MXPA99005631A - Process for the preparation of acids 3-arilosulfuro hidroxami - Google Patents

Abstract

The present invention relates to: This invention provides a process for the preparation of a compound of formula I: Y-C (0) -C (R1) (R2) -CH2-S (O) nR3. Wherein: Y is hydroxy or XONX, wherein each X is independently hydrogen, lower alkyl or lower acyl, R1 is hydrogen or lower alkyl, R2 is hydrogen, lower alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, or R1 and R2 together with the carbon atom for which they are bound form a cycloalkyl or a heterocycle group, and R3 is aryl This invention also provides novel intermediates aryl alkyl sulfide and aryl sulfide alkylcarboxylates for the preparation of compounds of formula I and novel process preparation of aryl sulphides

Description

PROCESS FOR THE PREPARATION OF 3-ARYLOSULPHIDE HYDROXYMIC ACIDS This invention describes the processes for preparation of the etaloprotease matrix inhibitors, particularly hydroxamic 3-arylsulfide acids to novel aryl haloalkyl sulfides and aryl alkyl sulfide intermediates and novel processes for preparing such aryl alkyl sulfides.

The matrix of mataloproteases ("MMPs") are a family of proteases (enzymes) involved in the degradation and remodeling of connective tissues. The MMP expression is stimulated by growth factors and cytokines in the local tissue environment, where these enzymes act specifically to degrade the proteins of the extracellular matrix components, such as collagen, proteoglycans (protein core) fibronectin and laminin. Excessive degradation of the extracellular matrix by MMP 's is implicated in the pathogenesis of many diseases, including rheumatoid arthritis, osteoarthritis, multiple sclerosis, in bone resorptive diseases (such as osteoporosis), chronic pulmonary obstructive diseases, hemorrhages Cerebral associated with attacks, Ref .: 30409 - - periodontal diseases, aberrant anguiogenesis, tumor invasion and metastasis, cornea and gastric ulceration, skin ulceration, aneurysmal disease, and complications of diabetes.

In addition, MMP inhibitors are also known to substantially inhibit the release of tumor necrosis factor (TNF) from cells and can therefore be used in the treatment of conditions mediated by TNF. Such uses include, but are not limited to, the treatment of inflammation, fever, cardiovascular effects, bleeding, coagulation and acute phase response, cachexia and anorexia, acute infections, shock states, restenosis, host reactions against ingestion and autoimmune diseases. .

The inhibition of MMP is, therefore, recognized as a good point for therapeutic intervention. Consequently, MMP 'inhibitors provide useful treatments for diseases associated with excessive degradation of the extracellular matrix and diseases mediated via TNF and many inhibitors of MMP are currently developed for such uses.

A particular class of MMP inhibitors are the 3-arylsulfide hydroxamic acids described in EP 0 780 386 A1, published June 25, 1997. This publication describes MMP inhibitors of formula I, Y-C (= 0) -C (R1) (R2) -CH2-S (0) nR3 where n, Y, R1, R2 and R3 are as described below.

WO 97/24117, published on July 10, 1997, describes the hydroxamic 3-aryl sulphide acids of the formula HON (H) -C (= 0) -CP (Ri) (R2) -C (R3) (R4) ) -S (O) n-Cm (R5) (R6) -Ar, where p, m, n and Ri, R2, R3, R4, R5, Re and Ar, are as described in WO 97/24117. WO 98/05635, published February 12, 1998, describes the hydroxamic 3-aryl suturo acids of formula BS (O) or -? - CHR ^ C ^ -CO-NHOH, where B and R1 are as described in WO 98/05635, the. WO 98/13340, published on April 2, 1998, describes the ß-sulfonyl hydroxamic acids of the formula HONHC (= 0) -CHR2-CH2-S (0) 2R? where Ri and R2 are as described here.

- However, the processes described in these publications to prepare the 3-arylsulfide hydroxamic acids proceed via the nucleophilic attack of a thiol on the β-carbon of a carboxylate derivative, whether it displaces a residual group in the β-carbon or to prepare a Michael reaction in an unsaturated α, β ester or acid. In this way, the processes described are limited by the availability of the corresponding thiols and the β-substituted carboxylate derivatives and the α, β-unsaturated esters. Accordingly, it is an object of the present invention to provide novel novelty and intermediary processes that do not depend on the availability of the reagents used in the prior publications.

More particularly, with respect to the aspect of providing novel intermediates, the invention discloses novel halomethyl aryl sulphides and novel methods for their preparation. Such aryl haloalkyl sulfides are valuable intermediates in synthetic organic processes and they are commonly produced by halogenation free radicals of an aryl alkyl sulfide precursor. The aryl alkyl sulfide is typically converted to the sulfonation pathway of an aryl hydrocarbon precursor, the reduction of an aryl thiol and the alkylation of the thiol. It would be useful to have methods of direct conversion of the arylsulfonyl derivatives to aryl methyl sulfides.

