MXPA02005396A

MXPA02005396A - Chemical processes and intermediates.

Info

Publication number: MXPA02005396A
Application number: MXPA02005396A
Authority: MX
Inventors: Barry Gravestock Michael
Original assignee: Astrazeneca Ab
Priority date: 1999-12-03
Filing date: 2000-11-28
Publication date: 2002-11-29
Also published as: CA2395052A1; WO2001040236A2; WO2001040236A3; HUP0204052A2; EE200200282A; GB9928499D0; KR20020058072A; BR0016087A; NO20022605L; CO5271712A1; BG106728A; IL149641A0; IS6401A; AU1715601A; CZ20021912A3; NO20022605D0; AU762241B2; ZA200203876B; EP1237895A2; AR026700A1

Abstract

The invention relates to chemical processes and chemical intermediates which are useful in the selective formation of a primary mono phosphoryl group ( OPO(OH2)) in a terminal 1, 2 diol propanoyl (HO CH2CH(OH) CO ) containing system, and to chemical processes and chemical intermediates (and processes for their manufacture) particularly useful for the manufacture of anti Gram positive oxazolidinone bacterial agents containing such functionality, in particular for the preparation of 5(R) Isoxazol 3 yloxymethyl 3 (4 (1 (2(S) hychoxy 3 phosphoryl propanoyl) 1,2,5, 6 tetrahydropyridy 4 il)3,5 difluorophenyl)oxazolidin 2 one.

Description

PROCESSES AND CHEMICAL INTERMEDIATES Field of the Invention The invention relates to chemical processes and intermediate chemical compounds. More particularly, it relates to processes and intermediates which are useful in the selective formation of a primary mono-phosphoryl group in a terminal 1,2-diol-propanoyl-containing system, more particularly to certain Gram-positive oxazolidinone antibacterial agents. that contain such functionality. The invention also relates to processes for the manufacture of said intermediates and to processes for the manufacture of such oxazolidinone compounds using the intermediates.

BACKGROUND OF THE INVENTION Copending International Patent Application No. GB99 / 01753 (WO 99/64417) discloses a new class of antibacterial oxazolidinone compounds which are effective as Gram-positive antibacterial agents, and certain methods for their preparation. Of the compounds described, those of the formula (I) are included: Ref.139375 (D wherein HET is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, such ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from alkyl (1 -4C), amino, alkylamino (1-4C), alkoxy (1-4C) and halogen, and / or on an available nitrogen atom (provided that the ring is not quaternized by means of this) by alkyl (1-4C) ); R2 and R3 are independently hydrogen or fluoro; Rep is of the formula R13pCO- (wherein R13p is (1-10C) alkyl substituted by two or more hydroxy groups; 2 of which are in an 1,2-diol orientation, ie there is a terminal primary alcohol with a secondary secondary alcohol), or pharmaceutically acceptable salts, or in vivo hydrolysable esters thereof.

Of the above compounds, those in which HET is isoxazol-3-yl, 1, 2, 4-oxadiazol-3-yl, isothiazol-3-yl or 1, 2, 5-thiadiazol-3-yl (unsubstituted) , they are preferred. In vivo hydrolysable esters include compounds of the formula (I) and (1-1) in which any free hydroxy group independently forms a phosphoryl ester of the formula (PD3): HO (PD3) Of the compounds of the formula (I), those of the formula (1-1) are the pharmaceutically active anti-bacterial enantiomer. The pure enantiomer shown in (I-1), or mixtures of the 5R and 5S enantiomers, for example a racemic mixture, are included in GB99 / 01753. If a mixture of enantiomers is used, a larger amount (depending on the ratio of the enantiomers) will be required to achieve the same effect as the same weight of the pharmaceutically active enantiomer. To avoid confusion, the enantiomer shown below is the 5R enantiomer.

-D In addition, some compounds of formulas (I) and (1-1) may have other chiral centers. It will be understood that the invention encompasses all such optical isomers and diastereoisomers, and racemic mixtures, which possess antibacterial activity. It is well known in the art how to prepare the optically active forms (for example by resolution of the racemic form by recrystallization techniques, by chiral synthesis, by enzymatic resolution, by biotransformation or by chromatographic separation) and how to determine the antibacterial activity. Of the above compounds of the formulas (I) and (1-1), 5 (R) -isoxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy-3-phosphoryl-propanoyl) -1, 2, 5 is especially preferred. β-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one (hereinafter "said compound").

