MXPA01010768A

MXPA01010768A - Processes and intermediates for preparing substituted chromanol derivatives

Info

Publication number: MXPA01010768A
Application number: MXPA/A/2001/010768A
Authority: MX
Inventors: Stephane Caron; Anthony D Piscopio; Joel M Hawkins; Sarah E Kelly; Jeffrey W Raggon; Michael J Castaldi; Robert W Dugger; Sally G Ruggeri
Original assignee: Stephane Caron; Michael J Castaldi; Robert W Dugger; Joel M Hawkins; Sarah E Kelly; Pfizer Inc; Anthony D Piscopio; Jeffrey W Raggon; Sally G Ruggeri
Priority date: 1996-09-16
Filing date: 2001-10-23
Publication date: 2002-06-05

Abstract

The invention relates to processes for preparing a compound of formula (X) and the enantiomer of said compound, wherein the benzoic acid moiety is attached at position 6 or 7 of the chroman ring, and R1, R2, and R3 are as defined herein. The invention further relates to intermediates that are useful in the preparation of the compound of formula (X).

Description

INTERMEDIARIES TO PREPARE SUBSTITUTEED CHROMANOL DERIVATIVES BACKGROUND OF THE INVENTION This invention relates to the preparation of substituted chromanol derivatives and intermediates useful in said preparation. The substituted chromanol derivatives that are prepared in accordance with the present invention are disclosed in U.S. Patent Application Serial No. 08 / 295,827, filed January 9, 1995 and entitled "Benzopyran And Related LTB4 Antagonists", in the publication of the PCT international application number WO 96/11925 (published on April 25, 1996), in the publication of the PCT international application number WO 96/11920 (published on April 25, 1996), and in the publication of the PCT international application number WO 96/15066 (published August 5, 1993). All of the US and PCT patent applications indicated above are hereby incorporated by reference in their entirety. The substituted chromanol derivatives which are prepared according to the present invention, inhibit the action of LTB4, as described in the aforementioned US Patent Application Serial No. 08 / 295,827. As LTB4 antagonists, the substituted chromanol derivatives that are prepared according to the present invention are useful in the treatment of LTB-induced diseases, such as inflammatory disorders including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis, eczema, erythema, pruritis, acne, cerebrovascular accidents, rejection of grafts, autoimmune diseases and asthma.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing a compound of the formula: or the enantiomer of said compound, wherein in said compound of formula X the benzoic acid radical substituted with R3 is attached to carbon 6 or 7 of the chroman ring; R1 is - (CH2) qCH5R6. where q is 0 to 4; each R2 and R3 is independently selected from the group consisting of H, fluoro, chloro, Ci-Cß alkyl. Ci-Cβ alkoxy, phenylsulfinyl, phenylsulfonyl and -S (0) n (Ci-Cß alkyl). where n is 0 to 2 and wherein said alkyl group, the alkyl radical of said alkoxy groups and -S (0) n (Ci-Cß alkyl) and the phenyl radical of said phenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1 to 3 groups fluoro; R 5 is H, C 1 -C 7 alkyl or phenyl substituted by R 2; R6 is H, Ci-Cß alkyl. or cycloalkyl CtrCβ, aryl Ce-Cιo or heteroaryl of 5 to 10 links, wherein said aryl and heteroaryl groups are optionally substituted by 1 or 2 substituents independently selected from phenyl, R 2 and phenyl substituted by 1 or 2 R 2; which comprises treating a compound of the formula: or the enantiomer of said compound of formula IX, in the preparation of the enantiomer of said compound of formula X, wherein R1, R2 and R3 are as defined above, R4 is Ci-Cß alkyl and the benzoate radical is attached to the position 6 or 7 of the chroman ring, with a base. In said process of preparing the compound of formula X, the compound of formula IX is preferably treated with an aqueous hydroxide base, R1 is preferably benzyl, 4-fluorobenzyl, 4-phenylbenzyl, 4- (4-fluorophenyl) benzyl or phenethyl, R2 is preferably hydrogen or fluoro, R3 is preferably fluoro, chloro or methyl optionally substituted by 1 to 3 fluoros and R4 is preferably ethyl or 2,2-dimethylpropyl. More preferably, said compound of formula IX is treated with a base comprising aqueous sodium hydroxide, said compound of formula IX is ethyl ester of (3S, 4R) -2- (3-benzyl-4-hydroxy-chroman-7-) il) -4-trifluoromethyl-benzoic acid and said compound of formula X is (3S, 4R) -2- (3-benzyl-4-hydroxy-chroman-7-yl) -4-trifluoromethyl-benzoic acid. In another aspect of the present invention, said compound of formula IX or the enantiomer of said compound, wherein R1, R2, R3 and R4 are as defined above, is prepared by the treatment of a compound of the formula: or the enantiomer of said compound of formula VII, in the preparation of the enantiomer of the compound of formula IX, wherein R1 and R2 are as defined above and the boronic acid radical is attached to position 6 or 7 of the chroman ring , with compound of the formula: wherein R3 and R4 are as defined above and Z is halo or C1-C4 perfluoroalkylsulfonate, in the presence of a base or a fluoride salt and a palladium catalyst. In said method of manufacturing the compound of formula IX, or of the enantiomer of said compound, the preferred substituents for R1, R2, R3 and R4 are as indicated above for said manufacturing process of the compound of formula X. In another preferred embodiment , Z is halo, the base salt or fluoride is selected from sodium carbonate, triethylamine, sodium bicarbonate, cesium carbonate, tripotassium phosphate, potassium fluoride, cesium fluoride, sodium hydroxide, barium hydroxide and tetrabutylammonium fluoride, the catalyst of palladium is selected from tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (ll), palladium acetate (ll), allyl palladium chloride dimer, tris (dibenzylideneacetone) dipalladium (0), and 10% palladium on carbon . More preferably, the base or fluoride salt is potassium fluoride, the palladium catalyst is 10% palladium on carbon, the compound of formula VII is (3S, 4R) - (3-benzyl-4-hydroxy-chroman-7) -yl) -boronic acid and the compound of formula VIII is ethyl 2-iodo-4-trifluoromethyl-benzoate. In a further aspect of the invention, the compound of formula VII or the enantiomer of said compound, wherein R1 and R2 are as defined above, is prepared by the treatment of a compound of the formula: or the enantiomer of said compound of formula VI, in the preparation of the enantiomer of the compound of formula VII, wherein R1 and R2 are as defined above and X is a halide and is attached to position 6 or 7 of the chroman ring , with (1) alkyl (C? -C4) lithium and (2) a borating agent. In said method of manufacturing the compound of formula VII or of the enantiomer of said compound, the preferred substituents for R1 and R2 are as indicated above for said manufacturing process of the compound of formula X. In another preferred embodiment, X is bromine or iodine and said compound of formula VI is treated with (1) methyl lithium. (2) Butyl lithium and (3) said borating agent is selected from a complex of borane-tetrahydrofuran, triisopropyl borate and trimethyl borao. More preferably, the compound of formula VI is (3S, 4R) -3-benzyl-7-bromo-chroman-ol and said borating agent is a borane-tetrahydrofuran complex. In another aspect of the invention, the compound of formula VI or the enantiomer of said compound, wherein R1, R2 and X are as defined above, is prepared by the treatment of a compound of the formula: or the enantiomer of said compound of formula V, in the preparation of the enantiomer of the compound of formula VI, wherein R1, R2 and X are as defined above, X is attached to the 4 or 5 position of the phenyl ring and And it is halo or nitro, with a base, optionally in the presence of added copper salts. In said method of manufacturing the compound of formula VI or the enantiomer of said compound, the preferred substituents for R1, R2 and X are as indicated above for said manufacturing process of the compound of formula VII. In another preferred embodiment, Y is halo and said base is potassium tert-butoxide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, cesium carbonate or sodium hydride. More preferably, said base is potassium tert-butoxide and compound of formula V is (1 R, 2S) -2-benzyl-1- (4-bromo-2-fluoro-phenyl) -propanol-1,3-diol. In another aspect of the invention, the compound of formula V or the enantiomer of said compound, wherein R1, R2 X and Y are as defined above, is prepared by the treatment of a compound of the formula: or the enantiomer of said compound of formula IV, in the preparation of the enantiomer of the compound of formula V, wherein R1, R2, X and Y are as defined above, X is attached to the 4 or 5 position of the ring of phenyl and Xc is a chiral auxiliary, with a hydride agent as a reducing agent. In said process for manufacturing the compound of formula V or the enantiomer of said compound, the preferred substituents for R1, R2, X and Y are as indicated above for said manufacturing process of the compound of formula VI. In another preferred embodiment, Xc is (R) -4-benzyl-2-oxazolidinone, (S) -4-benzyl-2-oxazolidinone, (4R, 5S) -4-methyl-5-phenyl-oxazolidin-2-one or (4S, 5R) -4-methyl-5-phenyl-oxazolin-2-one, wherein said Xc is attached to the nitrogen of the oxazolin-2-one ring and said reducing agent is lithium borohydride, lithium aluminum hydride , sodium borohydride or calcium borohydride. More preferably, the compound of formula IV is 1-methyl-2-pyrrolidinone solvate of [4R- [3 (2R, 3R)]] - 4-benzyl-3- [2-benzyl-3- (4-bromo- 2-fluoro-phenyl) -3-hydroxy-propionyl] -oxazolidin-2-one or [4R- [3 (2R, 3R)]] - 4-benzyl-3- [2-benzyl-3- (4-bromo -2-fluoro-phenyl) -3-hydroxy-propionyl] -oxazolidin-2-one, and said reducing agent is lithium borohydride.

In another aspect of the invention, the compound of formula IV or the enantiomer of said compound, wherein R1, R2, X, Xc and Y are as defined above, is prepared by the treatment of a compound of the formula R1 -CH2C (0) -Xc, wherein R1 and Xc are as defined above, with (1) a Lewis acid, (2) a base and (3) a compound of the formula: wherein R2, X and Y are as defined above and X is attached to the 4 or 5 position of the phenyl ring. In said method of manufacturing the compound of formula IV or the enantiomer of said compound, the preferred substituents for R1, R2 X, Xc and Y are as indicated above for said manufacturing process of the compound of formula V. In another preferred embodiment said Lewis acid is a boron or sulphonate halide, and said base is triethylamine or diisopropylethylamine. More preferably, said compound of formula R1-CH2C (0) -Xc is (R) -4-benzyl-2-fluoro-3- (3-phenyl-β-pyrionyl) -oxazolidin, said compound of formula III is 4-bromine -2-f-uoro-benzaldehyde, said Lewis acid is dibutylborolate triflate and said base is triethylamine.

