformamide (50 ml) solution of thiophenol potassium salt (obtained by adding thiophenol (7.1 ml, 6.9 mmol) to a solution of potassium hydroxide (3.84 g, 6.84 mmol) in methanol, followed by removal of methanol in vacuo After stirring at 105 ^° C for 2.5 hours, the mixture was poured into ice water, filtered, the collected solid was washed with water , dissolved in 300 ml of reflux of ethanol (activated carbon), filtered, treated with 35 ml of water and frozen. The resulting pale yellow solid compound weighed 13.3 g (76%), mp 82-84 ^o C.

Spectrum ¹ H-NMR (250 MHz, CDCl ₃ ): 6.93 (d. 1H, J = 9.0 Hz, aromatic), 7.51-7.62 (m, 5H, aromatic), 8.12 ( dd. 1H, J = 9.2 and 2.5 Hz, aromatic), 8.46 (d. 1H, J = 2.5 Hz, aromatic).

Mass spectrum (Cl, CH ₄ ): 257 (M + 1).

Elemental analysis for C ₁₃ H ₈ N ₂ O ₂ S.

Calculated, C 60.93; H 3.15; N, 10.93;
Found, C, 60.87; H 3.41; N, 10.95.

 Example 5

 N- (4-phenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methyl-propanamide.

To a stirred solution of 3.3,3-trifluoro-2-hydroxy-2-methylpropionic acid (3.96 g, 25 mmol) in N, N-dimethylacetamide (36 ml) cooled to -20 ^° C, thionyl chloride ( 3.10 g, 26 mmol) and the mixture (precipitate formed after several minutes) was stirred at (-15) - (-5) ^° C for 1 h. Then 4- (phenylsulfonyl) benzeneamine (3.97 g, 17 mmol) was added. ) in one portion and the mixture was left overnight with stirring at room temperature. The solution was poured into water, the resulting solid was filtered off, washed with 3 N hydrochloric acid, then water and dried at 65 ^° C. for 2 hours. The solid was dissolved in 300 ml of reflux of methylene chloride and heated with the addition of hexane to replace boiling methylene chloride. When 250 ml of hexane was added (precipitation began with the addition of 180 ml), the mixture was concentrated to 250 ml and frozen. The yield of light brown solid was 5.92 g (93%), melting point 164-166 ^o C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.59 (s. 3H, CH ₃ ), 7.57-7.72 (m. 4H, OH, aromatic), 7.92-8, 04 (m. 6H, aromatic), 10.43 (s. 1H, NH).

Elemental analysis for C ₁₆ H ₁₄ F ₃ NO ₄ S.

Calculated, C 51.47; H 3.78; N, 3.75;
Found, C 51.22; H 3.83; N 3.72.

 Example 6

 N- (4- (4-pyridylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (4.28 g, 30.5 mmol) in N, N-dimethylacetamide (30 ml) cooled to -20 ^° C was added thionyl chloride (3.63 g, 30.5 mmol), and the mixture was stirred at (-10) (-15) ^° C for 1 hour. 4- (4-Pyridylsulfonyl) benzeneamine (4.77 g, 20.4 mmol) was added in one portion, and the mixture was left overnight with stirring at room temperature. The solution was poured into water, the yellow solid was filtered off and purified by flash chromatography (ethyl acetate-methylene chloride mixture in a ratio of 1: 1 by volume). The eluent was evaporated and trituration of the obtained solid with hot methylene chloride gave the target propanamide (4.61 g, 60%) as an off-white solid, melting point 255-257 ^° C.

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 1.71 (s. 3H, CH ₃ ), 7.71 (s. 1H, OH), 8.01 (d. 2H, J = 4, 5 Hz, aromatic), 8.12 (d. 2H, J = 7.1 Hz, aromatic), 8.19 (d. 2H, J = 7.1 Hz, aromatic) 9.00 (d. 2H, J = 4.5 Hz, aromatic), 10 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 375 (M + 1).

Elemental analysis for C ₁₅ H ₁₃ F ₃ N ₂ O ₄ S.

Calculated, C 48.12; H 3.51; N, 7.48;
Found, C, 48.02; H 3.59; N, 7.42.

 The starting 4- (4-pyridylsulfonyl) benzeneamine is described.

 Example 7

 N- (4- (2-pyrimidinylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.01 g, 6.4 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (0.76 g, 6.4 mmol), and the mixture was stirred at (-10) (-15) ^° C for 1 hour. 4- (2-Pyrimidylsulfonyl) benzeneamine (1.0 g, 4.2 mmol) and the mixture was left at room temperature with stirring overnight. The brown mixture was poured into water and extracted with ethyl acetate (twice 50 ml). The combined organic parts were washed with water, dried (magnesium sulfate), filtered and a brown solid was obtained after distilling off the solvent. Evaporation chromatography of a solid (eluted 10% by volume with ethyl acetate in methylene chloride) and evaporation of the eluent afforded the desired propanamide (1.05 g, 66%) as a white solid, melting point 187-190 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 1.60 (s. 3H, CH ₃ ), 7.59 (s. 1H, OH), 7.79 (t. 1H, J = 4, 9 Hz, aromatic), 7.96 (d. 2H, J = 8.9 Hz, aromatic), 8.06 (d, 2H, J = 8.9 Hz, aromatic), 9.02 (d. 2H, J = 4.8 Hz, aromatic), 10.49 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 376 (M + 1).

Elemental analysis for C ₁₄ H ₁₂ F ₃ N ₃ O ₄ S.

Calculated, C 44.80; H 3.2; N, 11.20;
Found, C 44.86; H 3.36; N, 11.06.

 4- (2-pyrimidylsulfonyl) benzeneamine is described.

 Example 8. N- (5- (2-phenylsulfonylpyridyl)) - 3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of N- (5- (2-phenylthiopyridyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (1.50 g, 4.4 mmol) in glacial acetic acid (125 ml) was added a solution potassium permanganate (0.83 g, 5.3 mmol) in distilled water (85 ml). The dark brown mixture was stirred at room temperature for 45 minutes, then treated with solid sodium sulfite until the color disappeared. The mixture was diluted with water and extracted with chloroform (three times). 250 ml each). The combined organic parts were dried (magnesium sulfate), filtered, the solvent was distilled off and the whole was obtained howling propanamide in the form of a white solid, melting point 175-177 ^o C.

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 1.59 (s. 3H, CH ₃ ), 7.65 (m, 4H, OH, aromatic), 7.95 (d. 2H, J = 7.5 Hz, aromatic), 8.22 (d. 1H, J = 8.7 Hz, aromatic), 8.54 (dd. 1H, J = 8.7 and 2.4 Hz, aromatic), 9, 00 (d. 1H, aromatic), 10.73 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 375 (M + 1).

Elemental analysis for C ₁₅ H ₁₃ F ₃ N ₂ O ₄ S.

Calculated, C 48.12; H 3.51; N, 7.48;
Found, C 47.96; H 3.62; N, 7.43.

The starting N- (5- (2-phenylthiopyridyl)) - 3,3,3-trifluoro-2-hydroxy-2-methylpropanamide was prepared as follows:
N- (5- (2-phenylthiopyridyl)) - 3,3,3-trifluoro-2-hydroxy-2-methylpropanamide
To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (0.59 g, 3.7 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (0.44 g, 3.7 mmol) and the mixture was stirred at (-10) (-15) ^° C for 1 h. 5-amino-2-phenylthiopyridine (0.50 g, 2, 5 mmol) and the mixture was left stirring at room temperature overnight. The brown mixture was poured into water, and the aqueous solution was extracted with ethyl acetate (two times 50 ml). The combined organic extracts were washed with water, dried (magnesium sulfate). Filtered, the solvent was distilled off to obtain a yellow oil.

Evaporative chromatography of oil (eluted with 10% by volume ethyl acetate in methylene chloride) and evaporation of the eluent gave the desired propanamide (0.59 g, 69%) as a white solid, melting point 147-150 ^o C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 1.57 (s. 3H, CH ₃ ), 7.04 (d. 1H, J = 8.7 Hz, aromatic), 7.47 (m 5H, OH, aromatic), 8.05 (dd. 1H, J = 7 and 2.6 Hz, aromatic), 8.77 (d. 1H, J = 2.4 Hz, aromatic), 10.30 ( s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 343 (M + 1).

Elemental analysis for C ₁₅ H ₁₃ F ₃ N ₂ O ₂ S.

Calculated, C 52.63; H 3.83; N, 8.18;
Found, C, 52.25; H 3.86; N, 8.13.

 5-amino-2-phenylthiopyridine is described by H.C. Winter and F.E. Reinhart, J. Amer. Chem. Soc. 62, 3508 (1940).

 Example 9

 N- (4- (4-fluorophenylcarbonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (1.58 g, 10 mmol) in N, N-dimethylacetamide (15 ml) cooled to -20 ^° C was added thionyl chloride (1 25 g, 10.5 mmol) and the mixture was stirred at (-20) (-5) ^° C for 1 h. 4-amino-4'-fluorobenzophenone (1.44 g, 6.7 mmol) was added in one portion, and the reaction mixture was left overnight at room temperature and stirred. The reaction mixture was poured into water, the turbid solution was poured from the resin and filtered through a thin layer of celite. Celite was washed with methylene chloride, and the solution was added to a solution of the resin in methylene chloride. The combined methylene chloride solution was dried (magnesium sulfate), filtered, and the solvent was removed to give an oil. The oil was treated with 50 ml of hexane and enough methylene chloride to dissolve the oil. The volume of the solution was slowly reduced in a steam bath, the solution was cooled and scraped off with a spatula until crystals formed. The volume was further reduced in a steam bath, the mixture was frozen for several hours, and the resulting solid was filtered. 1.60 g of the crude product was further purified by chromatography on 80 g of silica gel using ethyl ether as the eluent. The solvent was distilled off from the first 150 ml of eluent, the residual oil was dissolved in 15 ml of methylene chloride and 250 ml of hexane was added with rapid stirring. The resulting solid was collected, dried and the desired propanamide (0.22 g, 58%) was obtained as a pale yellow solid, melting point 131-133 ^° C.

Spectrum ¹ H-NMR (250 MHz, CDCl ₃ ): 1.77 (s. 3H, CH ₃ ); 4.09 (s. 1H, OH), 7.14-7.28 (m. 2H, aromatic), 7.69-7.85 (m. 6H, aromatic), 8.68 (s. 1H, NH )

Mass spectrum (Cl, CH ₃ ): 356 (M + 1).

Elemental analysis for C ₁₇ H ₁₃ F ₃ NO ₃ S.

Calculated, C 57.47; H 3.69; N, 3.94;
Found, C, 57.30; H 3.65; N, 3.90.

 The starting 4-amino-4-fluorobenzophenone is described.

 Example 10

 N- (4- (3-pyridylsulfonyl) phenyl)) - 3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (0.76 g, 4.8 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (0.57 g, 4.8 mmol), and the mixture was stirred at (-10) (-15) ^° C for 1 h. To the orange solution was added in one portion 4- (3-pyridylsulfonyl) benzeneamine (0.75 g, 3.2 mmol) and the mixture was left overnight at room temperature with stirring. The brown solution was poured into water and extracted with ethyl acetate (twice 50 ml). The combined organic extracts were dried (magnesium sulfate), filtered, the solvent was distilled off, and a brownish solid was obtained. Recrystallization from ethyl acetate-hexane gave the target compound propanamide, indicated in the title of the example (0.89 g, 74%) as an off-white solid, melting point 207-209 ^° C.

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 1.57 (s. 3H, CH ₃ ), 7.58 (s. 1H, OH), 7.65 (dd. 1H, J = 8, 1 and 4.9 Hz, aromatic), 8.02 (d. 4H, J = 4.6 Hz, aromatic), 8.34 (dd. 1H, J = 8.3 and 1.9 Hz, aromatic), 8.85 (dd. 1H, J = 4.8 and 1.6 Hz, aromatic), 9.12 (d. 1H, J = 2.2 Hz, aromatic), 10.61 (s. 1H, NH) .

Mass spectrum (Cl, CH ₄ ): 375 (M + 1).

Elemental analysis for C ₁₅ H ₁₃ F ₃ N ₂ O ₄ S.

Calculated, C 48.12; H 3.51; N, 7.48;
Found, C, 48.21; H 3.56; N, 7.40.

 The starting 4- (3-pyridylsulfonyl) benzeneamine was prepared as follows.

 a) 4- (3-pyridylsulfonyl) benzeneamine.

A stirred solution of 4-nitrophenyl-3-pyridylsulfone (1.60 g, 6.1 mmol) and tin (II) chloride dihydrate (6.83 g, 30.2 mmol) in absolute ethanol (20 ml) was heated at reflux temperature refrigerator for 45 minutes. The reaction mixture was poured into ice water, the aqueous solution was made basic with sodium bicarbonate (pH 8-9) and extracted with ethyl acetate (two times 200 ml). The organic extracts were combined, dried (magnesium sulfate), filtered, the solvent was distilled off to obtain the desired benzamine (1.10 g, 79%) as a pale yellow solid, melting point 182-184 ^o C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 6.29 (broad singlet, 2H, NH ₂ ), 6.64 (d. 2H, J = 11.2 Hz, aromatic), 7.58 ( m. 1H, aromatic), 7.61 (d. 2H, J = 11.1 Hz, aromatic), 8.21 (dd. 1H, J = 9.8 and 2.4 Hz, aromatic), 8.78 (dd. 1H, J = 9.9 and 1.4 Hz, aromatic), 9.01 (d. 1H, J = 2.4 Hz).

Mass spectrum (Cl, CH ₄ ): 235 (M + 1).

Elemental analysis for C ₁₁ H ₁₀ N ₂ O ₂ S.

Calculated, C 56.40; H 4.30; N, 11.96;
Found, C 56.64; H 4.54; N, 11.48.

 The starting 4-nitrophenyl-3-pyridylsulfone is described in US Pat. No. 2,761,866.

 Example 11

 N- (4- (2-thienylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred and cooled to -20 ^° C solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.50 g, 3.1 mmol) in N, N-dimethylacetamide (7 ml) was added thionyl chloride (0.37 g, 3.1 mmol), and the mixture was stirred at (-10) (-15) ^° C for 1 hour. 4- (2-Thienylsulfonyl) benzeneamine (0.50 g, 2.1) was added in one portion. mmol) to an orange solution, and the mixture was left overnight at room temperature with stirring. The brown solution was poured into water, and the aqueous solution was extracted with ethyl acetate (two times 50 ml). The organic extracts were combined, dried (magnesium sulfate), filtered, the solvent was distilled off, and a brownish solid was obtained. Evaporation chromatography of a solid (eluted 5% by volume with ethyl acetate in methylene chloride) and evaporation of the eluent gave the desired compound propanamide (0.61 g, 77%) as an off-white solid, melting point 158-161 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.57 (s. 3H, CH ₃ ), 7.21 (dd, 1H, J = 4.9 and 4.0 Hz, aromatic), 7 56 (s. 1H, OH), 7.81 (dd, 1H, J = 3.8 and 1.5 Hz, aromatic), 8.00 (m. 5H, aromatic), 10.43 (s. 1H , NH).

Mass spectrum (Cl, CH ₄ ): 380 (M + 1).

Elemental analysis for C ₁₄ H ₁₂ F ₃ NO ₄ S ₂ .

Calculated, C 48.12; H 3.51; N, 7.48;
Found, C, 48.21; H 3.56; N, 7.40.

 4- (2-thienylsulfonyl) benzeneamine is described by H. Burtor and W.A. Dawy, J. Chem. Soc. 527, (1948).

 Example 12. N- (4- (2-pyridylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (0.76 g, 4.8 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (0.57 g, 4.8 mmol) and the mixture was stirred at (-10) (-15) ^° C for 1 h. To the orange solution, 4- (2-pyridylsulfonyl) benzeneamine (0.75 g, 3.2 mmol), and the mixture was left overnight with stirring at room temperature. The brown solution was poured into water, and the aqueous solution was extracted with ethyl acetate (two times 25 ml). The organic extracts were mixed, dried (magnesium sulfate), filtered, the solvent was distilled off, and a brown solid was obtained. Recrystallization from ethyl acetate-hexane gave the desired propanamide (0.95 g, 79%) as an off-white solid, melting point 162-163 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.58 (s. 3H, CH ₃ ), 7.59 (s. 1H, OH), 7.67 (m. 1H, aromatic), 7 92 (d. 2H, J = 8.9 Hz, aromatic), 8.02 (d. 2H, J = 8.9 Hz, aromatic), 8.15 (m. 2H, aromatic), 8.67 ( d. 1H, J = 4.2 Hz, aromatic), 10.44 (s. 1H, NH).

 Mass spectrum (Cl, methane): 375 (M + 1).

Elemental analysis for C ₁₅ H ₁₃ F ₃ N ₂ O ₄ S.

Calculated, C 48.31; H 3.62; N, 7.36;
Found, C 48.12; H 3.51; N, 7.48.

 The starting 4- (2-pyridylsulfonyl) benzeneamine was prepared as follows.

 a) 4- (2-pyridylsulfonyl) benzeneamine.

A stirred solution of 4-nitrophenyl-2-pyridyl sulfone (6.50 g, 24.6 mmol) and tin (II) chloride dihydrate (27.72 g, 123.0 mmol) in absolute ethanol (200 ml) was heated under reflux in for 25 minutes The reaction mixture was poured into ice water, the aqueous solution was made basic with sodium bicarbonate (pH 8-9) and extracted with ethyl acetate (two times 400 ml). The organic extracts were mixed, dried (magnesium sulfate), filtered, the solvent was distilled off to obtain the desired benzeneamine (5.12 g, 89%) as a white solid, melting point 158-160 ^o C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 6.27 (broad singlet, 2H, NH ₂ ), 6.66 (dd. 2H, J = 8.7 Hz, aromatic), 7.61 ( m. 3H, aromatic), 8.00 (d. 2H, J = 4.9 Hz, aromatic) 8.68 (d. 1H, J = 4.9 Hz, aromatic).

 Mass spectrum (Cl, methane): 235 (M + 1).

Elemental analysis for C ₁₁ H ₁₀ N ₂ O ₂ S.

Calculated, C 56.40; H 4.30; N, 11.96;
Found, C 56.38; H 4.43; N, 11.91.

 4-nitrophenyl-2-pyridylsulfone is described by J. C. Pappalardo and A. Scarlata, Farmaco Ed. Science, 33 (12), 945 (1978).

 Example 13

 N - ((3-chloro- (4-phenylsulfonyl) phenyl)) - 3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred and cooled to -20 ^° C solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (0.66 g, 4.2 mmol) in N, N-dimethylacetamide (10 ml) was added thionyl chloride (0.50 g, 4.2 mmol) and the mixture was stirred at (-10) (-15) ^° C for 1 hour. To the orange solution, 3-chloro-4-phenylsulfonylbenzeneamine (0.75 g, 2, 8 mmol), and the mixture was left overnight with stirring at room temperature. The brown solution was poured into water, and the aqueous solution was extracted with ethyl acetate (two times 50 ml). The organic phases were mixed, washed with water, dried (magnesium sulfate), filtered, the solvent was distilled off, and a reddish foam was obtained. Evaporation chromatography of a solid (eluted 10% by volume with ethyl acetate in methylene chloride) and evaporation of the eluent gave the desired propanamide (1.07 g, 94%) as an off-white solid, melting point 141-143 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.58 (s. 3H, CH ₃ ), 7.68 (m. 4H, aromatic, OH), 7.89 (d. 1H, J = 8.5 Hz, aromatic), 8.11 (d. 2H, J = 8.2 Hz, aromatic), 8.26 (d. 2H, J = 8.4 Hz, aromatic), 10.60 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 408 (M + 1).

Elemental analysis for C ₁₆ H ₁₃ ClF ₃ NO ₄ S.

Calculated, C 47.13; H 3.22; N 3.43;
Found, C 46.72; H 3.32; N, 3.34.

 The starting 3-chloro-4-phenylsulfonylbenzolamine is described in US Pat. No. 3,576,872.

 Example 14

 N- (4- (2-chlorophenylsulfonyl) phenyl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (0.89 g, 5.6 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (0.67 g, 5.6 mmol), and the mixture was stirred at (-10) (-15) ^° C for 1 h. To the orange solution was added in one portion 4- (2-chlorophenylsulfonyl) benzeneamine (1.00 g, 3.7 mmol) and the mixture was left overnight at room temperature with stirring. The brown solution was poured into water, and the aqueous solution was extracted with ethyl acetate (two times 50 ml). The organic extracts were mixed, dried (magnesium sulfate), filtered, the solvent was distilled off, and a tan solid was obtained. Recrystallization from a mixture of methylene chloride gave the desired propanamide (1.43 g, 94%) as an off-white solid, melting point 136-138 ^o C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.58 (s. 3H, CH ₃ ), 7.57 (s. 1H, OH), 7.67 (m. 3H, aromatic), 7 88 (d. 2H, J = 8.8 Hz, aromatic), 8.02 (d. 2H, J = 8.8 Hz, aromatic), 8.26 (d. 1H, J = 6.6 Hz, aromatic), 10.46 (s. 1H, NH).

 Mass spectrum (Cl, methane): 408 (M + 1).

Elemental analysis for C ₁₆ H ₁₃ ClF ₃ NO ₄ S.

Calculated, C 47.13; H 3.22; N 3.43;
Found, C 46.93; H 3.17; N, 3.40.