The preparation of said compound is described within GB99 / 01753, and the preparation is illustrated in the Reaction Scheme which is attached here (entitled "Existing Route"). The described preparation includes the isolation of the primary mono-phosphoryl compound (Example 15 of the Intermediate Compound) from a mixture of compounds (including, for example, the bis-phosphoryl and cyclic phosphoryl compounds) by the use of Intermediate Resolution Liquid Chromatography using ethyl acetate as the eluent. Other compounds of the formulas (I) and (I-1) above can be prepared using analogous chemical methods. The detailed chemical and reaction conditions employed herein are described in the accompanying non-limiting Examples, or are within the ordinary experience of the chemist specialized in medicine / organic chemistry (see also WO 97/30995, the procedural sections relevant of which are incorporated here, for details on the preparation of certain intermediate compounds). The Coherent International Patent Application No. GB99 / 01753 describes that for a compound of the formulas (I) and (1-1) containing a number of free hydroxy groups, these groups which are not converted to a prodrug functionality can be protected (e.g., using a t-butyl-dimethylsilyl group), and subsequently deprotected . Also, enzymatic methods can be used to selectively phosphorylate or dephosphorylate alcohol functionalities. Groups containing prodrugs (PD3) can be prepared by the reaction of a compound of formulas (I) and (1-1) containing suitable hydroxy group (s) with a suitably protected phosphorylating agent (which contains, for example, a leaving group of chloro or dialkylamino), followed by oxidation (if necessary) and deprotection. The "Existing Route" for said compound, although satisfactory, is not particularly suitable for the manufacture of large quantities of such products. There are a large number of chemical stages, and as such, the loss of performance in each stage can contribute to the total yield of the final product is not optimal. The selectivity of the reaction is important and may influence the yield of the desired product obtained. Poor selectivity can also lead to the formation of undesirable byproducts which require removal. Therefore there is a need to contemplate chemical routes that are efficient and make good use of raw materials and intermediate compounds. In particular, the "Existing Route" has potential difficulties associated with the selective formation, with good performance, of the primary mono-phosphoryl / secondary hydroxy moiety. Such difficulties of preparation are found in the preparation of any primary mono-phosphoryl group in a terminal 1,2-diol-propanoyl-containing system. Apart from the "Existing Route", other routes for said compound (and by analogy with other compounds of the formulas (I) and (1-1)), are possible. These include, for example, (i) a final step reaction of 3-hydroxyisoxazole with 5-hydroxymethyl-oxazolidinone (with the left-hand side of the assembled or attached molecule); (ii) the reaction of the piperidine on the left-hand side (having a 4-triflate or 4-enol phosphate group) with an oxazolidinone treated with a metal 4-phenyl (such as a 4-tin compound with the right hand of the assembled or joined molecule) using the Pd or Ni binding chemistry; (iii) the reaction of a pyridine on the left-hand side (or pyridine N-oxide) having, for example, a leaving group of 4-chloro, with a 4- (metallo) -phenyl oxazolidinone (with the side at hand right of the assembled or attached molecule), followed by reduction of the pyridine to 1, 2, 5, 6-tetrahydropyridine; (iv) the reaction of a pyridine on the left-hand side having a boronic acid group, with a 4- (leaving group) -phenyl oxazolidinone (with the right-hand side of the assembled or attached molecule) using the chemistry of the Pd, followed by reduction of pyridine to 1, 2, 5, 6-tetrahydropyridine. Suitable leaving groups include halo (for example iodine, bromine, chlorine), triflate and enol phosphate.

Reaction Scheme - Existing Ruta chlorop oppiato Ex: 2 Comp. Continuous Reaction Scheme - Existing Route (Cont.) < IK) Notes: 1. The protected aniline used as the initial starting material can alternatively be protected as -N- [SiR3] 2 wherein each R is independently an (1-4C) alkyl group, for example -N- (SiMe3 )2.

Detailed Description of the Invention A number of additional, convenient and useful methods for the manufacture of said compound (and by analogy other compounds of the formulas (I) and (1-1)), which reduce and / or they coincide, with the number of reaction steps and, reduce or eliminate the need for a chromatographic purification of the intermediates and / or the final products. The invention also relates to the application of the chemistry described herein to any system that requires information of a primary mono-phosphoryl group in a system containing 1, Terminal 2-diol-propanoyl (such as, for example, 2,3-dihydroxypropanoyl and 3,4-dihydroxy-2-oxo-butyl). In particular, the invention relates to such systems containing 1,2-diol-propanoyl in a compound of formulas (I) and (1-1), and more particularly to said compound. The invention also relates to systems containing 1,2-diol-propanoyl in a compound of formulas (I) and (1-1) wherein HET is a 6-membered heteroaryl ring linked in C containing 1 or 2 N , such ring is optionally substituted on any available C atom (provided that when the N atom is adjacent to the bond, there is no substitution on any C atom that is adjacent to this N atom) for 1, 2 or 3 selected substituents independently of (1-4C) alkyl, amino, alkylamino (1-4C), alkoxy (1-4C), alkoxycarbonyl (1-4C) and halogen. Preferred 6-membered heteroaryl rings are pyridin-2-yl, pyridazyl-3-yl or pyrazin-2-yl. The invention also relates to systems containing 1,2-diol-propanoyl in a compound of formulas (I) and (1-1) wherein HET is a 5- or 6-membered heteroaryl ring bonded in C as described herein, wherein the bond to the oxazolidinone ring is by means of a thiomethyl bond (-CH2-S-) in place of an oxymethyl bond (-CH-0-) (see claim 2 for the compounds of the invention). formula (1-2)). The invention can also be used in systems containing 1,2-diol-propanoyl in a compound of formulas (I) and (1-1) wherein HET is a 5- or 6-membered heteroaryl ring linked in C as described in WO 00/21960 (incorporated herein by reference), wherein the bond to the oxazolidinone ring is via an aminomethyl bond (-CH2-NH2-). In the Reaction Schemes that are annexed, the conditions indicated are for illustration. In the Reaction Schemes, the protective groups have also been referred. For examples of protective groups see one of the many general texts on the subject, for example, "Protective Groups in Organic Synthesis" by Theodora Green (editor: John Wiley & amp;; Sons). The protecting groups may be used and removed by any convenient method as described in the literature or known to the skilled chemist when appropriate for the removal of the protective group in question, such methods being chosen to effect the removal of the protective group with minimal alterations. of the groups in another part of the molecule. Intermediate Compounds (Reaction Schemes IA to IC) In one embodiment, certain useful intermediates are provided, and methods for the preparation thereof, in particular, the compounds (IE), (IF) and (IK), and the Reaction Schemes. shown in ÍA, IB and 1C. Reaction Schemes may be generalized to cover other analogous compounds of formulas (I) and (1-1).