In another aspect of the invention, the compound of formula IV or the enantiomer of said compound, wherein R1, R2 X, Xc and Y are as defined above, is prepared by the treatment of a compound of the formula R1- CH2C (O) -Xc, wherein R1 and Xc are as defined above, with (1) a titanium (IV) halide, (2) a base optionally followed by treatment with a donor ligand and (3) a compound of formula: wherein R2, X and Y are as defined above and X is attached to the 4 or 5 position of the phenyl ring. In said manufacturing process of the compound of formula IV or of the enantiomer of said compound, the preferred substituents for R1, R2, X, Xc and Y are as indicated above for said manufacturing process of the compound of formula V. In another embodiment preferred, said titanium (IV) halide is titanium tetrachloride and said base is a tertiary amine base or a tertiary diamine base. In another preferred embodiment, said base is triethylamine or NNN'.N'-tetramethylethylenediamine, and said treatment with said base is followed by a treatment with a donor ligand selected from 1-methyl-2-pyrrolidinone, dimethylformamide, 1, 3- dimethyl-3,4,5,6-tetrahydro-2 (1 H) -pyrimidinone, triethylphosphate and 2,2, -dipyridyl. More preferably, said compound of formula R1-CH2C (0) -Xc is (R) -4-benzyl-3- (3-phenyl-propionyl) -oxazolidin-2-one, said compound of formula III is 4-bromo- 2-fluoro-benzaldehyde, said base is NN N '. N'-tetramethylethylenediamine. and said donor ligand is 1-methyl-2-pyrrolidinone. In another aspect of the invention, said compound of formula IX or the enantiomer of said compound, wherein R1, R2, R3 and R4 are as defined above, is prepared by coupling a compound of the formula: or the enantiomer of said compound in the preparation of the enantiomer of the compound of formula IX, wherein R1 and R2 are as defined above and X ', which is attached to position 6 or 7 of the chroman ring is halo or perfluoroalkylsulfonate C1-C4, with a compound of the formula: XIV wherein R3 and R4 are as defined above, in the presence of a base or salt fluoride and a palladium catalyst. In the process for preparing the compound of formula IX or the enantiomer of said compound, as mentioned directly in the foregoing text, the preferred substituents for R 1, R 2 and R 4 are as indicated above for the compound manufacturing process of formula X. In another preferred embodiment, X 'is preferably bromine, iodine or trifluoromethanesulfonate, the palladium catalyst is preferably selected from tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), palladium acetate (II). ), allyl palladium chloride dimer, tris (dibenzylideneacetone) dipalladium (O) and 10% palladium on carbon, and the base or fluoride salt is selected from sodium carbonate, triethylamine, sodium bicarbonate, cesium carbonate, tripotassium phosphate, fluoride potassium, cesium fluoride, sodium hydroxide, barium hydroxide and tetrabutylammonium fluoride. More preferably, the compound of formula VI is (3S, 4R) -3-benzyl-7-bromo-chroman-4-ol), the compound of formula XIV is 2- (2,2-dimethyl-propoxycarbonyl-5-) trifluoromethyl-benzeneboronic, the base or salt fluoride is sodium carbonate and the palladium catalyst is tetrakis (triphenylphosphine) palladium (O). In another aspect of the invention, the compound of formula XIV, wherein R3 and R4 are as defined above, is prepared by hydrolysis of a compound of the formula: wherein R and R4 are as defined above, the dashed line indicates a bond or the absence of bond between the atoms of B and N, n and m are independent 2 to 5 and R8 is H alkyl Ci-Cß. R8 is preferably H and the preferred substituents for R3 and R4 are those indicated above for said manufacturing process of a compound of formula X. Preferably, said hydrolysis is carried out with an acid, such as hydrochloric acid, and each is, 2. More preferably, said compound of formula XVI is 2- [1, 3,6,2] dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid 2,2-dimethyl-propyl ester. In another aspect of the invention, the compound of formula XVI, wherein R3 and R4 and R8 are as defined above, is prepared by the reaction of a compound of formula XIV, wherein R3 and R4 are as defined above, with a compound of formula HO (CH 2) mN (R 8) - (CH 2) n OH (formula XV), wherein n, m and R 8 are as defined above. In said process for the preparation of the compound of formula XVI, the preferred substituents for R3 and R4 are as indicated above for said process of preparing a compound of formula X. More preferably, said compound of formula XIV is acid 2- (2,2-dimethyl-propoxycarbonyl) -5-trifluoromethyl-benzeneboronic acid and said compound of formula XV is diethanolamine. In another aspect of the invention, the compound of formula XIV, wherein R 4 and R 3 are as defined above, is prepared by the hydrolysis of a compound of the formula: wherein R3 and R4 are as defined above and R7 is C? -C6 alkyl. Said hydrolysis is preferably carried out with an acid, such as hydrochloric acid. Preferred substituents for R3 and R4 are as indicated above for said method of manufacturing a compound of formula X. In another aspect of the invention, the compound of formula XIII, wherein R3, R4 and R7 are as defined above, is prepared by treating a compound of the formula: wherein R3 and R4 are as defined above with a metal amide base in the presence of a tri (Ci-Cß alkyl) borate. In said process for manufacturing the compound of formula XIII, the preferred substituents for R3 and R4 are as indicated above for said method of manufacturing a compound of formula X. In another preferred embodiment, said metal amide base is selected from lithium diisopropylamide, lithium diethylamide, 2.2, Lithium 6,6-tetramethylpiperidine, lithium diethylamide, lithium 2,2,6,6-tetramethylpiperidine and bis (2,2,6,6-tetramethyl piperidino) magnesium, and said tri (C 1 -C 4) alkyl )) is selected from triisopropyl borate, triethyl borate and trimethyl borate. More preferably, the compound of formula XII is 4-trifluoromethyl-benzoic acid 2,2-dimethyl-propyl ester, said metal amide base is lithium diisopropylamide and said tri (Ci-Cß alkyl) borate is triisopropyl borate, In another aspect of the invention, the compound of formula X or the enantiomer of said compound, wherein R 1, R 2 and R 3 are as defined above, is reacted with a secondary amine of the formula NHR 5 R 6, wherein R 5 and R6 are as defined above, to form an ammonium carboxylate of the formula XVII or the enantiomer of said compound of formula XVII, wherein R1, R2, R3 R5 and R6 are as defined above. Preferred substituents for R1, R2 and R3 are as defined above for said process for the manufacture of a compound of the formula X. In said secondary amine, R5 and R6 are each, preferably, cyclohexyl. More preferably, said compound of formula XVII is (3S, 4R) -dicyclohexylammonium-2- (3-benzyl-4-hydroxy-chroman-7-yl) -4-trifluoromethyl benzoate. The invention also relates to a process for preparing a compound of the formula: XIX or the enantiomer of said compound, wherein R1 and Xc are as defined above for said process of preparing a compound of the formula V, and R11 is C1-C9 alkyl, C2-Cg alkenyl or phenyl substituted by Y in position 2, X is in position 4 or 5, and R2 in one of the remaining positions of the phenyl radical, where Y, X and R2 are as defined above for said process of preparing a compound of formula V, by treating a compound of the formula R1-CH2C (0) -Xc, wherein R1 and Xc are as defined above, with (1) a titanium (IV) halide, (2) a base, optionally followed by treatment with a donor ligand and (3) less equivalents, of a compound of formula R11-C (O) H, wherein R11 is as defined above, with respect to the amount of said compound of formula R1 -CH2C (O) -Xc. Preferred substituents and reagents for said method of preparing said compound of formula XIX or of the enantiomer of said compound, are as indicated above for said process of preparing a compound of formula IV, using said titanium (IV) halide. The invention also relates to a compound of the formula: and the enantiomer of said compound, wherein R1 and R2 X and Y are as indicated above for said process of preparing a compound of the formula VI. In said compound of the formula V and in the enantiomer of said compound, the preferred substituents for R1, R2, X and Y are as indicated above for said process for the preparation of a compound of the formula VI. More preferably, said compound of the formula V is (1 R, 2S) -2-benzyl-1- (4-bromo-2-fluoro-phenyl) -propane-1,3-diol.

The invention also relates to a compound of the formula: and the enantiomer of said compound, wherein R1 and R2 are as indicated above for said compound of formula V and X 'is halo or perfluoroalkyl C1-C4 sulfonate and is attached to position 6 or 7 of the chroman ring . In said compound of formula VI and in the enantiomer of said compound, the preferred substituents for R 1, R 2 are as indicated above for said compound for the preparation of a compound of formula VI. More preferably, said compound of formula V and X 'is preferably said compound of formula VI is (3S, 4R) -3-benzyl-7-bromo-chroman-4-ol. The invention also relates to a compound of the formula: and the enantiomer of said compound, wherein R1 and R2 are as indicated above for said compound of formula VI. In said compound of formula VII and in the enantiomer of said compound, the preferred substituents for R1, R2 are as indicated above for said compound for the preparation of a compound of formula VI. More preferably, said compound of formula VII is (3S, 4R) - (3-benzyl-4-hydroxy-chroman-7-yl) -boronic acid. The invention also relates to a compound of the formula: And to the enantiomer of said compound, wherein R1, R2 R3 and R4 are as indicated above for said process of preparing a compound of the formula X and the benzoate radical is attached to the 6 or 7 position of the chroman ring . In said compound of formula IX and in the enantiomer of said compound, the preferred substituents for R1, R2, R3 and R4 are as indicated above for said process of preparing a compound of formula X. More preferably, the compound of Formula IX is the ethyl ester of (3S, 4R) -2- (3-benzyl-4-hydroxy-chroman-7-yl) -trifluoromethyl benzoic acid. The invention also relates to a compound of formula: Wherein R3, R4 and R7 are as indicated above, for said process of preparing a compound of formula XIV, using a compound of formula XIII. In said compound of the formula XIII, the preferred substituents for R7, R3 and R4 are as indicated above for said process of preparing a compound of the formula XIV, using a compound of the formula XIII. The invention also relates to a compound of the formula: Wherein R3 and R4 are as indicated above for said compound of formula XI 11. In said compound of formula XIV, preferred substituents for R3 and R4 are as indicated above for said compound of formula XIII. More preferably, said compound of formula XIV is 2- (2,2-dimethyl-propoxycarbonyl) -5-trifluoromethyl-benzeneboronic acid.