 4- (2-chlorophenylsulphonyl) benzeneamine is described by H. Gilman and H. Smith Broatbend, J. Amer. Soc. 69, 2053 (1947).

 Example 15

 N- [4- (4-cyano-3-phenylsulfonylphenyl)] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 1.50 g (4.1 mmol) of N- (4-cyano-3-phenylthiophenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide and 120 ml of glacial acetic acid was added a solution potassium permanganate (0.78 g, 4.9 mmol) and 78 ml of water in one portion. The mixture was stirred at room temperature for 45 minutes, poured into 300 ml of water, clarified with a small amount of solid sodium bisulfite, and extracted three times with 275 ml of chloroform. The extracts were dried (magnesium sulfate), filtered, and the solvent was removed, yielding a white solid, which was recrystallized from ethyl acetate-hexane, and after drying at 100 ^° C and 0.1 mm Hg vacuum. Art. 1.38 g (85%) of the desired propanamide were obtained as a white solid, melting point 185-187 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.62 (s. 3H, CH ₃ ), 7.67-7.79 (m. 4H, aromatic), 7.97-8.01 ( m 2H, aromatic, OH), 8.07 (d. 1H, J = 8.6 Hz, aromatic), 8.26 (dd. 1H, J = 8.5 and 2.0 Hz, aromatic), 8 90 (d. 1H, J = 2.1 Hz); 10.90 (s. 1H, NH).

 Mass spectrum (Cl, methane): 399 (M + 1).

Elemental analysis for C ₁₇ H ₁₃ F ₃ N ₂ O ₄ S.

Calculated, C 51.26; H 3.29; N, 7.03;
Found, C, 51.52; H 3.28; N, 6.96.

 The starting N- (4-cyano-3-phenylthiophenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide was prepared as follows.

 a) N- (4-cyano-3-phenylthiophenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (1.62 g, 10.2 mmol) in N, N-dimethylacetamide (15 ml) cooled to -20 ^° C was added quickly thionyl (1.30 g, 10.9 mmol), and the mixture (precipitate formed after a few minutes) was stirred at (-20) (-5) ^° C for 1 hour. Then 4-cyano-3-phenylthiobenzenamine (1) was added in one portion. 55 g, 6.85 mmol) and the mixture was left at room temperature and stirring overnight. The solution was poured into water, extracted with ethyl ether (twice 100 ml), the ether extracts were dried (magnesium sulfate), filtered, and the solvent was removed in vacuo. The residue was chromatographed over 315 g of silica gel using ethyl ether (0, 10 and 20%) in methylene chloride as a gradient solvent. The desired fractions were mixed, the solvent was removed in vacuo, and the residue was dissolved in 150 ml of methylene chloride in a mixture with 100 ml of hexane. Most of the methylene chloride was distilled off as the solution was scraped off to cause crystal growth. After cooling, the solid was collected, dried at 85 ^° C. and a dilution of 0.1 mm Hg. and the desired propanamide (2.38 g, 91%) was obtained, melting point 111-113 ^o C.

¹ H-NMR spectrum (250 MHz, CDCl ₃ ): 1.67 (s. 3H, CH ₃ ), 3.68 (s. 1H, OH), 7.27 (d. 1H, J = 1.9 Hz aromatic), 7.40-7.51 (m. 5H, aromatic), 7.59-7.69 (m. 2H, aromatic), 8.51 (s. 1H, NH).

 Mass spectrum (Cl, methane): 367 (M + 1).

Elemental analysis for C ₁₇ H ₁₃ F ₃ N ₂ O ₂ S.

Calculated, C 55.73; H 3.58; N, 7.65;
Found, C 55.27; H 3.69; N, 7.51.

 b) 4-cyano-3-phenylthiobenzenamine.

3-chloro-4-cyanobenzolamine (20.0 g, 13.1 mmol) was added to a solution of the thiophenol potassium salt in N, N-dimethylformamide (115 ml) obtained by adding thiophenol (13.5 ml, 13.1 mmol) to a solution of potassium hydroxide (7.35 g, 13.1 mmol) in methanol, followed by removal of methanol in vacuo and washing with an additional 15 ml of N, N-dimethylformamide. After stirring at 140 ^° C. for 16 hours, the mixture was poured into water, extracted with ethyl acetate (three times 150 ml), the solvent was removed in vacuo and a red oil was obtained. The oil was chromatographed on silica gel using methylene chloride as eluent. The fractions containing the product (thin layer chromatography on silica gel, 2% methanol-chloroform) were mixed, the solvent was removed, and the material was rechromatographed using a 2: 1 methylene chloride mixture as eluent. The desired fractions were combined, concentrated to a small volume, treated with hexane, cooled (dry ice) and scraped off to form crystals. The white solid weighed 8.29 g (30%), melting point 59-71 ^o C.

Spectrum ¹ H-NMR (250 MHz, CDCl ₃ ): 4.07 (s, 2H, NH ₃ ); 6.29 (d. 1H, J = 2.2 Hz, aromatic), 6.46 (dd. 1H, J = 8.3 and 2.2 Hz, aromatic), 7.36-7.50 (m. 6H, aromatic).

 Mass spectrum (Cl, methane): 227 (M + 1).

Elemental analysis for C ₁₃ H ₁₀ N ₂ S.

Calculated, C 69.00; H 4.45; N, 12.38;
Found, C, 69.05; H 4.59; N, 12.39.

 Example 16

 N- (4- (2-thiazolylsulfonyl) phenyl)) - 3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

To a stirred solution of 3.3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.12 g, 7.1 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (0.85 g, 7.1 mmol), and the mixture was stirred at (-10) (15) ^{° C. for} 1 hour. 2 - ((4-aminophenyl) sulfonyl) thiazole (1.14 g, 4.7 mmol), and the reaction mixture was left overnight at room temperature with stirring.

The reaction mixture was poured into water, and the resulting solid was filtered, recrystallized from a mixture of methylene chloride and hexane to obtain the desired propanamide (1.13 g, 63%) as a white solid, melting point 161-163 ^o C.

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 1.57 (s. 3H, CH ₃ ), 7.58 (s. 1H, OH), 7.98 (d, 2H, J = 8, 8 Hz, aromatic), 8.06 (d. 2H, J = 8.8 Hz, aromatic), 8.08 (d. 1H, J = 3.3 Hz, aromatic), 8.25 (d. 1H, J = 3.2 Hz, aromatic), 10.51 (s. 1H, NH).

 Mass spectrum (Cl, methane): 381 (M + 1).

Elemental analysis for C ₁₃ H ₁₁ F ₃ N ₂ O ₄ S.

Calculated, C 41.04; H 2.92; N, 7.37;
Found, C, 40.96; H 2.93; N, 7.36.

 The starting 2 - ((4-aminophenyl) sulfonyl) thiazole was prepared as follows.

 a) 2 ((4-aminophenyl) sulfonyl) thiazole.

A stirred solution of 2 - ((4-nitrophenyl) sulfonyl) thiazole (1.50 g, 5.6 mmol) and tin (II) chloride dihydrate (6.26 g, 27.7 mmol) in absolute ethanol (25 ml ) was heated under reflux for 1 h. The reaction mixture was poured into ice water, and the aqueous solution was made alkaline with 15% sodium hydroxide and extracted with ethyl acetate (two times 200 ml). The combined organic portions were dried (magnesium sulfate), filtered and the solvent removed to give a solid which, when triturated with diethyl ether, gave the desired thiazole (1.21 g, 89%) as a pale yellow solid, melting point 148-150 ^° C.

Spectrum ¹ H-NMR (250 Hz, DMCO-d ₆ ): 6.44 (broad singlet, 2H, NH ₂ ), 6.66 (d. 2H, J = 8.8 Hz, aromatic), 7.61 ( d. 2H, J = 8.7 Hz, aromatic), 8.03 (d. 1H, J = 3.2 Hz, aromatic), 8.14 (d. 1H, J = 3.2 Hz, aromatic).

 Mass spectrum (Cl, methane): 241 (M + 1).

Elemental analysis for C ₉ H ₈ F ₂ O ₂ N ₂ S • 0.25H ₂ O.

Calculated, C 44.14; H 3.30; N, 11.44;
Found, C, 44.37; H 3.35; N, 11.44.

 b) 2 - ((4-nitrophenyl) sulfonyl) thiazole.

To a stirred solution of 2 - ((4-nitrophenylthio) thiazole (7.20 g, 30.2 mmol) in glacial acetic acid (200 ml) was added a solution of potassium permanganate (5.73 g, 36.0 mmol) in distilled water (90 ml) The dark brown mixture was stirred at room temperature for 2 hours, then treated with solid sodium bisulfate to decompose the excess permanganate.The mixture was diluted with water, filtered and a brownish solid was obtained. Recrystallization from absolute ethanol gave the desired thiazole (1.63 g, 20%) as a cream solid, melting point 159-163 ^o C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 6.66 (d. 2H, J = 8.6 Hz, aromatic), 7.61 (d. 2H, J = 8.7 Hz, aromatic) 8.03 (d. 1H, J = 3.2 Hz, aromatic); 8.14 (d. 1H, J = 3.2 Hz, aromatic).

 Mass spectrum (Cl, methane): 271 (M + 1).

Elemental analysis for C ₉ H ₆ N ₂ O ₄ S ₂ .

Calculated, C 40.00; H 2.24; N, 10.37;
Found, C, 39.94; H 2.27; N, 10.37.

 The starting 2-4-nitrophenylthiothiazole is described by M. Bosco, V. Liturri, Z. Troisi, Z. Foriani and P.E. Todesco, J. Chem. Soc. Perkin Trans, II, 508 (1974).

 Example 17

 N- (4 - ((5-thiazolylsulfonyl) phenyl)) - 3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (1.03 g, 6.5 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (0.77 g, 6.5 mmol), and the mixture was stirred at (-10) (15) ^° C. for 1 hour. 5 - ((4-aminophenyl) sulfonyl) thiazole (1.04 g, 4.3 mmol) was added in one portion and the reaction mixture was left overnight at room temperature with stirring. The reaction mixture was poured into water and filtered through a pad of celite. The celite was washed with methylene chloride (twice 50 ml each), and the combined organic phases were dried over magnesium sulfate, filtered, the solvent was evaporated in vacuo and a tan solid was obtained. Recrystallization from ethyl acetate-hexane gave the desired product propanamide (1.21 g, 74%) as a white solid, melting point 191-193 ^° C.

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 1.58 (s. 3H, CH ₃ ), 7.59 (s. 1H, OH), 7.99 (d. 2H, J = 7, 5 Hz, aromatic), 8.06 (d. 2H, J = 7.5 Hz, aromatic), 8.57 (s. 1H, aromatic), 9.47 (s, 1H, aromatic), 10.49 ( s. 1H, NH).

 Mass spectrum (Cl, methane); 381 (M + 1).

Elemental analysis of C ₁₃ H ₁₁ F ₃ N ₂ O ₄ S ₂ .

Calculated, C 41.05; H 2.91; N, 7.37;
Found, C, 41.05; H 2.93; N, 7.37.

 The starting 5 - ((4-aminophenyl) sulfonyl) thiazole was prepared as follows.

 a) 5 - ((4-aminophenyl) sulfonyl) thiazole.

A stirred solution of 5 - ((4-nitrophenyl) sulfonyl) thiazole (1.72 g, 6.4 mmol) and tin (II) chloride dihydrate (7.17 g, 31.8 mmol) in absolute ethyl alcohol (25 ml) was heated under reflux for 1 h. The reaction mixture was poured into water, the aqueous solution was made basic with solid sodium bicarbonate and extracted with ethyl acetate (two times 200 ml). The combined organic parts were dried (magnesium sulfate), filtered, the solvent was removed and an orange solid was obtained. Evaporation chromatography (eluting with 10% ethyl acetate in methylene chloride) and evaporating the solvent gave the desired thiazole (1.20 g, 78%) as a yellow solid, melting point 158-160 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 6.35 (broad singlet, 2H, NH ₂ ), 6.65 (d. 2H, J = 8.9 Hz, aromatic), 7.61 ( D. 2H, J = 8.7 Hz, aromatic), 8.89 (s. 1H, aromatic), 9.38 (s. 1H, aromatic).

 Mass spectrum (Cl, methane): 241 (M + 1).

Elemental analysis for C ₉ H ₈ N ₂ O ₂ S ₂ .

Calculated, C 44.99; H 3.36; N, 11.66;
Found, C, 44.94; H 3.38; N, 11.68.

 b) 5 - ((4-nitrophenyl) sulfonyl) thiazole.

To a stirred solution of 2-amino-5 - ((4-nitrophenyl) sulfonyl) thiazole (5.15 g, 18.1 mmol) and 85% phosphoric acid (200 ml), cooled to -5 ^° C a solution of sodium nitrate (1.56 g, 22.6 mmol) in distilled in water (10 ml) was added at a rate such that the internal temperature of the reaction was maintained between -5 and 5 ^° C. When the addition was completed, the reaction mixture was stirred 1 h at 0 ^o C, then was treated dropwise with 50% hypophosphoric acid (15 ml). After addition, the ice bath was removed, the reaction mixture was stirred at room temperature for 3 hours, during which moderate foaming was observed. The brown solution was diluted with water (total volume 1.0 l), neutralized with 28% ammonium hydroxide and filtered. By flash chromatography of the resulting brown solid (eluted with 5% v / v ethyl acetate in methylene chloride), the desired thiazole (1.72 g, 35%) was obtained as a yellow solid, melting point 168-170 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 8.32 (d. 2H, J = 12.6 Hz, aromatic), 8.45 (d. 2H, J = 12.8 Hz, aromatic) 8.74 (s. 1H, aromatic); 9.578 (s. 1H, aromatic).

 Mass spectrum (Cl, methane): 271 (M + 1).

Elemental analysis for C ₉ H ₆ N ₂ O ₄ S ₂ .

Calculated, C 39.40; H 2.24; N, 10.34;
Found, C 39.68; H 2.33; N, 10.22.

 The starting 2-amino-5 - ((4-nitrophenyl) sulfonyl) thiazole was commercially available.

 Example 18

 N - ((4- (2-pyrazinylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.01 g, 6.4 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (0.76 g, 6.4 mmol) and the mixture was stirred at (-10) (-15) ^° C for 1 hour. 4-aminophenylsulfonylpyridine (1.00 g, 4.2 mmol) was added in one portion and the reaction mixture left overnight at room temperature and with stirring. The reaction mixture was poured into water, and the solid was collected by suction filtration. Evaporation chromatography (elution of 20% by volume with ethyl acetate in methylene chloride) of a solid, evaporation of the eluent and trituration with diethyl ether gave the desired propanamide (1.26 g, 81%) as an off-white solid, melting point 181-183 ^o C .

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.58 (s. 3H, CH ₃ ), 7.57 (s. 1H, OH), 7.98 (d. 2H, J = 8, 9 Hz, aromatic), 8.06 (d. 2H, J = 9.0 Hz, aromatic), 8.81 (d. 1H, J = 2.2 Hz, aromatic), 8.97 (d. 1H, J = 2.2 Hz, aromatic), 9.39 (s. 1H, aromatic), 10.48 (1H, NH).

 Mass spectrum (Cl, methane), 376: (M + 1).

Elemental analysis for C ₁₄ H ₁₂ F ₃ N ₃ O ₄ S.

Calculated, C 44.80; H 3.22; N, 11.20;
Found, C, 44.84; H 3.29; N, 11.11.

 The starting 4-aminophenylsulfonylpyridine was prepared as follows.

 a) 4-aminophenylsulfonylpyrazine.

A stirred solution of 4-nitrophenylsulfonylpyridine (2.50 g, 9.4 mmol) and tin (II) chloride dihydrate (10.62 g, 47.1 mmol) in absolute ethanol (30 ml) was heated under reflux for 1 h. The reaction mixture poured into ice water, the aqueous solution was made basic with solid sodium bicarbonate and extracted with ethyl acetate (two times 200 ml). The combined organic extracts were dried (magnesium sulfate), filtered, the solvent was distilled off, and an off-white solid was obtained. Recrystallization from absolute ethanol gave the desired pyrazine (1.90 g, 86) as a white solid, melting point 174-177 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 6.37 (broad singlet, 2H, NH ₂ ), 6.65 (d. 2H, J = 8.6 Hz, aromatic), 7.61 ( d. 2H, J = 8.6 Hz, aromatic), 8.78 (d. 1H, J = 2.3 Hz, aromatic), 8.90 (d. 1H, J = 2.2 Hz, aromatic), 9.27 (s. 1H, aromatic).

 Mass spectrum (Cl, methane): 236 (M + 1).

Elemental analysis for C ₁₀ H ₉ N ₃ O ₂ S.

Calculated, C 51.05; H 3.86; N, 17.86;
Found, C 51.06; H 3.94; N, 17.76.

 b) 4-nitrophenylsulfonylpyrazine.

To a stirred solution of 4-nitrophenylthiopyrazine (3.0 g, 12.9 mmol) in glacial acetic acid (150 ml) was added potassium permanganate (2.44 g, 15.4 mmol) in distilled water (90 ml). The dark brown mixture was stirred at room temperature for 30 minutes, then treated with solid sodium sulfite to decompose excess permanganate. The mixture was diluted with water, filtered and the target pyrazine (2.68 g, 78%) was obtained as an off-white solid, melting point 159-161 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 8.30 (d. 2H, J = 8.3 Hz, aromatic), 8.46 (d. 2H, J = 8.4 Hz, aromatic) 8.85 (d. 1H, J = 3.4 Hz, aromatic), 9.03 (d. 1H, J = 3.4 Hz, aromatic), 9.40 (s. 1H, aromatic).

Mass spectrum (Cl, CH ₄ ): 266 (M + 1).

Elemental analysis for C ₁₀ H ₇ N ₃ O ₄ S.

Calculated, C 45.28; H 2.66; N, 15.84;
Found, C, 45.26; H 2.64; N, 15.95.

 c) 4-nitrophenylthiopyrazine.

A stirred solution of chlorpyrazine (6.71 g, 58.6 mmol) and potassium 4-nitrophenylate (12.45 g, 64.4 mmol) in dimethylformamide (40 ml) was heated at 110 ^° C. for 4 hours. The reaction mixture was poured into water with ice, and the precipitated brown solid was collected by filtration. Recrystallization from absolute ethanol gave the desired pyrazine (4.30 g, 30%) as a yellow solid, melting point 88-90 ^° C.

¹ H NMR spectrum (300 MHz, DMCO-d ₆ ): 7.77 (d, 2H, J = 6.7 Hz, aromatic), 8.24 (d, 2H, J = 6.6 Hz, aromatic) 8.57 (m. 2H, aromatic); 8.72 (d. 1H, J = 1.2 Hz, aromatic).

 Mass spectrum (CH, methane): 234 (M + 1).

Elemental analysis for C ₁₀ H ₇ N ₃ O ₂ S.

Calculated, C 51.50; H 3.02; N, 18.02;
Found, C, 51.50; H 3.00; N, 17.96;
Example 19

 N- (4- (2-pyridylcarbonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (1.20 g, 7.6 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (0.90 g, 7.6 mmol) and the mixture was stirred at (-10) (-15) ^° C for 1 hour. 2- (4-aminobenzoyl) -pyridine (100 g, 5.00 mmol) was added in one portion. and the reaction mixture was left overnight with stirring at room temperature.

The reaction mixture was poured into water, and the aqueous solution was extracted with ethyl acetate (two times 50 ml). The combined organic phases were dried (magnesium sulfate), filtered, the solvent was removed in vacuo and a brown oil was obtained. Evaporation chromatography (elution with 5% v / v ethyl acetate in methylene chloride) oil, evaporation of the solvent and trituration with diethyl ether gave the desired propanamide (1.07 g, 63%) as a white solid, melting point 151-154 ^° C.

¹ H-NMR spectrum (250 MHz, DMCO-d ₆ ): 1.58 (s. 3H, CH ₃ ), 7.58 (s. 1H, OH), 7.98 (d. 2H, J = 8, 9 Hz, aromatic), 8.06 (d. 2H, J = 9.0 Hz, aromatic), 8.81 (m, 2H, aromatic), 8.97 (d. 1H, J = 2.2 Hz, aromatic), 9.39 (s. 1H, aromatic), 10.48 (s. 1H, 11H).

 Mass spectrum (Cl, methane): 339 (M + 1).

Elemental analysis for C ₁₆ H ₁₃ F ₃ N ₂ O ₃ S.

Calculated, C 56.81; H 3.87; N, 8.28;
Found, C 56.50; H 3.91; N, 8.21.

 The starting 2- (4-aminobenzoyl) -pyridine is described by E. Kocnigs, H. Menscing and P. Kirsh. Ber. 59B. 1717 (1926).

 Example 20

 N- (4- (3-chlorophenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.22 g, 1.4 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (0.17 g, 1.4 mmol) and the mixture was stirred at (-10) (-15) ^° C for 1 h. 4-amino-3-chlorodiphenylsulfone (0.75 g, 2.8 mmol) was added in one portion. and the reaction mixture was left overnight with stirring at room temperature.

The reaction mixture was poured into water, and the aqueous solution was filtered through a pad of celite. Celite was extracted with methylene chloride (200 ml), which was dried (magnesium sulfate), filtered, the solvent was removed and a brownish solid was obtained. flash chromatography of a solid (elution with 5% v / v ethyl acetate in methylene chloride) and evaporation of the eluent gave the desired propanamide (0.22 g, 58%) as a white solid, melting point 154-156 ^° C.