There are several reports of the reactions between the trialkyl phosphites and the aryl sulfonyl derivatives. See, for example, R.W. Hoffman, T.R. Moore and B.J. Kagan, ("The Reaction between Triethil Phosphite and Alkyl and Aryl Sulfonyl Chlorides ") J. Am. Chem. Soc, 78: 6413-6414 (1956); J.M. Klunder and K. Barry Sharpless, ("A Convenient Synthesis of Sulfinate Esters from Sulfonyl Chlorides ") J.

Org. Chem., 52: 2598-2602 (1987); and J. Cadogan ("Oxidation of Tervalent Organic Compounds of Phosphorous") Quarterly Reviews, 1_6: 208-239 (1962). The reaction of benzenesulfenyl chloride with triethylphosphite in proportion to ethyl phenyl sulfide have also been reported, T. Mukaiyama and H. Ueki, ("The Reactions of Sulfur-containing Phosphoniu Salts") Tetr. Lett2, 35: 5429-5431 (1967). The aryl sulfonyl chlorides have also been converted to aryl methyl sulphides in three stages by treatment of an aryl sulphonyl chloride with lithium diphenyl phosphide Ph2PLi, to give a sulfophosphamide of P-diphenyl-aryl - followed by a cathodic reduction and a methylation of the resulting aryl thiolate, J. Pilard and J. Simonet. ("The cathodic Cleavage of the S-P Bond. Synthesis and Electrocheal Behavior of Sulfonamide Phosphorous Analogues"). Tetr. Lett., 38: (21): 3735-3738 (1997).

DEFINITIONS As used herein, the term "alkyl (Cp_q)" means a fully saturated straight or branched hydrocarbon radical having carbon atoms from p to q; for example, a "C ?4 alkyl" means a fully saturated straight or branched hydrocarbon radical having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl.

Unless otherwise specified, the term "lower alkyl" means a C? -4 alkyl radical.

As used herein, the term "(C 3-6) cycloalkyl" means a fully saturated cyclic hydrocarbon radical of 3 to 6 rings of carbon atoms, e.g., cyclopropyl, cyclopentyl, and the like.

As used herein, the term "lower acyl" refers to a group -C (= 0) R, where R is a (1-4C) alkyl radical.

As used herein, the term "lower alkoxy" refers to a group -OR, where R is a (1-4C) alkyl radical.

As used herein, the term "(C7-10) alkoxy" refers to a group -OR, where R is an alkyl radical (C7-10) • As used herein, the term "aryl" means a monovalent monocyclic or aromatic bicyclic hydrocarbon radical of 6 to 10 ring atoms, and optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, cycloalkyl, halo, nitro, cyano, optionally substituted phenyl, -OR (where R is hydrogen, alkyl, haloalkyl, cycloalkyl, optionally substituted phenyl), acyl, -COOR (where R is a hydrogen or alkyl), More specifically the term aryl includes but is not limited to phenyl, 1-naphthyl, 2-naphthyl, and derivatives thereof.

As used herein, the term "arylene" means a monocyclic divalent hydrocarbon radical or an aromatic bicyclic of 6 to 10 ring atoms, and optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, cycloalkyl, halo, nitro , cyano, optionally substituted phenyl, -OR (where R is hydrogen, alkyl, haloalkyl, cycloalkyl, optionally substituted phenyl), acyl, -COOR (where R is hydrogen or alkyl). More specifically, the term "aryl" includes, but is not limited to, 1,4-phenylene and 1,2-phenylene.

"Optionally substituted phenyl" means a phenyl group which is optionally substituted independently with one, two, or three substituents selected from alkyl, haloalkyl, halo, nitro, cyano, -OR (where R is hydrogen or alkyl), -NRR '( where R and R 'are independently of each other hydrogen or alkyl), -COOR (where R is hydrogen or alkyl) or -CONR' R "(where R 'and R" are independently selected from hydrogen or alkyl).

- - "Heterocycle" means a monovalent saturated cyclic group of 3 to 8 rings of atoms wherein one or two rings of atoms are heteroatoms selected from N, O, or S (0) n, where n is an integer from 0 to 2, The remaining ring atoms are C. The heterocycle ring may be optionally fused to a benzene ring or may be optionally substituted independently with one or more substituents, preferably one or two substituents selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, halo, cyano, acyl, monosubstituted amino, disubstituted amino, carboxy, or alkoxycarbonyl. More specifically the term heterocycle includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, and thiomorpholino, and derivatives thereof.

"The residual group" has the meaning conventionally associated with it in synthetic organic chemistry ie, an atom or group capable of being displaced by a nucleophile and include a halogen, alkanesulfonyloxy, arenesulphonyloxy, amino, alkylcarbonyloxy, arylcarbonylcxy, such as chlorine, bromine , iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, N, O-dimethylhydroxylamino, acetoxy, and the like.

- - The present invention will be described in more detail later.