The invention also relates to compounds of the formula: in the dashed line indicates a bond or the absence of a bond between atoms B and N, n and m are independently 2 to 5, R 3 and R 4 are as defined above for said compound of formula XIV and R 8 is H or C 1 alkyl -C6 In said compound of formula XVI, n and m are each, preferably, 2, the preferred substituents for R 3 and R 4 are as defined above for said compound of formula XIV and R 8 is preferably H. More preferably, the compound of formula XVI is 2- [1,3,6,2] dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid 2,2-dimethyl-propyl ester. The invention also relates to an ammonium carboxylate compound of the formula: XVII and the enantiomer of said compound, wherein R1, R2, R3, R5 and R6 are as defined above for said method of preparing a compound of formula X. Preferred substituents for R1, R2 and R3 are as It has been indicated to < The above-mentioned process for the manufacture of a compound of formula X. In the ammonium radical, R5 and R6 are each, preferably, cyclohexyl. More preferably, said compound of formula XVII is (3S, 4R) -diclohexylammonium-2- (3-benzyl-4-hydroxy-chroman-7-yl) -4-trifluoromethyl benzoate. The present invention also relates to a compound of formula: and to the enantiomer of said compound, in R1, R2, X, Y and Xc are as defined above for said method of preparing a compound of formula V. The present invention also relates to solvates of said compound of formula IV . Preferred solvates of said compound of formula IV and of the enantiomer of said compound of formula IV. Preferred solvates of said compound of formula IV and of the enantiomer of said compound are those formed with a donor ligand selected from 1-methyl-2-pyrrolidinone, dimethylformamide, 1,3-dimethyl-3,4,5,6-tetrahydro. -2 (1 H) -pyrimidinone, triethylphosphate and 2,2-dipyridyl. The preferred compound of formula IV is [4R- [3 (2R, 3R)]] - 4-benzyl-3- [2-benzyl-3- (4-bromo-2-fluoro-phenyl) -3-hydroxy-propionyl ] -oxazolidin-2-one and the preferred solvate of said compound is 1-methyl-2-pyrrolidinone solvate of [4R- [3 (2R, 3R)]] - 4-benzyl-3- [2-benzyl-3] - (4-bromo-2-fluoro-phenyl) -3-hydroxy-propionyl] -oxazolidin-2-one. The term "halo", as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. The "term", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic radicals or combinations thereof. The term "alkoxy," as used herein, includes O-alkyl groups, wherein "alkyl" is as defined above. The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of a hydrogen, such as phenyl naphthyl. The term "heteroaryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound, by removal of a hydrogen, such as pyridyl, furyl, thienyl, isoquinolyl, pyrimidyl. and pyrazinyl. The term "enantiomer", as used herein in reference to the compound of formula X: means a compound of the formula: The term "enantiomer", as used herein in reference to the compound of formula IX: means a compound of the formula: The term "enantiomer", as used herein in reference to a compound of formula VII: means a compound of the formula: The term "enantiomer", as used herein in reference to a compound of formula VI: SAW means a compound of the formula: The term "enantiomer", as used herein in reference to the compound of formula V: means a compound of the formula: The term "enantiomer", as used herein in reference to a compound of formula IV: means a compound of the formula: The term "enantiomer", as used herein in reference to a compound of formula XVII: XVII means a compound of the formula: The term "enantiomer", as used herein in reference to a compound of formula XIX: XIX means a compound of the formula: DETAILED DESCRIPTION OF THE INVENTION The process of the present invention and the preparation of the compounds of the present invention are illustrated in the following schemes. In the following schemes and in the discussion shown below unless otherwise indicated, R1, R2, R3 R4, R5, R6, R7, R8 R11, Y, Z, X, Xc, and X 'are as defined above. The following schemes and the discussion shown below describe the preparation of the compounds of formulas I-XIX. The following schemes and. the description shown below, also apply to the enantiomers of the compounds of the formulas I-XIX, where the term "enantiomer" is as defined above.

SCHEME 1 lll IV Vil SCHEME 1 (CONTINUED) IX SCHEME 2 XI XI XIII IX SCHEME 3 XIV SCHEME 4 XVIII XIX In general, the synthetic sequence of scheme I involves the binding of a chiral auxiliary Xc to a compound I containing R1 (step 1), the asymmetric aldol condensation with aldehyde III (step 2 or 2 '), the reductive elimination of the auxiliary aldol chiral IV (step 3), the cyclization mediated by a base of the diol V (step 4), the lithiation and boration of halochromanol VI (step 5), the coupling of the boronic acid Vil with aryl halide or sulfate VIII (step 6) and hydrolysis of ester IX (step 7). In step 1 of scheme 1, the chiral auxiliary HXc is converted into the corresponding anion by treatment with a suitable strong base, such as an alkyl lithium base, preferably butyl lithium, in an aprotic solvent, such as a solvent ethereal, preferably tetrahydrofuran (THF), at a temperature of about -80 to 0 ° C, preferably -78 to -55 ° C, over a period of about 20 minutes to one hour. The substituent Xc is a chiral auxiliary which is suitable for controlling the relative and absolute stereochemistry in asymmetric aldol reactions. Examples of HXc include (R) -4-benzyl-2-oxazolidinone, (S) -4-benzyl-2-oxazolidinone, (4R, 5S) -4-methyl-5-phenyl-oxazolidin-2-one and ( 4S, 5R) -4-methyl-5-phenyl-oxazolidin-2-one. The resulting anion is treated with acylating agent I, where the group W is a halide, preferably chloride, and R1 is as defined above, in the same solvent, at a temperature of about -80 to 0 ° C, preferably at about -75 ° C, for a period of about one hour, and then heated to a temperature of about -20 to 20 ° C, preferably at about 0 ° C, before the aqueous treatment, which is preferably carried out by the treatment with aqueous sodium bicarbonate, to produce the chiral acylated auxiliary II. Stage 2 of scheme 1 is an "Evans aldol reaction" which is carried out under conditions that are analogous to those described in Evans, D.A.; Bartroli, J .; Shih, T.L., J. Am. Chem. Soc. 103, 2127, and Gage J. R. Evans, D.A., Org. Syn. 1989, 68, 83, the two references being incorporated herein by reference. In particular, in step 2 of scheme 1, the acylated chiral auxiliary II is treated with a Lewis acid, a base and a substituted benzaldehyde III to produce the IV alcohol with a high degree of stereoselectivity. The benzaldehyde III is replaced with an ortho substituent Y which serves as a leaving group during cyclization step 4, group X (or X 'for scheme 2, in particular, coupling step 4 of scheme 2) which is replaced by the aryl side chain during coupling step 6, and substituent R2 which is as defined above. The substituent X (or X 'for scheme 2) is attached to the 4 or 5 position of the phenyl radical of benzaldehyde III. The leaving group Y is typically a halo or nitro group and X is a halide (and for scheme 2, X 'is a halide or a C1-C4 perfluoroalkyl sulfonate). To prepare the IV aldol product, the acylated chiral auxiliary II is treated with a boron halide or sulphonate, such as dialkylboronate sulfonate, preferably dibutylborolate triflate, in an aprotic solvent such as dichloromethane, 1,2-dichloroethane, toluene, or diethyl ether, preferably dichloromethane, at a temperature of about -8 to 40 ° C, preferably at -5 ° C, for a period of about 20 minutes, followed by treatment with a tertiary amine base, such as triethylamine or diisopropylethylamine, preferably triethylamine, at a temperature of about -78 to 40 ° C, preferably -5 to 5 ° C, for a period of about one hour. This mixture is treated with a substituted benzaldehyde III at a temperature of about -100 to 0 ° C, preferably at about -70 ° C, for a period of about 30 minutes. This mixture is allowed to warm to a temperature of about -20 to 25 ° C, preferably at about -10 ° C, for a period of about one hour, and then treated with a protic oxidative inactivator, preferably, by successive addition of a buffer solution of pH 7, methanol and aqueous hydrogen peroxide, at a temperature of less than about 15 ° C, to produce the IV alcohol. Stage 2"of scheme 1 is an alternative process and preferably to provide alcohol IV using a Lewis acid containing titanium In step 2 of scheme 1, the chiral auxiliary II is treated with titanium (IV) halide, preferably titanium tetrachloride, in an aprotic solvent such as dichloromethane, 1,2-dichloroethane or toluene, preferably dichloromethane, at a temperature from about -80 ° C to 0 ° C, preferably from -80 to -70 ° C, over a period about 30 minutes, with further agitation for about 30 minutes, followed by treatment with a tertiary amine or tertiary diamine base, such as triethylamine or / V,? /,? / ',? /' - tetramethylethylenediamine, preferably N, N, N ', N' -tetramethylethylenediamine, at a temperature of about -80 to 0 ° C, preferably -80 to -65 ° C, over a period of about 30 minutes.This is followed, optionally and preferably, by the treatment with a ligand or a donor such as 1-methyl-pyrrolidinone, dimethylformamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone, triethylphosphate or 2,2'-dipyridyl, preferably 1-methyl-2 -pyrrolidone, at a temperature of about -80 to 0 ° C, preferably -80 to -65 ° C, followed by stirring for a period of about 30 minutes. This mixture is treated with substituted benzaldehyde III at a temperature of about -100 to 0 ° C, preferably -80 to -65 ° C, over a period of about 30 minutes, and allowed to warm to a temperature of -30 to 30 ° C, preferably 0 to 25 ° C, for a period of about 1 to 24 hours, preferably about 4 hours. This mixture is treated with protic inactivator, preferably aqueous ammonium chloride, at a temperature of -30 to 30 ° C, preferably 0 to 25 ° C, to produce the IV alcohol. When the treatment is performed with a donor ligand, the IV alcohol, in some cases, is provided in the form of a crystalline solvate with the donor ligand. Agitation of the inactivated reaction mixture with a solid support such as Celite® for a period of about 12 hours at a temperature of about 20 ° C, improves the filtration of the reaction mixture to remove titanium by-products.

The conditions of the titanium aldol of step 2 'of scheme 1 are preferable and more simple from the operational point of view, than the conditions of the boron aldol of stage 2 of scheme 1, since they avoid the pyrophoric tributylborane reagent, the corrosive reactive triflic acid and its exothermic combination in the preparation of dibutylboro Lewis triflate acid. In addition, in contrast to the aldol reactions of titanium described in the literature, such as in Evans, D.A .; Rieger, D.L .; Bilodeau, M.T .; Urpi, F., J. Am. Chem. Soc. 1991, 113, 1047, the titanium aldol conditions of step 2 'of scheme 1 provide high selectivity with less than two equivalents of aldehyde III. Preferably, in this step about one equivalent of the aldehyde III is used. The phrase "about one equivalent" as used herein with reference to aldehyde III or to a compound of formula R11C (0) H (as mentioned in the claims) means less than 1.5 equivalents of said compound. In the previous article by Evans et al, it is indicated that two equivalents of aldehyde would be required for an aldol reaction of titanium analogous to step 2 'of scheme 1. In addition to having utility in the preparation of the therapeutic agents of formula X, the titanium aldol conditions of step 2 'of scheme 1 are useful in the preparation of HIV protease inhibitor compounds which are described in United Kingdom Patent Application No. 2,270,914 (published March 30, 1994) and in BD Dorsey and others, Tetrahedron Letters. 1993, 34 (12), 1851. Scheme 4 illustrates the application of the aldol reaction of titanium to the amino acid XVIII, wherein R 11 is C 1 -C 9 alkyl, C 2 -C 9 alkenyl or phenyl substituted by Y at the 2, X position. in the 4 or 5 position and R2 in one of the other positions of the phenyl radical, where Y, X and R2 are as defined above. The reaction conditions for Scheme 4 are the same as those described above for Step 2 'of Scheme 1. Aldehyde XVIII includes aldehyde III of Scheme 1 and alcohol XIX includes alcohol IV of Scheme 1. The reaction of the Scheme 4 can be used to prepare the HIV protease inhibitor compounds described in UK Patent Application No. 2,270,914, mentioned above, wherein R 11 is C 1 -C 9 alkyl or C 2 -C 9 alkenyl, preferably 3-cyclohexylpropenyl . Table 1 below shows how the product of Scheme 4 or Step 2 'of the Scheme can vary, depending on the reaction conditions used and, in particular, how diastereoselectivity increases by increasing the amount of TMEDA of 1.2. to 3 equivalents and by the addition of 2 equivalents of NMP. In Table 1, 1.0 equivalents of the RCHO aldehyde were used for each reaction, x and y represent base equivalents and NMP, respectively, NMP means 1-methyl-2-pyrrolidinone, TMEDA means N, N, N ', N' -tetramethylethylenediamine, NetiPr2 means diisopropylethylamine, and proportion of diastereomers was determined by HPLC. The aldol isomers were identified by separation and conversion to known carboxylic acid isomers by hydrolysis with LiOH / H202 according to procedures analogous to those described in Van Draanen, N.A .; Arseniyadis, S. K .; Crimmins, M. T .; Heathcock, C. H., J. Org. Chem. 1991, 56, 249 and Gage, J.R., Evans, D.A., Org. Syn. 1989, 68.83. The desired isomer is indicated in bold.