¹ H-NMR spectrum (250 MHz, DMCO-d ₆ ): 1.58 (s. 3H, CH ₃ ), 7.57 (s. 1H, OH), 7.65 (t. 1H, J = 8, 0 Hz, aromatic), 7.77 (d. 1H, J = 7.8 Hz, aromatic), 7.91 (d. 1H, J = 7.8 Hz, aromatic), 8.01 (5H, aromatic) 10.60 (s. 1H, NH).

 Mass spectrum (Cl, methane): 408 (M + 1).

Elemental analysis for C ₁₆ H ₁₃ ClF ₃ NO ₄ S.

Calculated, C 47.13; H 3.22; N 3.43;
Found, C 46.81; H 3.37; N, 3.34.

 The starting 4-amino-3-chlorodiphenylsulfone is commercially available.

 Example 21

 N- (4- (3-methylphenylsulfonyl) phenyl)) - 3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

To a stirred solution of 3.3,3-trifluoro-2-hydroxy-2-methylpropionic acid (0.43 g, 2.7 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (0.32 g, 2.7 mmol), and the mixture was stirred at (-10) (-15) ^° C. for 1 hour. 4 - ((3-Methylphenyl) sulfonyl) benzene (0.45 g, 1.8 mmol), and the reaction mixture was left overnight with stirring at room temperature. The mixture was poured into water, and the aqueous solution was filtered through a pad of celite. Celite was washed with methylene chloride (100 ml), the organic extract was dried (magnesium sulfate), filtered, the solvent was removed in vacuo and a reddish solid was obtained, which was purified by flash column chromatography (eluent was 10% by volume ethyl acetate in methylene chloride). Evaporation of the solvent from the desired fractions and recrystallization of the obtained solid from a mixture of methylene chloride and hexane gave the desired propanamide (0.52 g, 74%) as a white solid, melting point 164-166 ^o C.

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 1.57 (s. 3H, CH ₃ ), 2.38 (s. 3H, CH ₃ aryl), 7.49 (dd. 2H, J = 5.1 and 1.0 Hz, aromatic), 7.56 (s. 1H, OH), 7.73 (m. 2H, aromatic), 7.91 (d. 2H, J = 8.9 Hz, aromatic ), 8.00 (d. 2H, J = 8.9 Hz, aromatic) 10.42 (s. 1H, NH).

 Mass spectrum (Cl, methane): 388 (M + 1).

Elemental analysis for C ₁₇ H ₁₆ F ₃ NO ₄ S.

Calculated, C 52.71; H 4.16; N 3.62;
Found, C, 52.71; H 4.28; N, 3.54.

 The starting 4 - ((3-methylphenyl) sulfonyl) benzamine was prepared as follows.

 a) 4 - ((Methylphenyl) sulfonyl) benzeneamine.

A stirred solution of 3-methylphenyl-4-nitrophenyl sulfone (0.50 g, 1.8 mmol) and tin (II) chloride dihydrate (2.03 g, 9.0 mmol) in absolute ethanol (5 ml) was heated under reflux 1 h. The reaction mixture was poured into ice water, the aqueous solution was basified with 15% sodium hydroxide and extracted with ethyl acetate (two times 100 ml). The combined organic extracts were dried (magnesium sulfate), filtered, the solvent was removed in vacuo and an off-white solid was obtained. Recrystallization from a mixture of absolute ethanol hexane gave the desired benzene amine (0.45 g, 100%) as a white solid, melting point 183-185 ^o C.

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 2.36 (s. 3H, CH ₃ ), 6.17 (s. 2H, NH ₂ ), 6.61 (dd. 2H, J = 7 , 0 and 1.8 Hz, aromatic), 7.43 (d. 2H, J = 7.1 Hz, aromatic), 7.54 (2H, J = 8.7 Hz, aromatic), 7.63 (m . 2H, aromatic).

 Mass spectrum (Cl, methane); 248 (M + 1).

Elemental analysis for C ₁₃ H ₁₃ NO ₂ S.

Calculated, C 63.14; H, 5.30; N, 5.66;
Found, C, 63.13; H 5.28; N, 5.64.

 The starting 3-methylphenyl-4-nitrophenylsulfone was commercially available.

 Example 22

 N - ((4-phenylcarbonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

Thionyl chloride (7.94) was added to a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (10.54 g, 66 mol) in NN-dimethylacetamide (100 ml) cooled to -20 ^° C. g, 66 mmol) and the mixture was stirred at (-10) (-15) ^° C for 1 h. 4-amino-benzophenone (8.67 g, 44 mmol) was added in one portion and the reaction mixture was left overnight with stirring at room temperature.

The mixture was poured into water, and the white solid precipitated was filtered off from the solution, dried on the filtrate for 1 h, and recrystallized from ethyl acetate-hexane in a ratio of 1: 2 by volume. The first yield gave the target propanamide (9.51 g, 64%) as a white solid, melting point 151-153 ^° C. A second yield was obtained by filtration of the cooled filtrate in 72 hours, and an additional 3.21 g (2%) of white solid a substance that was identical to the first in melting point and spectral properties.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 1.61 (s. 3H, aromatic), 7.75 (d. 2H, J = 8.5 Hz, aromatic), 7.8 (d. 2H, J = 8.5 Hz, aromatic), 10.35 (s. 1H, H).

 Mass spectrum (Cl, methane): 388 (M + 1).

Elemental analysis for C ₁₇ H ₁₄ F ₃ NO ₃ .

Calculated, C 60.54; H 4.23; N, 4.15;
Found, C, 60.33; H 4.23; N, 4.12.

 The starting 4-aminobenzophenone was purchased on the market.

 Example 23

 N- (4 - ((3-pyridylcarbonyl) phenyl)) - 3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3.3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.63 g, 4.0 mmol) in N, N-dimethylacetamide (7 ml) cooled to -20 ^° C was added thionyl chloride (0.48 g, 4.0 mmol), and the mixture was stirred at (-10) (-15) ^° C for 1 h. 3- (4-aminobenzoyl) -pyridine (0.66 g, 3.3) was added in one portion. mmol), and the reaction mixture was left overnight with stirring at room temperature.

The mixture was poured into water, and the aqueous solution was extracted with ethyl ether (two times 100 ml). The combined organic extracts were dried (magnesium sulfate), filtered, the solvent was removed in vacuo and a pale yellow solid was obtained. Recrystallization from a mixture of absolute ethanol hexane gave the desired propanamide indicated in the title of the example (0.42 g, 37%) as a white solid, melting point 206-208 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 1.60 (s. 3H, CH ₃ ), 7.57 (s. 1H, OH), 7.58-7.62 (m. 1H, aromatic), 7.79 (dd. 2H, J = 7.0 and 1.7 Hz, aromatic), 7.98 (dd. 2H, J = 7.0 and 1.7 Hz, aromatic), 8.08 -8.12 (m, 1H, aromatic), 8.83 (dd. 1H, J = 4.8 and 1.7 Hz, aromatic), 8.87 (d. 1H, J = 1.7 Hz, aromatic ), 10.38 (s, 1H, NH).

 Mass spectrum (Cl, methane): 339 (M + 1).

Elemental analysis for C ₁₆ H ₁₃ F ₃ N ₂ O ₃ .

Calculated, C 56.81; H 3.87; N, 8.28;
Found, C 56.60; H 3.88; N, 8.23.

 The starting 3- (4-aminobenzoyl) pyridine was prepared as follows.

 a) 3- (4-aminobenzoyl) -pyridine.

A stirred solution of 3- (4-nitrobenzoyl) -pyridine (1.08 g, 4.7 mmol) and tin (II) chloride dihydrate (5.34 g, 23.7 mmol) in absolute ethanol (50 ml) was refluxed refrigerator for 1 h. The reaction mixture was poured into ice water, the aqueous solution was made basic with solid sodium bicarbonate and extracted with ethyl acetate (twice 150 ml). The combined organic extracts were dried (magnesium sulfate), filtered, the solvent was removed in vacuo and a yellow solid was obtained. Purification of the solid by column chromatography (ethyl ether eluent) and evaporation of the eluent gave the desired pyridine (0.71 g, 76%) as a yellow solid, melting point 103-105 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 6.31 (s. 2H, NH ₂ ), 6.64 (d. 2H, J = 8.6 Hz, aromatic), 7.52-7 58 (m 3H, aromatic), 7.97-8.01 (m 1H, aromatic), 8.74-8.77 (m 2H, aromatic).

 Mass spectrum (Сl-methane): 199 (M + 1).

 The starting 3- (4-nitrobenzoyl) -pyridine is described.

 Example 24

 N- (4- (phenylsulfonyl) phenyl) -1-hydroxycyclopropyl) carboxamide.

A solution of 1-hydroxy-cyclopropanecarboxylic acid (0.66 g, 6.44 mmol) in dry dimethylacetamide (10 ml) was stirred under nitrogen at -15 ^° C. Thionyl chloride (0.77 g, 6.44 mmol) was added, and the resulting mixture was left stirring at -15 ^° C for 1 h. Then 4-phenylsulfonylaniline (1.0 g, 4.29 mmol) was added and the reaction mixture was stirred at -15 ^° C for an additional 15 minutes. Then the solution was warmed to room temperature, at which it was left overnight with stirring. The reaction mixture was poured onto ice, extracted with 1 M hydrochloric acid. After drying (magnesium sulfate), ethyl acetate was removed by evaporation and a dark yellow solid was obtained. Crystallization of this material from ethyl acetate-hexane gave the desired tertiary carbonyl (0.82 g, 60%) as a white solid, melting point 214-216 ^° C.

¹ H-NMR spectrum (250 MHz, DMCO-d ₆ ): 0.98 (m 2H, 2CH ₂ ), 1.15 (m 2H, CH ₂ ), 6.63 (s. 1H, OH), 7.65 (m. 3H, ArH), 7.95 (m. 6H, ArH), 10.29 (s. 1H, NH).

 Mass spectrum (Cl, methane): 318 (M + 1), 100.

Elemental analysis for C ₁₆ H ₁₅ NO ₄ S.

Calculated, C 60.55; H 4.76; N, 4.41;
Found, C, 60.51; H 4.77; N, 4.40.

 Example 25

 N- (4- (phenylsulfonyl) phenyl) -2-hydroxy-2-ethylbutanamide.

A solution of 2-ethyl-2-hydroxybutyric acid (1.14 g, 8.69 mmol) in dry dimethylacetamide was stirred under nitrogen at -15 ^° C. Thionyl chloride (1.03 g, 8.69 mmol) was added. and the resulting mixture was stirred at -15 ^° C for 1 hour. Then 4-phenylsulfonylaniline (1.34 g, 5.74 mmol) was added and the reaction mixture was stirred at -15 ^° C for a further 15 minutes.

 The solution was warmed to room temperature and stirred for 48 hours. The reaction mixture was poured into ice, extracted with ethyl acetate, basified to pH 12 and then extracted with ether. The combined ether fractions were dried (magnesium sulfate), evaporated to give a golden-colored solid.

By flash chromatography of this material, eluted from a silica gel stationary phase with methylene chloride, the desired tertiary carbonyl (0.16 g, 8%) was obtained as a white solid, melting point 116-119 ^° C.

Spectrum ¹ H-NMR (260 MHz, DMCO-d ₆ ): 0.80 (t, 6H, 2CH ₃ ), 1.54 (m 2H, CH ₂ ), 1.73 (m 2H, CH ₂ ) 5.37 (s. 1H, OH); 7.94 (m. 3H, ArH); 7.94 (m. 6H, ArH); 9.89 (s. 1H, NH).

 Mass spectrum (Cl, methane): (M + 1, 100).

Elemental analysis for C ₁₈ H ₂₁ NO ₄ S • 0.25H ₂ O.

Calculated, C 61.43; H, 6.16; N, 3.98;
Found, C, 61.57; H, 6.02; N, 4.09.

 Example 26

 N- (4- (phenylsulfonyl) phenyl-2-hydroxy-2-methylbutanamide.

A solution of 2-hydroxy-2-methylbutyric acid (0.76 g, 6.4 mmol) in dry dimethylacetamide (15 ml) was stirred under nitrogen at -10 ^° C. Thionyl chloride (0.76 g, 6.4 mmol) was added. ), and the resulting mixture was stirred at -10 ^° C for 1 hour. Then 4-phenylsulfonylaniline (1.0 g, 4.29 mmol) was added and the reaction mixture was stirred at -10 ^° C for another 15 minutes. Then the solution was warmed to room temperature, at which it was left with stirring overnight. The resulting reaction mixture was poured into water, extracted with ethyl acetate, and the combined ethyl acetate fractions were washed with water and brine. After drying (magnesium sulfate), ethyl acetate was removed by evaporation. Crystallization from ethyl acetate-hexane gave the desired tertiary carbinol (0.89 g, 62.5%) as a colorless crystalline solid, melting point 163-165 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 0.82 (t. J = 7 Hz, 3H, CH ₃ ), 1.32 (s. 3H, CH ₃ ), 1.56 (m. J = 7 Hz, 1H, CH ₂ ), 1.76 (m. J = 7 Hz, 1H, CH ₂ ), 5.65 (s. 1H, OH), 7.64 (m. 3H, ArH), 7.91 (m. 4H, ArH), 8.01 (d. J = 11.1 Hz, 2H, ArH), 9.98 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 334 (M + 1, 100).

Elemental analysis for C ₁₇ H ₁₉ NO ₄ S.

Calculated, C 61.24; H 5.74; N, 4.20;
Found, C, 61.15; H 5.60; N, 4.52.

 Example 27

 N- (4- (phenylsulfonyl) phenyl) -1-hydroxy-cyclopentacarboxamide.

A solution of 2-hydroxy-cyclopentacarboxylic acid (0.76 g, 6.4 mmol) in dry dimethylacetamide (15 ml) was stirred under nitrogen at -10 ^° C. Thionyl chloride (0.76 g, 6.4 mmol) was added. and the resulting mixture was stirred at -10 ^° C for 1 hour. Then 4-phenylsulfonylaniline (1.0 g, 4.29 mmol) was added and the reaction mixture was stirred at -10 ^° C for another 15 minutes.

Then the solution was warmed to room temperature and left overnight with stirring. The reaction mixture was poured into water, extracted with ethyl acetate, and the combined ethyl acetate fractions were washed with water and brine. After drying (magnesium sulfate), ethyl acetate was removed by evaporation. Crystallization from ethyl acetate-hexane gave the desired tertiary carbinol (0.70 g, 47%) as a white solid, melting point 214-216 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 1.73 (m. 6H, CH ₂ ), 1.97 (m. 2H, CH ₂ ), 5.67 (s. 1H, OH), 7.64 (m. 3H, ArH), 7.94 (m. 6H, ArH), 10.13 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 346 (M + 1, 100).

Elemental analysis for C ₁₈ H ₁₉ NO ₄ S.

Calculated, C 62.59; H 5.54; N, 4.06;
Found, C, 62.67; H 5.58; N, 4.00.

 Example 28

 N- (4- (phenylsulfonyl) phenyl) -3-fluoro-2-hydroxy-2-methyl-propanamine.

A solution of 2-hydroxy-2-fluoromethylpropionic acid (0.78 g, 6.4 mmol) in dry dimethylacetamide (15 ml) was stirred under nitrogen at -10 ^° C. Thionyl chloride (0.76 g, 6.4 mmol) was added. ), and the resulting mixture was stirred at -10 ^° C for 1 hour. Then 4-phenylsulfonylaniline (1.0 g, 4.29 mmol) was added and the reaction mixture was stirred at -10 ^° C for a further 15 minutes. Then the solution was warmed to room temperature and under these conditions was left overnight with stirring. The reaction mixture was poured into water, extracted with ethyl acetate, and the combined ethyl acetate fractions were washed with water and brine. After drying (sodium sulfate), ethyl acetate was removed by evaporation to give an amber foam. Trituration with a mixture of methylene chloride and ether gave the desired tertiary carbinol (0.75 g, 52%) as a light brown solid, melting point 189-192 ^° C.

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 1.31 (s. 3H, CH ₃ ), 4.38 (dd. J = 7.2 and 9.2 Hz, 1H, CH ₂ F) 4.58 (dd. J = 7.2 and 9.3 Hz, 1H, CH ₂ F), 6.29 (s. 1H, OH), 7.58-7.68 (m. 4H, ArH) 7.89-8.02 (m. 5H, ArH); 10.16 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 338 (M + 1, 100).

Elemental analysis for C ₁₈ H ₁₆ FNO ₄ S • 0.1H ₂ O.

Calculated, C 56.66; H 4.81; N, 4.13;
Found, C 56.40; H 4.74; N, 4.02.

 Example 29

 N- (4-pyridylsulfonyl) phenyl) -3-fluoro-2-hydroxy-2-methylpropanamide.

A solution of 2 hydroxy-2-fluoromethylpropionic acid (0.53 g, 4.33 mmol) in dry dimethylacetamide (12 ml) was stirred under nitrogen at -10 ^° C. Thionyl chloride (0.52 g, 4.33 mmol) was added. and the resulting mixture was stirred at -10 ^° C for 1 hour. Then 4-phenylsulfonylaniline (0.68 g, 2.89 mmol) was added and the reaction mixture was stirred at -10 ^° C for a further 15 minutes. Then the solution was warmed to room temperature and left under these conditions overnight with stirring. The reaction mixture was poured into water and pH was adjusted to 8.0 with sodium bicarbonate solution. The aqueous solution was extracted with ethyl acetate, and the combined ethyl acetate fractions were washed with water and brine. After drying (sodium sulfate), ethyl acetate was removed by evaporation to give a yellow-orange solid. The solid was washed with methylene chloride ether to give the desired tertiary carbinol (0.32 g, 32%) as a pale yellow solid, melting point 209-211 ^° C.

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 1.31 (s. 3H, CH ₃ ), 4.38 (dd. J = 7.2 and 9.4 Hz, 1H, CH ₂ F) 4.58 (dd. J = 7.2 and 9.3 Hz, 1H, CH ₂ F), 6.31 (s. 1H, OH); 7.87 (d. J = 6 Hz, 2H, PyN ), 7.96 (d. J = 8.9 Hz, 2H, PhH), 8.06 (d. J = 8.9 Hz, 2H, PhH), 8.86 (d. J = 6 Hz, 2H , PyH), 10.22 (s, 1H, NH).

Mass spectrum (Cl, CH ₄ ): 339 (M + 1, 100).

Elemental analysis for C ₁₅ H ₁₅ FN ₂ O ₄ S.

Calculated, C 53.25; H 4.47; N, 8.28;
Found, C, 52.85; H 4.50; N, 8.05.

 Example 30

 N- (4- (phenylcarbonyl) phenyl) -3-fluoro-2-hydroxy-2-methylpropanamide.

A solution of 2-hydroxy-2-fluoromethylpropionic acid (0.93 g, 7.65 mmol) in dry dimethylacetamide (20 ml) was stirred under nitrogen at -10 ^o C. Thionyl chloride (0.91 g, 7.65 mmol) was added and the resulting mixture was stirred at -10 ^° C for 1 hour. Then 4-phenylsulfonylaniline (1.0 g, 4.29 mmol) was added and the reaction mixture was stirred at -10 ^° C for a further 15 minutes. Then the solution was warmed to room temperature and left overnight with stirring. The reaction mixture was poured into water, extracted with ethyl acetate, and the combined ethyl acetate portions were washed with water and brine. After drying (sodium sulfate), ethyl acetate was removed by evaporation and a straw dye foam was obtained. Chromatography on silica gel, eluting with 1: 1 ethyl acetate-hexane, afforded tertiary carbinol (0.75 g, 48%) as a white powder, melting point 146-148 ^° C.

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 1.36 (s. 3H, CH ₃ ), 4.38 (dd. J = 72 and 9.4 Hz, 1H, CH ₂ F), 4 58 (dd. J = 72 and 9.3 Hz, 1H, CH ₂ F), 6.32 (s. 1H, OH), 7.56 (t. J = 7.7 Hz, 2H, ArH), 7.65-7.76 (m. 5H, ArH), 7.97 (d. J = 8.7 Hz, 2H, ArH), 10.08 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 302 (M + 1, 100).

Elemental analysis for C ₁₇ H ₁₆ FNO ₃ .

Calculated, C 67.76; H 6.35; N 4.65;
Found, C, 67.45; H 5.41; N, 4.58.

 Example 31

 N- (4- (phenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanamide.

A solution of 4'-phenylsulfonyl-2-benzyloxy-2,2-bis (trifluoromethyl) -acetanilide (0.32 g, 0.62 mmol) in absolute ethanol (120 ml) was hydrogenated using 10% palladium on carbon as catalyst for 3.5 hours. The mixture was filtered through celite, the filtrate was evaporated and an oil was obtained which crystallized on standing to give the desired tertiary carbinol (89%) as a white solid, melting point 94-98 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 7.86 (m, 3H, ArH), 7.92 (m, 6H, ArH), 9.8 (wide singlet, 1H, OH).

 Mass spectrum / (fast particle bombardment (-ve ion) / 426 (M-1, 100%).

Elemental analysis for C ₁₆ H ₁₁ F ₆ NO ₄ S.

Calculated, C 44.97; H, 20.60; N, 3.28;
Found, C, 44.60; H 2.57; N, 3.14.

 a) N- (4- (phenylsulfonyl) phenyl) -3,3,3-trifluoro-2-benzyloxy -2-trifluoromethylpropanamide.