In one aspect, this invention provides a process for the preparation of a compound of formula I: Y-C (= 0) -C (R1) (R2) -CH2-S (0) nR3 I Where: Y is hydroxy or XONX, where each X is independently hydrogen, lower alkyl or lower acyl; R1 is hydrogen or lower alkyl; R2 is hydrogen, lower alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, or R1 and R2 together with the carbon atom for which they have been linked form a cycloalkyl or heterocycle group; R3 is aryl; Y n is 0, 1 or 2; - - comprising the steps of: (1) alkylation of a compound of formula II, RO-C (= 0) -CH (R1) (R2) Where R is an alkyl or hydrogen, with an arylmethylthio derivative of formula III, ArSCH2-Z, where Ar is an aryl group and Z is a residual group, to provide a compound of formula IV, RO-C (= 0) -C (R1) (R2) -CH2SAr IV (2) which converts the compound of formula IV to a compound of formula I by substituting the group RO- with XONH- and optionally oxidized the group ArS. The conversion can be done as necessary in any order.

The methods described in EP 0 780 386 Al, published June 25, 1997, WO 97/24117, published July 10, 1997, WO 98/05635, published February 12, 1998 and 98/13340, published in April, are different. 2 of 1998, for the synthesis of hydroxamic 3-arylsulfide acids, the processes of the present invention proceed via the alkylation of the - to carbon of a carbonyl group with an aryl halomethyl sulfide. Although the processes described herein can be used to prepare a variety of hydroxamic 3-arylsulfide acids and their corresponding carboxy and ester derivatives, they are particularly useful for preparing compounds of formula I wherein the aryl group Ar has the formula A 2 - A-Ar2, wherein Ar1 and Ar2 are phenyl rings, each independently optionally substituted and A is a bond, -CH2- or -0-, In a preferred aspect of the residue group Z is halo. More particularly, the compounds of formula I are prepared in which A is oxygen, A1 is phenyl and Ar2 is 4-chlorophenyl.

With respect to the optional oxidizing step in step (2) of the process of the present invention, oxidation is preferred since it provides a compound of formula I wherein n is 2.

Other useful compounds can also be made by the methods of the present invention and include compounds of formula I wherein R1 and R2 together with the carbon atom are attached in the form of a cycloalkyl group or heterocycle, particularly a tetrahydropyranyl group. More preferably, the compound of formula I is 4- [4- (4-chlorophenoxy) phenylsulfonylmethyl] -4- (N-hydroxy-carboxamido) -tetrahydropyranyl which is prepared by the process of the present invention.

Some additional useful hydroxamic acids that can be prepared include those that are a, disubstituted, i.e., no R1 and R2 are hydrogen.

In another aspect this invention also provides a novel halomethyl aryl sulfide, such as chlorofenoxyphenyl chloromethyl sulphide and novel methods for its preparation. As resulting compounds of formula I can be prepared by novel processes that are not previously available. This aspect will also be described in greater detail within the description of the entire process.

With respect to the preparation of the compounds of formula I, these reaction processes are shown in scheme A, below.

- - SCHEME 4 ArSCH2Z Formula II Formula III Alkylation C ClH2SAr m Q R11 Q RZ Formula IV Formula I n = 1 oí 2 The compounds of formula II, RO-C (= 0) -CH (R1) (R2), may be purchased from commercial suppliers or be readily available through advertising procedures known to those skilled in the art. See, for example, EP 0 780 386 Al.

The compounds of formula III, ArSCH2-Z, are produced by the oxidation of the arylmethylthioether precursor. The ArSCH2Cl compounds are produced by oxidation with a sulfuryl chloride in aprotic solvents such as methylene chloride, t-butylmethyl ether or hexane. The oxidation can be done at room temperature or at low temperature, e.g., of about 0-10 ° C. Other reagents, such as N-chlorosuccimide, can also be used. The ArSCH2Br compounds are produced by oxidation with a sulfuryl bromide or other reagents such as N-bromosuccimide.

The compounds of formula III, ArSCH2-Z, where Z is chloro or bromo can also be produced from the corresponding thiol as shown below: - - ArSH ArSCH2Br Hlasta, D.J.St. at Synlett, 423, 1995 [CHzO ,, HCl ArSH ArSCH2CI Arylmethylthioethers are generally available either by commercial vendors or by published literature procedures. For example, they can be produced by the sulfonylating of an aryl compound to the corresponding sulfonic acid, which reduces the sulfonic acid to a thiol and methylate the thiol.

Alternatively, as shown in Scheme B, something unexpected has been discovered since the arylsulfonyl halides can be converted directly to arylmethylthioethers in one step by treatment with trimethyl phosphate. The conversion proceeds best if the trimethylphosphite treatment is followed by the treatment with a base. Any organic base such as an alkylamine (e.g. triethylamine) or a hydroxylic base such as an alkali metal hydroxide or an alkaline earth metal hydroxide can be used. However, the conversion can also be performed, although in a certain way, with low yields, without the addition of a base. In such processes, the yield of the aryl methyl sulfide can be increased by heating at elevated temperatures, e. g., as high as about 100 ° C, preferably as high as about 130 ° C (internal temperature).