SCHEME FOR TABLE 1 TABLE 1 In Step 3 of Scheme 1, the chiral auxiliary Xc is removed (and optionally recovered to be used again in Table 1) and the oxidation state of the compound IV (acid number) is reduced to the desired alcohol V according to a procedure analogous to the procedure described in Penning, TD; Djuric, S. W .; Haack, R. A .; Kalish, V. J .; Miyashiro, J. M .; Rowell, B. W .; Yu, S. S., Svn. Commun. 1990, 20, 307, which is incorporated herein by reference. In this process, the alcohol IV is treated with a reducing hydride agent, such as lithium borohydride, lithium aluminum hydride, sodium borohydride or calcium borohydride, preferably lithium borohydride, in an ethereal solvent such as THF, diisopropyl ether or methyl tert-butyl ether, preferably THF, which typically contains a protic solvent, such as water, ethanol or isopropane, at a temperature of about -78 ° C at the reflux temperature, preferably from 0 ° C to room temperature ( 20-25 ° C). After a period of one to 24 hours, typically 12 hours, the reaction is interrupted with water and with the subsequent and optional addition of hydrogen peroxide. The chiral auxiliary HXc can be recovered for reuse in Step 1, by selective precipitation or by extraction of HXc in aqueous acid, preferably in hydrochloric acid, from a solution of diol V in an organic solvent such as diisopropyl ether or a mixture of ethyl acetate and hexane, followed by neutralization of aqueous acidic extracts with a base and extraction of HXc in an organic solvent.

Step 4 of Scheme 1 is an intramolecular aromatic substitution whereby the primary hydroxyl of the diol V displaces the leaving group Y in the ortho position to generate the chromanol ring system of VI. In particular, the diol V, in which the leaving group Y is a halo or nitro group, preferably a fluoro group, is treated with a base, such as potassium ferro-butoxide, potassium bis (trimethylsilyl) amide, cesium carbonate or Sodium hydride, preferably potassium-ferric peroxide, in an aprotic solvent such as THF, dimethylsulfoxide or 1-methyl-2-pyrrolidinone, preferably THF, optionally in the presence of added copper salts, at a temperature between room temperature and 130 ° C. C, preferably at about four hours, giving chromanol VI. In chromanol VI, the substituent X (or X 'for Scheme 2) is attached to position 6 or 7 of the chroman ring. In Step 5 of Scheme 1, the substituent X of chromanol VI is converted to lithium and then to a boronic acid group. For lithiation, chromanol VI is preferably treated first with methyl lithium to form the lithium alkoxide, followed by butyl lithium to form the aryl lithium. In this process, chromanol VI, wherein X is a halide, preferably bromide or iodide, is treated with two equivalents of lithium alkyl, preferably first with one equivalent of methyl lithium and then with one equivalent of lithium butyl, an ethereal solvent, preferably THF, at a temperature of -78 to 0 ° C, preferably -70 to 65 ° C, for a period of about one hour, followed by treatment with a borating agent, such as a borane complex -tetrahydrofuran, triisopropyl borate or trimethyl borate, preferably, borane-THF complex, at a temperature of -78 to 0 ° C, preferably -70 to 65 ° C, for a period of about 30 minutes, followed by inactivation with water or optionally an aqueous acid, at a temperature of about -65 ° C at room temperature, preferably at about 0 ° C, giving the boronic acid VII in which the boronic acid radical is attached to the 6 or 7 position of the chroman ring. Step 6 of Scheme 1 is a Suzuki coupling between the boronic acid VII and the compound VIII to form the biarylic linkage of the compound IX. in compound VIII, Z is a halide or sulfanate, preferably bromide, iodide or trifluoromethanesulfonate, R4 is Ci-β alkyl and R3 is as defined above. This procedure is analogous to the procedure described in Miyaura, N .; Suzuki, A., chem. Rev. 1995, 95, 2457, which is incorporated herein by reference. This process is preferable for the coupling of zinc or tin species due to the difficulty of preparing organozinc compounds on a large scale and the toxicity of the organotin compounds. In this process, at a temperature between room temperature and 130 ° C, preferably at reflux temperature, for a period of about one to about 24 hours, preferably for about three hours, a mixture of boronic acid VII, arene VIII, a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0) acetate or 10% palladium carbon, preferably 10% palladium on carbon and a base or fluoride salt, such as sodium carbonate, triethylamine, sodium bicarbonate, cesium carbonate, tripotassium phosphate, potassium fluoride, cesium fluoride or tretabutylammonium fluoride, preferably potassium fluoride, in a solvent such as ethanol, dimethoxyethane or toluene, which optionally contains water, preferably ethanol, giving biaryl IX in which the ester radical The nylon is attached to position 6 or 7 of the chroman ring. In Step 7 of Scheme 1, ester IX is treated with an aqueous hydroxide base, such as aqueous sodium hydroxide, in an alcoholic solvent, such as isopropyl alcohol, at a temperature comprised between 40 ° C and the reflux temperature, preferably at the reflux temperature, for a period of about one to about 24 hours, preferably for about six hours. The reaction mixture is cooled to room temperature and divided between an aqueous base and an organic solvent such as ethyl acetate. This process for extracting compound X with organic solvents removes the neutral impurities, which is particularly advantageous in the last stage of this synthesis. To facilitate handling of the carboxylic acid X, this compound can be treated with a secondary amine of the formula NHR5R5, wherein R5 and R5 are as defined above, in a solvent such as toluene, to form an ammonium carboxylate of the formula Wherein R1, R2R3, R5, and R6 are as defined above. The ammonium carboxylate XVII can be treated with an aqueous acid such as a hydrochloric acid or sulfuric acid, preferably hydrochloric acid, in a solvent such as ethyl acetate, toluene or methylene chloride, preferably ethyl acetate, at a temperature ranging from 0 ° C and room temperature, for a period of 30 minutes to 3 hours, preferably 1 hour, to provide the carboxylic acid X. Scheme 2 illustrates an alternative to the coupling sequence of Steps 5 and 6 of Scheme 1. The The procedure of Scheme 2 is preferred. Step 1 of Scheme 2 is an esterification of the carboxylic acid XI with an alcohol R 0H, where R 3 and R 4 are as defined above, to generate the ester XII. In this process, the carboxylic acid XI is treated with an alcohol R4OH, preferably a primary or secondary alcohol, such as 2,2-dimethylpropyl alcohol, and an acid such as sulfuric acid, hydrochloric acid, methanesulfonic acid , toluenesulfonic acid or camphorsulfonic acid, preferably sulfuric acid, in a solvent such as toluene, dichloromethane or dichloroethane, preferably toluene, at a temperature of 0 ° C at reflux temperature, preferably at reflux temperature, for a period of 24 hour period, typically 4 hours, to provide ester XII. In Step 2 of Scheme 2, the ester XII is treated with a base and the resulting ortho metal species is trapped with a trialkylborate to give the boronate ester XII is hydrolysed to give the corresponding boronic acid XIV, Step which is carried out by procedures known to those skilled in the art. In Steps 2 and 3 of Scheme 2, ester XII is treated with a metal amide base such as lithium diisopropylamide, lithium diethylamide, lithium 2, 2, 6,6-tetramethylpiperidine or bis (2, 2, 6). , 6, -tetramethylpiperidino) magnesium preferably lithium diisopropylamide in the presence of a tri (Ci-Cß alkyl) borate, such as triisopropyl borate, in an ethereal solvent, such as THF, diisopropyl ether, dioxane or methyl tert-butyl ether , preferably THF, in a temperature range from about -78 ° C to room temperature (20-25 ° C), preferably at about 0 ° C. After a period of 10 minutes to 5 hours, typically 1 hour, the reaction is quenched with an aqueous acid to provide the boronic acid XIV. To facilitate the handling of the boronic acid XIV before proceeding to Step 4 of Scheme 2, the boronic acid XIV can be reacted with an aminodiol as illustrated in Scheme 3. In Scheme 3, the boronic acid XIV is reacted with aminodiol XV wherein R8, mn are as defined above, in a solvent such as isopropanol, ethanol, methanol, hexanes, toluene or a combination of the above solvents, preferably isopropanol, at a temperature within the range of 0 ° C to reflux temperature, preferably at room temperature, for a period of 15 minutes to 10 hours, preferably 10 hours, to provide the amine XVI complex. To proceed to Step 4 of Scheme 2, the amine complex XV is hydrolyzed to obtain the boronic acid XIV according to procedures known to those skilled in the art. Such methods include the use of an aqueous acid, such as hydrochloric acid. Step 4 of Scheme 2 is the Suzuki coupling between boronic acid XIV and chromanol VI to form the biaryl linkage of IX. In this process, a mixture containing boronic acid XIV, chromanol VI, a palladium catalyst such as tetrakis (triphenylphosphine) -palladium (0), dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, dimer is prepared of allyl palladium chloride, tris (dibenzylideneacetone) dipalladium (0) or 10% palladium on carbon, preferably tetrakis (triphenylphosphine) -palladium (0), a base or fluoride salt, such as sodium carbonate, triethylamine, sodium bicarbonate, cesium carbonate, tripotassium phosphate, potassium fluoride, cesium fluoride, sodium hydroxide, barium hydroxide or fluoride of tetrabutylammonium, preferably sodium carbonate, and a solvent such as toluene, ethanol, dimethoxyethanol, optionally containing water, preferably toluene containing water. In chromanol VI, which is prepared according to Scheme 1, X ', which is attached to position 6 or 7 of the chroman ring, represents a halide or perfluoroalkyl sulphonate Ci-C, preferably bromide, iodide or sulfonate of trifluoromethane. The mixture is stirred at a temperature between room temperature and reflux temperature, preferably at reflux temperature, for a period of about 10 minutes to about 6 hours, preferably 1 hour, to provide biaryl IX. In Step 5 of Scheme 2, ester IX is hydrolyzed to provide carboxylic acid X as described above for Step 7 of Scheme 1. The present invention is illustrated by the following examples, but is not limited to the details of the same. In the following examples, the term "room temperature" means a temperature in the range of about 20 ° C to about 25 ° C.