Chemistry of the Diol (Reaction Schemes 2A to 2C) In another embodiment a procedure for the preparation of 5 (R) -isoxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy) is provided. 3-phosphoryl-propanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one ("said compound" - (2F)) comprising the steps illustrated in either of the Reaction Schemes 2A to 2C that are attached. Reaction Schemes may be generalized to cover other analogous compounds of formulas (I) and (1-1) and (1-2) mentioned herein (see claim 2 for (1-2)). In addition, the invention also relates to the application of the chemistry described herein to any system that requires the formation of a primary mono-phosphoryl group (-OPO (OH) 2) in a system containing terminal 1,2-diol-propanoyl (H0-CH2CH (OH) -CO-). A particularly preferred method is that illustrated in Scheme 2B. Accordingly, the use of the hydroxy acid (2H) allows the formation of a protected primary 1,2-diol species (PgO-CH2CH (OH) -CO-, where Pg is a suitable protective group for protecting alcohols and removable by an acid, such as, for example, t-butyl, as in Compound (21) in the case of said compound). This then allows the formation of the secondary phosphoryl compound (which can optionally be protected, for example in the form of a phosphate ester, such as the t-butyl ester as in Compound (2J) in the case of said compound). During the treatment with the acid, the protected primary alcohol is deprotected and the secondary phosphoryl compound (deprotected where appropriate and) is rearranged favorably (possibly by means of a cyclic intermediate) to the primary phosphoryl compound to give a functionality ( HO) 20P0-CH2CH (OH) -C0- (Compound (2F) in the case of said compound). In a preferred embodiment, the secondary phosphoryl compound is in the form of a phosphate ester. A secondary phosphoryl compound suitable for use in the process can be obtained, for example, by standard phosphorylation chemistry, for example as described herein, using tert-butyl tetraethylphosphorodimidite, or using phosphorous oxychloride or (Et0) 2P0Cl. Union Chemistry (Reaction Schemes 3A to 3D) In a further embodiment a procedure is provided for the preparation of 5 (R) -Isoxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy) 3-phosphoryl-propanoyl) -1,2,5,6,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one comprising the steps illustrated in any of the accompanying Schemes 3A to 3D. The Reaction Schemes may be generalized to cover other analogous compounds of the formulas (I) and (1-1) and (1-2) mentioned herein. The 3C reaction scheme is particularly preferred, and offers the advantageous use of the hydroxy acid (2H) to give the protected primary alcohol, and then the selective secondary phosphorylation to give (3D); followed by the binding, and then by the deprotection of the protected primary alcohol and the predominant rearrangement of the secondary phosphoryl compound to the primary phosphoryl compound. In summary, Reaction Scheme 3C offers a particularly favorable route for the compound, which comprises comparatively few reaction steps in a convergent manner. The binding reaction of Reaction Schemes 3A to 3D can be carried out in the presence of a suitable base, for example, nBuLi at almost -70 ° C, in a suitable inert solvent or diluent, such as, for example, dimethyl sulfoxide, 1,2-dimethoxyethane, tetrahydrofuran (THF), tetrahydropyran, diglyme or toluene. A preferred solvent is a mixture of THF and toluene. A preferred solvent is a mixture of THF and toluene. The reaction is conveniently carried out at a temperature in the range, for example, from -100 to -70 ° C, conveniently at or near -70 ° C.

The joining of Schemes 3A to 3D can also be achieved by Grignard chemistry, using, for example, an appropriate 4-bromo-phenyl compound in place of (IF). The starting materials for the reactions described herein can be obtained as described herein, or by analogy with such methods, or by standard procedures of organic chemistry. The procedures and intermediates described herein are illustrated within the accompanying non-limiting Examples, which are provided for the purpose of illustration only. According to a further feature of the invention there is provided the use of an intermediate compound as described herein for the manufacture of a compound of the formulas (I) and (1-1) (or of said compound).

Reaction Scheme IA - Routes for Intermediates (R) -Isoxazol-3-yloxymethyl-3- (3,5-di luorofenyl) oxazolidin-2-one ? H r N ..

(IF) Notes: 1. Intermediate Compounds (IE) and (IF) are preferred intermediate compounds, especially (IF). 2. In the reaction from (IB) to (IC), and from (IE) to (IF), a different leaving group of Br could also be used.