Therefore, the invention provides in this aspect a novel process for the preparation of aryl methyl sulphides that directly reduces / alkylates an arylsulfonyl halide with trimethyl phosphite (see Scheme B where X is halo and Ar is aryl). SCHEME B P (OCH3) 3 Base ArSCH, In particular, the invention provides a process for preparing a compound of formula ArSCH3 wherein Ar is an aryl group, by treatment of a compound of formula ArS02Cl with trimethyl phosphite and optionally, followed by a treatment with a base, to form a compound of formula ArSCH3.

The process is particularly useful for forming compounds of a formula ArSCH wherein Ar has the formula A ^ -A-Ar2, where Ar1 and Ar2 are phenyl rings, each independently and optionally substituted, and A is a bond, CH2 or - O-, and more particularly where A is oxygen, Ar1 is phenyl and Ar2 is 4-chlorophenyl. This process is preferably used in connection with the aforementioned processes for preparing compounds of formula I. In another aspect of the present invention it also discloses compounds of formula ArSCH3, yes, especially to the sulfide of 4- (4'-chlorophenoxy) phenylmethyl.

The subsequent halogenation of the compounds of formula ArSCH3 then provides intermediates of formula ArSCH2-Z where the residue group Z is a halo which is also an object of the present invention. This process is characterized in general by the formation of compounds of formula III, Ar1-A-Ar2-S-CH2-Z characterized by (i) the treatment of a compound of formula VI, Ar1-A-Ar2-S (0) 2C1 with the trimethyl phosphite; (ii) optionally followed by the treatment with a base and - - (iii) an oxidation. Preferred key intermediates for this purpose include those of the formula Z-CH2S-Ar1-A-Ar2, where Ar1 and Ar2 are independently phenyl optionally substituted, Z is halo, A is oxygen, or CH2. A particularly preferred intermediate is that wherein Ar 1 is a phenyl, Ar 2 is a halophenyl, and A is oxygen. More preferably Ar1 is phenyl; Ar2 is 4-chlorophenyl; A is oxygen; R1 and R2 together with the carbon atom are in bound form to the tetrahydropyranyl groups; and Y is HONH; i.e., 4- (4-chlorophenoxy) phenyl-chloromethyl sulfide.

A compound of formula III, wherein Z is halo, can be converted by known methods to an alcohol which is then converted to another residual group e.g., tosylate or mesylate. Then such compounds can also be used in the reaction with a compound of formula II according to the processes of the present invention as mentioned below.

In an aspect of the preparation of a compound of formula I the alkylation of a compound of formula II with a compound of formula III according to step (1) of the processes of the present invention can be carried out by conditions known per se. those persons with skills in the field such as converting a compound of formula II to an enolate or enol followed by the alkylation of said enolate of a compound of formula III with a compound of formula III. Other conditions that influence the formation of acid dianion (ie, the compound of formula II where R = H) by treatment with two equivalents of a base such as lithium diisopropylamide or lithium hexamethyldisilazide and by alkylation with one equivalent of a compound of formula III.

In another aspect, step (1) is performed by converting a compound of formula II to a silylletone acetal of formula V, RO (OTMS) C = CR1R2 and by alkylation with a compound of formula III. More particularly, a compound of formula II is converted to a silyllethane acetal as shown in reaction scheme C (where silyl represents a silyl group), followed by a Mukaiyama coupling of the acetal with a compound of formula III. The coupling is generally made in an anhydrous aprotic solvent such as the halocarbon or hydrocarbon (methylene chloride, chloroform, benzene, toluene, etc.) in the presence of a Lewis acid such as zinc chloride, zinc bromide, iodide zinc, ferric bromide or titanium tetrachloride. Acetals siliquetenes can be rapidly prepared from compounds of formula II by processes such as those described in C. Ainsworth, F. Chen, YN Kuo "Ketene Alkyltrialkylsilyl Acetates: Synthesis,, Pyrolysis and NMR Studies") J. Organometallic Chem., 46: 59-87 (1972). A variety of silyl protecting groups e.g., t-butyldimethylsilyl, trimethylsilyl, etc. They can be used. Acetals silylketenes can be formed from ester (R = alkyl) or acids (R = H) of formula II. The formation of the silylketene acetal from the acid can be carried out using two equivalents of base and is quenched with two equivalents of the silylated reagent. The subsequent alkylation with a compound of formula III followed by a hydrolytic preparation then directly produces a carboxylic acid of formula IV. Reagents that can be used to form the silyllethane acetal include trimethylsilyl triflate, trimethylsilyl chloride or bromide, tert-butyldimethylsilyl chloride, and bis-trimethylsilyl acetamide.

- - SCHEME C Formula II Alternatively, an enolate of a compound of formula II can be directly alkylated with a compound of formula III, thus avoiding the intervention of the silylletone acetal. The enolate is formed under standard conditions, by treatment with a non-nucleophilic organic base such as lithium diisopropylamide or lithium hexamethyldisilazide, or a hydride metal such as potassium hydride, under anhydrous conditions, typically at room temperature in an aprotic solvent polar such as tetrahydrofuran, dimethoxyethane or glyme and the like. The subsequent addition of a compound of formula III followed by heating if necessary at reflux temperatures, e.g., 60-80 ° C, provides an alkylated product of formula IV. The enolate can also be formed from the corresponding a-bromoester of a compound of formula II by treatment with zinc to form the zinc enolate which can then be alkylated.