A solution of 2-benzyloxy-2,2-bis- (trifluoromethyl) acetic acid (0.10 g, 0.33 mmol) in dry benzene (3 ml) was stirred under a nitrogen atmosphere. Thionyl chloride (0.18 g, 1.52 mmol) was added, followed by three drops of dimethylformamide, and the resulting solution was heated under reflux for 20 minutes. After cooling, the solution was evaporated to dryness in vacuo. Benzene (10 ml) was added and the evaporation was repeated to give the acid chloride as a viscous oil. The crude acid chloride was dissolved in methylene chloride (3 ml) and cooled to 0 ^° C. To the stirred solution were added 4-phenylsulfonylaniline (0.154, 0.66 mmol), triethylamine (0.067 g, 0.66 mmol) and dimethylaminopyridine (0.05 g ) After stirring for 10 minutes, the solution was warmed to room temperature and allowed to stir for 18 hours. Then, the reaction mixture was poured into water (10 ml). The organic layer was washed with 3 M hydrochloric acid and brine. Drying (magnesium sulfate) and evaporation gave a golden straw oil. Chromatography on silica gel, eluting with methylene chloride, gave the desired tertiary carbinol (0.10 g, 59%) as a tan solid, melting point 103-108 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 4.97 (s. 2H, CH ₂ ), 7.41 (m. 5H, ArH), 7.86 (m. 3H, ArH), 7 98 (m. 8H, ArH); 11.02 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 518 (M + 1, 50%).

Elemental analysis for C ₂₃ H ₁₇ F ₆ NO ₄ S.

Calculated, C 67.76; H 5.35; N 4.65;
Found, C, 67.45; H 5.41; N, 4.58.

 Example 32

 N- (4- (phenylsulfonyl) phenyl) -3,3,3-difluoro-2-hydroxy-2-methylpropanamide.

A solution of 2-hydroxy-2-difluoromethylpropionic acid (0.9 g, 6.4 mmol) in dry dimethylacetamide (15 ml) was stirred under nitrogen at -10 ^° C. Thionyl chloride (0.76 g, 6.4 mmol) was added. ), and the resulting mixture was stirred at -10 ^° C for 1 hour. Then 4-phenylsulfonylaniline (1.0 g, 4.3 mmol) was added and the reaction mixture was stirred at -10 ^° C for a further 15 minutes. Then the solution was warmed to room temperature and left overnight with stirring. The reaction mixture was poured into a solution of ammonium chloride and was extracted with ethyl acetate. The combined ethyl acetate fractions were washed with water and brine. After drying (sodium sulfate) and decolorization (activated carbon), the solution was evaporated in vacuo. A foam was obtained which was triturated with toluene and crystallized from ethyl acetate-hexane to give the desired tertiary carbinol (0.72 g, 47%) as white crystals, melting point 168-169 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 1.41 (s. 3H, CH ₃ ), 6.13 (t. J = 54.9 Hz, 1H, CHF ₂ ), 6.76 ( s. 1H, OH), 7.58-7.68 (m. 3H, ArH), 7.89-8.01 (m. 6H, ArH), 10.27 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 356 (M + 1, 100%).

Elemental analysis for C ₁₆ H ₁₅ F ₂ NO ₄ S.

Calculated, C 54.08; H 4.25; N, 3.94;
Found, C, 53.75; H 4.40; N, 3.78.

 Example 33

 N- (4- (phenylcarbonyl) phenyl) -3,3-difluoro-2-hydroxy-2-methylpropanamide.

A solution of 2-hydroxy-2-difluoromethylpropionic acid (1.07 g, 7.65 mmol) in dry dimethylacetamide (15 ml) was stirred under nitrogen at -10 ^° C. Thionyl chloride (0.91 g, 7.65 mmol) was added. ), and the resulting mixture was stirred at -10 ^° C for 1 hour. Then 4-aminobenzophenone (1.0 g, 5.1 mmol) was added and the reaction mixture was stirred at -10 ^° C for another 15 minutes.

Then the solution was warmed to room temperature and left overnight with stirring. The reaction mixture was poured into a solution of hydrochloric acid (1 M) and extracted with ethyl acetate. The combined ethyl acetate fractions were washed with water and brine. After drying (sodium sulfate) and decolorization (activated carbon), the solvent was evaporated in vacuo. A completely white foam was obtained, which was triturated with hexane-ethyl acetate. The crude product was filtered through a short column of silica gel with chloroform and crystallized from chloroform-hexane to give the desired tertiary carbinol (0.89 g, 55%) as brilliant crystals, melting point 123-124 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 1.45 (s. 3H, CH ₃ ), 6.17 (t. J = 55 Hz, 1H, CHF ₂ ), 6.77 (s. 1H, OH), 7.56 (t. 2H, ArH), 7.65-7.76 (m. 5H, ArH), 7.96 (d. J = 8.7 Hz, 2H, ArH), 10 19 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 320 (M + 1, 100%).

Elemental analysis for C ₁₇ H ₁₅ F ₂ NO ₃ • 0.2H ₂ O.

Calculated, C 63.23; H 4.81; N, 4.34;
Found, C, 63.21; H 4.74; N, 4.30.

 Example 34

 N- (4- (phenylcarbonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanamide.

Tetrahydrofuran was added (35 ml, dry) to a mixture of 2,2-bistrifluoromethyl ether (2-hydroxyacetic acid (1.08 g, 5.1 mmol) and 1,1'-carbonyldiimidazole (0.83 g, 5.1 mmol) in an atmosphere of nitrogen. Immediate release of carbon dioxide was observed. The reaction mixture was heated under reflux for 0.5 h and cooled to 23 ^° C. The reaction mixture was treated with 4-amino-benzophenone (1.01 g, 5.1 mmol), stirred at 23 ^o C 1.5 h, then refluxed for 18 h. The reaction was evaporated to give a yellow oil-solid mixture. The mixture was dissolved in ethyl m ether, treated with hydrogen chloride in ethyl ether and filtered. The filtrate was evaporated to a yellow oil-solid mixture. Chromatography of this mixture on silica gel, eluting with 5% ethyl ether in methylene chloride, gave the title compound as an off-white solid, dot melting point 143-146 ^o C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 7.56 (m 2H, ArH), 7.83 (m 5H, ArH), 7.96 (d. J = 8.8 Hz, 2H, ArH), 9.82 (s. 1H, OH), 10.82 (s. 1H, H).

Mass spectrum (Cl, CH ₄ ): 392 (M + 1).

Elemental analysis for C ₁₇ H ₁₁ F ₆ NO ₃ .

Calculated, C 52.18; H 2.83; N 3.58;
Found, C, 52.25; H 3.10; N, 3.50.

 2,2-bis-trifluoromethyl-2-hydroxyacetic acid was obtained from Fairfield reagents (conventional synthesis).

 Example 35

 N- (4- (4-pyridylsulfonyl) phenyl) -) - 3,3-difluoro-2-hydroxy -2-difluoromethylpropanamide.

Thionyl chloride (0.34 g, 2.84 mmol) was added to a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g, 2.84 mmol) in dimethylacetamide (10 ml) at -10 ^° C. drop by drop. The resulting solution was stirred at -10 ^° C for approximately 30 minutes. 4- (4-Pyridylsulfonyl) -aniline (0.58 g, 2.5 mmol) was added and the reaction mixture was left overnight with stirring at room temperature. Then the reaction mixture was poured into water, sodium bicarbonate solution was added to obtain a pH of 7.0-7.5. A pink-orange precipitate formed. The solid was filtered, washed with water and dried. Recrystallization and decolorization (charcoal) from a mixture of ethyl acetate, methanol, hexane gave the target compound (0.45 g, 46%) as a straw-colored solid, melting point 248-250 ^o C.

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 6.45 (t. J = 52.6 Hz, 2H, HCF ₂ ), 7.88 (d. J = 6.1 Hz, 2H, ArH ), 8.04 (m. 5H, OH and ArH), 8.86 (s. J = 6.1 Hz, 2H, ArH), 10.58 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 393 (M + 1).

Analysis for C ₁₅ H ₁₂ F ₄ N ₂ O ₄ S.

Calculated, C 45.92; H 3.08; N, 7.14;
Found, C, 45.80; H 3.13; N, 7.13.

 2,2-bis-difluoromethyl-2-hydroxyacetic acid was prepared as follows.

Trimethylsilyl cyanide (13.1 g, 0.13 mmol) was added dropwise to 1,1,3,3-tetrahydrofluoroacetone (17.17 g, 0.13 mmol) with stirring at a temperature of about 0 ^° C. The reaction flask was sealed and left at room temperature. The clear reaction mixture was added dropwise to concentrated sulfuric acid (60 ml). An exothermic reaction was observed. Then water (220 ml) was added dropwise and the resulting solution was stirred and left overnight under reflux. The reaction solution was cooled to room temperature, saturated with sodium chloride and extracted with ethyl acetate (two times with 150 ml). The combined ethyl acetate extracts were dried (sodium sulfate) and evaporated to give a syrup that slowly cured to a white solid (12.8 g, 56%), melting point 72.5-73.5 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 6.27 (s. 1H, OH), 6.26 (t. J = 57.4 Hz, 2H, HCF ₂ ).

 Mass spectrum (Cl): 177 (M + 1, 100%).

 1,1,3,3-tetrafluoroacetone was prepared according to the method of W.J. Middleton and R.V. Zindsey. J. Amer. Chem. Soc. 86, 4948 (1964).

 Example 36

 N- (3-hydroxy-4- (phenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

To a stirred suspension of N- (3-methoxy-4- (phenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (0.75 g, 1.9 mmol) in dry methylene chloride ( 22 ml) was added boron tribromide (3.8 ml of a 1.0 M solution of boron tribromide in methylene chloride, 3.8 mmol). The resulting solution was stirred at room temperature for 3 hours, diluted with methylene chloride (50 ml) and washed with water. The organic layer was dried (magnesium sulfate), concentrated in vacuo to give an off-white foam. Purification by flash column chromatography (10-30% by volume gradient of ethyl acetate in methylene chloride) gave the desired propanamide as a white solid (0.34 g, 46%), melting point 155-156 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.58 (s. 3H, CH ₃ ), 7.30 (dd. 1H, J = 8.8 and 1.8 Hz, aromatic), 7 48 (s. 1H, OH), 7.51-7.66 (m. 4H, aromatic), 7.80-7.86 (m. 3H, aromatic), 10.19 (s. 1H, NH) 10.60 (s. 1H, OH).

Mass spectrum (Cl, CH ₄ ): 390 (M + 1).

Elemental analysis for C ₁₆ H ₁₄ F ₃ NO ₅ S.

Calculated, C 49.36; H 3.62; N, 3.60;
Found, C, 49.24; H 3.58; N, 3.57.

 Example 37

 N- (3-methoxy-4- (phenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.80 g, 11.4 mmol) in N, N-dimethylacetamide (40 ml) cooled to 20 ^° C was added thionyl chloride ( 1.36 g, 11.4 mmol) and the mixture was stirred at (-10) (-15) ^° C for 1 hour. 3-Methoxy-4- (phenylsulfonyl) benzeneamine (2.00 g, 7, 6 mmol), and the reaction mixture was left overnight with stirring at room temperature. The mixture was poured into water, and the aqueous solution was filtered through a pad of celite. The celite was washed with methylene chloride (200 ml), the organic extract was dried (magnesium sulfate), the solvent was removed in vacuo and a brown oil was obtained, which was purified by flash column chromatography (10% by volume ethyl acetate in methylene chloride). The resulting white solid (2.52 g, 82%) melted at 202-204 ^o C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.56 (s. 3H, CH ₃ ); 3.87 (s. 3H, OCH ₃ ); 7.70-7.54 (m. 6H, aromatic + OH), 7.85-7.88 (m. 2H, aromatic), 7.93 (d. 1H, J = 8.7 Hz, aromatic), 10.32 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 404 (M + 1).

Elemental analysis for C ₁₇ H ₁₆ F ₃ NO ₅ S.

Calculated, C 50.62; H 4.00; N 3.47;
Found, C, 50.38; H 3.97; N, 3.44.

 The starting benzolamine was prepared as follows.

 a) 3-methoxy-4- (phenylsulfonyl) -) benzeneamine.

 A stirred solution of 2-methoxy-4-nitrodiphenylsulfone (6.15 g, 2.1 mmol) and tin (II) chloride dihydrate (23.64 g, 10.5 mmol) in absolute ethanol (100 ml) was heated under reflux 1 h. The reaction mixture was poured into ice water, the aqueous solution was basified with 15% sodium hydroxide and extracted with ethyl acetate (two times 500 ml).

The combined organic extracts were dried (magnesium sulfate), filtered, the solvent was removed in vacuo and an off-white solid was obtained. Recrystallization from absolute ethanol gave the desired benzeneamine (4.49 g, 81%) as a white solid, melting point 149-151 ^° C.

¹ H-NMR spectrum (250 MHz, DMCO-d ₆ ): 3.61 (s. 3H, OCH ₃ ), 5.14-6.15 (m. 3H, aromatic), 6.23 (dd. 1H, J = 8.4 and 1.9 Hz, aromatic), 7.50-7.60 (m. 4H, aromatic), 7.78-7.82 (m. 2H, aromatic).

Mass spectrum (Cl, CH ₄ ): 264 (M + 1).

Elemental analysis for C ₁₃ H ₁₃ NO ₃ S.

Calculated, C 59.30; H 4.98; N, 5.32;
Found, C, 58.85; H 5.00; N, 5.22.

 b) 2 methoxy-4-nitrodiphenylsulfone.

To a stirred solution of 5-nitro-2-phenylthioanisole (8.25 g, 31.6 mmol) in glacial acetic acid (250 ml) was added potassium permanganate (6.0 g, 38.0 mmol) in distilled water (100 ml) . The dark brown mixture was stirred at room temperature for 1 h, then treated with solid sodium sulfite until the solution was clarified. The mixture was diluted with water, filtered and a brownish solid was obtained. Recrystallization from absolute ethanol gave the desired sulfone (7.71 g, 83%) as an off-white solid, melting point 173-176 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 3.89 (s. 3H, CH ₃ ), 7.64 (t. 2H, J = 7.4 Hz, aromatic), 7.74 (d .1H, J = 7.4 Hz, aromatic), 7.95 (d. 2H, J = 7.4 Hz, aromatic), 8.02 (dd. 1H, J = 8.6 and 2.1 Hz, aromatic), 8.30 (d. 1H, J = 8.6 and 2.1 Hz, aromatic) 8.30 (d. 1H, J = 8.7 Hz, aromatic).

Mass spectrum (Cl, CH ₄ ): 294 (M + 1).

Elemental analysis for C ₁₃ H ₁₁ NO ₅ S.

Calculated, C 53.24; H 3.78; N, 4.78;
Found C, 52.96; H 3.87; N, 4.76.

 c) 5-nitro-2-phenylthioanisole.

A solution of 2-bromo-5-nitroanisole (10.0 g, 43.1 mmol) and potassium phenylthiolate (6.12 g, 41.2 mmol) in dimethylformamide (50 ml) was stirred at room temperature for 24 hours. The reaction mixture was poured into water with ice and filtered. The resulting solid was recrystallized on 95% ethanol to obtain the desired episode (8.33 g, 74%) as a yellow solid, melting point 89-91 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 4.02 (s. 3H, OCH ₃ ), 6.71-6.75 (m. 1H, aromatic), 7.56-7.61 ( m. 5H, aromatic), 7.74-7.78 (m. 2H, aromatic).

Mass spectrum (Cl, CH ₄ ): 262 (M + 1).

Elemental analysis for C ₁₃ H ₁₁ NO ₃ S.

Calculated, C 59.76; H 4.24; N, 5.36;
Found, C 59.79; H 4.31; N, 5.14.

 Example 38

 N- (4- (phenylsulfoxyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3.3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.09 g, 6.9 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (0.82 g, 6.9 mmol), and the mixture was stirred at -15 ^° C. for 1 hour.

4-aminodiphenyl sulfoxide (1.0 g, 4.6 mmol) was immediately added in one portion, and the reaction mixture was left overnight with stirring at room temperature. The mixture was poured into water, and the aqueous solution was filtered through celite. The celite was washed with methylene chloride (100 ml), the organic extract was dried (magnesium sulfate), filtered, the solvent was removed in vacuo and a brown oil was obtained, which was purified by column chromatography (10% by volume diethyl ether in methylene chloride). The resulting oil was mixed with hexane, filtered, and the target propenamide was obtained as a white solid, melting point 156-158 ^o C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 1.56 (s. 3H, CH ₃ ), 7.49-7.56 (m. 4H, aromatic + OH), 7.65-7, 70 (m. 4H, aromatic), 7.91 (d. J = 8.7 Hz, aromatic), 10.24 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 358 (M + 1).

Elemental analysis for C ₁₆ H ₁₄ F ₃ NO ₃ S.

Calculated, C 50.62; H 4.00; N 3.47;
Found, C, 50.38; H 3.97; N, 3.44.

 4-Aminyl diphenyl sulfoxide is described by H.H. Szmant. J.J. Mc Jntosh, J. Amer. Chem. Soc. 73, 4356 (1951).

 Example 39

 N- (4- (2-hydroxyphenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred suspension of N- (4- (2-methoxyphenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (1.14 g, 2.8 mmol) in dry methylene chloride (30 ml ) boron tribromide (8.5 ml of a 1.0 m solution of boron tribromide in methylene chloride, 8.5 mmol) was added. The resulting solution was stirred at room temperature for 3 hours, diluted with methylene chloride (50 ml) and washed with water. The organic layer was dried (magnesium sulfate), concentrated in vacuo to give an off-white solid, which was dissolved in ethyl acetate (10 ml) and added dropwise to hexane (300 ml). Collecting the precipitate by filtration gave the desired propanamide as a white solid (0.84 g, 77%), melting point 184-186 ^o C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.57 (s. 3H, CH ₃ ), 6.90 (d. 1H, J = 8.3 Hz, aromatic), 7.01 (t . 1H, J = 7.5 Hz, aromatic), 7.50 (m. 1H, aromatic), 7.56 (s. 1H, OH), 7.85-7.97 (m. 5H, aromatic), 10.37 (s. 1H, NH); 10.74 (s. 1H, OH).

Mass spectrum (Cl, CH ₄ ): 390 (M + 1).

Elemental analysis for C ₁₆ H ₁₄ F ₃ NO ₅ S.

Calculated, C 49.34; H 3.83; N 3.42;
Found, C, 49.36; H 3.62; N, 3.60.

 Example 40

 N- (4- (2-methoxyphenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.42 g, 9.0 mmol) in N, N-dimethylacetamide (13 ml) cooled to -20 ^° C was added thionyl chloride ( 1.13 g, 9.5 mmol), and the mixture was stirred at (-15) (-5) ^° C. for 1 hour. 4- (2-methoxy-phenyl) -sulfonylbenzenamine (1.58 g, 6, 0 mmol), and the reaction mixture was stirred at room temperature, leaving overnight. The mixture was poured into 250 ml of 0.5 N. hydrochloric acid. The transparent supernatant was poured from the obtained resin. The resin was crystallized from methylene chloride - hexane to give the desired propanamide, which contained about 10% methylene chloride according to NMR analysis. Methylene chloride was not removed by heating at 140 ^° C. and a vacuum of 0.1 mm Hg. within 40 hours. The yield of white solid was 1.70 g (69%), melting point 209-211 ^o C.

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 1.55 (s. 3H, CH ₃ ), 3.7 (s. 3H, OCH ₃ ), 5.73 (s. CH ₂ Cl), 7.11-7.17 (m 2H, aromatic), 7.53 (s. 1H, OH), 7.60-7.63 (s. 1H, aromatic), 7.80-7.83 (m . 2H, aromatic), 7.92-7.97 (m. 3H, aromatic), 10.36 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 294 (M + 1).

Elemental analysis for C ₁₇ H ₁₆ F ₃ NO ₅ S.

Calculated, C 49.87; H 3.96; N, 3.40;
Found C, 49.71; H 3.96; N, 3.35.

 The starting benzolamine was prepared as follows.

 a) 4- (2-methoxyphenyl) sulfonylbenzenamine.

To a stirred suspension of 2-methoxy-4'-nitride-phenylsulfone (12.36 g, 4.2 mmol) in absolute ethanol (90 ml) was added immediately with one portion tin (II) chloride dihydrate (47.4 g, 21 mmol) and the mixture was heated to 50 ^° C. when an exothermic reaction manifested itself. The reaction mixture was stirred at ambient temperature for 30 minutes, poured into ice water, the aqueous solution was basified with 15% sodium hydroxide and extracted with methylene chloride (three times 275 ml). The combined organic extracts were dried (magnesium sulfate), filtered, the solvent was removed in vacuo and a white solid was obtained. Recrystallization from ethyl acetate gave the desired benzeneamine (5.38 g, 49%) as a white solid, melting point 206-208 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 3.75 (s. 3H, OCH ₃ ), 6.10 (s. 2H, NH ₂ ), 6.56-6.61 (m. 2H aromatic), 7.08-7.13 (m 2H, aromatic), 7.49-7.61 (m 3H, aromatic), 7.91 (dd. 1H, J = 8.2 and 1, 8 Hz aromatic).

Mass spectrum (Cl, CH ₄ ): 264 (M + 1).

Elemental analysis for C ₁₃ H ₁₃ NO ₃ S.