For the reaction from (IB) to (IC), the allyl alcohol could be used and the substitution effected in a reverse direction to that shown with a leaving group (for example chlorine or mesylate) on (IB).

Reaction Scheme IB - Routes for Intermediates 5 (R) -Igoxazol-3-yloxymethyl-3- (3,5-difluorophenyl) oxazolidin-2-one 5 (R) -isoxazol-3-yloxymethyl-3- (4) - (1, 2,5,6-tetrahydropyrid-4-yl) -3,5-di-luo-phenyl) -oxazolidin-2-one Notes: 1. The nosylate and the mesylate can also be used in place of the tosylate in the epoxide (IH-1). Preferably the nosylate is used. 2. Protective groups other than benzyl (for example t-BOC) can also be used in the compounds (II) and (IJ) • 3. The chiral integrity of (IH) and (IF) can be determined by chiral or non-chiral CLAR. 4. For the. details on the preparation of (IB) see Example 1 hereinafter. In the reaction of (IB) with the epoxide (IH-1) of Example 1 hereinafter, it shows the retention of the stereochemistry, ie the (R) - and (S) -glycidyl nosylates give, respectively, the product of the ether (R) -, (S) -glycidyl. However, if the chirality is not retained in such a reaction then the other epoxide isomer can be used as a starting material. If a racemate is obtained, the chiral resolution / chromatography can be used to obtain the desired isomer. 5. The reaction of (IG) with (IH-2) is effected in the presence of a base such as n-BuLi. Weaker bases are to be preferred, such as triethylamine, Triton-B (TM) and CsF (see Tetrahedron, 55, 14381 (1999)). 6. DIPEA is di-isopropyl-ethylamine.

Reaction Scheme IC - Routes for the intermediate compounds l- [4- (l-Benzyl-l, 2,3,6-tetrahydro-pyridin-4-yl) -3,5-di luoro-phenylamino] -3- ( isoxazol-3-yloxy) -propan-2-ol (m-2) (IN) Notes: 1. (IN) can be treated, for example, with phosgene or dimethyl carbonate to form the oxazolidin-2-one ring.

Reaction Scheme 2A - Dxol Chemistry: Route for the Diol and Cyclic Phosphoryl Chemistry (2F) Notes: - 1. The opening of the cyclic phosphoryl (2E) provides predominant selectivity as the monophosphoryl compound (eg 85: 15 - primary : secondary).

Reaction Scheme 2B - Diol Chemistry: Route for the protected diol and rearrangement to the primary mono-phosphoryl dinitro- OH 7 0 genac ± dn «.ßuo- JL -o OK) eoc O t-Bu Serine Hydroxy acid Butyl Ether > yrHCl txií'orl lo S Seeccuunnddaarriiio Notes: 1. The reaction from (2G) to (2H) is carried out under standard conditions, with retention of stereochemistry. The dinitrogenation reaction can be carried out using aqueous sulfuric acid and aqueous sodium nitrite at room temperature. Reduction of the temperature with sulfamic acid, extraction with TBME and washing with brine, provides the product (2H). 2. The use of hydroxy acid allows the formation of a protected primary 1,2-diol species. This allows the formation of the secondary phosphoryl compound (2J). During the treatment with the acid (for example 4M HCl at room temperature), this secondary phosphoryl compound rearranges favorably (possibly by means of a cyclic intermediate) to the primary phosphoryl compound (2F). The speed of rearrangement is dependent on the concentration of the acid and the temperature. 3. Other non-bulky protecting groups in place of t-Bu may be used in (2G) and (2H), for example, any (1-4C) alkyl group; any silyl group (for example trimethylsilyl); or a benzyl group (using for example acid catalyzed removal, or a reductive removal using for example hydrogenation). 4. (2F) can be converted at room temperature, for example, to the disodium salt by the treatment with 2 eq. mol. of sodium carbonate and the work in acetone and then in IMS. 5. (IK) can be prepared as shown in the Existing Route Reaction Scheme or as described in Example 4 hereinafter, in which, for example, Example 2 of the Intermediate Compound can be prepared as follows: A solution of the 3, 5-difluoroaniline in THF is cooled to -70 ° C. A solution of n-butyl lithium in toluene is added and the chlorotrimethylsilane is then added to complete the bis-trimethylsilyl protection of the 3, 5-difluoroaniline. A solution of n-butyl lithium in toluene is added to the cooled solution and a solution of l-benzyl-4-piperidone in toluene is then added while maintaining the temperature. When the reaction is complemented, after heating to near room temperature, a solution of aqueous hydrochloric acid is added. The aqueous layer of the intermediate alcohol compound (Example 1 of the Intermediate Compound) is separated and heated to reflux while tetrahydrofuran is simultaneously distilled off to supplement the formation of Example 2 of the Intermediate Compound. The reaction is then diluted with water and butanol before adjusting the pH with aqueous ammonia at 40 ° C. The aqueous layer is separated and discarded. The cyclohexane is added to the organic phase to precipitate the product, which is then removed by filtration after cooling to room temperature, washed with a mixture of butanol / cyclohexane, cyclohexane and dried under vacuum. The Intermediate Compound of Example 4 can be prepared as described in Example 4 hereinafter, or using a solution of n-butyl lithium in toluene. 6. (21) can be converted to Diol (2D) by deprotection, for example using - acid conditions, such as HCl / dioxane. 7. Hydrogen peroxide can be used in place of mCPBA in the conversion of (21) to (2J). The reaction is carried out in a suitable solvent, "such as dioxane.