- - Preferably, a compound of formula III is reacted with a compound of formula II wherein A is oxygen, Ar1 is phenyl and Ar2 is 4-chlorophenyl.

The compounds of formula IV can be converted to compounds of formula I by conversion of the carboxyl group to the group -C (= 0) -L, where L is a residual group under nucleophilic substitution conditions followed by the displacement of L with hydroxylamine ( or an alkylated derivative). The resulting hydroxamic acid is then oxidized as necessary to produce the desired sulfoxide or sulfone. Oxidation of the sulfoxide is carried out by a treatment with mild oxidation agents such as potassium or sodium metaperiodate or a potassium peroxymonosulfate equivalent (Oxone ™). Other oxidants that can be used include peracides (e.g., performic or peracetic acid) or mixtures of perborate / organic sodium acid (e.g., performic or peracetic acid). The reaction can be balanced to the sulfoxide state by limiting the amount of reagents, the temperature and the reaction time. The additional oxidation to the sulfone is carried out by a treatment under more vigorous conditions with organic peracids - such as m-chloroperbenzoic acid or two equivalents of sodium peroxymonosulfate. Alternatively, other oxidizing agents such as perborates, e.g., sodium perborate, in a carboxylic acid solvent such as formic, acetic or propionic acid can be used. These last two stages can also be reversed, i.e., the oxidation of the sulfide radical can proceed in the conversion of the acid to the hydroxamate. However, the total yields are usually high with the previous sequence.

As described above, the compounds produced by those processes are MMP inhibitors, useful in the treatment of a variety of diseases as described in EP 0 780 386 A1, published June 25, 1997; WO 97/24117, published July 10, 1997; and WO 98/05635, published February 12, 1998.

The abbreviations used in the examples are defined as follows: "DMF" for dimethylformamide, "NaOH" for sodium hydroxide, "DMSO" for dimethylsulfoxide, "PTLC" for preliminary thin layer chromatography, "EtOAc" for ethyl acetate, "LDA" - - for lithium diisopropylamide and "TMSCI" for trimethylsilylchloride.

E¿TEMPLE Synthesis of 4- [4- (4-chlorophenoxy) phenylsulfonylmethyl] -4- (N-hydroxycarboxamide) tetrahydropyran.

Scheme D shows a representative method of this invention for the preparation of 14, 4- [4- (4-chlorophenoxy) phenylsulfonylmethyl] -4- (N-hydroxycarboxamido) tetrahydropyran, a compound of formula I, wherein: And it is NHOH; R1 and R2 together with the carbon atom which are attached represents a tetrahydropyran-4-yl group; Y R3 is 4-chlorophenoxyphenyl.

- - SCHEME D Stage 1 Stage 2 Stage 3 a CISOjH b. SOjCt, OR PÍOCHah H, CS CXO «5 +% Oxalloy-xyl chloride (X" KOH «H) - \ T CrS1 ~ t s * 60-65 3 (X-Ct) ^ J 6 w ° Et Although Scheme D is directed towards the synthesis of a specific hydroxamic 3-arylsulfide acid, it is understandable that a similar placement of the reactions can be used to prepare other hydroxamic arylsulfide acids, carboxylic acids and esters by appropriate substitution of raw materials and reagents as mentioned in the AC reaction schemes.

A. Preparation of 4- (4-chlorophenoxy) phenyl chloromethylsulfide, Stage 1 - - Diphenylether 1 is available from Aldrich (Milawaukee, Wisconsin) and can be converted to 4- (4-chlorophenoxy) phenyl sulfonyl chloride, compound 3, using known procedures as described in WO 97/20824.

Stage 2 The sulfonyl chloride of 4- (4-chlorophenoxy) phenyl (3.0 Kg), 3, is dissolved in three liters of toluene and the solution is added dropwise, with stirring, to 3.6 Kg of trimethyl phosphite which has been preheated at 60 ° C. The reaction is exothermic and this is allowed to warm to 80-90 ° C during the addition. Thin layer chromatography indicates a mixture of the desired thioether and two base products. The mixture is refluxed until the temperature of the vessel rises to ~ 130 ° C. The mixture is cooled to ~60 ° C and one liter of methanol is added. A solution of potassium hydroxide (4.5 Kg of a 45% aqueous solution) is added dropwise, slowly, with rapid stirring to the reaction mixture. The addition is very exothermic and the temperature of the vessel is controlled at 65-80 ° C. The mixture is then refluxed for 2 hours. More toluene (6 liters) is added and the mixture is cooled to ~60 ° C. The low aqueous layer is separated and the organic layer is washed with 3 liters of water. The organic layer is stabilized at low volume and 9 liters of isopropanol are charged to the hot mixture. The solution is distilled until ~ 3.5 liters of the distillate have been collected. The mixture is kept at 45 ° C for many hours and is then cooled to -10 ° C and stirred for many hours. The white crystalline product is collected, washed with cold and dry isopropanol to yield 1.9 Kg of 4- [4-chlorophenoxy) phenylmethyl sulfide, 4 (mp 59-60 ° C).