Calculated, C 59.30. H 4.98; N, 5.32;
Found, C 59.28; H 5.04; N, 5.20.

 c) 2-Methoxy-4'-nitrodiphenylsulfone.

To a stirred solution of 2-methoxy-4'-nitrodiphenyl sulfide (13.73 g, 52.5 mmol) in glacial acetic acid (800 ml) was added potassium permanganate (9.97 g, 63 mmol) in distilled water (350 ml). The dark brown mixture was stirred at room temperature for 45 minutes, poured into 2 L of water, treated with solid sodium sulfite until the solution became clear, and the solid was collected by filtration. Recrystallization twice from absolute ethanol (300 ml) gave the desired sulfone (7.71 g, 83%) as white plates, melting point 140-142 ^o C.

Spectrum ¹ H-NMR (300 MHz, CDCl ₃ ): 3.79 (s. 3H, CH ₃ ), 6.94 (d. 1H, J = 8.4 Hz, aromatic), 7.16 (t, 1H , J = 7.6 Hz, aromatic) 7.58-7.64 (m 1H, aromatic), 8.13-8.19 (m 3H, aromatic), 8.31-8.35 (m. 2H, aromatic).

Mass spectrum (Cl, CH ₄ ): 294 (M + 1).

Elemental analysis for C ₁₃ H ₁₁ NO ₅ S.

Calculated, C 53.24; H 3.78; N, 4.78;
Found, C, 52.23; H 3.79; N, 4.79.

 c) 2-methoxy-4'-nitrodiphenyl sulfide.

A solution of 1-chloro-4-nitrobenzene (11.23 g, 71.3 mmol) and potassium 2-methoxybenzenethiolate (4.00 g, 71.3 mmol) in dimethylformamide (90 ml) was stirred at room temperature for 10 hours. The resulting mixture poured into ice water, stirred for 1 h and filtered. The resulting solid was recrystallized once from 85% ethanol (150 ml) and twice from hexane (700 ml) to obtain the desired sulfide (13.83 g, 74%) as pale yellow needles, melting point: 90-92 ^° C.

Spectrum ¹ H-NMR (300 MHz, CDCl ₃ ): 3.82 (s. 3H, OCH ₃ ), 7.01-7.15 (m, 4H, aromatic), 7.46-7.55 (m. 2H, aromatic), 8.02-8.07 (m, 2H, aromatic).

Mass spectrum (Cl, CH ₄ ): 262 (M + 1).

Elemental analysis for C ₁₃ H ₁₁ NO ₃ S.

Calculated, C 59.76; H 4.24; N, 5.36;
Found, C 59.70; H 4.25; N 4.71.

 Example 41

 N- (4- (4-fluorophenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3.3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.94 g, 6.0 mmol) in 11.11-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (0.71 g, 6.0 mmol) and the mixture was stirred at (-10) (-15) ^° C for 1 hour. 4- (4-fluorophenylsulfonylbenzolamine (1.00 g, 4.0 mmol) and the reaction mixture was left overnight with stirring at room temperature.The mixture was poured into water, the aqueous solution was filtered and a brown solid was obtained. Purification by flash column chromatography (5% by volume ethyl acetate in chlorine surfer chloride) gave the title propanamide as a white solid (1.11 g, 71%), mp 168-170 ^o C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 1.57 (s. 3H, CH ₃ ), 7.46 (t. 2H, J = 8.8 Hz, aromatic) 7.57 (s. 1H, OH), 7.93 (d. 2H, J = 8.8 Hz, aromatic), 7.99-8.04 (m. 4H, aromatic) 10.43 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 392 (M + 1).

Elemental analysis for C ₁₆ H ₁₃ F ₄ NO ₄ S.

Calculated, C 49.11; H 3.35; N 3.58;
Found, C, 48.92; H 3.37; N, 3.45.

 4 - ((4-fluorophenyl) sulfonyl) benzeneamine is described by N. Sharghi, J. Zallrari, J. Chem. Eng. Data, 8, 276, (1963).

 Example 42

 N- (4- (3-fluorophenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.94 g, 6.0 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (0.71 g, 6.0 mmol) and the mixture was stirred at (-10) (-15) ^° C for 1 h. 4- (3-fluorophenylsulfonylbenzolamine (1.0 g, 4.0 mmol) was added in one portion, and the reaction mixture was stirred at room temperature with stirring, leaving overnight.The mixture was poured into water and the aqueous solution was filtered to obtain a brown solid, which was purified by column chromatography (5% by volume ethyl acetate in methylene chloride). Trituration of the obtained solid with ethyl ether gave the desired propanamide as a white solid (1.15 g, 73%), melting point 147-148 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 1.57 (s. 3H, CH ₃ ), 7.56-7.58 (m. 2H, aromatic + OH), 7.68-7, 69 (m. 1H, aromatic), 7.78-7.82 (m. 2H, aromatic), 7.97 (d. 2H, J = 8.9 Hz, aromatic), 8.03 (d. 2H, J = 9.1 Hz, aromatic), 10.45 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 392 (M + 1).

Analysis for C ₁₆ H ₁₃ F ₄ NO ₄ S.

Calculated, C 49.11; H 3.35; N 3.58;
Found, C, 49.03; H 3.43; N, 3.50.

 4- (3-fluorophenyl) sulfonylbenzeneamine was prepared by the method described by N. Sharghi, J. Zalezari, J. Chem. End. Data, 8, 276, (1963).

 Example 43

 N- (4- (3-hydroxyphenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

To a stirred suspension of N- (4- (3-methoxyphenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (1.25 g, 3.1 mmol) in dry methylene chloride (30 ml ) boron tribromide (9.3 ml of a 1.0 M solution of boron tribromide in methylene chloride, 9.3 mmol) was added. The resulting solution was stirred at room temperature for 2 hours, diluted with methylene chloride (50 ml) and washed with water. The organic layer was dried (magnesium sulfate) and concentrated in vacuo. The resulting tan solid was triturated with methylene chloride to give the desired propanamide indicated in the title of the example as a white solid (0.98 g, 78%), melting point 164-167 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 1.57 (s. 3H, CH ₃ ), 7.00-7.05 (m. 1H, aromatic), 7.24 (t. 1H, J = 1.6 Hz, aromatic) 7.31-7.40 (m 2H, aromatic), 7.55 (s. 1H, OH), 7.89 (d. 2H, J = 8.9 Hz, aromatic), 8.00 (d. 2H, J = 9.0 Hz, aromatic), 10.22 (s. 1H, NH), 10.41 (s. 1H, ArOH).

Mass spectrum (Cl, CH ₄ ): 390 (M + 1).

Elemental analysis for C ₁₆ H ₁₄ F ₃ NO ₅ S.

Calculated, C 48.20; H 3.51; N 3.51;
Found, C, 47.90; H 3.71; N, 3.44.

 Example 44

 N- (4- (3-methoxyphenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.68 g, 11.4 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (1.36 g, 11.4 mmol) and the mixture was stirred at (-10) (-15) ^° C for 1 hour. 4 - ((3-Methoxyphenyl) sulfonyl) benzeneamine (2.00 g) was added in one portion. , 7.6 mmol), and the reaction mixture was stirred at room temperature, leaving overnight. The mixture was poured into water, the aqueous solution was filtered, and a brown solid was obtained. Purification by column chromatography (10% by volume ethyl acetate in methylene chloride) gave the desired propanamide as a white solid (2.75 g, 90%), melting point 147-148 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 1.58 (s. 3H, CH ₃ ), 3.83 (s. 3H, OCH ₃ ), 7.22-7.25 (m. 1H aromatic), 7.41-7.42 (m 1H, aromatic), 7.47-7.56 (m 3H, aromatic + OH), 7.93-8.01 (m 4H, aromatic) 10.42 (s, 1H, NH).

Mass spectrum (Cl, CH ₄ ): 404 (M + 1).

Elemental analysis for C ₁₆ H ₁₆ F ₃ NO ₅ S.

Calculated, C 50.52; H 3.40; N 3.47;
Found, C, 50.14; H 3.40; N, 3.40.

 a) 4 - ((3-methoxyphenyl) sulfonyl) benzeneamine.

A stirred solution of 3 methoxy-4'-nitrodiphenylsulfone (7.56 g, 25.8 mmol) and tin (II) chloride dihydrate (29.06 g, 129 mmol) in absolute ethanol was heated under reflux for 1 h. The reaction mixture was poured. in ice water, the aqueous solution was made alkaline with 15% sodium hydroxide and extracted with ethyl acetate (two times 200 ml). The combined organic extracts were dried (magnesium sulfate), filtered, the solvent was removed in vacuo and an off-white solid was obtained. Recrystallization from absolute ethanol gave the desired benzeneamine (4.63 g 68%) as a white solid, melting point 116-117 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 3.81 (s. 3H, OCH ₃ ), 6.20 (s, 2H, NH ₂ ), 6.62-6.66 (m. 2H aromatic), 7.51-7.19 (m. 1H, aromatic + OH), 7.32-7.60 (m. 5H, 5H, aromatic).

Mass spectrum (Cl, CH ₄ ): 264 (M + 1).

Elemental analysis for C ₁₃ H ₁₃ NO ₃ S.

Calculated, C 59.30; H 4.98; N, 5.32;
Found, C 59.11; H 5.04; N, 5.28.

 b) 3-methoxy-4'-nitrodiphenylsulfone.

To a stirred solution of 3- (4-nitrophenylthio) anisole (7.79 g, 29.8 mmol) in glacial acetic acid (200 ml) was added potassium permanganate (5.65 g, 35.8 mmol) in distilled water (75 ml). The dark brown mixture was stirred at room temperature for 1 h, then treated with solid sodium sulfite until the solution was clarified. The mixture was diluted with water, filtered and a tan solid was obtained. Recrystallization from absolute ethanol gave the desired sulfone (7.56 g, 86%) as an off-white solid, melting point 123-125 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 3.86 (s. 3H, OCH ₃ ), 7.29-7.33 (m. 1H, aromatic), 7.51 (wide singlet, 1H aromatic), 7.59 (d. J = 3.8 Hz, aromatic), 8.27 (dd. 2H, J = 7.0 and 1.9 Hz, aromatic), 8.39 (dd. J = 7.0 and 1.9 Hz, aromatic).

Mass spectrum (Cl, CH ₄ ): 294 (M + 1).

Elemental analysis for C ₁₃ H ₁₁ NO ₅ S.

Calculated, C 53.24; H 3.78; N, 4.78;
Found, C, 53.19; H 3.85; N, 4.90.

 c) 3- (4-nitrophenylthio) anisole.

A solution of potassium 3-methoxybenzenethiolate (6.37 g, 35.7 mmol) and 4-chloronitrobenzene (5.11 g, 32.5 mmol) in dimethylformamide (30 ml) was stirred at room temperature for 4 hours, the reaction mixture was poured into water with ice, and the yellow solid was collected by filtration. Recrystallization from 90% ethanol gave the target anisole (7.79 g, 92%) as a yellow solid, melting point 81-83 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 3.80 (s. 3H, OCH ₃ ), 7.10-7.19 (m. 3H, aromatic), 7.32 (d, 2H, J = 7.1 Hz, aromatic), 7.43 (m, 1H, aromatic), 8.15 (d, 2H, J = 7.0 Hz, aromatic).

Mass spectrum (Cl, CH ₄ ): 262 (M + 1).

Elemental analysis for C ₁₃ H ₁₁ NO ₃ S.

Calculated, C 59.76; H 4.24; N, 5.36;
Found, C 59.74; H 4.40; N, 5.34.

 Example 45

 N- (3-methyl-4- (phenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.72 g, 4.5 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (0.54 g, 4.5 mmol) and the mixture was stirred at (-10) (-15) ^° C for 1 hour. 3-Methyl-4- (phenylsulfonyl) benzeneamine (0.75 g, 3) was added in one portion. , 0 mmol), and the reaction mixture was left overnight with stirring at room temperature. The mixture was poured into water, the aqueous solution was filtered, and a brown solid was obtained, which was purified by flash column chromatography (5% v / v ethyl acetate in methylene chloride). Trituration of the obtained solid with hexane gave the desired propanamide as a white solid (0.95 g, 82%), melting point 141-143 ^° C.

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 1.58 (s, 3H, CH ₃ ), 2.32 (s. 3H, ArCH ₃ ), 7.55-7.70 (m, 4H aromatic), 7.79-8.85 (m 3H, aromatic), 7.92 (dd. 1H, J = 8.8 and 1.9 Hz, aromatic), 8.10 (d, 1H, J = 8.8 Hz, aromatic), 10.30 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 388 (M + 1).

Elemental analysis for C ₁₇ H ₁₆ F ₃ NO ₄ S.

Calculated, C 52.71; H 4.16; N 3.62;
Found, C, 52.59; H 4.24; N, 3.59.

 The starting benzolamine was prepared as follows.

 a) 3-methyl-4- (phenylsulfonyl) benzeneamine.

A stirred solution of 2-methyl-4-nitrodiphenylsulfone (2.72 g, 9.8 mmol) and tin (II) chloride dihydrate (11.06 g, 49.0 mmol) in absolute ethanol (30 ml) was heated under reflux 1 h. The reaction mixture was poured into ice water, the aqueous solution was basified with 15% sodium hydroxide and extracted with ethyl acetate (two times 200 ml). The combined organic extracts were dried (magnesium sulfate), filtered, the solvent was removed in vacuo and an off-white solid was obtained. Recrystallization from ethyl acetate gave the desired benzeneamine (2.12 g, 88%) as a white solid, melting point 163-165 ^° C.

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 2.17 (s. 3H, ArCH ₃ ), 6.10 (s. 2H, NH ₂ ), 6.38 (d. 1H, J = 2 , 1 Hz, aromatic), 6.53 (dd. 1H, J = 8.7 and 2.2 Hz, aromatic), 7.54-7.62 (m. 4H, aromatic), 7.73-7, 77 (m, 2H, aromatic).

Mass spectrum (Cl, CH ₄ ): 248 (M + 1).

Elemental analysis for C ₁₃ H ₁₅ NO ₂ S.

Calculated, C 63.14; H, 5.30; N, 5.66;
Found, C, 63.10; H, 5.30; N, 5.62.

 b) 2-methyl-4'-nitrodiphenylsulfone.

To a stirred solution of 2-phenylthio-5-nitrotoluene (3.24 g, 13.2 mmol) in glacial acetic acid (70 ml) was added potassium permanganate (2.50 g, 15.8 mmol) in distilled water (30 ml) . The dark brown mixture was stirred at room temperature for 2 hours, then treated with solid sodium sulfite until the solution became clear. The mixture was diluted with water, filtered and an off-white solid was obtained. Recrystallization from 95% ethanol gave the desired sulfone indicated in the title of the item as an off-white solid (2.75 g, 75%), melting point 113-114 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 2.48 (s, 3H, ArCH ₃ ), 7.63-7.80 (m, 3H, aromatic).

Mass spectrum (Cl, CH ₄ ): 278 (M + 1).

Elemental analysis for C ₁₃ H ₁₁ NO ₅ S.

Calculated, C 56.31; H 4.00; N, 5.05;
Found, C 56.10; H 4.14; N, 4.95.

 2-phenylthio-5-nitrotoluene is described by A.B. Sakla et al. Acta Chim. Acad Sci. Hung, 96 (4), 479 (1978); Chem. Abstr. 90: 203595d.

 Example 46

 N- (4- (2-fluorophenylcarbonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2- (hydroxy-2-methylpropanoic acid (1.10 g, 7.0 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl (0.83 g, 7.0 mmol), and the mixture was stirred at (-10) (-15) ^° C for 1 h. 4-amino-2-fluoro-benzophenone (1.0 g, 4, 6 mmol) and the reaction mixture was allowed to stir overnight at room temperature, the mixture was poured into water, the aqueous solution was filtered to obtain a brown solid, by purification by flash column chromatography (5% by volume ethyl acetate in chloride) m methylene) received the target propanamide as a white solid (1.23 g, 75%), melting point 141-142 ^o C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 1.60 (s. 3H, CH ₃ ), 7.35-7.42 (m. 2H, aromatic), 7.53-7.59 ( m. 2H, aromatic + OH), 7.65-7.68 (m. 1H, aromatic), 7.75 (d. 2H, J = 8.5 Hz, aromatic), 7.96 (dd. 2H, J = 8.6 and 1.7 Hz, aromatic), 10.37 (s. 1H, NH).

Mass spectrum (Cl, CH ₃ ): 356 (M + 1).

Elemental analysis for C ₁₇ H ₁₃ F ₄ NO ₃ .

Calculated, C 57.47; H 3.69; N, 3.94;
Found, C 57.44; H 3.77; N, 3.91.

 The starting benzophenone was prepared as follows.

 a) 4-amino-2'-fluorobenzophenone.

To stirred at 90 ^° C. polyphosphoric acid (200 g) was added 14.29 g (10.2 mmol) of 2-fluorobenzoic acid and aniline (9.32 g, 10.0 mmol) and the temperature of the bath was raised to 180-190 ^° C. and kept there for 1 hour. A solution was obtained at a temperature of about 140 ^° C. The heating bath was removed and the stirred mixture (sublimate above the solution) was carefully treated with 80 ml of water. The mixture was stirred at 140-155 ^° C for 1 h, the heating bath was removed, 66 ml of 3 N were added. hydrochloric acid, the mixture was poured into 1 liter of water and filtered through a pad of celite. The filtrate was made basic with 15% sodium hydroxide, and the solid formed with stirring was collected. The celite layer was washed with methylene chloride, methylene chloride was removed, and the residue was mixed with the solid obtained after alkalization of the aqueous phase. The combined materials were treated with 125 ml of hot water. Upon cooling, a brown solid was obtained, which was further recrystallized twice from ethyl acetate-hexane. Final purification by flash column chromatography (methylene chloride) afforded aniline as a white solid (5.45 g, 25%), melting point 128-130 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 6.32 (s. 2H, NH ₂ ), 6.60 (dd. 2H, J = 8.6 and 1.5 Hz, aromatic), 7 28-7.35 (m, 2H, aromatic); 7.40-7.60 (m, 4H, aromatic).

Mass spectrum (Cl, CH ₄ ): 216 (M + 1).

Elemental analysis for C ₁₃ H ₁₀ FNO.

Calculated, C 72.55; H 4.68; N, 6.51;
Found, C, 72.46; H 4.82; N, 5.21.

 Example 47

 N- (3-hydroxy-4- (4-pyridylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred suspension of N- (3-methoxy-4- (4-pyridylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide (1.05 g, 2.6 mmol) in dry chloride boron tribromide (10.4 ml, 1.0 M solution of boron tribromide in methylene chloride, 10.4 mmol) was added to methylene (30 ml). The resulting solution was stirred under reflux for 2 hours. An additional 5 ml of a 1.0 M solution of boron tribromide in methylene chloride was added, and the reaction mixture was left overnight with stirring at room temperature. The reaction mixture was diluted with methylene chloride (50 ml) and washed with water. The organic layer was dried (magnesium sulfate), concentrated in vacuo to give an oil. Purification of the oil by flash column chromatography (20% methanol in ethyl acetate) gave the desired propanamide as a white solid (0.18 g, 18%), melting point 188-189 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.54 (s. 3H, CH ₃ ), 7.35 (d. 1H, J = 9.0 Hz, aromatic), 7.51 (s . 1H, OH), 7.61 (s. 1H, aromatic), 7.77 (d. 2H, J = 5.5 Hz, aromatic), 7.84 (d. 1H, J = 8.9 Hz, aromatic), 8.83 (d. 2H, J = 5.5 Hz, aromatic), 10.26 (s. 1H, H), 11.04 (s. 1H, ArOH).

Mass spectrum (Cl, CH ₄ ): 391 (M + 1).

Elemental analysis for C ₁₅ H ₁₃ F ₃ N ₂ O ₅ • 0.25H ₂ O.

Calculated, C 45.63; H 3.44; N, 7.09;
Found, C, 45.51; H 3.58; N, 6.98.

 Example 48

 N- (3- (methoxy-4- (4-pyridylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.79 g, 11.3 mmol) in N, N-dimethylacetamide (20 ml) cooled to -20 ^° C was added thionyl chloride (1.34 g, 11.3 mmol) and the mixture was stirred at (-10) (-15) ^° C for 1 hour. 3-Methoxy-4- (4-pyridylsulfonyl) benzeneamine (2.00 g) was added in one portion. , 7.6 mmol), and the reaction mixture was left overnight with stirring at room temperature. The mixture was poured into water, and the aqueous solution was filtered through celite. The celite was washed with methylene chloride (100 ml), the methylene chloride solution was dried (magnesium sulfate) and concentrated in vacuo to an off-white solid. Rubbing with ethyl acetate gave the desired propanamide as a white solid (1.65 g, 45%), melting point 238-240 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.58 (s. 3H, CH ₃ ), 3.70 (s. 3H, OCH ₃ ), 7.60 (s. 1H, OH), 7.71 (cf, 1H, J = 4.6 Hz, aromatic), 7.75-7.79 (m. 3H, aromatic), 7.96 (d. 1H, J = 8.8 Hz, aromatic), 8.85 (dd. 2H, J = 4.6 and 1.1 Hz, aromatic), 10.39 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 405 (M + 1).

Elemental analysis for C ₁₆ H ₁₅ F ₃ N ₂ O ₅ S.

Calculated, C 47.53; H 3.74; N, 6.93;
Found, C, 47.45; H 3.79; N, 6.79.