Reaction Scheme 2C - Diol Chemistry: Route for the primary mono-phosphoryl (ROfeHOJOM, t Notes: 1. R includes (1-4C) alkyl, for example, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl; hydrogen and benzyl. In this specification the generic term "(1-4C) alkyl" includes both straight chain and branched chain alkyl groups. However, references to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched chain alkyl groups such as "isopropyl" are specific for the branched chain version only. A similar convention applies to any other generic forms. 2. Reaction with the epoxide (1M) predominantly provides the primary phosphoryl compound.

Reaction Scheme 3A - Union Reaction 1 « Vofu or Ksq? Tim of Reaction 2? Notes: 1. In the reaction of (IF) with (3A), other treatment agents with a metal other than BuLi can be used (e.g., LDA). 2. In the reaction of (IF) with (3A), after treatment of (IF) with Bu-Li, the lithiated compound can be transmetalized for example, with titanium chloride, titanium i-propoxide or cerium chloride a temperature of about -30 ° C. Such transmetalization restricts the enolization of piperidinone and thus aids the reaction at the desired center.

Reaction Scheme 3B - Union Reaction 2 (IB) See reaction scheme 2A Notes: 1. (3B) can be prepared from (2B) - see reaction scheme 2A - using standard chemistry.

Reaction Scheme 3C - Union Reaction 3 phosphorylation Notes: 1. (2H) can be prepared from O-t-Bu-serine (2G) using standard chemistry - see Scheme Reaction 2B. 2. A cyclic phosphoryl equivalent of (3D) can also be used, which (after the binding reaction) is then opened to give the primary monophosphoryl compound (see Reaction Scheme 2A). (3D) is a preferred Intermediate Compound. 3D Reaction Scheme - Union Reaction 4 Like Reaction Scheme 2C to give (2F) The invention is illustrated, but not limited, by the following Examples in which (here before and hereinafter) unless stated otherwise: (i) evaporations were carried out by rotary evaporation in vacuo and the procedures of work were carried out after the removal of residual solids by filtration; (ii) the operations were carried out at room temperature, which is typically in the range of 18-26 ° C and in air unless stated otherwise, or unless the skilled person could otherwise work under a inert atmosphere; (iii) column chromatography (by the instantaneous procedure) was used to purify the compounds and was carried out on Merck Kieselgel silica (Art. 9385) unless otherwise stated; (iv) the returns are given for illustration only and are not necessarily the maximum that can be obtained; (v) the structure of the final products of formulas (I) and (1-1) was generally confirmed by NMR and mass spectral techniques [the proton magnetic resonance spectra were generally determined in DMSO-D6 unless establish otherwise using a Varían Gemini 2000 spectrometer operating at a field strength of 300 MHz, or a Bruker AM250 spectrometer operating at a field strength of 250 MHz; displacements or chemical changes are reported in parts per million downfield of tetramethylsilane as an internal standard (scale d) and the multiplicities of the peaks are shown as follows: s, singlet; d, doublet, AB or dd, doublet of doublets; t, triplet, m, multiplet; the spectral data of the mass by bombardment of fast atoms (FAB) were obtained generally using a Platform spectrometer (supplied by Micromass) working under electrorrocy and, where appropriate, positive ion data or negative ion data were collected]; (vi) intermediate compounds in general were not fully characterized and purity was evaluated in general by thin layer, infrared (IR), mass spectral (MS) or NMR analysis; and (vii) in which the following abbreviations may be used: ® or TM is a Registered Trademark; DMF is N, N-dimethylformamide; DMA is N, N-dimethylacetamide; DCM is dichloromethane; CCD is thin layer chromatography; CLAR is high performance liquid chromatography; CLRI is intermediate resolution liquid chromatography; DMSO is dimethyl sulfoxide; CDC13 is deuterated chloroform; EM is mass spectroscopy; ESP is electro-rounded; THF is tetrahydrofuran; TFA is trifluoroacetic acid; NMP is N-methylpyrrolidone; EtOAc is ethyl acetate; MeOH is methanol; phosphoryl is (H0) 2-P (O) -0-; EDC is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (hydrochloride); PTSA is para-toluenesulfonic acid; DIPEA is di-isopropyl-ethylamine; TMBE is t-butylmethyl ether.

Example 1: Preparation of Intermediate Compounds - Reaction Scheme IB Preparation of 3- (2,3-oxiranopropyloxy) isoxazole (Compound (IH-2)) ONs + A suspension of cesium carbonate (45.7 g, 140 mmol, 1.2 equiv.), 3-hydroxyisoxazole (11.9 g, 140 mmol, 1.2 equiv.) And glycidyl nosylate (30.2 g, 116 mmol, 1.0 equiv.) In isobutyl methyl Ketone (MIBK, 302 ml) was refluxed for 30 minutes (CLAR indicated a complete reaction). The reaction mixture was cooled to 20-25 ° C, filtered and the filtrate was washed with H20 (151 ml). The organic layer was concentrated to give the glycidyl ether product (10.8 g, 66%) as an orange oil.