Stage 3 A separating reactor is charged with 4- (4-chlorophenoxy) phenylmethyl sulfide, 4, and CH2C12 (26 Kg). The resulting solution is cooled to less than 10 ° C and is then treated with S02C12 in a proportion such that the temperature does not exceed 10 ° C (30 minutes is required for the addition). An additional 2 Kg of CH2C12 is used to wash in S02C12. After stirring for 1 hour, the mixture is warmed to room temperature (degassing occurs) and then warmed to reflux for 30 minutes. In cooling to room temperature the product solution is washed with water (15.5 Kg) and then - - with brine (10.3 Kg). The stirred organic solution is then treated with a slurry of MgSO4 (2.6 Kg) in CH2C12 (5 Kg). The drying is allowed to proceed overnight and the mixture is filtered to remove the drying agent. The solids are washed with CH2C12 (20.7 Kg) and the combined organics are concentrated to perform azeotropic drying (38 Kg of collected distillate, Karl Fischer shows 0.026% of water in concentrate). The product is treated with CH2C12 (19.8 Kg) and reconcentrated (19.8 Kg of the distillate, Karl Fischer now at 0.014%). HPLC analysis shows 94.7% chloromethylsulfide of 4- (4-chlorophenoxy) phenyl, 5.

B. Preparation of acetal siliquetene Stages 4 to 5 Tetrahydropyran-4-carboxylic acid ethyl ester, 9, is prepared from commercially available diethylmalonate via steps 4 and 5 using known literature methods as described for example in, U.S.

Patent No. 5,412,120; 5,414,097; and EP 584663 A2.

Stage 6 - - A 26.8 Kg (67.37 mole) of an LDA solution is charged to a reactor purged with nitrogen. This is cooled to -15 ° C and then a mixture of TMSC1 (7.32 Kg, 67.37 mole) and ethyl ester of tetrahydropyran-4-carboxylic acid, 9, (10.32 Kg, 65.3 mole) are added in a proportion such that the temperature do not exceed -10 ° C (lh of additional time). An additional amount of 0.2 Kg of TMSC1 is added in one portion. The resulting mixture is heated to 20 ° C and, after 4 hours, a vacuum of 28 mm Hg is applied. The mixture is heated to 65 ° C to remove the volatiles. Toluene (11.95 Kg) is added and the distillation continues. When no more distillate is collected, the mixture is cooled to 25 ° C. A slurry of celite (2.7 Kg) in hexane (20.6 Kg) is added. After stirring for 1 h, the mixture is filtered through a Nutsche pre-coated filter (1.5 Kg of Celite in 5 Kg of hexane for precoating). The reactor is washed with hexane (11 Kg), and this is used to wash the filter. The combined organics are concentrated to an oil using 19-25 mm Hg and a gentle heating. The concentrate is transferred to a storage tank purged with nitrogen with the addition of CH2C12, (7Kg) to give 17.5 Kg of a solution of acetal silylletone 10.

- C. Preparation of 4- [4- (4-chlorophenoxy) phenylsulfonylmethyl] -4- (N-hydroxycarboxamido) tetrahydropyran STAGE 7 90% of the acetal sililquetens solution from step 6 are charged to the reactor containing 4- (4-chlorophenoxy) phenyl chloromethylsulfide 5, followed directly by a slurry of ZnCl 2 (0.59 Kg, 4.34 moles) in CH 2 C 12 (5 Kg). The red reaction mixture is heated to reflux for 14 h (minimum heating required during the first hour because it is exothermic), point at which the HPLC shows about 10% of the starting material. The remaining 10% of the acetal ketene is added and the mixture is heated to reflux with the CH2C12 collection at the container temperature of 68 ° C. HPLC analysis of an aliquot shows < 1% of raw materials. Ethanol (15.5 Kg), water (20.6 Kg), and 45% KOH (20.3 Kg) are added to the concentrated product mixture. The two phases of the mixture are stirred at 65 ° C overnight (17 h) and warmed to the container temperature of 90 ° C to complete the saponification and distill the ethanol. The mixture is cooled to 60-65 ° C and hexane (41 Kg) is added. After shaking - - for 10 min. the layers are allowed to separate, the lower layer is transferred to another reactor containing water (24 Kg) and 37% HCl (21.6 Kg). Simultaneously with this transfer, the EtOAc (134.5 Kg) is pumped to the receiving reactor. The hexane solution is washed once with water at 65 ° C (25 liters) which is then transferred to the receiving reactor. This reactor contains an EtOAc solution of the acid product and the base layer. The base layer is separated and replaced with 50 L of water at 65 ° C. After a brief stirring, the layers are separated. The organic solution is concentrated as possible using partial vacuum. CH2CN (93.5 Kg) are added and the distillation continues at atmospheric pressure to a final volume of 90 liters. The mixture is collected for more than 8 hours at 5 ° C and is maintained for 8 hours. The solids are collected on a filter and washed with CH3CN (15 Kg) and hexane (15.5 Kg). Then they are dried at 78 ° C and 24 mm Hg at a constant mass, and 16.34 Kg of the acid product, 12, is obtained as a dense, white solid formed. The purity of the HPLC is 99%.