 The starting benzolamine was prepared as follows.

 a) 3-methoxy-4- (4-pyridylsulfonyl) benzeneamine.

A stirred solution of 5-nitro-2- (4-pyridylsulfonyl) anisole (3.00 g, 102 mmol) and tin (II) chloride dihydrate (11.49 g, 51 mmol) in absolute ethanol (35 ml) was heated with 1 hour under reflux. The reaction mixture was poured into ice water, the aqueous solution was made basic with 15% sodium hydroxide and extracted with ethyl acetate (two times 200 ml). The combined organic extracts were dried (magnesium sulfate) b and the solvent was removed in vacuo to give the desired benzeneamine as a pale yellow solid (2.23 g, 83%), melting point 150-152 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 3.62 (s. 3H, OCH ₃ ), 6.18 (d. 1H, J = 1.8 Hz, aromatic), 6.24 (d . 1H, J = 1.9 Hz, aromatic), 6.28 (s. 2H, NH ₂ ), 7.28 (d. 1H, J = 8.8 Hz, aromatic), 7.70 (dd. 2H , J = 4.5 and 1.5 Hz, aromatic). 8.79 (dd. 2H, J = 4.4 and 1.6 Hz, aromatic).

Mass spectrum (Cl, CH ₄ ): 265 (M + 1).

Elemental analysis for C ₁₂ H ₁₂ N ₂ O ₃ S.

Calculated, C 54.53; H 4.58; N, 10.60;
Found, C 54.36; H 5.56; N, 10.44.

b) 5-nitro-2- (4-pyridylsulfonyl) anisole
To a stirred solution of 5-nitro-2- (4-pyridylthio) anisole (5.00 g, 19.1 mmol) in glacial acetic acid (150 ml) was added potassium permanganate (3.61 g, 22.9 mmol) in distilled water (75 ml). The dark brown mixture was stirred at room temperature for 1 h, then treated with solid sodium sulfite until the solution became clear. The mixture was diluted with water, filtered and a brown solid was obtained. Recrystallization from absolute ethanol gave the desired sulfone (3.63 g, 65%) as a brown solid, melting point 173-175 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 3.90 (s. 3H, OCH ₃ ), 7.90-7.94 (m. 3H, aromatic), 8.06 (d. 1H, J = 7.8 Hz, aromatic), 8.33 (d. 1H, J = 7.9 Hz, aromatic), 8.92 (broad singlet, 2H, aromatic).

Mass spectrum (Cl, CH ₄ ): 295 (M + 1).

Elemental analysis for C ₁₂ H ₁₀ N ₂ O ₅ S • 0.5 H ₂ O.

Calculated, C 48.24; H 3.54; N, 9.38;
Found, C 48.20; H 3.48; N, 9.46. c) 5-nitro-2- (4-pyridylthio) anisole.

A solution of potassium 4-pyridinothiolate (20.00 g, 134 mmol) and 2-chloro-5-nitroanisole (20.91 g, 112 mmol) in dimethylformamide (80 ml) was stirred at room temperature for 24 hours. The reaction mixture was poured into water with ice, and a brown solid was collected by filtration. The solid was stirred with 3 N. hydrochloric acid (400 ml) for 30 minutes, and the solution was filtered. The filtrate was made basic with ammonium hydroxide while cooling in an ice bath. Filtration of the alkaline solution gave the target anisole as an orange solid (26.23 g, 90%), melting point 132-135 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 3.95 (s. 3H, OCH ₃ ), 7.24 (dd. 2H, J = 4.6 and 1.7 Hz, aromatic), 7 53 (d. 1H, J = 8.3 Hz, aromatic), 7.86 (dd. 2H, J = 8.3 and 2.3 Hz, aromatic), 8.48 (2H, J = 4.7 and 1.3 Hz aromatic).

Mass spectrum (Cl, CH ₄ ): 263 (M + 1).

Elemental analysis: for C ₁₂ H ₁₀ N ₂ O ₃ S.

Calculated, C 54.95; H 3.84; N, 10.68;
Found, C 54.81; H 3.92; N, 10.70.

 Example 49

 N- (3-fluoro-4- (phenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.71 g, 4.5 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (0.54 g, 4.5 mmol) and the mixture was stirred at (-10) (-15) ^° C for 1 hour. 3-Fluoro-4- (phenylsulfonyl) benzeneamine (0.75 g, 3 , 0 mmol), and the reaction mixture was left overnight with stirring at room temperature. The mixture was poured into water, and the aqueous solution was filtered through celite. The celite was washed with methylene chloride (75 ml), the organic extracts were dried (magnesium sulfate), concentrated in vacuo, and a tan solid was obtained. Purification by flash column chromatography (5% ethyl acetate in volume ratio to methylene chloride) gave the desired propanamide as a white solid (0.79 g, 68%), melting point 147-149 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.58 (s, 3H, CH ₃ ), 7.65-7.69 (m, 4H, aromatic + OH), 7.74 (d. 1H, J = 7.2 Hz, aromatic), 7.83-7.94 (m 3H, aromatic), 8.02 (t. 1H, J = 8.3 Hz, aromatic), 10.61 (s . 1H, NH).

Mass spectrum (Cl, CH ₄ ): 392 (M + 1).

Elemental analysis for C ₁₆ H ₁₃ F ₄ NO ₄ S.

Calculated, C 49.12; H 3.35; N 3.58;
Found, C, 48.91; H 3.28; N, 3.53.

 The starting benzene amine was prepared as follows.

 a) 3-fluoro-4- (phenylsulfonyl) benzeneamine.

A stirred solution of 2-fluoro-2-nitro-diphenylsulfone (4.78 g, 17.0 mmol) and tin (II) chloride dihydrate (21.62 g, 95.9 mmol) in absolute ethanol (50 ml) was heated under reflux for 1 h. The reaction mixture was poured into ice water, the aqueous solution was made alkaline with 15% sodium hydroxide and extracted with ethyl acetate (three times with 200 ml). The combined organic extracts were dried (magnesium sulfate), filtered, the solvent was removed in vacuo and an off-white solid was obtained. Recrystallization from absolute ethanol gave the desired benzeneamine (3.43 g, 80%) as a white solid, melting point 161-163 ^° C.

¹ H-NMR spectrum (250 MHz, DMCO-d ₆ ): 6.32 (dd. 1H, J = 13.5 and 1.8 Hz, aromatic), 6.47 (d. 1H, J = 2.0 Hz, aromatic), 6.50 (s. 2H, NH ₂ ), 7.59-7.67 (m. 4H, aromatic), 7.85 (d. 2H, J = 7.6 Hz, aromatic).

Mass spectrum (Cl, CH ₄ ): 252 (M + 1).

Elemental analysis for C ₁₂ H ₁₀ NO ₂ S.

Calculated, C 57.36; H 4.01; N 5.57;
Found, C 57.27; H 4.15; N, 5.58.

 b) 2-fluoro-4-nitrodiphenylsulfone.

To a stirred solution of 3-fluoro-4- (phenylthio) nitrobenzene (5.65 g, 22.7 mmol) in glacial acetic acid (200 ml) was added potassium permanganate (4.30 g, 27.2 mmol) in distilled water (75 ml). The dark brown mixture was stirred at room temperature for 1 h, then treated with solid sodium sulfate until the solution was clarified. The mixture was diluted with water, filtered and an off-white solid was obtained. Recrystallization from absolute ethanol gave the desired sulfone (4.80 g, 75%) as an off-white solid, melting point 124-125 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 7.68-7.73 (m, 2H, aromatic), 7.79-7.84 (m, 1H, aromatic), 8.00 (d . 2H, J = 8.2 Hz, aromatic), 8.28-8.38 (m, 3H. Aromatic).

Mass spectrum (Cl, CH ₄ ): 282 (M + 1).

Elemental analysis for C ₁₂ H ₈ NO ₄ S.

Calculated, C 51.25; H 2.87; N, 4.98;
Found, C, 51.30; H 2.87; N, 4.53.

 c) 3-fluoro-4- (phenylthionitrobenzene).

A solution of potassium phenylthiolate (9.50 g, 64.1 mmol) and 3,4-difluoronitrobenzene (10.00 g, 64.1 mmol) in dimethylformamide (40 ml) was stirred at room temperature for 24 hours, the reaction mixture was poured into water with ice, and the yellow solid was collected by filtration. Recrystallization from 95% ethanol afforded the desired sulfide compound (10.68 g, 67%) as a yellow solid, melting point 54-55 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 7.03 (t, 1H, J = 7.8 Hz, aromatic), 7.52-7.62 (m, 5H, aromatic), 8, 00 (dd. 1H, J = 8.9 and 2.3 Hz, aromatic), 8.17 (dd. 1H, J = 8.8 and 2.3 Hz, aromatic).

Mass spectrum (Cl, CH ₄ ): 250 (M + 1).

Elemental analysis for C ₁₂ H ₈ NO ₂ S.

Calculated, C 57.82; H 3.23: N 5.62;
Found, C 57.71; H 3.21; N, 5.35.

 Example 50

 N- (4- (2,5-difluorophenylcarbonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

To a stirred solution of 3.3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.95 g, 6.0 mmol) in N, N-dimethylacetamide (15 ml) cooled to -20 ^° C was added thionyl chloride (0.72 g, 6.0 mmol) and the mixture was stirred at (-10) (-15) ^° C for 1 h. 4-amino-2,5-difluorobenzophenone (1.00 g, 4.3) was added in one portion. mmol), and the mixture was left overnight with stirring at room temperature. The mixture was poured into water, the aqueous solution was filtered, and a brown solid was obtained. Recrystallization from a mixture of methylene chloride and hexane gave the desired propanamide as a white solid (1.03 g, 69%), melting point 145-147 ^o C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.59 (s. 3H, CH ₃ ), 7.44-7.47 (m. 3H, aromatic), 7.57 (s. 1H, OH), 7.77 (d. 2H, J = 8.0 Hz, aromatic), 7.97 (d. 2H, J = 8.0 Hz, aromatic), 10.40 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 374 (M + 1).

Elemental analysis for C ₁₇ H ₁₂ F ₅ NO.

Calculated, C 54.70; H 3.24; N, 3.75;
Found, C, 54.29; H 3.16; N 3.72.

 The starting benzophenone was prepared as follows.

 a) 4'-amino-2,5-difluorobenzophenone.

To the polyphosphoric acid stirred at 90 ^° C. (125 g) was added 2,5-difluoro-benzoic acid (10.0 g, 6.32 mmol) and aniline (5.87 g, 6.3 mmol), the temperature of the bath was increased to 180-190 ^o C and kept so for 1 hour. The heating bath was removed, and the stirred mixture (sublimate over solution) was carefully treated with 50 ml of water. The mixture was stirred at 140-155 ^° C. for 1 hour, the heating bath was removed, 45 ml of 3 N was added. hydrochloric acid, the mixture was poured into 650 ml of water and filtered through a pad of celite. The filtrate was made basic with 15% sodium hydroxide, and the mixture was filtered through a pad of celite. The celite layer was washed well with methylene chloride, methylene chloride was dried (magnesium sulfate), filtered, and the solvent was removed in vacuo. Purification by flash column chromatography (methylene chloride) followed by recrystallization twice from 50% ethanol (80 ml) gave aniline as a yellow solid (3.08 g, 21%), melting point 101-103 ^° C.

Spectrum ¹ H-NMR (300 MHz, CDCl ₃ ): 4.27 (s, 2H, NH ₂ ), 6.63-6.67 (m, 2H, aromatic), 7.09-7.19 (m. 3H, aromatic), 7.68-7.71 (m, 2H, aromatic).

Mass spectrum (Cl, CH ₄ ): 234 (M + 1).

Elemental analysis for C ₁₃ H ₉ F ₂ NO.

 Calculated, C 66.95; H 3.89; N, 6.01.

 Found, C, 66.86; N, 4.04; N, 5.95.

 Example 51

 N- (4- (2,3-difluorophenylcarbonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

To a stirred chilled (220 ^° C) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.02 g, 6.4 mmol) in N, N-dimethylacetamide (10 ml) was added thionyl chloride ( 0.77 g, 6.4 mmol) and the mixture was stirred at (-10) (-15) ^° C for 1 h. 4-amino-2,3-difluorobenzophenone (1.00 g, 4.3 mmol) was added in one portion. ) in one portion, and the reaction mixture was left overnight with stirring at room temperature. The mixture was poured into water, and the aqueous solution was extracted with methylene chloride (two times 50 ml). The combined organic extracts were washed with water and 3 N. hydrochloric acid (once, 50 ml), dried (magnesium sulfate), concentrated in vacuo to give a tan solid. The solid was purified by flash column chromatography (5% v / v ethyl acetate in methylene chloride). Recrystallization of the obtained solid from a mixture of methylene chloride and hexane gave the desired propanamide as a white solid (1.13 g, 70%), melting point 154-155 ^o C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.60 (s. 3H, CH ₃ ), 7.36-7.40 (m. 2H, aromatic), 7.57 (s. 1H, OH), 7.65-7.72 (m 1H, aromatic), 7.89 (d. 2H, J = 8.6 Hz, aromatic), 7.98 (d. 2H, J = 8.6 Hz aromatic), 10.40 (s. 1H).

Mass spectrum (Cl, CH ₄ ): 374 (M + 1).

Elemental analysis for C ₁₇ H ₁₂ F ₅ NO ₃ • 0.25H ₂ O.

Calculated, C 54.05; H 3.33; N, 3.70;
Found, C 54.01; H 3.17; N, 3.68.

 The starting benzophenone was prepared as follows.

 a) 4'-amino-2,3-difluorobenzophenone.

To stirred polyphosphoric acid (125 g), heated to 90 ^° C., 2,3-difluorobenzoic acid (10.00 g, 63.3 mmol) was added, followed by aniline (5.72 g, 61.7 mmol). The reaction mixture was heated at 180-185 ^° C for 1 h (the solid was dissolved at 135 ^° C), then the oil bath was removed and distilled water (35 ml) was carefully added in small portions through the condenser. The oil bath was returned again and 3N was added to the solution. hydrochloric acid (55 ml), the reaction mixture was then poured into water (750 ml) and stirred for 1 h. The aqueous solution was filtered through targets, and the filtrate was basified to pH 8.0 with 15% sodium hydroxide. The green solid was collected by filtration and purified by flash column chromatography (methylene chloride). Rubbing with hexane gave the desired benzophenone (1.43 g, 10%) as a yellow solid, melting point 104-106 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 6.41 (s. 2H, NH ₂ ), 6.60 (d. 2H, J = 8.7 Hz, aromatic), 7.22-7 37 (m. 2H, aromatic), 7.50 (d. 2H, J = 8.6 Hz, aromatic), 7.53-7.64 (m. 1H, aromatic).

Mass spectrum (Cl, CH ₄ ): 234 (M + 1).

Elemental analysis for C ₁₃ H ₉ F ₂ NO.

Calculated, C 66.94; H 3.90; N, 6.00;
Found, C, 66.87; H 3.80; N, 5.91.

 Example 52

 N- (4- (2-cyanophenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20 ^° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.82 g, 5.2 mmol) in N, N-dimethylacetamide (10 ml) was added thionyl (0.62 g, 5.2 mmol), and the mixture was stirred at (-10) (-15) ^° C. 1 hour. 4 - ((2-Cyanophenyl) sulfonyl) benzeneamine (1, 00 g, 3.8 mmol), and the reaction mixture was left overnight with stirring at room temperature. The mixture was poured into water, the aqueous solution was poured from an oily solid, which was purified by flash column chromatography (5% by volume ethyl acetate in methylene chloride). Recrystallization from a mixture of methylene chloride and hexane gave the desired propanamide as a white solid (1.08 g, 72%), melting point 156-158 ^o C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.58 (s. 3H, CH ₃ ), 7.59 (s. 1H, OH), 7.88-8.13 (m. 7H, aromatic), 8.31 (d. 1H, J = 6.9 Hz, aromatic), 10.50 (1H, OH, s).

Mass spectrum (Cl, CH ₄ ): 399 (M + 1).

Elemental analysis for C ₁₇ H ₁₃ F ₃ N ₂ O ₄ S • 0.50H ₂ O.

Calculated, C 50.12; H 3.46; N, 6.87;
Found C, 49.86; H 3.17; N, 6.80.

 The starting benzolamine was prepared as follows.

 a) 4 - ((2-cyanophenyl) sulfonyl) benzolamine.

A stirred solution of 2-cyano-4-nitrodiphenyl sulfone (2.54 g, 8.8 mmol) and iron powder (5.39 g, 96.5 mmol) in absolute ethanol (70 ml) was heated under reflux. An ethanol solution of hydrochloric acid (0.53 ml of concentrated hydrochloric acid in 20 ml of ethanol) was added dropwise over 30 minutes. The reaction mixture was refluxed for 4 hours, diluted with absolute ethanol (100 ml) and filtered while hot through celite. Celite was washed with additional hot ethanol (100 ml). The combined ethanol fractions were reduced in volume by 75 ml and placed in the refrigerator overnight. The desired benzeneamine was collected by filtration as a white solid (1.81 g, 80%), melting point 177-179 ^o C.

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 6.37 (s. 2H, NH ₂ ), 6.65 (d. 2H, J = 8.8 Hz, aromatic), 7.61 (d .2H, J = 8.8 Hz, aromatic), 7.81 (dd. 1H, J = 7.5 and 1.0 Hz, aromatic), 7.93 (dd. 1H, J = 7.6 and 1 , 1 Hz, aromatic), 8.06 (dd. 1H, J = 7.5 and 1.1 Hz, aromatic), 8.17 (d. 1H, J = 7.4 Hz, aromatic).

Mass spectrum (Cl, CH ₄ ): 259 (M + 1).

Elemental analysis for C ₁₃ H ₁₀ N ₂ O ₂ S • 0.25H ₂ O.

Calculated, C 59.41; H 3.84; N, 10.66;
Found, C 59.39; H 3.82; N, 10.60.

 b) 12-cyano-4'-nitrodiphenylsulfone.

To a stirred solution of 2- (4-nitrophenylthio) benzonitrile (3.25 g, 12.7 mmol) in glacial acetic acid (200 ml) was added potassium permanganate (2.41 g, 15.2 mmol) in distilled water (75 ml). The dark brown mixture was stirred at room temperature for 1.5 hours, then treated with solid sodium sulfite until the solution became clear. The mixture was poured into water, filtered, and a tan solid was obtained. Recrystallization from ethyl acetate-hexane gave the desired sulfone (2.56 g, 70%) as a white solid, melting point 172-174 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 7.98-8.11 (m, 2H, aromatic), 8.19 (dd. 1H, J = 7.1 and 1.0 Hz, aromatic ), 8.28 (d. 2H, J = 8.8 Hz, aromatic), 8.45 (m. 1H, aromatic), 8.49 (d. 2H, J = 8.9 Hz, aromatic).

Mass spectrum (Cl, CH ₄ ): 289 (M + 1).

Elemental analysis for C ₁₃ H ₈ N ₂ O ₄ S.

Calculated, C 54.16; H 2.80; N, 9.72;
Found, C, 53.83; H 2.46; N, 9.63.

 c) 2- (4-Nitrophenyl) benzonitrile.

A stirred solution of potassium 4-nitrophenylthiolate (10.61 g, 54.9 mmol) and 2-bromobenzonitrile (10.00 g, 54.9 mmol) in dimethylformamide (50 ml) was heated at 95 ^° C. for 22 hours. Reaction mixture poured into ice water and a yellow solid was collected by filtration. Purification by flash column chromatography (40% by volume mixture of methylene chloride / hexane) followed by recrystallization from 90% ethanol gave the desired benzonitrile (3.25 g, 23%) as a yellow solid, melting point 151-153 ^° C.

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 7.39 (dd. 2H, J = 6.9 and 2.2 Hz, aromatic), 7.73-7.75 (m, 1H, aromatic ), 7.81-7.84 (m 2H, aromatic), 8.08 (dd. 1H, J = 7.7 and 1.1 Hz, aromatic), 8.19 (dd. 2H, J = 6 , 9 and 2.1 Hz, aromatic).

Mass spectrum (Cl, CH ₄ ): 257 (M + 1).

Analysis for C ₁₃ H ₈ N ₂ O ₂ S.

Calculated, C 60.92; H 3.15; N, 10.83;
Found, C, 60.70; H 3.32; N, 10.99.

 Example 53

 N- (3- (hydroxy-4- (phenylcarbonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.78 g, 4.9 mmol) in N, N-dimethylacetamide (10 ml) cooled to -20 ^° C was added thionyl chloride (0.59 g, 4.9 mmol), and the mixture was stirred at (-10) (-15) ^° C for 1 h. 4-amino-2-hydroxybenzophenone (0.70 g, 3.3 mmol) was added in one portion. and the reaction mixture was stirred at room temperature, leaving overnight. The mixture was poured into water, the aqueous solution was poured from an oily precipitate, which was dissolved in methylene chloride, dried (magnesium sulfate), concentrated in vacuo and a brown solid (oil) was obtained. Purification by flash column chromatography (5% v / v ethyl acetate in methylene chloride) gave the desired propanamide as a white solid (0.83 g, 71%), melting point 173-175 ^° C.

¹ H-NMR spectrum (250 MHz, CDCl ₃ ): 1.74 (s. 3H, CH ₃ ), 3.49 (s. 1H, OH), 7.14 (dd. 1H, J = 8.7 and 2.2 Hz, aromatic), 7.28 (d. 1H, J = 2.1 Hz, aromatic), 7.46-7.65 (m. 6H, aromatic), 8.49 (s. 1H, N ), 12.3 (s. 1H, phenolic OH).