EXAMPLE 1 (R) -4-Benzyl-3- (3-phenyl-propionyl) -oxazolidin-2-one To a solution of (R) - (+) - 4-benzyl-2-oxazolidinone (910 g, 5.14 mol) and 500 mg of 2,2-dipyridyl as indicator, in tetrahydrofuran (9) I) at -78 ° C, a 2.5 M solution of BuLi in hexanes (2.03 I, 5.14 mol) was added over 30 minutes. The temperature of the reaction mixture was maintained at less than -55 ° C during the addition. The reaction mixture was cooled to -75 ° C and hydrocinnamoyl chloride (950 g, 5.63 moles) was added over 5 minutes. The reaction mixture was considered complete by thin layer chromatography (hexanes / ethyl acetate, 2: 1). The reaction was stopped by the addition of 10% aqueous sodium bicarbonate (3.6 I) and water (3.6 I). The aqueous phase was separated and extracted with ethyl acetate (3 I). The combined organic layers were washed with 5% aqueous sodium carbonate (3.6 l) and saturated aqueous sodium chloride (2 l), dried over magnesium sulfate and concentrated in vacuo to obtain approximately 2 l of the viscous yellow suspension. This suspension was dissolved in ethyl acetate (3 I), concentrated to a solid and dissolved in ethyl acetate at 50 ° C. Hexanes (10J I) were added and the mixture was slowly cooled to 10 ° C, resulting in the precipitation of solids which were stirred at 10 ° C for 30 minutes. The solids were collected by filtration, washed with hexanes and air dried at room temperature to yield 1.4 kg (88%) of (R) -4-benzyl-3- (3-phenylpropionyl) -oxazolidin-2-one in the form of pale yellow needles: 1 H NMR (300 MHZ, CDCL3) d 7.14-7.33 (m, 10 H), 466 (m, 1 H), 4.17 (t, j = 3.4 Hz, 2 H), 3.26 (m, 3H), 3.03 (t, J = 7 Hz, 2H), 2.75 (dd, j = 9.5, 13.4 Hz, 1 H); IR 1787, 1761, 1699, 1390, 1375, 1308, 1208, 1208, 1203, 746, 699 p.f. 102-104 ° C.

EXAMPLE 2 \ 4R- \ Z (2R.3R) 1-BencM-3-r2-benzyl-3- (4-bromo-2-fluoride-phenyl) -3-hydroxy-propionyl-oxazolidin-2-one.

To a solution of (R) -4-benzyl-3- (3-phenyl-propynyl) -oxazolidin-2-one (1604 g, 3.44 mol) in dichloromethane (5.6 I) at -5 ° C, dibutylborolate triflate was added (1133g, 4.13 moles) for 20 minutes, followed by the addition of triethylamine (719 ml, 5.16 moles) while maintaining a reaction temperature of less than 5 ° C. This mixture was cooled to -70 ° C and a solution of 4-bromo-2-fluoride-benzaldehyde (699g, 3.44 moles) in dichloromethane (2 I) was added over 30 minutes. The mixture was allowed to reach a temperature of -10 ° C for one hour, at which time it was considered complete by thin layer chromatography (hexanes / ethyl acetate, 2: 1). The reaction was stopped by the addition of potassium phosphate monobasic-sodium hydroxide buffer at pH 7 (3.5 I) for 30 minutes, followed by methanol (1.8 I) and 35% aqueous hydrogen peroxide (1.8 I) for 1.5 hours, while a reaction temperature of less than 15 ° C was maintained. The organic layer was separated, washed with saturated aqueous sodium bicarbonate (6.7 I) and diluted with anhydrous ethanol (4 I) and 25% aqueous sodium bisulfite. The organic layer was separated, washed with water (4 L), dried over magnesium sulfate and concentrated in vacuo to give 1818 g (103% .- crude weight) of [4R- [3 (2R, 3R)] ] -4-benzyl-3- [2-benzyl-3- (4-bromo-2-fluoride-phenyl) -3-hydroxy-propionyl] -oxazolin-2-one as a highly viscous amber oil: 1 H NMR (400 MHZ, CDL 387.46 (t, J = 8.0 HZ, 1 H), 7.16-7.32 (m, 1oH), 6.94-6.96 (m, 2H), 5.35 (d, J = 4.7 Hz, IH), 4.92-5.29 (m, IH), 4.45-4.51 (m, IH), 3.92 (m, 2H), 3.01-3.14 (m, 3H), 2.83 (dd, J = 3.1, 13.6 Hz, IH), 2.05 ( dd, J = 10.0, 13.5 Hz, IH), IR3460 (width), 1780, 1696, 1483, 13388, 1350, 1209, 1106, 1068, 877, 760, 747, 701, 583, 512, 486 cm "1.

EXAMPLE 3 1- Methyl-2-pyrrolidinone solvate of T4R-r2R.3R) 11-4-benzyl-3-r2-benzyl-3- (4-bromo-2-fluoride-phenyl) -3-hydroxypropyl-H -oxazolidin- 2-one To a solution of (R) -4-benzyl-3- (3-phenyl-propionyl) -oxazolidin-2-one (12.0 kg, 38.8 moles) in dichloromethane (180 I) at a temperature of -70 ° C at - 80 ° C, titanium tetrachloride (8.8 kg, 46.6 moles) was added over 30 minutes, to give a slurry which was stirred for a further 30 minutes at a temperature of -70 ° C to -80 ° C. N, N, N1, N-tetramethylethylenediamine (17. 6 I, 116.4 moles) was added over 30 minutes to give a more fluid reaction mixture. 1- Methyl-2-pyrrolidinone (7.6 g, 77.6 moles) was added and the reaction mixture was stirred for 30 minutes, all while maintaining a reaction temperature lower than -65 ° C. A solution of 4-bromo-2-fluoride-benzaldehyde (7.9 kg, 38.3 moles) in dichloromethane (38 I) was added over 30 minutes, while maintaining a reaction temperature less than or equal to -68 ° C. The reaction mixture was allowed to warm to 20 ° C for 8 hours, at which time it was cooled to 10 ° C and quenched with a 5.0 kg solution. of ammonium chloride in 11 l of water, inducing the formation of a white precipitate and an exotherm of 28 ° C. Celite® (12 kg) was added and the reaction mixture was stirred for 12 hours at 20 ° C. The reaction mixture was filtered, concentrated to atmospheric pressure to an oil, treated with hexanes (120 I), concentrated to about 50 I, cooled slowly to 0 ° C and granulated for 24 hours. The crude product, 24.3 kg, was isolated by filtration, combined with the crude products of two similar reactions in 110 I of dichloromethane, treated with 320 I of hexanes, concentrated at atmospheric pressure to a final volume of about 250 I (Distillate temperature 65 ° C), seeded with the authentic product and cooled slowly with granulation for 18 hours at 20 ° C. Filtration yielded 67.4 kg (94%) of solvate of 1-methyl-2-pyrrolidinone from 1-methyl-2-pyrrolidinone solvate of [4R- [2R, 3R)]] - 4-benzyl-3- [2-benzyl] 3- (4-bromo-2-fluoride-phenyl) -3-hydroxypropionyl] -oxazolidin-2-one as a light brown granular solid: 1 H NMR (400 MHz, CDCl 3 87.46 (t, J = 8.0 Hz, 1 H), 7.5-7.29 (m, 10H), 6.94 (dd, J = 1.9, 7.2, Hz, 2H), 5.34 (d, J = 4.8 Hz, 1 H), 4.91-4.96 (m, 1 H) , 4.44-4.49 (m, 1 H), 3.90-3.95 (m, 2H), 3.55 (sa, 1 H), 3.37 (dd, J = 7.2, 7.2 Hz, 2H) 3.00- 3.13 (m, 2H), 2.83 (s, 3H), 2.82 (dd, J = 3.3, 13.3 Hz, 1 H), 2.36 (dd, J = 8.2, 8.2 Hz, 2H), 1.97-2.06 (m, 3H); IR 33150 (width), 1776, 1695, 1652, 1600, 1221, 1050, 996, 953, 875 cm "1; p.p. 80-83 ° C.

EXAMPLE 4 (IR.2S) -2-Benzyl-f4-Bromo-2-fluoride-phenylH-propane-1,3-diol A 2M solution of lithium borohydride in tetrahydrofuran (1.7 I, 3. 4 moles) was diluted with tetrahydrofuran (1.7 I) and carefully treated with water (61 ml, 3.4 moles) for 15 minutes. This mixture was stirred at room temperature until the evolution of hydrogen ceased (0.5 to 1 hour) and then it was added to a solution of 4R- [2R, 3R)] - 4-benzyl -3- [2-benzyl] 3- (4-bromo-2-fluoride-phenyl) -3-hydroxypropionyl] -oxazolidin-2-one (1.75 kg, 3.4 moles) in tetrahydrofuran (8.75 I) at 0 ° C for 30 minutes. The resulting white and milky suspension was allowed to warm to room temperature for 12 hours, at which time it was considered complete by thin layer chromatography (hexanes / ethyl acetate, 2: 1). The reaction mixture was cooled to 15 ° C, quenched with water (5.25 L) for 15 minutes and stirred 10 minutes more before adding 35% aqueous hydrogen peroxide (2.6 L) for 20 minutes. The reaction mixture was stirred for 15 minutes and then diluted with ethyl acetate (5.3 I) and water (4.1). The organic layer was separated and washed with water (5.3 I), 5% aqueous sodium bisulfite (5.25 L) and 50% saturated aqueous sodium chloride (7.5 L). Peroxides were detected in the organic layer, so that it was further washed with 5% aqueous sodium bisulfite (5 I) and 50% saturated aqueous sodium chloride (6 I). The organic layer was concentrated in vacuo to an oil, diluted with ethyl acetate (4 L) and hexanes (13 L) and washed with 1N aqueous hydrochloric acid (6 times with 17 L) to remove (R) - (+) - 4-benzyl-2-oxazolidinone. The organic layer was washed with saturated aqueous sodium bicarbonate (5.3 I), diluted with toluene (2 I) and concentrated in vacuo to yield 1138g (98%) of) 1 R, 2S) -2-benzyl-1- ( 4-bromo-2-fluoro-phenl) -propane-1,3-diol as an oil 1 H NMR (400 MHZ, CDCL 3) 87.47-7.51 (m.hour), 7.33 (dd, J = 1.9, 8.3 Hz, 1 H), 7.15-7.25 (m 4H), 7.04-7.06 (m, 2H), 5.39 (d J = 20.6 HZ, 1 H), 3.77 (dd J = 3.0, 10.7 HZ, 1 H), 3.64 (dd) , J = 5.0, 10.8 Hz, 1 H), 3.44 (sa, 1 H) 2.68 (dd, J = 11.0, 13.8 HZ), 2.59 (dd, J = 4.1 13.9 Hz, 1 H), 2.15 - 2.20 (m , 1 H), 2.01 (ss, 1 H); IR 3370 (width), 3269 (width), 1485,1406,1213, 1033,1021, 870, 700 cm-1-.