Stage 8 A dry, clean 100-gallon reactor is charged with 4-carboxy-4- [4- (4- (chlorophenoxyphenyl) thiomethyl] tetrahydropyran (15.45 Kg, 40.7 moles). To this reactor is added dichloromethane (77.2 L, 102 Kg). The suspended carboxylic acid is cooled to 0-5 ° C under N, with stirring. A catalytic amount of N, N-dimethylformamide (0.1 1) is loaded, followed by the slight addition of oxalyl chloride (5.3 Kg, 3.6 L). The contents of the reactor are stirred and the internal temperature is allowed to rise to the environment for a period of more than 4-12 hours to allow the convection of the hydrochloric acid. Another clean, dry, 100-gallon reactor is charged with tert-butanol (26.8 Kg, 34.5 L), tetrahydrofuran (75.4 Kg, 84 L) and hydroxylamine (50 aqueous, 17 Kg, 15.8 L). The contents of this reactor are stirred at room temperature. The contents of the reactor containing the hydrochloric acid are cooled to 0-5 ° C. A slow addition of a hydroxylamine solution is started. The addition rate is regulated in such a way that the internal temperature of the hydrochloric acid solution does not rise above 10 ° C. When the addition is complete, the reactor contents containing the new hydroxamic acid formation are warmed to 20-25 °. After completing the integrity of the reaction (HPLC or TLC), the solvent is removed in vacuo keeping the contents of this reactor below - - 45 ° C. When a little solvent is allowed to distill, the reactor is charged with acetonitrile (48.6 Kg, 61.7 L). The contents are heated to reflux, and water (61.7 L) is added for a period of 30-50 minutes. The contents of the reactor are cooled to 0-5 ° C for a period of 2-4 hours and slowly stirred for a period of 4-14 hours. The solid hydroxamic acid 13 is collected by filtration and washed with water. Typically, the obtained wet layer is not dried since it is used as such. However, drying can be carried out in vacuo at 50 ° C. The solid (21.5 Kg of layer, 14.45 Kg dry, 90.1%) has a purity of 99.8% by normalization of HPLC area.

Stage 9 A clean, dry 100-gallon reactor is charged with oxone® (potassium peroxymonosulfate, 37.07 Kg, 60.3 moles). Deionized water (88.3 Kg) is added and the contents of the reactor are stirred and heated (to ca. 35-40 ° C) to dissolve the oxone. In another clean, dry 100-gallon reactor it is charged with hydroxamic acid 13 (21.18 Kg wet layer of water, 14.45 dry weight, 36.7 moles) and dissolved in N-methyl-2-pyrrolidine (100.5 Kg) with stirring. The contents of this reactor are - - heated to 30-35 C. The aqueous solution oxone ™ is added to the reactor containing the hydroxamic acid in a proportion such that the external temperature does not exceed 49 ° C. After the addition of oxone ™ is completed, the mixture is examined by HPLC and TLC. When the reaction is complete, typically from 0 to 1 hour of post addition (the HPLC area normalization purity data are typically> 98.5% of the desired product) the product is treated with deionized water (25 Kg) and cooled to 20 ° C. Crystallization of the crude product typically occurs at 20 to 25 ° C (22 ° C in this example). The mixture is then cooled to 5 ° C and stirred for 10-14 hours (12 in this example). The precipitated product is collected by filtration and washed very well with deionized water followed by hexanes. This wet layer (47.9 Kg) is loaded into a reactor that is clean, dry, and free of debris, 100 gallons in capacity. Ethyl acetate (140 Kg) is charged to the solid followed by deionized water (120.6 Kg). The contents of the reactor are stirred and heated (ca. 60 ° C). The agitation is interrupted and the layers are allowed to separate. The aqueous layer is separated. Optionally, you can follow an aqueous wash with NaHCO2, washed with water. The organic layer is filtered through a 5-10 micron cotton filter in a clean, dry, residue-free reactor. The mixture is concentrated in vacuo at approximately 50% (ca 50 L) of the initial volume. The solid is prepared and recrystallized from ethyl acetate then heated to about 70 ° C and cooled to 5 ° C. The solid is collected by filtration on a clean, dry filter and dried at 40-45 ° C under a stream of nitrogen (a stirred filter is used in this example). Obtained 11.82 Kg of the final product, 4- [4 - (- chlorophenoxy) phenylsulfonyl-methyl] -4- (N-hydroxycarboxamido) tetrahydropyran, compound 14, yields 75.6% of (99.8% pure by HPLC area normalization) ) in vacuum dryer.