Mass spectrum (Cl, CH ₄ ): (M + 1).

Elemental analysis for C ₁₆ H ₁₄ F ₃ NO ₄ .

Calculated, C 57.79; H 3.99; N, 3.96;
Found, C 57.66; H 4.05; N, 3.95.

 4-amino-2-hydroxybenzophenone is described by B. Arventier, H. Offenberg, Jasi, Sect. I, Chem. IIC (I), 79-85 (1965), (CA, 63, 14795d).

 Example 54

 N- (4- (3-fluorophenylcarbonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.58 g, 10 mmol) in N, N-dimethylacetamide (15 ml) cooled to -20 ^° C was added thionyl chloride (1 25 g, 10.5 mmol) and the mixture was stirred at (-10) (-15) ^° C for 1 h. 4-amino-3-fluorobenzophenone (1.44 g, 6.7 mmol) was added in one portion, and the reaction mixture was left overnight with stirring at room temperature. The mixture was poured into water to obtain an oil and a cloudy solution. The turbid solution was poured from the oil, filtered by drawing through a layer of celite. The celite layer was washed with methylene chloride, and the solution was added to the resin solution in methylene chloride. The solution was dried (magnesium sulfate), filtered, and the solvent was removed in vacuo. The resulting oil was chromatographed on silica gel (ethyl ether), the desired fractions were mixed, the solvent was removed and an oil was obtained. The oil was dissolved in 50 ml of hexane containing enough methylene chloride to obtain a clear solution, and the solution was concentrated in a steam bath until the solution became cloudy. The resulting pale yellow solid was collected by filtration, dried, and 1.51 g (63%) of N- (4- (3-fluorophenylcarbonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropane was obtained, melting point 121.5-123.0 ^o C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.59 (s. 3H, CH ₃ ), 3.32 (s. 1H, OH), 7.46-7.60 (m. 4H, aromatic), 7.75 (d. 2H, J = 9.1 Hz, aromatic), 7.96 (d. 2H, J = 8.2 Hz, aromatic), 10.33 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 356 (M + 1).

Elemental analysis for C ₁₇ H ₁₃ F ₄ NO ₃ .

Calculated, C 57.47; H 3.69; N, 3.94;
Found, C, 57.40; H 3.65; N, 3.94.

 The starting benzophenone was prepared as follows.

 a) 4-amino-3'-fluorobenzophenone.

To the polyphosphoric acid (150 g) stirred at 90 ^° C, 10.72 g (7.65 mmol) of 3-fluorobenzoic acid and 6.98 g (7.5 mmol) of aniline were added, and the bath temperature was raised to 180-190 ^° C. and kept for 1 h. The heating bath was removed, and the stirred mixture (sublimate over solution) was carefully treated with 60 ml of water. The mixture was stirred at 140-155 ^° C. for 1 hour, the heating bath was removed, 50 ml of 3 N was added. hydrochloric acid, the mixture was poured into 750 ml of water and filtered through a pad of celite. The filtrate was basified with 15% sodium hydroxide, and the resulting solid was extracted with methylene chloride. Dried (magnesium sulfate) solution was filtered, the solvent was removed and a brown solid was obtained. Recrystallization from ethanol hexane 1: 3 gave a greenish-yellow solid, which was chromatographed on silica gel (methylene chloride) to obtain 4.83 g (30%) of yellow 4-amino-3-fluorobenzophenone, melting point 98-100 ^° C.

Spectrum ¹ H-NMR (300 MHz, CDCl ₃ ): 4.21 (s. 2H, NH ₂ ), 6.66-6.70 (m. 2H, aromatic), 7.23-7.26 (m. 1H, aromatic), 7.39-7.51 (m, 3H, aromatic), 7.72-7.69 (m, 2H, aromatic).

Mass spectrum (Cl, CH ₄ ): 216 (M + 1).

Elemental analysis for C ₁₃ H ₁₀ FNO.

Calculated, C 72.55; H 4.68; N, 6.51;
Found, C, 72.66; H 4.72; N, 6.25.

 Example 55

 N- (4-phenylcarbonyl) -3-fluorophenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxymethylpropanoic acid (1.19 g, 7.5 mmol) in N, N-dimethylacetamide (11 ml) cooled to -20 ^° C was added thionyl chloride (0 92 g, 7.7 mmol), and the mixture was stirred at (-20) (-10) ^° C for 1 h. 4-amino-3'-fluorobenzophenone (1.08 g, 5.0 mmol) was added in one portion, and the reaction mixture was left overnight with stirring at room temperature.

 The mixture was poured into water to give an oil and a cloudy solution. The turbid solution was poured from the oil and filtered by drawing through a layer of celite. The celite layer was washed with methylene chloride, and the solution was added to the resin solution in methylene chloride. The solution was dried (magnesium sulfate), filtered, and the solvent was removed in vacuo. The resulting oil was chromatographed on silica gel (ethyl ether), the desired fractions were combined, the solvent was removed in vacuo and a brown oil was obtained. The oil was dissolved in a sufficient amount of methylene chloride (about 25 ml) and a clear solution was obtained, which was controlled until the latter became cloudy. The solution was scraped off to initiate crystallization and an additional 25 ml of hexane was added.

The resulting light brown solid was collected by filtration, dried, and 1.43 g (80%) of N- (4-phenylcarbonyl-3-fluorophenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide was obtained, melting point 132-134 ^o C.

Spectrum ¹ H-NMR (300 MHz, CDCl ₃ ): 1.78 (s, 3H, CH ₃ ), 3.86 (s. 1H, OH), 7.29-7.83 (m, 8H, aromatic) 8.68 (s. 1H, H).

Mass spectrum (Cl, CH ₄ ): 356 (M + 1).

Elemental analysis calculated for C ₁₇ H ₁₃ F ₄ NO ₃ .

Calculated, C 57.47; H 3.69; N, 3.94;
Found C, 57.42; H 3.83; N, 3.91.

 The starting benzophenone was prepared as follows.

 a) 4-amino-2-fluorobenzophenone.

To the polyphosphoric acid (150 g) stirred at 90 ^° C., 18.32 g (15.0 mmol) of benzoic acid and 8.33 g (7.5 mmol) of 3-fluoroaniline were added, and the bath temperature was raised to 220 ^° C. the solution had a temperature of about 130 ^o C.

The heating bath was removed and the stirred mixture (sublimate over solution) was carefully treated with 60 ml of water. The mixture was stirred at 140-155 ^° C. for 1 hour, the heating bath was removed, 50 ml of 3 N was added. hydrochloric acid, the mixture was poured into 750 ml of water and filtered through a pad of celite. The filtrate was basified with 15% sodium hydroxide and the resulting solid was collected. 1.88 g of solid were chromatographed on silica gel (methylene chloride) to give 1.15 g (7%) of white fluffy 4-amino-2-fluorobenzophenone, melting point 133-135 ^° C.

Spectrum ¹ H-NMR (250 MHz, CDCl ₃ ): 4.20 (s, 2H, NH ₂ ), 6.33-6.50 (m. 2H, aromatic), 7.27-7.55 (m. 4H, aromatic), 7.76-7.79 (m, 2H, aromatic).

Mass spectrum (Cl, CH ₄ ): 216 (M + 1).

Elemental analysis for C ₁₃ H ₁₀ FNO.

Calculated, C 72.55; H 4.68; N, 6.51;
Found, C, 72.20; H 4.64; N, 6.45.

 Example 56

 N- (4- (3-fluorophenylcarbonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-trifluoromethylpropanamide.

To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanoic acid (1.17 g, 5.5 mmol) in dry tetrahydrofuran (35 ml) was added 1,1-carbonyldiimidazole (0.89 g, 5 5 mmol). The mixture was heated under reflux for 45 minutes, then cooled to room temperature. 4-amino-3-fluorobenzophenone (1.08 g, 5.0 mmol) was added in one portion and the reaction mixture was refluxed for 48 hours. Tetrahydrofuran was removed from the reaction mixture in vacuo and the residue was dissolved in ethyl ether and filtered. The filtrate was washed with 3 N. hydrochloric acid (50 ml) and water. The ether extract was dried (magnesium sulfate) in vacuo and concentrated to an off-white solid. Purification by flash column chromatography (5% v / v ethyl ether in methylene chloride) gave the desired propanamide as a brown solid (1.13 g, 55%), melting point 169-171 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 7.50-7.65 (m, 4H, aromatic), 7.77-7.82 (m, 2H, aromatic), 7.94-7 98 (m. 2H, aromatic), 9.84 (s. 1H, NH), 10.85 (br s. 1H, OH).

Mass spectrum (Cl, CH ₄ ): 410 (M + 1).

Elemental analysis for C ₁₇ H ₁₀ F ₇ NO ₃ .

Calculated, C 48.89; H 2.46; N 3.42;
Found, C, 49.60; H 2.43; N, 3.34.

 Example 57

 N- (4- (2-fluorophenylcarbonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-trifluoromethylpropanamide.

 To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanoic acid (1.17 g, 5.5 mmol) in dry tetrahydrofuran (35 ml) was added 1,1'-carbonyldiimidazole (0.89 g, 5.5 mmol). The mixture was heated under reflux for 45 minutes, then cooled to room temperature. 4-amino-2-fluorobenzophenone (1.08 g, 5.0 mmol) was added in one portion, and the reaction mixture was heated under reflux for 48 h. Tetrahydrofuran was removed from the reaction mixture in vacuo, the residue was dissolved in ethyl ether and filtered.

The filtrate was washed with 3 N. hydrochloric acid (50 ml) and water. The ether extract was dried (magnesium sulfate) and concentrated in vacuo to an off-white solid, which was purified by flash column chromatography (5% v / v ethyl ether in methylene chloride). Recrystallization of the obtained solid from hexane gave the desired propanamide as a reddish solid (0.83 g, 40%), melting point 137-139 ^° C.

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 7.36-7.42 (m 2H, aromatic), 7.54-7.60 (m 1H, aromatic), 7.63-7 69 (m. 1H, aromatic), 7.76-7.79 (m. 2H, aromatic), 7.92-7.96 (m. 2H, aromatic), 9.84 (s. 1H, NH) 10.86 (broad singlet, 1H, OH).

Mass spectrum (Cl, CH ₄ ): 410 (M + 1).

Elemental analysis for C ₁₇ H ₁₀ F ₇ NO ₃ .

Calculated, C 49.89; H 2.46; N 3.47;
Found, C, 50.05; H 2.46; N, 3.36.

 Example 58

 N- (3-fluoro-4- (phenylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-trifluoromethylpropanamide.

To a solution of 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanoic acid (1.26 g, 5.9 mmol) in dry tetrahydrofuran (35 ml) was added 1,1'-carbonyldiimidazole (0.89 g, 5 5 mmol). The mixture was heated to 45 ^° C. in an ultrasonic bath for 30 minutes, then 3-fluoro-4-phenylsulfonylbenzenamine was added in one portion. The reaction mixture was heated at 65 ^° C. in an ultrasonic bath for 30 hours. Tetrahydrofuran was removed from the reaction mixture in vacuo and the residue was partitioned between water and ethyl ether.

The aqueous layer was extracted with ethyl ether (twice 50 ml), the combined ether fractions were dried (magnesium sulfate) and concentrated in vacuo to an off-white solid. The solid was dissolved in ethyl ether, treated with a mixture of hydrochloric acid and ethyl ether and filtered to remove unreacted 3-fluoro-4-phenylsulfonylbenzamine. The filtrate was concentrated in vacuo, a solid was crystallized from hexane-ethyl ether to give the desired propanamide as a white solid (0.32 g, 13%), melting point 188-189 ^° C.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 7.62-7.84 (m, 4H, aromatic), 7.91-7.94 (m, 3H, aromatic), 8.03-8 09 (m. 2H, aromatic); 9.60 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 446 (M + 1).

Elemental analysis for C ₁₆ H ₁₀ F ₇ NO ₄ S.

Calculated, C 43.16; H 2.26; N, 3.15;
Found, C, 43.17; H 2.43; N, 3.07.

 Example 59

 S - (-) - N- (4- (4-pyridylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To stirred, cooled to 0 ^o C N- (4- (4-pyridylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide (30.86 g, 82 mmol) and triethylamine (13 , 8 ml, 99, mmol) in dry methylene chloride (500 ml) cooled to 0 ^° C., 4-dimethylaminopyridine (catalytic) and S - (+) - alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride (24.90 g, 99 mmol), the mixture was stirred in an ice bath for 30 minutes, then at room temperature for 7 hours. The reaction mixture was diluted with methylene chloride to a total volume of about 900 ml, treated with water, filtered through a celite pad. The organic layer was separated, and the aqueous phase was extracted with methylene chloride (two times 700 ml). The combined organic extracts were dried (magnesium sulfate), filtered, the solvent was removed and a tan foam was obtained. The diastereomers were separated by repeated column chromatography (10% by weight of ethyl ether in methylene chloride). The ester (S, S), which was eluted second, was isolated as a white solid (7.04 g, 15%), melting point 159-160 ^° C. Optical purity greater than 99% excluding error was determined by high pressure chiral liquid chromatography (Ultron ES OVM column, a mixture of 12% by volume acetonitrile and acidic potassium pyrophosphate (KH ₂ PO ₄ ) (0.013 M, pH 5.5), flow rate 1 ml / min).

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 2.12 (s, 3H, CH ₃ ), 3.60 (s. 3H, OCH ₃ ), 7.51-7.60 (m. 5H aromatic), 7.89 (d. 2H, J = 2.1 Hz, aromatic), 7.95 (d. 2H, J = 8.9 Hz, aromatic), 8.09 (d. 2H, J = 3.8 Hz, aromatic), 8.88 (d. 2H, J = 5.8 Hz, aromatic), 10.51 (s, 1H, NH).

Mass spectrum (Cl, CH ₄ ): 591 (M + 1).

To a stirred chilled (ice bath) suspension of Moshere (S, S) ester (7.04 g, 11.9 mmol) in methanol (100 ml) was added a solution of sodium hydroxide (0.52 g, 13.1 mmol) in water (10 ml). After adding a solution of sodium hydroxide, the mixture was stirred for 15 minutes in an ice bath and an additional 15 minutes with the ice bath removed. The reaction mixture was then diluted with water to a final volume of 250 ml, methanol was removed in vacuo, and a white solid was collected by filtration and dried. Acidification of the filtrate provided additional material. The combined yield was 4.25 g (96%), melting point 216-217 ^o C (α) ²⁷ = -5.9 ^o , C = 1.02 in dimethylformamide. The optical purity was set higher than 99% taking into account the error by high pressure chiral liquid chromatography (Ultrom ES OVM column, 12% by volume mixture of acetonitrile and KH ₂ PO ₄ (0.013 M, pH 5.5). The compound was determined as having a configuration by X-ray crystallography.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.58 (s. 3H, CH ₃ ), 7.61 (s. 1H. OH), 7.89 (dd. 2H, J = 4, 4 and 1.5 Hz, aromatic), 8.0 (d. 2H, J = 9.0 Hz, aromatic), 8.07 (d. 2H, J = 9.0 Hz, aromatic), 8.88 ( dd. 2H, J = 4.5 and 1.7 Hz, aromatic), 10.51 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 375 (M + 1).

Elemental analysis for C ₁₅ H ₁₃ F ₃ N ₂ O ₄ S.

Calculated, C 48.12; H 3.51; N, 7.48;
Found, C, 48.02; H 3.57; N, 7.41.

 Example 60

 S - (-) - N- (4- (4-pyridylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of S - (-) - 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (15.01 g, 94.9 mmol) in N, N-dimethylacetamide, cooled to -20 ^° C ( 225 ml) thionyl chloride (11.29 g, 94.9 mmol) was added dropwise over 5 minutes, and the mixture was stirred at (-10) (-15) ^° C. for 1 hour. 4- (4-pyridylsulfonyl) was added in one portion. ) -aniline (14.82 g, 63.2 mmol) to an orange solution, and the mixture was left overnight with stirring at room temperature. The solution was poured into ice water (1 L), and an off-white solid precipitated was filtered out of the solution. The solid was dissolved in boiling absolute ethanol (300 ml), left overnight at room temperature, and the solid was collected. The second yield was obtained after reducing the volume of the filtrate to 70 ml and cooling the resulting solution to room temperature. The combined yield was crystallized from absolute ethanol (150 ml) to give the desired propanamide (17.00 g, 74%) as a white solid, melting point 215-217 ^° C. (α) ²⁵ = -5.9 ^° , c = 1.025 in dimethylformamide. The optical purity was determined above 99% taking into account the error by high pressure chiral liquid chromatography (Ultron ESOVM column 12% by volume mixture of acetonitrile in KH ₂ PO ₄ (0.013 M, pH 5.5).

¹ H-NMR spectrum (300 MHz, DMCO-d ₆ ): 1.71 (s. 3H, CH ₃ ), 7.71 (s. 1H, OH), 8.01 (d. 2H, J = 4, 5 Hz, aromatic), 8.12 (d. 2H, J = 7.1 Hz, aromatic), 8.19 (d. 2H, J = 7.1 Hz, aromatic), 9.00 (d. 2H, J = 4.5 Hz, aromatic), 10.61 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 375 (M + 1).

Elemental analysis for C ₁₅ H ₁₃ F ₃ N ₂ O ₄ S.

Calculated, C 48.12; H 3.51; N, 7.48;
Found, C, 48.02; H 3.59; N, 7.42.

 The starting material was prepared as follows.

 a) S - (-) - 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid.

The solvent was removed in vacuo from a solution of R, S - (+) - 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (316.2 g, 3.0 mmol) and S - (-) - α- methylbenzylamine (363.5 g, 3.0 mmol) in ethanol (1.5 L), the residue was triturated with toluene, the solid was collected, washed with toluene and dried in vacuo. Recrystallization from 10% n-butanol in toluene gave 126.0 g ≥ 97% enantiomerically pure S, S salt (based on the analysis of the nuclear magnetic resonance spectrum on fluorine-19 nuclei), melting point 162-165 ^o C. 150.0 g of enantiomerically pure salt (97% purity) was recrystallized twice from 10% n-butanol in toluene to obtain 85 g ≥ 99.5% enantiomerically pure S, S-salt (according to ¹⁸ F-NMR spectrum), melting point 162 , 6-164 ^o C.

¹ H-NMR (300 MHz, CDCl ₃ ): 1.25 (s. 3H, CH ₃ ), 1.52 (d. 3H, J = 6.8 Hz, CH ₃ ), 4.16 (m. 1H , aliphatic CH), 7.25-7.35 (m, 5H, aromatic), R, S salt shows an acid CH ₃ peak at 1.18 ppm, and it is not clear in this proton spectrum.

Spectrum ¹⁹ F-NMR (376.5 MHz, CDCl ₃ ): -79.83, R, S-salt is shifted down 13 Hz and is visible in this spectrum below the satellite peak C-13 (0.5%). Recrystallization liquids of 97% enantiomerically pure salt were distilled off in vacuo, and the residue was recrystallized three times from 10% n-butanol in toluene to obtain an additional 31.5 g ≥ 99% of pure enantiomeric S, S-salt (spectrum ¹⁹ F- NMR).

85 g ≥ 99.5% of pure salt was partitioned between aqueous hydrochloric acid (105 ml of concentrated hydrochloric acid and 700 ml of water) and ethyl ether (400 ml). The phases were separated, and the aqueous phase was extracted further with ethyl ether (five times 400 ml each). The dried extracts (magnesium sulfate) were filtered, the solvent was removed, and 47.0 g of S - (-) - 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid were obtained, melting point 105-108 ^o C, (α) ²³ = -18.9 ^° , c = 8.04 in methanol.

Spectrum ¹ H-NMR (300 MHz, CDCl ₃ ): 1.67 (s. CH ₃ ).

 Mass spectrum (Cl, methane): 159 (M + 1).

Elemental analysis for C ₄ H ₅ F ₃ O ₃ .

Calculated, C 30.39; H 3.19;
Found, C, 30.14; H 3.19.

31.5 g of this S, S salt ≥ 99% pure were similarly partitioned between hydrochloric acid and ethyl ether, and 17.4 g of S - (-) - 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid were obtained melting point 107-109 ^o C, (α) ²³ = -18.7 ^o , s = 4.27 (in methanol).

 Example 61

 S - (-) - N- (4-phenylcarbonylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of N- (4-phenylcarbonylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (6.87 g, 20.4 mmol) and triethylamine (3.2 ml, cooled to 0 ^° C) 23 mmol) in methylene chloride (70 ml), a catalytic amount of 4-dimethylaminopyridine was added, followed by dropwise addition of 1S - (-) - campanoic acid chloride (5.00 g, 23.1 mmol). The mixture was stirred at room temperature for 2 h, diluted with methylene chloride (70 ml) and washed with water, 3 N. hydrochloric acid (200 ml) and water. The dried organic fractions (magnesium sulfate) were filtered, the solvent was removed in vacuo and a white foam was obtained. The diastereomers were separated by repeated column evaporation chromatography (from 0 to 3% by volume gradient of ethyl ether in methylene chloride). Campanic acid ester (S, S), which was first eluted, was isolated as a white foam (3.20 g, 30%). The optical purity was higher than 98% was determined by high pressure chiral liquid chromatography (Chiralcee OD column, 15% by volume ethanol in hexane, flow rate 1 ml / min).