'H-NMR (CDCI3): delta = 2.74 (dd, ÍH, J = 2.6 and 4.9 Hz), 2.91 (dd, ÍH, J = 4.1 and 4.9 Hz), 3.37-3.41 (m, ÍH), 4.14 (dd) , ÍH, J = 11.8 and 6.4 Hz), 4.60 (dd, 1H, J = 11.8 and 2.8 Hz), 6.00 (d, 1H, J = 1.8 Hz), 8.14 (d, ÍH, J = 1.8 Hz). 13 C-NMR (CDCl 3): 44.5, 49.4, 70.6, 76.6, 96.1, 159.8, 171.2. CLAR: retention time 3.2 minutes. The following CLAR method was used: Mobile phase A: 10 mM ammonium acetate pH 4.5. Mobile phase B: 10 mM ammonium acetate pH 4.5 in 90% acetonitrile. Column: Zorbax SB-CN, 4.6 mm x 15 cm. Flow rate 1.5 ml / min, detention time 8 minutes, subsequent time 5 min. Gradient: 0 min - 5% B, 3 min - 5% B, 8 min - 100% B. Wavelength: 225 nm Bw 4 nm, reference wavelength 400 nm, bw 80 nm. Injection 2.5 ul. Solvent of the sample: acetonitrile: water 50:50. Concentration up to 1 mg / ml. Oven: 45 ° C. The reaction has been carried out using both (R) and (S) glycidyl nosylate as well as the racemic glycidyl nosylate to give, respectively, the glycidyl ether product (R) -, (S) - and racemic, ie the Retention of the stereochemistry was confirmed (using chiral CLAR and NMR). The following oligomers have also been used in the binding reaction in place of MIBK: DMF, acetone, toluene, MeCN, DME, NMP, THF, EtOAc, TBME, EtOH, MeOH. The following bases have been used in the binding reaction in place of cesium carbonate: NaH, K2CO3, NaOH, NaOMe, NaOEt, KOMe, KOEt, KO'Bu, LDA, NEt3, NBu3, N ^ rzEt. The starting materials are commercially available. The 3-hydroxyisoxazole can be prepared by cyclization of CH = C-CO-NHOH (prepared from CH = C-CO-O-alkyl (1-4C)) as described in Chem. Pharm.Bull .Japan, 14 , 92, (1966). For additional information, see also JP 43014704 (1968), FR 1534601 (1968), DE 1918253 (1970), JP 45038327 (1970), DE 1795821 (1980) and WO 94/18201 (Sankyo) and DE 2251910 (1973) ( Nippon Chem. Ind.). For example, 3-Hydroxyisoxazole can also be prepared as follows: Hydroxylamine hydrochloride is neutralized with sodium hydroxide to liberate the free base. Ethyl propiolate in EtOH is then added dropwise maintaining the reaction temperature at 20-25 ° C and the reaction is stirred before gradually heating to 50-55 ° C. The heating is continued at 50-55 ° C for 2.5 h and the reaction is then acidified to pH ~ 3 with concentrated HCl. The addition is completed with almost 90% of the ethanol in the reaction that is removed by distillation and the residue extracted with hot toluene. The toluene is removed by distillation to precipitate the 3-hydroxyisoxazole, and the precipitation is complemented by the addition of cyclohexane. The resulting suspension is cooled and filtered prior to the material being dried in vacuo at room temperature. Alternatively, the hydroxylamine hydrochloride is neutralized with sodium hydroxide. The hydroxylamine free base is reacted with a solution of ethyl propiolate in THF at 55 ° C. The reaction mixture is cooled and acidified with hydrochloric acid, and the resulting solution extracted with butyronitrile, washed with dilute hydrochloric acid and the concentrated organic solution under reduced pressure to remove the ethanol, THF and water. The solution can be used directly in a next stage.

Preparation of 5-Isoxazol-3-yloxymethyl-3- (3,5-di-luo-phenyl) -oxazolidin-2-one (Compound (IF)) or TrHon B,? > «¥ - CHjClj Al (3- (2, 3-oxiranpropyloxy) isoxazole, 0.6 g, 4.2 mmol, 1.1 equiv.) And N-benzyloxycarbonyl-3, 5-difluoroaniline (1.0 g, 3.8 mmol) in DCM (15 mL) is added Triton-B (TM) (0.1 ml, 0.76 mol, 40% in H2O). The reaction mixture is heated at reflux for 10 hours. During its complement, the reaction mixture is cooled to 20-25 ° C, diluted with DCM (10 ml) and washed with H20 (10 ml). The organic layer is separated, dried (MgSO) and concentrated to give the crude product (1.4 g) which was purified by flash chromatography to give the desired product (0.8 g., 71%). ^ -RMN (CDC13): 3.95 (dd, ÍH, J = 6.4 and 8.9 Hz), 4.13 (dd, ÍH, J = 9.0 and 8.9 Hz), 4.51 (dd, ÍH, 4.4 and 11.7 Hz), 4.60 (dd) , ÍH, J = 3.9 and 11.7 Hz), 5.00 - 5.07 (m, ÍH), 6.00 (d, ÍH, J = 1.9 Hz), 6.61 (dt, ÍH, J = 1.9 and 11.0 Hz), 7.1 - 7.2 ( m, 2H), 8.16 (d, '1H, J = 1.9 Hz). CLAR: retention time (method as above) 7.6 min. The following solvents have also been used in the binding reaction in place of DCM: - MIBK, THF, Toluene, TBME. N.B. : Retention of the stereochemistry exists in the reaction, ie the (R) -glycidyl ether provides 5 (R) -Isoxazol-3-yloxymethyl-3- (3, 5-difluorophenyl) oxazolidin-2-one.The N-benzyloxycarbonyl-3, 5-difluoroaniline intermediate is prepared by the reaction of 3,5-difluoroaniline with benzyl chloroformate (1.5 eq mol.) As shown in Scheme IB (at 0 ° C to temperature environment) in 5 vol. EtOAc / 5 vol. water, using the base of potassium carbonate (2 eq. mol.).