The above invention is described here in some detail by way of illustration and example, for the purposes of clarity and understanding. It is obvious to anyone with skill within the scope that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is understandable that the above description is intended to be illustrative.

Claims (19)

- - CLAIMS

1. A process for the preparation of a compound of formula I: Y-CÍOJ-CÍR1) (R2) -CH2-S (0) nR3 I Where: Y is hydroxy or XONX, where each X is independently hydrogen, lower alkyl or acyl lower; R1 is hydrogen or lower alkyl; R2 is hydrogen, low alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, or R1 and R2 together with the carbon atom for which they are attached form a cycloalkyl or heterocycle group; Y R is aryl; Y n is 0, 1 or 2; Characterized because it comprises the following stages: - - (1) alkylation to a compound of formula II, RO-C (= 0) -CHIR1) (R2), wherein R is an alkyl or hydrogen, with an arylmethylthio derivative of formula III, ArSCH2-Z, wherein Ar is an aryl group and Z is a residual group, to provide a compound of formula IV, RO-C (= 0) -CIR1) (R2) -CH2SAr: and (2) which converts the compound of formula IV to a compound of formula I by substituting the group RO- with X0NH- and optionally oxidized the group ArS.

2. The process according to claim 1 characterized in that: Ar has the formula Ar1-A-Ar2 where Ar1 and Ar2 are phenyl rings, each independently optionally substituted and A is a bond, -CH2- or -O-,

3. The process according to claim 1 or 2, characterized in that Z is halo,

4. The method according to claim 2 or 3, characterized in that: - - A is oxygen; Ar1 is phenyl; and Ar2 is 4-chlorophenyl.

5. The process according to any of claims 1-4, characterized in that the optional oxidation in step (2) provides a compound of formula I wherein n is 2.

6. The process according to any of claims 1-5 characterized in that R1 and R2 together with the carbon atom for which they are bound form a heterocycle group.

7. The process according to claim 6 characterized in that the heterocycle group formed by R1 and R2 is tetrahydropyranyl.

8. The process according to claim 7 characterized in that the compound is 4- [4- (4-chlorophenoxy) -phenylsulfonimethyl] -4- (N-hydroxycarboxamido) tertahydropyran.

9. The process according to claims 1 to 2, which further comprises forming the compound of formula III Ar1-A-Ar2-S-CH2-Z characterized by - (i) treating (i) a compound of formula VI, Ar1- A-Ar2-S- (0) 2C1 with trimethyl phosphite; (ii) optionally followed by a treatment with a base; and (iii) an oxidation.

10. The process according to claim 9, characterized in that: Ar1 is phenyl; Ar2 is 4-chlorophenyl; A is oxygen; R1 and R2 together with the carbon atom for which they are attached form a tetrahydropyranyl group; Y And it's HONH.

11. The process according to claim 4 characterized in that step (1) is carried out by conversion of a compound of formula II to a silylletone acetal of formula V, RO (OTMS) C = CR1R2 and alkylation with a compound of formula III . -

12. The process according to claim 4 characterized in that step (1) is performed by the alkylation of an enolate of a compound of formula II with a compound of formula III.

13. The process of preparing a compound of formula ArSCH, characterized in that Ar is an aryl group, by treating a compound of formula ArSo 2 Cl with trimethyl phosphite and optionally, followed by a treatment with a base, to form a compound of formula ArSCH 3.

14. The process according to claim 13, characterized in that Ar has the formula A ^ -A-Ar2, wherein Ar1 and Ar2 are phenyl rings, each independently optionally substituted, and A is a bond, CH2 or -O-.

15. The process according to claim 14, characterized in that: A is oxygen; Ar1 is phenyl; Y - - Ar is 4-chlorophenyl.

16. A compound Z-CH ^ -A ^ -A-Ar2, characterized in that: Ar1 and Ar2 are independently optionally substituted phenyl; Z is halo; Y A is oxygen or CH2,

17. The compound according to claim 16, characterized in that: Ar1 is phenyl; Ar is halophenyl; Y A is oxygen,

18. The compound according to claims 16 to 17, characterized in that it is 4- (4-chlorophenoxy) -phenyl chloromethylsulfide. - -

19. The process according to claim 4 characterized in that it is 4- (4-chlorophenoxy) phenyl methyl sulfide. - - SUMMARY OF THE INVENTION This invention provides a process for the preparation of a compound of formula I: Y-C (0) -C (R1) (R1) -CH-S (O) nR Where: Y is hydroxy or XONX, wherein each X is independently hydrogen, lower alkyl or lower acyl; R1 is hydrogen or lower alkyl; R2 is hydrogen, lower alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, or R1 and R2 together with the carbon atom for which they are attached form a cycloalkyl or a heterocycle group; Y R3 is aryl; This invention also provides novel intermediates haloalkyl aryl sulfide and aryl alkyl sulfide useful for the preparation of compounds of formula I and novel processes for the preparation of aryl alkyl sulfides.