EXAMPLE 5 (3S, 4R) -3-benzyl-7-bromo-chroman-4-ol A 1 M solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (6.55 I. 6.55 mol) was added over 20 minutes to a solution of (1 R, 2S) -2-benzyl-1- (4-bromo-2-fluoro) phenyl) -propane-1,3-diol (1975 g, 5.82 mol) in dimethyl sulfoxide (9.88 I) at room temperature. The mixture was slowly heated to 60 ° C in vacuum, produced by a vacuum cleaner to slide the tetrahydrofuran from the reaction mixture and then heated to a temperature of 60 to 65 ° C for 5 hours, under vacuum, produced by a vacuum cleaner. , at which time the reaction was considered complete according to thin layer chromatography (hexanes / ethyl acetate, 2: 1). The reaction mixture was cooled to room temperature and quenched by the addition of water (10 L), followed by 1 N aqueous hydrochloric acid (10 L). The resulting brown suspension was filtered, washed with water (2 I) and dissolved in ethyl acetate (12 1). This solution was washed with water (twice with 12 I), concentrated to a low volume, dissolved in isopropyl ether (4 I) and concentrated under atmospheric pressure at a temperature of 50 to 60 ° C to obtain 1.0 I, moment in which the solids began to precipitate. The resulting suspension was cooled to room temperature, stirred for 12 hours, concentrated to half its volume, cooled to a temperature of 0 to 5 ° C and filtered to give 916 g (49%) of ( 3S, 4R) -3-benzyl-7-bromo-chroman-4-ol as a white solid. The filtrate was concentrated to a dark oil (906 g), dissolved in isopropyl ether (1.5 I) at reflux, it was cooled to room temperature, stirred and filtered to yield an additional 82 g of solid. The filtrate was concentrated and chromatographed on silica gel (60-230 mesh) eluting with 3: 1 hexanes / ethyl acetate. The product-rich fractions were concentrated and recrystallized from isopropyl ether to yield an additional 82 g of solid. The total yield of (3S, 4R) -3-benzyl-7-bromo-chroman-4-ol was 1080 g (58%): 1 H NMR (400 MHz CDC) 87.29-7.33 (m, 2 H), 7.21- 7.25 (m, 1H), 7.15-7.19 (m, 3H), 7.06-7.09 (m, 2H), 4.44 (sa, 1 H), 4.21 (dd, J = 2.6, 11.3, Hz 1 H) 3.97 (dd) , J = 4.5, 11.3 Hz, 1 H) 2.68 (dd, J = 6.5, 13.8 Hz, 1 H), 2.51 (dd, J = 9.1, 13.8 Hz, 1 H), 2.18-2.23 (m, 1 H) , 1.85 (d., J = 4.3 Hz, 1 H); IR 3274 (broad), 1598, 1573, 1493, 1480, 1410, 1219, 1070, 1052. 1023, 859, 700, cnrr1; p.f. 143.5-144.0 ° C EXAMPLE 6 (3S, 4R) -3-benzyl-7-bromo-chroman-4-ol To a solution of (1 R, 2S) -2-benzyl-1- (4-bromo-2-fluoro-phenyl) -propane-1,3-diol (prepared from 33.5 kg (54.8 moles of solvate of 1 -methyl-2-pyrrolidinone of [4R- [3 (2R, 3R)]] -4-Ben? l-3- [2-benzyl-3- (4-bromo-2-fluoride-phenyl) -3-hydroxy- propionyl] -oxazolidin-2-one without isolation) in 185 I of tetrahydrofuran, 12.9 kg (115 moles) of potassium tert-butoxide was added.The reaction mixture was heated to reflux for 4 hours, at which time it was observed that the reaction was complete by thin layer chromatography (hexanes / ethyl acetate, 3: 1) .The reaction mixture was cooled to room temperature, quenched with 170 I of water, diluted with 83 I of ethyl acetate, Ethyl and acidified to pH 5.3 (aqueous layer) with 7.5 I of concentrated hydrochloric acid The organic layer was concentrated in vacuo to about 38 I of a suspension, diluted with 76 I of isopropyl ether, heated to dissolve the solids, it cooled slowly at 0 ° C and granulated at 0 ° C for 12 hours. It was isolated by filtration (3S, 4R) -3-benzyl-7-bromo-chroman-4-ol, 5.1 kg of white solid. The mother liquor was washed with 4 I of saturated aqueous sodium chloride, concentrated to a final volume of 57 I and granulated at 0 ° C for 12 hours to produce a second harvest of 4.3 kg of (3S, R4) -3- benzyl-7-bromo-chroman-4-ol. A second identical reaction mixture was inactivated, diluted with ethyl acetate and acidified as described above. The organic layer was dried over 10 kg of magnesium sulfate, concentrated at atmospheric pressure to about 30 l of a suspension, diluted with 38 l of isopropyl ether, concentrated to about 57 l, cooled slowly and granulated to a temperature of 0 to 10 ° C for 12 hours. It was isolated by filtration (3S, 4R) -3-benzyl-7-bromo-chroman-7-ol, 8J kg. The mother liquors were combined with the mother liquor from the second collection of the first reaction, concentrated to obtain an oil, solidified by cooling, granulated in 6 I of isopropyl ether at 20 ° C for 12 hours and at 0 ° C for 2 hours. hours, and filtration gave 6.3 kg of (3S, 4R) -3-benzyl-7-bromo-chroman-4-ol, after washing with cold isopropyl ether. The combined collections of the two reactions were dried to give 20.8 kg (59%) DE (3s, 4r) -3-benzyl-7-bromo-chroman-4-ol.

EXAMPLE 7 Acid (3R.4RH3-benzyl-4-hydroxy-chroman-7-yl) -boronic acid To a solution of (3S, 4R) -3-benzyl-7-bromo-chroman-4-ol (377 g, 1.18 mol) in tetrahydrofuran (5.6 I) at -75 ° C, a 1.48 M solution of metii was added. -litium in ether (1.6 I, 2.37 moles) for 45 minutes, while maintaining a temperature lower than -65 ° C for 1 hour, followed by the addition of a 2.5 M solution of butyllithium in hexanes (440 ml, 1.3 moles) for 15 minutes. The reaction mixture was stirred at less than -65 ° C for 1 hour, followed by the addition of a 1.0 M solution of boranotetrahydrofuran complex (5.91, 5.9 moles) for 30 minutes. The reaction mixture was warmed to 0 ° C, quenched by the addition of water (4.4 L), adjusted to pH 2 with 1N aqueous hydrochloric acid (4 L) and extracted with isopropyl ether (4 L). The aqueous layer was extracted with isopropyl ether (4 L) and the combined organic layers were washed with 0.5 N aqueous sodium hydroxide (7.2 L). The aqueous layer was adjusted to pH 3 with 1 N aqueous hydrochloric acid (5.5 I) and extracted with ethyl acetate (5.4 I and 2.7 I). The ethyl acetate layers were pooled over magnesium sulfate and concentrated in vacuo to yield 304.5 g (91%) of (3S, R4) - (3-benzyl-4-hydroxy-chroman-7-yl) -boronic acid in shape of a yellow foam: 1 H NMR (300 MHz, CDCl 3) 87.35-7.00 (m, 8H), 4.42 (d, J = 4.1 Hz, 1 H), 4.19 (d, J = 11 Hz, 1 H), 3.90 (m, 1 H), 2.68 (dd, J = 6.2, 13.8 Hz, 1 H), 2.47 (m, 1 H), 2.15 (m, 1 H); IR 3330 (wide), 1413, 1348, 1320, 1211, 1025, 749, 730, 700 cnr? 1.

EXAMPLE 8 Ethyl ester of (3R.4R) -2- (3-benzyl-4-hydroxy-chroman-7-yl) -4- trifluoromethyl-benzoic acid A mixture of ethyl 2-iodo-4-trifluoromethyl-benzoate (723 g, 2. 1 mol), (3S, 4R) - (- 3-benzyl-4-hydroxy-chroman-7-yl) -boronic acid (627 g, 2. 2 moles), potassium fluoride (366 g, 6.3 moles), 10% palladium on carbon (157 g, with 50% water) and anhydrous ethanol (6.27 I) was heated to reflux for 3 hours, at which time thin layer chromatography (toluene / acetic acid, 5: 1) indicated that the reaction was complete. The reaction mixture was diluted with isopropyl ether (8 L), filtered through Celite® and washed with 10% aqueous sodium bicarbonate (1.5 L). The aqueous layer was separated and extracted with isopropyl ether (3 I). The combined organic layers were washed with water (6 l), dried over magnesium sulfate and treated with Darco® G-60 (1.0 kg) and silica gel (1 kg, 70-230 mesh) at room temperature. This mixture was filtered through a layer of silica gel (70-230 mesh) and concentrated in vacuo to obtain 922 g of dark oil. The oil was diluted with ethyl acetate (1 L) and filtered through a column of silica gel (2 kg) eluting with ethyl acetate to give a light amber solution which was concentrated to yield 897 g (92%). %) of (3S, 4R) -2- (E-benzyl-4-hydroxy-chroman-7-yl) -4-trifluoromethyl-benzoic acid 1 H NMR (400 MHz, CDCI3) 87.89 (d, J = 8.1 Hz , 1 H, 7.63-7.67 (m, 2H), 7.18-7.38 (m, 6H), 6.91 (dd, J = 1.8 7.8 Hz, 1H), 6.86 (d, J = 1.7 Hz, 1H), 4.55 (sa , 1H), 4.25 (dd, J = 2.7, 11. 2, Hz 1 H), 4.17 (q, J = 7.1 Hz, 2H), 4.00 (ddd, J = 1.0, 4.5, 11.2 Hz, 1 H), 2J5 (dd, j = 6.4, 13.9 Hz, 1 H), 2.56 (dd, J = 9.3, 13.8 Hz, 1 H), 2. 26 (m, 1 H), 1.93 (d, j = 4.3 Hz, 1 H), 1.09 (t, j = 7.2 Hz, 3H); go 3307 (width), 3216 (width), 1734,1339, 1298, 1247, 1191, 1175, 1118, 1097, 1050, cm "1.

EXAMPLE 9 Acid (3S.4R) -2-3-benzyl-4-hydroxy-chroman-7-yl) -4-trifluoromethyl-benzoic acid A mixture of (3S, 4R) -2- (3-benzyl-4-hydroxy-chroman-7-yl) -4-trifluoromethyl-benzoic acid ethyl ester (897 g, 1.93 mol) and 10% aqueous sodium hydroxide (980 ml, 2.72 moles) in isopropyl alcohol (9 I) was heated to reflux for 6 hours, cooled to room temperature and stirred for 12 hours. The reaction mixture was diluted with water (13.5 I), hexanes (9 I) and isopropyl ether (4.5 I). The aqueous layer was separated and extracted with hexanes (9 I) and isopropyl ether (4.5 I), adjusted to pH 2 with 2 N aqueous hydrochloric acid and extracted with ethyl acetate (8 I and 4 I). The combined ethyl acetate extracts were washed with water (6 L), dried over magnesium sulfate and concentrated in vacuo to a dark amber oil which was diluted with toluene (2 L) and concentrated again to obtain a oil. The oil was dissolved in toluene (4.2 I) at 60 ° C and hexanes (8.8 I) were added at a suitable rate to maintain a temperature higher than 50 ° C. The brown solids that precipitated after the slow cooling at room temperature for several hours were filtered and washed with 2: 1 hexane / toluene (2 I). These solids were dissolved in toluene (5 I) at 60 ° C, treated with Darco® G-60, filtered, washed with toluene and concentrated in vacuo to obtain approximately 4.0 I. This mixture was heated to 50-60. ° C, was treated dropwise with hexanes (8.6 I), cooled and granulated at 5 ° C for 1 to 2 hours. The resulting solids were filtered, washed with 2: 1 hexanes / toluenes (2 L), and the wet pulp was stirred with hexanes (4 L) at reflux for 30 minutes. This mixture was cooled to room temperature, granulated for one hour, filtered and the resulting solids were dried under vacuum overnight to provide 450 g (55%) of (3S, 4R) -2- (3-benzyl) acid. 4-hydroxy-chroman-7-yl) -4-trifluoromethyl-benzoic acid as a white solid: 1 H NMR (400 MHz, CDCb) d 7.99 (d, J = 8.1 Hz, 1 H), 7.66 (dd, J = 1.1, 8.1 Hz, 1 H), 7.63 (s, 1 H), 7.15-7.32 (m, 6H), 6.89 (d, J = 1.7, 7.9 Hz, 1H), 6.85 (d, J = 1.7 Hz, 1H), 6.1 (bs, 2H), 4.50 (d, J = 4.3, Hz, 1 H), 4.18 (dd, J = 2.7, 11.2 Hz, 1 H), 3.94 (dd, J = 4.6, 11.0 Hz, 1 H), 2.74 (dd, J = 6.1 13.8 Hz, 1 H), 2.51 (dd, J = 9.4, 13.9 Hz, 1 H), 2.22 (m, 1 H); IR 3454, 3218 (width), 1699, 1431, 1337, 1299, 1275, 1258, 1191, 1178, 1135, 1123, 700 cm "1; MP 142 ° c.