Example 2: Preparation of intermediate compounds - Reaction Scheme IB Preparation of 5-isoxazol-3-yloxymethyl-3- (4- (1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) -3 , 5-difluorophenyl) oxazolidin-2-one (Compound (IJ)) Tolueo Al (3- (2, 3-oxiranpropyloxy) isoxazole (1.0 g, 7.1 mmol, 1.2 equiv.) And N-benzyloxycarbonyl-3,5-difluoro-4- (1-benzyl-1,2,5,6-tetrahydropyrid) -4-yl) aniline (2.6 g # 6.0 mmoles) in toluene (15 ml) is added tetrabutylammonium chloride (0.18 g, 0.6 mmol) and potassium carbonate (0.83 g, 6 mmol) .The reaction mixture is heated for 24 hours at reflux During its complement, the mixture • The reaction is cooled to 20-25 ° C, and washed with H20 (20 ml). The organic layer was separated, dried (MgSO 4) and concentrated to give the crude product which was purified by flash chromatography to give the desired product (IJ) (1.5 g, 53%). 1H-RM (CDC1): d = 1.60 (s, 2H), 2.43 (s, 2H), 2.71 (t, 2H, J = 6.0 Hz), 3.18 (m, 2H), 3.65 (s, 2H), 3.95 (dd, 1H, J = 6.4 and 8.9 Hz), 4.13 (dd, ÍH, J = 9.0 and 8.9 Hz), 4.51 (dd, ÍH, 4.4 and 11.7 Hz), 4.60 (dd, ÍH, J = 3.9 and 11.7 Hz), 5.00 - 5.07 (, 1H), 5.82 (s, ÍH), 6.00 (d, ÍH, J = 1.9 Hz), 7.12-7.40 (m, 7H), 8.14-8.16 (m, ÍH). CLAR: retention time (see below) 5.3 minutes. Mobile phase A: 0.1% TFA in water. Mobile phase B: 0.1% TFA in 90% MeCN. Column: Genesis C18 10 x 0.3 cm. Flow rate 0.6 ml / min, detention time 15 min, time after 5 min. Isocratic 40% B. Wavelength: 225 nm. Injection 2.5 ml. Solvent of the sample MeCN: water 50:50. Concentration up to 1 mg / ml. Oven at 45 ° C. The following solvents have been used in the binding reaction in place of Toluene: - MIBK, THF, Toluene, TBME.

Example 3: Preparation of intermediates-Reaction Scheme IC Preparation of 1- [4- (1-Benzyl-1, 2, 3, 6-tetrahydro-pyridin-4-xl) -3,5-difluoro-phenylamino] -3- (isoxazole-3-xloxy) -propan-2-ol (Compound (IN)) To 3- (2, 3-oxiranpropyloxy) isoxazole (2.5 g, 17.7 mmol, 1.0 equiv.) And zinc chloride (2.4 g, 17.7 mmol) in acetonitrile (3.5 ml) is added 3, 5-difluoro-4- ( 1-benzyl-1, 2, 5, 6-tetrahydropyrid-4-yl) aniline (5.3 g, 17.7 mmol). The reaction mixture was stirred at room temperature for 4 hours. After this time the HPLC showed 56% conversion to 1- [4- (1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl) -3,5-difluorophenylamino] -3- (isoxazol-3-yloxy) -propan-2-ol (with reference to an external standard isolate in another reaction, which can be prepared by hydrolysis of the compound (IJ)). CLAR: retention time (see below) 2.1 minutes.

Mobile phase A: 0.1% TFA in water. Mobile phase B: 0.1% TFA in 90% MeCN. Column: Genesis C18 10 x 0.3 cm. Flow rate 0.6 ml / min, detention time 15 min, time after 5 min. Isocratic 40% B. Wavelength: 225 nm. Injection 2.5 ml. Solvent of the sample MeCN: water 50:50. Concentration up to 1 mg / ml. Oven at 45 ° C.