Spectrum ¹ H-NMR (300 MHz, DMCO-d ₆ ): 0.97 (s. 3H, CH ₃ ), 1.037 (s. 3H, CH ₃ ), 1.044 (s. 3H, CH ₃ ), 1.58 -1.61 (m. 1H, aliphatic), 2.00-2.10 (m. 5H, CH ₃ , aliphatic), 2.43-2.47 (m. 1H, aliphatic), 7.54-7 59 (m. 2H, aromatic), 7.66-7.82 (m. 7H, aromatic), 10.34 (s. 1H, NH).

To a suspension of S, S-campanic acid ester (3.20 g, 6.2 mmol) in methanol (40 ml) was added 2 N. sodium hydroxide (3 ml), and the yellow solution was stirred at room temperature for 1 h. Methanol was removed in vacuo, the residue was treated with water, and the mixture was extracted with methylene chloride (two times 50 ml). Dried (magnesium sulfate) organic extracts were filtered, the solvent was removed in vacuo, a white solid was recrystallized from a mixture of methylene chloride and hexane to obtain 1.80 g (86%) S - (-) - N- (4-phenylcarbonyl-phenyl) -3 , 3,3-trifluoro-2-hydroxy-2-methylpropanamide, melting point 171-173 ^o C, (α) ²⁷ = 18.8 ^o , C = 1.01 in methanol: optical purity:> 98%, taking into account the error high pressure chiral liquid chromatography (Chiralcel OD column, 15% v / v ethanol in hexane, flow rate 1 ml / min). The compound, as determined by x-ray crystallography, had an S configuration.

Spectrum ¹ H-NMR (250 MHz, DMCO-d ₆ ): 1.60 (s. 3H, CH ₃ ), 7.35-7.59 (m. 3H, aromatic, OH), 7.46-7, 76 (m. 5H, aromatic), 7.96 (d. 2H, J = 8.7 Hz, aromatic), 10.33 (s. 1H, NH).

Mass spectrum (Cl, CH ₄ ): 338 (M + 1).

Elemental analysis for C ₁₇ H ₁₄ F ₃ NO.

Calculated, C 60.54; H 4.18; N, 4.15;
Found, C, 60.49; H 4.20; N, 4.13.

 Example 62

 N- (4- (2-pyridylcarbonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-trifluoromethylpropanamide.

Tetrahydrofuran (15 ml, dry) was added to a mixture of 2.2 bis-trifluoromethyl-2-hydroxyacetic acid (1.08 g, 5.1 mmol) and 1,1'-carbonyldiimidazole (0.83 g, 5.1 mmol) in an atmosphere of nitrogen. Immediate release of carbon dioxide was observed. The reaction vessel was placed in an ultrasonic bath at 23 ^° C. for 15 minutes. The reaction mixture was treated with 4- (2-pyridylcarbonyl) benzeneamine (1.01 g, 5.1 mmol) and heated to 43 ^° C. in an ultrasonic bath for 48 hours. The unfinished reaction was treated with a solid mixture of 2,2-bis-trifluoromethyl-2 -oxyacetic acid (0.22 g, 1.04 mmol) and 1,1-carbonyldiimidazole (0.20 g, 1.2 mmol) and heated to 53 ^° C. in an ultrasonic bath for 72 hours. The reaction mixture was evaporated to a golden oil which was treated with water (100 ml) and extracted with ethyl acetate (two times 100 ml). The combined organic fractions were dried (magnesium sulfate) and evaporated to a golden oil. Chromatography of this oil on silica gel, eluting with a mixture of methylene chloride and ethyl acetate (first at a ratio of 100: 0 and then 85:15), gave a tan solid (0.37 g, 19%), melting point 197-200 ^° C.

¹ H-NMR spectrum (250 MHz, DMCO-d ₆ ): 7.68 (m, 1H, ArH), 8.0 (m. 6H, ArH), 8.74 (d. J = 4.33 Hz, 1H, ArH), 9.93 (broad singlet, 1H, NH).

Mass spectrum (Cl, CH ₄ ): 393 (M + 1).

Elemental analysis for C ₁₆ H ₁₀ F ₆ N ₂ O ₃ .

Calculated, C 48.90; H 2.57; N, 7.14;
Found C, 49.23; H 2.69; N, 7.23.

 Example 63

 N- (4- (2-pyridine) sulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-trifluoromethylpropanamide.

Tetrahydrofuran (5 ml, dry) was added to a mixture of 2,2-bis-trifluoromethyl-2-hydroxyacetic acid (0.98 g, 4.6 mmol) in 1,1-carbonyldiimidazole (0.75 g, 4.6 mmol) in an atmosphere of nitrogen. There was an immediate release of carbon dioxide. The reaction mixture was heated at 35 ^° C. in an ultrasonic bath for 15 minutes. The reaction mixture was treated with a solution of 4- (2-pyridylsulfonyl) -benzamine (1.08 g, 4.6 mmol) in dimethylformamide (11 ml, dry), heated at 46 ^° C. for 16 hours and then at 60 ^° C. for 24 h. The unfinished reaction was treated with a solid mixture of 2,2-bis-trifluoromethyl-2-hydroxyacetic acid (0.22 g, 1.0 mmol) and 1,1-carbonyldiimidazole (0.20 g, 1.2 mmol) and heated to 52 ^o C in an ultrasonic bath for 18 hours. The reaction mixture was evaporated to a viscous golden liquid, which was treated with water (100 ml) and extracted with ethyl acetate (two times 100 ml). The combined organic fractions were dried (magnesium sulfate), evaporated to give a golden oil. Chromatography of this oil on silica gel, eluting with a 98: 2 chloroform-methanol mixture, afforded the title compound as the example title (0.37 g, 14%) as a white solid, melting point 199-200 ^° C.

 Spectrum [[[H-NMR (250 MHz, DMCO-d [[)]: 7.7 (m, 1H, ArH), 8.02 (m, 4H, ArH), 8.19 (m, 2H, ArH) 8.71 (d. J = 4.0 Hz, 1H, ArH); 9.88 (s. 1H, OH); 10.94 (s. 1H, NH).

 Mass spectrum (Cl, CH [[): 429 (M + 1).

 Elemental analysis for C [[H [[F [[N [[O [[S.

Calculated, C 42.06; H 2.35; N, 6.53;
Found, C, 41.99; H 2.34; N, 6.57.

 Example 64

 N- (4- (4-pyridylsulfonyl) phenyl) -3,3,3-trifluoro-2-hydroxy -2-trifluoromethylpropanamide.

 Tetrahydrofuran (5 ml, dry) was added to a mixture of 2,2-bis-trifluoromethyl-2-hydroxyacetic acid (1.29 g, 6.1 mmol) and 1,1'-carbonyldiimidazole (0.99 g, 6.1 mmol ) in a nitrogen atmosphere.

 There was an immediate release of carbon dioxide. The reaction mixture was heated at 35 [[C for 15 minutes The reaction was treated with a solution of 4- (4-pyridylsulfonyl) benzeneamine (1.43 g, 6.1 mmol) in dimethylformamide (15 ml, dry) and heated to 69 [[C in an ultrasonic bath for 19.5 hours. The reaction mixture was poured into water (300 ml) and was extracted with ethyl ether (three times in 300 ml). The combined organic fractions were evaporated and pre-absorbed with silica gel (10 g). Chromatography of this material on silica gel, eluting with a mixture of methylene chloride and ethyl acetate (first at a ratio of 100: 0 and then at 70:30), yielded a white solid. Recrystallization from acetone gave the starting 4- (4-pyridylsulfonyl) -N-benzolamine. The filtrate was evaporated and chromatographed on silica gel, eluting with a mixture of chloroform-methanol (first in a ratio of 100: 0 and then 98: 2), and the title compound was obtained as indicated in the title of the example (0.115 g, 6%) as a white solid, melting point 235-237 [[C.

 Spectrum [[H-NMR (250 MHz, DMCO-d [[): 7.90 (d. J = 4.6 Hz, 2H, ArH), 8.04 (d. 4H, ArH), 8.89 ( d.J = 4.68 Hz, 2H, ArH), 9.90 (s. 1H, OH), 10.97 (s. 1H, NH).

 Mass spectrum (Cl, CH [[): 429 (M + 1).

 Elemental analysis: for C [[H [[F [[N [[O [[S.

Calculated, C 42.06; H 2.35; N, 6.53;
Found, C, 42.11; H 2.46; N, 6.38.

 Example 65

 N-4- (3- (pyridylsulfonyl) phenyl -) - 3,3,3-trifluoro-2-hydroxy -2-trifluoromethylpropanamide.

 Tetrahydrofuran (15 ml, dry) was added to a mixture of 2,2-bis-trifluoromethyl-2-hydroxyacetic acid (0.44 g, 2.1 mmol) and 1,1-carbonyldiimidazole (0.34 g, 2.1 mmol) in an atmosphere of nitrogen. There was an immediate release of carbon dioxide. The reaction was heated to 35 [[C in an ultrasonic bath for 15 min.

 The reaction mixture was treated with 4- (3-pyridylsulfonyl) benzeneamine (0.49 g, 2.1 mmol) and heated to 55 [[C in an ultrasonic bath for 42 hours. The reaction mixture was evaporated to a viscous yellow oil. Chromatography of this oil on silica gel, eluting with a 85:15 mixture of methylene chloride and ethyl acetate followed by chromatography of silica gel, eluting with a 98: 2 mixture of chloroform-methanol, gave the target compound (0.09 g, 10%) as an off-white solid substances, melting point 264-267 [[C.

 Spectrum [[H-NMR (250 MHz, DMCO-d [[): 7.68 (m, 1H, ArH), 8.03 (m, 4H, ArH), 8.35 (dt, J = 8.4 and 1.9 Hz, 1H, ArH), 8.86 (dd. J = 10.0 and 1.2 Hz, 1H, ArH), 9.13 (d. J = 2.35 Hz, 1H, ArH) 9.87 (s. 1H, OH); 10.94 (s. 1H, NH).

 Mass spectrum (Cl, CH [[): 429 (M + 1).

 Analysis for C [[H [[F [[N [[O [[S.

Calculated, C 41.19; H 2.53; N, 6.41;
Found, C, 41.25; H 2.46; N, 6.19;
Example 66

 N- (4- (phenylcarbonyl) phenyl -) - 3,3-difluoro-2-hydroxy-2-difluoromethylpropanamide.

 To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (1.76 g, 10 mmol) in tetrahydrofuran (40 ml) was added carbonyldiimidazole (0.81 g, 5 mmol). The flask was placed in an ultrasonic bath, and the reaction mixture was sonicated for 20 minutes, followed by the addition of 4-amino-benzophenone. The reaction was sonicated for 18 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness. The resulting pasty solid was washed with ether, and the combined ether washes were evaporated. The resulting solid was crystallized from ethyl acetate-hexane to give the target compound (0.89 g, 25%) as yellow crystals, melting point 139-142 [[C.

 Spectrum [[H-NMR (300 MHz, DMCO-d [[): 6.48 (t. J = 53.7 Hz, 2H, HCF [[), 7.53-7.77 (7H, ArH, OH ), 7.95-7.98 (m. 3H, ArH), 10.48 (s. 1H, NH).

 Mass spectrum (Cl, methane): 356 (M + 1, 100%).

 Elemental analysis for C [[H [[F [[NO [[[0.25H [[O.

Calculated, C 56.75; H 3.98; N, 3.89;
Found, C 57.03; H 3.39; N, 3.84.

 Example 67

 N- (4- (2-pyridylsulfonyl) phenyl) -3,3-difluoro-2-hydroxy -2-difluoromethylpropanamide.

 To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g, 2.84 mmol) in dimethylacetamide (10 ml) at -10 [Thionyl chloride (0.34 g, 2.84 mmol) was added) drop by drop. The resulting solution was stirred at -10 [C for about 30 minutes. 4- (2-Pyridylsulfonyl) -aniline (0.58 g, 2.5 mmol) was added and the reaction mixture was left overnight with stirring at room temperature. Then the reaction mixture was poured into water and sodium bicarbonate solution was added to pH 7.0-7.5. A brown precipitate formed. The solid was filtered off, washed with water and dried. Crystallization and decolorization (charcoal) from a mixture of ethyl acetate, methanol and hexane gave the target compound (0.42 g, 43%) as not quite leaves, melting point 200-202 [[C.

 Spectrum [[H-NMR (300 MHz, DMCO-d [[): 6.45 (t. J = 54.09 Hz, 2H, HCF [[), 7.68 (t. J = 6.24 Hz, 1H, ArH), 7.92-8.03 (m. 5H, ArH, OH), 8.11-8.21 (m. 2H, ArH), 8.68 (d. J = 4.4 Hz, 1H, ArH), 10.54 (s, 1H, NH).

 Mass spectrum (Cl, CH [[): 393 (M + 1, 100%).

 Elemental analysis for C [[H [[F [[N [[O [[S.

Calculated, C 45.92; H 3.08; N, 7.14;
Found, C, 45.89; H 3.17; N, 7.12.

 Example 68

 N- (4- (phenylsulfonyl) phenyl) -3,3-difluoro-2-hydroxy -2-difluoromethylpropanamide.

 To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g, 2.84 mmol) in dimethylacetamide (10 ml) at -10 [[Thionyl chloride (0.34 g, 2, 84 mmol).

 The resulting solution was stirred at -10 [[[C for about 30 minutes. 4- (Phenylsulfonyl) -aniline (0.58 g, 2.5 mmol) was added and the reaction mixture was left overnight with stirring at room temperature. Then the reaction mixture was poured into water, sodium bicarbonate solution was added to pH 7.0 and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with water, brine, dried (sodium sulfate), decolorized (charcoal) and evaporated. The crude solid was dissolved in ether, clarified by filtration and evaporated. Crystallization from methanol-water gave the title compound indicated in the title of the example (0.56 g, 57%) as white silky needles, melting point 105-108 [C.

 Spectrum [H-NMR (300 MHz, DMCO-d [): 6.44 (t. J = 53.94 Hz, 2H, HCF [), 7.58-7.68 (m. 3H, ArH), 7 92-8.01 (m. 7H, ArH, OH); 10.51 (s. 1H, NH).

 Mass spectrum (Cl, CH [): 392 (M + 1, 100%).

 Elemental analysis for C [H [F [NO [S.

Calculated, C 49.11; H 3.35; N 3.58;
Found, C, 49.15; H 3.48; N, 3.54.

 Example 69

 N- (4- (2-pyridylcarbonyl) phenyl -) - 3,3-difluoro-2-hydroxy -2-difluoromethylpropanamide.

 To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g, 2.84 mmol) in dimethylacetamide (10 ml) at -10 [Thionyl chloride (0.34 g, 2.84 was added dropwise). mmol).

 The resulting solution was stirred at -10 [C for about 30 minutes. 4- (2-Pyridylcarbonyl) -aniline (0.58 g, 2.5 mmol) was added and the reaction mixture was left overnight with stirring at room temperature. Then the reaction mixture was poured into water, sodium bicarbonate solution was added to pH 7.0 and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with water, brine, dried (magnesium sulfate), decolorized (activated carbon) and evaporated. The crude solid was dissolved in ether, clarified by filtration, evaporated to give a yellow-orange gum. Crystallization from a mixture of methylene chloride and hexane gave the target compound (0.35 g, 35%) as a reddish solid, melting point 158-161 [C.

 Spectrum [H-NMR (300 MHz, DMCO-d [): 6.48 (t. J = 54.12 Hz, 2H, HCF [), 7.67 (t. J = 6.18 Hz, 1H, ArH ), 7.91-8.10 (m. 7H, ArH, OH), 8.73 (d. J = 7.35 Hz, 1H, ArH), 10.40 (s. 1H, NH).

 Mass spectrum (Cl, CH [): 357 (M + 1, 100%).

 Elemental analysis for C [H [F [N [O [.

Calculated, C 55.94; H 3.39; N, 7.86;
Found, C, 53.76; H 3.41; N, 7.87.

 Example 70

 N- (4- (2-pyrimidinylsulfonyl) phenyl) -3,3-difluoro-2-hydroxy-2-difluoromethylpropanamide.

 To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g, 2.84 mmol) in dimethylacetamide (10 ml) at -10 [Thionyl chloride (0.34 g, 2.84 was added dropwise). mmol). The resulting solution was stirred at -10 [C for about 30 minutes. 4- (2-Pyrimidylsulfonyl) -aniline (0.59 g, 2.5 mmol) was added and the reaction mixture was left overnight at room temperature with stirring. The reaction mixture was poured into water and pH 7.0-7.5 was adjusted with sodium bicarbonate solution. A dark colored precipitate formed, which was filtered off, washed with water and dried. The crude material was pre-absorbed with silica gel and chromatographed on silica gel, eluting with 70-80% ethyl acetate-hexane.

 Evaporation of the product fractions and crystallization from a mixture of methylene chloride methanol hexane gave the target compound indicated in the title of the example (0.33 g, 34%) as a white solid, melting point 209-210 [C.

 Spectrum [H-NMR (300 MHz, DMCO-d [): 6.46 (t. J = 54.06 Hz, 2H, HCF [), 7.78 (t. J = 4.8 Hz, 1H, ArH ), 7.95-7.98 (m 3H, ArH, OH), 8.02-8.06 (m 2H, ArH), 9.01 (d.J = 5.01 Hz, 2H, ArH ), 10.58 (s, 1H, NH).

 Mass spectrum (Cl): 394 (M + 1, 100%).

 Elemental analysis for C [H [F [N [O [S.

Calculated, C 42.75; H 2.82; N, 10.68;
Found, C, 42.55; H 2.80; N, 10.57.

 Example 71. The pharmaceutical dosage forms containing a compound of formula I are presented below to illustrate, for example, as shown in any of the previous examples (referred to below as “Compound X”) for therapeutic or prophylactic use in humans.

н(a) Tablet Mg / tablet
Compound X 50.0
Mannitol (US Pharmacopoeia) 223.75
Croscarmeleza sodium 6.0
Corn Starch 15.0
Hydroxypropyl Methyl Cellulose (USP) 2.25
Magnesium Stearate 3.0
(b) Mg capsule / capsule
Compound X 10.0
Mannitol (USP) 488.5
Croscarmeleza sodium 15.0
Magnesium Stearate 1.5
The above dosage forms can be obtained by methods known in the pharmaceutical art. The tablets may be enteric coated by known methods, for example, to obtain cellulose acetate phthalate
Formula Structure

n

Claims (5)

1. Amides of the formula I

where a) E is nitrogen and X is phenylsulfonyl or b) E is a CZ group wherein C is not a ring carbon atom, Z is hydrogen, cyano, halogen, hydroxyl, C ₁ C ₄ alkyl or C ₁ C ₄ alkoxyl; X is an ArY group, wherein Y is a linking group selected from carbonyl, sulfonyl or sulfonyl; Ar is unsubstituted or substituted with 1-2 substituents selected from halogen, hydroxyl, cyano, C ₁ C ₄ alkyl or C ₁ C ₄ alkoxy, phenyl, provided that the 4-position of phenyl is substituted only by fluorine and that phenyl cannot be 3,5-disubstituted or pyridyl, pyrazinyl, pyrimidinyl, thienyl or thiazolyl group, provided that Ar is not 3-chloro, 3-iodo, 3-bromo or 3-C ₁ -C ₄ -alkylphenyl or 4-pyridyl, if Y is carbonyl, and that Ar is not 5-pyrimidinyl, if Y is sulfonyl or carbonyl, or c) X-cyano and Z-phenylsulfonyl; R ² and R ^{3 are} unsubstituted or substituted by C ₁ -C ₃ alkyl fluorine atoms, provided that R ² and R ³ are not methyl at the same time, or R ² and R ³ together with the carbon atom to which they are attached form 3 5 membered cycloalkyl.  2. Amides according to claim 1 of formula I, characterized in that they are N- [4- (4-pyridylsulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide; S - / - / - N- [4- (4-pyridylsulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide; - / 4- (phenylcarbonyl) phenyl / -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide; S - / - / - N- [4- (phenylcarbonyl) phenyl] -3,3,3-trifluoro-2-hydroxymethylpropanamide; N- [4- (4-pyridylsulfonyl) phenyl] 3,3-difluoro, -2-hydroxy-2-difluoromethylpropanamide; N- [4- (phenylcarbonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-trifluoromethylmethylpropanamide; N- [4- (4-pyridylsulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy2-trifluoromethylpropanamide; or N- [3-hydroxy-4- (4-pyridylsulfonyl) phenyl] -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.  3. A pharmaceutical composition having the properties of a channel opener for cellular potassium, including the active ingredient and target additives, characterized in that the amides of the formula I according to claim 1 are used as the active ingredient in the following ratio of ingredients, wt. Active ingredient 1 20
Target Supplements Else
4. The method of producing amides of formula I according to claim 1, characterized in that the aniline of formula II

where E and X have the indicated meanings, are reacted with an acid of formula III

where R ² and R ³ have the indicated meanings. 5. The method of producing amides of formula I according to claim 1, characterized in that the amide of formula IV

where E, X, R ² and R ³ have the indicated meanings;
PG protecting group,
carry out the removal of the protective group. 6. The method of producing amides of formula I according to claim 1 where X is phenylsulfinyl or phenylsulfonyl, characterized in that the corresponding amide of formula I, where X
phenyl sulfide is subjected to oxidation.

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