EXAMPLE 10 4-Trifluomethyl-benzoic acid 2,2-dimethylpropyl ester To a suspension of 4-trifluoromethylbenzoic acid (75.0 g, 394 mmol) and 2,2-dimethyl-propyl alcohol (70.5 g, 800 mmol) in toluene (500 ml) was added concentrated sulfuric acid (3.0 ml). This mixture was stirred under reflux for 4 hours, cooled to room temperature, poured into saturated aqueous sodium carbonate (250 ml) and the layers were separated. The organic layer was washed with saturated aqueous sodium carbonate (250 ml), and brine (100 ml), and concentrated to give 2,2-dimethylpropyl ester of 4-trifluoromethylbenzoic acid (102 g, 99% yield) as a liquid yellow; Ri: 0.66 (ethyl acetate / hexanes 25/75); IR 2932, 1727, 1327, 1280, 1133, 1066, 862, 775, 704 cm "1; 1 H NMR (400 MHz, CDCb) d 8.16 (d, J = 7.9 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2h), 4.04 (S, 2h), 1.04 (S, 9), 13C NMR (100 MHz, CDCb) d 26.51, 31.61, 74.72, 123.63 (q, J = 272.7 HZ), 125.4, 129.9, 133.7, 134.35 (q, J = 31.7 Hz) 165.35.

EXAMPLE 11 Acid 2- < 2.2-dimethyl-propoxycarbonyl) -5-trifluoromethyl-benzeneboronic To a solution of 2,2-dimethylpropyl ester of 4-trifluoromethylbenzoic acid (4.225 g, 16.23 mmol) in tetrahydrofuran (40 ml) was added triisopropylborate (9.00 ml, 39.0 mmol). The solution was cooled to -78 ° C and lithium diisopropylamide (12.0 ml of a 2.0 M solution in tetrahydrofuran / heptane, 24.0 mmol) was added dropwise for 5 minutes. The reddish solution was stirred for 30 minutes, warmed to 0 ° C, and quenched by the slow addition of 1 N hydrochloric acid (50 ml). The mixture was allowed to warm to room temperature, stirred for 30 minutes and added to hexanes (200 ml). The layers were separated and the organic layer was washed successively with 2N hydrochloric acid (twice with 100 ml), and brine (50 ml). The organic extracts were dried over magnesium sulfate, filtered and concentrated to an oil. The crude product was crystallized from heptane (40 ml) to provide 2- (2,2-dimethylpropoxycarbonyl) -5-trifluoromethyl-benzeneboronic acid (3.037 g, 62% yield) as a white solid: mp = 159- 160 ° C; IR 3377 (width), 2963, 1703, 1371, 1308, 1171, 1131, 794, 709 cm "1; 1 H NMR (400 MHz, DMSO / D20) d 8.05 (d.J = 8.1 Hz. 1 H), 7.78 (d, J = 8.3 Hz, 1 H), 7.66 (s, 1 H), 3.94 (s, 2H), 0.95 (s, 9H); 13C NMR (100 MHz, DMSO / D20) d 26.69, 31.69, 74.91 , 125.29, 125.75, 128.30, 129.62, 131.98 (q, J = 31.8 Hz), 136.28, 142.68, 166.90.

EXAMPLE 12 (3S. 4R) -2- (3-Benzyl-4-hydroxy-chroman-7-ip-4-trifluoromethyl-benzoic acid) 2,2-dimethylpropyl ester A biphasic solution of 2- (2,2-dimethyl-propoxycarbonyl) -5-trifluoromethyl-benzeneboronic acid (1.72 g, 5.66 mmol), (3S, 4R) -3-benzyl-7-bromo-chroman-4-ol ( 1.80 g, 5.63 mmol), sodium carbonate (1.82 g, 17.2 mmol), and tretrakis (triphenylphosphine) palladium (0) (12 mg, 0.19 mol%) in toluene (15 ml) and water (9 ml) was stirred at reflux for 100 minutes. The reaction mixture was cooled to room temperature, poured into water (40 ml) and extracted with diisopropyl ether (75 ml). The organic extracts were washed with brine (50 ml), treated with Darco® G-60, dried over magnesium sulfate, filtered through Celite®, and concentrated. The crude product was purified by chromatography on silica gel (20/80 ethyl acetate / hexanes) to provide (3S, 4R) -2- (3-benzyl-4-hydroxy-CToman-7-dimethylpropyl) -silyl ester. -yl) -4-trifluoromethyl-benzoic acid as a white foam (2.65 g, 84% yield): Ri; 0.32 (ethyl acetate / hexanes 25/75); IR 3407 (width), 2961, 17.21, T336, 1292, 1252, 1172, 1134, 1110, 1022, 848, 749 cm "1; 1 H NMR (400 MHz, CDCb) d 7.90 (d, J = 8.1 Hz, 1 H), 7.66 (d, J = 8.1 Hz, 1 H), 7.63 (s, 1 H), 7.19-7.37 (m, 6H), 6.88-6.93 (m, 2H), 4.53 (t, J = 4.4 Hz) , 1 H), 4.22 (dd, J = 11.2, 2.5 Hz, 1 H), 3.99 (dd, J = 11.2, 3.3 Hz, 1 H), 3.78 (s, 2H), 2J3 (dd, j = 13.8, 6.3 Hz, 1 H), 2.54 (dd, j = 13.6, 9.4 Hz, 1 H), 2.20-2.80 (m, 1H), 1.81 (d, J = 5.2 Hz, 1H), 0.74 (s, 9H); 13C NMR (100 MHz, CDCb) d 26.64, 3096, 34.62, 41.53, 64.76, 67.42, 75.33, 116.77, 121.07, 122.97, 124.13, 126.44, 127.50, 127.54, 128.45, 128.60, 128.92, 129.11, 130.25, 130.31, 139.08 , 141.69, 142.03, 154.44, 168.14.

EXAMPLE 13 Acid (3S, 4R) -2- (3-benzyl-4-hydroxy-chroman-7-ip-4-trifluoromethyl-benzoic acid) A solution of (3S, 4R) -2- (3-benzyl-4-hydroxy-chroman-7-yl) -4-trifluoromethylbenzoic acid 2,2-dimethyl-propyl ester (2.34 g, 4.69 mmoles) in isopropyl alcohol (23 ml) was treated with 10% aqueous sodium hydroxide (2.3 ml, 6.4 mmol) and heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, poured into water (34 ml), and extracted with hexanes (23 ml) and isopropyl ether (13 ml). The aqueous layer was separated and extracted with hexanes (23 ml) and isopropyl ether (13 ml), adjusted to a pH of 2 with 6N aqueous hydrochloric acid, and extracted with ethyl acetate (twice 40 ml). The combined ethyl acetate extracts were washed with brine (40 ml), dried over magnesium sulfate, and filtered and concentrated to a white foam which was recrystallized from toluene / hexanes. The resulting solids were filtered and washed with hexanes, and the wet paste was stirred with hexanes (20 ml) for 1 hour. The mixture was filtered and the resulting solids were dried under vacuum to provide 1.01 g (50% yield) of (3S, 4R) -2- (3-benzyl-4-hydroxy-chroman-7-yl) -4- acid. trifluoromethyl-benzoic acid as a white solid: 1 H NMR (400 MHz, CDC b) d 8.00 (d, J = 8.1 Hz, 1 H), 7.67 (d, J = 8.1 Hz, 1 H), 7.64 (S, 1 H) , 7.18-7.36 (m, 6H), 6.91 (dd, J = 7.9, 1.7 Hz, 1 H), 6.86 (d, J = 1.7 Hz, 1 H), 4.53 (d, J = 4.2 Hz, 1 H) , 4.24 (dd, J = 11.2, 2.7 Hz, 1 H), 3.97 (dd, J = 11.0, 4.0 HZ, 1 H), 2.76 (dd, J = 13.9, 6.4 Hz, 1 H), 2.53 (dd, J = 13.7, 9.3 Hz, 1 H), 2.24-2.26 (m, 1 H). • EXAMPLE 14 2-H.3.6.21Dioxazaborocan-2-yl-4-trifluoromethyl I -benzoic acid ester 2,2-dimethylpropyl ester To a solution of 4-trifluoromethyl-benzoic acid 2,2-dimethyl-propyl ester (35.8 g, 138 mmol) in tetrahydrofuran (250 ml) was added triisopropylborate (73.0 ml, 316 mmol). The solution was cooled to 0 ° C, lithium diisopropylamide (73.0 ml of a 2.0 M solution in tetrahydrofuran / heptane, 146.0 mmol) was added dropwise over 20 minutes, and the reddish solution was stirred for an additional 30 minutes. Hexanes (200 ml) were added followed by 1N hydrochloric acid (200 ml). The mixture was stirred for 10 minutes and poured into hexanes (200 ml). The organic layer was washed with 1 N hydrochloric acid (twice 150 ml), and brine (100 ml). The organic extracts were dried over magnesium sulfate, filtered and concentrated to approximately 200 ml. Isopropyl alcohol (100 ml), and diethanolamine (15.95 g, 151.7 mmol) were added and the mixture was stirred at room temperature for 10 hours. The solids were filtered and washed with a mixture of isopropyl alcohol (15 ml) and hexanes (30 ml) to give 2,2-dimethylpropyl 2- [1,3,6,2] dioxazaborocan-2-yl ester. -4-trifluoromethyl-benzoic acid (37.83 g, 74% yield) as a white solid. mp = 233-234 ° C; IR 3077, 2963, 2862, 1722, 1480, 1467, 1371, 1331, 1298, 1290, 1279, 1254, 1161, 1117, 1108, 1087, 1074, 995, 952, 862, cm "1; 1 H NMR (400 MHz , CDCb) d 8.23 (s, 1 H), 7.72 (d, J = 7.9 Hz, 1 H), 7.52 (dd, J = 7.9, 1.3 Hz, 1 H), 6.33 (widths, 1 H), 4.08- 4.14 (m, 2H), 3.98 (s, 2H), 3.93-3.98 (m, 2H), 3.42-3.50 (m, 2H), 2.88-2.94 (m, 2H), 1.02 (s, 9H); 13C NMR (100 MHz, CDCb) 26.51, 31.69, 50.92, 63.33, 74.72, 123.94, 128.59, 132.06, 139.61, 171.56.

EXAMPLE 15 (3S, 4R) -dicyclohexylammonium-2- (3-benzyl-4-hydroxy-chroman-7-yl) -4-trifluoromethyl benzoate A mixture of 2- [1, 3,6,2] dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid 2,2-dimethylpropyl ester (7.04 g, 18.9 mmol) in toluene (45 ml) and hydrochloric acid 1.5 N (45 ml) was stirred at room temperature for 45 minutes. The aqueous layer was removed and sodium carbonate (2.73 g, 25.8 mmol), (3S, 4R) -3-benzyl-7-bromo-chroman-4-ol (5.47 g, 17.1 mmol), tetrakis (triphenylphosphine) were added. palladium (0) (24.0 mg, 20.8 / mol), and water (20 ml). The biphasic solution was stirred at reflux for 100 minutes, it was cooled to room temperature and poured into water (50 ml). The layers were separated and the organic layer was treated with Darco® G-60, filtered and concentrated. The crude ester was dissolved in isopropyl alcohol (80 ml) and 10% aqueous sodium hydroxide (8.0 ml) was added. The solution was refluxed for 3 hours, cooled to room temperature, poured into water (120 ml), and extracted with hexanes (80 ml) and isopropyl ether (40 ml). The aqueous layer was washed with hexanes (80 ml) and isopropyl ether (40 ml), adjusted to a pH of 2 with 6N hydrochloric acid, and extracted with methyl tert-butyl ether (twice 75 ml). The organic extracts were dried over magnesium sulfate, filtered and concentrated. The crude product was dissolved in methyl tert-butyl ether (40 ml), and dicyclohexylamine (4.10 ml, 20.6 mmol) was added. The mixture was stirred overnight and filtered and washed the solid with methyl tert-butyl ether (20 ml) to yield benzoate (3S, 4R) -dicyclohexylammonium-2- (3-benzyl-4-hydroxy-chroman-7-). il) -4-trifluoromethylbenzoate (7.32 g, 70% yield): mp = 209-210 ° C; IR 3307, 3025, 2939, 2858, 1626, 1564, 1429, 1398, 1388, 1333, 1168, 1119, 903, 875, 846, 838 cm "1; 1 H NMR (400 MHz, CDCb) 7.62 (d, J = 7.7 Hz, 1 H), 7.55 (s, 1 H), 7.52 (d, J = 7.9 Hz, 1 H), 7.17-7.31 (m, 6H), 7.08 (dd, J = 7.9, 1.7 Hz, 1 H), 7.00 (d, J = 1.7 Hz, 1H), 4.48 (d, J = 4.4 Hz, 1H), 4.17 (dd, J = 11.0, 2.6 Hz, 1H), 3.90 (dd, J = 11.0, 5.0 Hz 1 H), 2.74-2.79 (m, 3H), 2.50 (dd, J = 13.8, 9.4 Hz, 1 H), 1.80-1.82 (m, 4H), 2.20 (widths, 1 H), 1.68-1.70 ( m, 4H), 1.56 (d, J = 12.2 Hz, 2H), 1.00-1.26 (m, 10H) .13C NMR (100 MHz, CDCb) 24.70, 24.73, 25.03, 28.94, 29.09, 34.75, 41.75, 52.64 , 65.00, 67.57, 116.50, 121.42, 122.59, 123.JJ, 126.38, 126.73, 128.03, 128.55, 129.06, 129.45, 138.95, 139.16, 142.51, 144.20, 154.04, 173.85.

EXAMPLE 16 Acid (3S, 4R) -2 3-benzyl-4-hydroxy-chroman-7-yl) -4-trifluoromethyl-benzoic acid A mixture of (3S, 4R) -dicyclohexylammonium-2- (3-benzyl-4-hydroxy-chroman-7-yl) -4-trifluoromethyl benzoate (2.37 g, 3.89 mmol) in ethyl acetate (25 ml), and 1N hydrochloric acid (25 ml) was stirred at room temperature for 1 hour. The mixture was poured into ethyl acetate (20 ml) and the aqueous layer was removed. The organic layer was washed with water (six times 50 ml), dried over magnesium sulfate, filtered and concentrated to give (3S, 4R) -2 (3-benzyl-4-hydroxy-chroman-7-yl) acid. -4-trifluoromethyl-benzoic acid (1.66 g, 100% yield); 1 H RMÑ (400 MHz, CDCb) d 8.00 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1 H), 7.64 (s, 1H), 7.18-7.36 (m, 6H), 6.91 (dd, J = 7.9, 1.7 Hz, 1 H), 6.86 (d, J = 1.7 Hz, 1 H), 4.53 (d, J = 4.2 Hz, 1 H), 4.24 (dd, J = 11.2, 2.7 Hz, 1 H), 3.97 (dd, J = 11.0, 4.0 Hz, 1H), 2.76 (dd, J = 13.9, 6.4 Hz, 1H), 2.53 (dd, J = 13.7, 9.3 Hz, 1 H), 2.24 -2.26 (m, 1 H).

EXAMPLE 17 rr3 (2R.3R) MR.SS1-3-f2-benzyl-3- (4-bromo-2-fluro-pheny1) -3-hydroxy-propionyl-1-4-methyl-5-phenyl-oxazolidin- 2-one To a solution of (4R, 5S) -4-methyl-5-phenyl-3- (3-phenyl-propionyl) -oxazolidin-2-one (1.50 g, 4.8 mmol) in dichloromethane (23 ml) at -70 ° C titanium tetrachloride (0.6 ml, 5.3 mmol) was added to give a yellow-orange solution which was stirred for 15 minutes at -70 ° C. N, N, N ', N'-tetramethylethylenediamine (2.2 ml, 15 mmol) was added over 10 minutes to give a dark red reaction mixture which was stirred for 70 minutes at -78 ° C. 1-Methyl-2-pyrrolidone (0.90 ml, 9.7 mmol) was added dropwise and the reaction mixture was stirred for 30 minutes at -70 ° C. A solution of 4-bromo-2-fluoro-benzoaldehyde (0.990 g, 4.9 mmol) in dichloromethane (5 ml) was added dropwise while maintaining a reaction temperature of or equal to -68 ° C. The reaction mixture was stirred at -70 ° C for 60 minutes and then allowed to warm to 0 ° C for 90 minutes, at which point it was quenched with 15 ml of saturated aqueous ammonium chloride and 1.2 g. of Celite®. This mixture was stirred overnight at room temperature and filtered. The phases were separated and the organic phase was washed three times with water and once with brine, dried over magnesium sulfate and concentrated in vacuo to 2.76 g of an oil containing the title compound and 1.2 equivalents of 1-methyl- 2-pyrrolidinone: 1 H NMR (400 MHz, CDCb) d 7.48 (t, J = 8.1 Hz, 1 H), 7.09-7.34 (m, 12 H), 5.35 (d, J = 7.3 Hz, 1 H), 5.32 ( d, J = 4.9 Hz, 1 H), 4.89-4.92 (m, 1 H), 4.51 ^ 1.55 (m, 1 H), 3.65 (broad, 1 H), 3.35 (dd, J = 7.1, 7.1 Hz, 2H), 3.03-3.06 (m, 2H), 2.81 (s, 3H), 2.34 (dd, J = 8.1, 8.1 Hz, 2H), 1.95-2.03 (m, 2H), 0.40 (d, J = 6.6 Hz , 3H).

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula V or the enantiomer of said compound, wherein R1 is - (CH2) qCHR5R6 in where q is 0 to 4; each R 2 is independently selected from the group consisting of H, fluoro, chloro, C 1 -C 6 alkyl, Ci-Cβ alkoxy, phenylsulfinyl, phenylsulfonyl, and -S (0) n (Ci-Cß alkyl), where n is 0 to 2, and wherein said alkyl group, the alkyl portion of said alkoxy groups and -S (0) n (Ci-Cß alkyl), and the phenyl portion of said phenylsulfinyl and phenylsulfonyl groups they are optionally substituted by 1 to 3 fluoro groups; R 5 is H, C 1 -C 6 alkyl or phenyl substituted by R 1; R 6 is H, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 5 -C 10 heteroaryl C 5 -C 10 aryl aryl, wherein said aryl and heteroaryl groups are optionally substituted by 1 or 2 substituents independently selected from phenyl, R2, and phenyl substituted by 1 or 2 R2; X is a halogen group and is attached to the 4 or 5 position of the phenyl ring; and Y is halogen or nitro. 2 - A compound of the formula SAW or the enantiomer of said compound, wherein R1 is - (CH2) qCHR5R6 in where q is 0 to 4; each R2 is independently selected from the group consisting of H, fluoro, chloro, Ci-Cß alkyl, Ci-Cß alkoxy, phenylsulfinyl, phenylsulfonyl, and -S (0) n (Ci-Cß alkyl), wherein n is 0 to 2, and wherein said alkyl group, the alkyl portion of said alkoxy groups and -S (0) n (Ci-Cß alkyl), and the phenyl portion of said phenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1 to 3 fluoro groups; R ^ is H, C ^ -CQ alkyl or phenyl substituted by R2; R6 is H, Ci-Cß alkyl, C3-C8 cycloalkyl, C 5 -C 10 heteroaryl aryl, 5- to 10-membered aryl, wherein said aryl and heteroaryl groups are optionally substituted by 1 or 2 substituents independently selected from phenyl , R2 and phenyl substituted by 1 or

2 R2; X 'is halogen or perfluoroalkyl sulfonate of C- | - C4 and is attached to position 6 or 7 of the chroman ring.

3. - A compound of the formula Vile or the enantiomer of said compound, wherein R1 is - (CH2) qCHR5R6 in where q is 0 to 4; each R2 is independently selected from the group consisting of H, fluoro, chloro, Cj-Cß alkyl, C ^-CQ alkoxy, phenylsulfinyl, phenylsulfonyl, and -S (0) n (C- | -C6 alkyl), wherein n is 0 to 2, and wherein said alkyl group, the alkyl portion of said alkoxy groups and -S (0) n (C < \ -CQ alkyl), and the phenyl portion of said phenylsulfinyl and phenylsulfonyl groups they are optionally substituted by 1 to 3 fluoro groups; R ^ is H, alkyl of C < \ -CQ O phenyl substituted by R2; R6 is H, alkyl of C < -CQ, C3-C8 cycloalkyl, CQ-C ^ QO aryl heteroaryl from 5 to 10 members, wherein said aryl and heteroaryl groups are optionally substituted by 1 or 2 substituents independently selected from phenyl, R2, and phenyl substituted by 1 or 2 R2; and the boronic acid moiety is attached to the 6 or 7 position of the chroman ring.