Example 4: Diol Chemistry - Reaction Scheme 2B Example 1 Intermediate Compound: 3,5-Difluoro-4- (1-benzyl-4-hydroxyhexahydropyrid-4-yl) aniline nBuLi (1.32M in hexanes, 350 ml, 0.462 mol) is added dropwise over 20 minutes to a solution of N, N- (1, 2-bis (dimethylsilyl) ethane) -3,5-difluoroaniline (108.4 g, 0.40 mol, J. Org. Chem., 60 , 5255-5261 (1995)) in 800 ml of dry THF at -70 ° C under argon. After stirring for an additional 4 hours at -70 ° C, N-benzyl-4-piperidone (87.8 g, 0.46 mmol) in 270 ml of dry THF is added dropwise over 40 minutes at the same temperature and the reaction is allowed to stir at room temperature overnight. The solvent was removed in vacuo and the resulting product was treated with ice and concentrated HCl and extracted with ether. The aqueous acid phase was then treated with 40% NaOH with cooling, it is extracted with ether (and it is worked by washing with water, with brine and drying with an anhydrous drying agent such as magnesium sulfate or sodium sulphate before evaporation - this work procedure is referred to as a work of the usual way here later) to give 144. 7 g of a mud or sediment. Analysis by CCD using 10% MeOH / dichloromethane on silica indicated that the desired alcohol was present as approximately 90% of the product, and the crude product was used without further purification. MS: ESP + (M + H) = 319.

Example 2 of the Intermediate: 3,5-Difluoro-4- (1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) aniline The crude product of Example 1 of the Intermediate Compound (144.7 g) was suspended in 400 ml of concentrated HCl and heated to reflux with stirring for 18 hours. The CCD showed that all the starting material had reacted, and after cooling in ice the reaction mixture was brought to pH 11 with concentrated NH3 (aq) and extracted three times with dichloromethane. The usual working procedure gave 119.5 g of a viscous oil. The CCD indicated a purity of almost 80% and the crude product was used without further purification. MS: ESP + (M + H) = 301.

Example 3 of the Intermediate Compound: N-benzyloxycarbonyl-3,5-difluoro-4- (1-benzyl-l, 2,5,6-tetrahydropyrid-4-yl) aniline The crude aniline of Example 2 of the Intermediate Compound (3.2 g , 10.7 mmoles) in 10 ml of acetone was added in one portion to a stirred solution of sodium diacid phosphate (3.0 g) in 30 ml of water. The resulting mixture was cooled to 5-10 ° C and a solution of benzyl chloroformate (2.18 g, 1.8 ml, 12.8 mmol) in 10 ml of acetone was added dropwise. The mixture is stirred for an additional hour at the temperature of the ice bath and then at room temperature for 2 hours. The mixture is diluted with 80 ml of water, basified with concentrated NH3 (aq) and extracted with EtOAc. The usual working procedure gave a viscous oil which was purified by flash chromatography (silica Merck 9385, EtOAc / isohexane (eluent 3: 7) and triturated with isohexane to give a solid (1.53 g, 33%). (M + H) = 434.

Example 4 Intermediate: 5 (R) -Hydroxymethyl-3- (4- (1-benzyl-l, 2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one The Benzylurethane from Example 3 of the Intermediate Compound (5.54 g, 12.76 mmol) in 50 mL dry THF is cooled to -70 ° C under nitrogen and 8.80 mL of nBuLi 1.6M in hexanes (14.08 mmol) is added dropwise thereto. temperature. After 20 minutes at the same temperature, a solution of (R) -glycidyl butyrate (2.00 g, 13.88 mmol in 5 ml of THF) is added dropwise and the mixture is stirred for 30 minutes at -70 ° C, and then it is stirred at room temperature overnight. After reducing the temperature with 100 ml of 10% ammonium chloride, the mixture is extracted with EtQAc and worked in the usual manner to give an oily solid, which was purified by flash chromatography (Merck C60 silica, eluent MeOH / 5% dichloromethane) to give a crystalline solid (4.40 g, 86%). MS: ESP + (M + H) = 401.? -NMR (250 MHz, DMSQ-d6] 2.32 (m, 2H), 2.63 (t, 2H) 3.05 (m, 2H), 3.50-3.72 (, 4H), 3.82 (dd, ÍH), 4.06 (t, ÍH), 4.73 (m, ÍH), 5.18 (t, 1H), 5.78 (m, ÍH).

Example 5 Intermediate: 5 (R) -isoxazol-3-yloxymethyl-3- (4- (1-benzyl-l, 2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin- 2-one Example 4 of the Intermediate (2.6 g, 6.5 mmol), 3-hydroxyisoxazole (see Example 1, 0.60 g, 7.06 mmol), triphenylphosphine (1.96 g, 7.48 mmol) and diisopropylazodicarboxylate (1.44 g, 7.13 mmol) in THF (40 ml) is reacted using the general method of Example 1. The resulting product was purified by flash chromatography (silica Merck 9385, eluent EtQAc / isohexane (3: 2) initially, then repeated using the methyl tertiary ether. butyl) to give the title product (2.6 g, 86%) as a gum. MS: ESP + (M + H) + = 468.

(R) -Isoxazol-3-yloxymethyl-3- (4- (1, 2,5,6-tetrahydropyrd-4-yl) -3,5-difluorophenyl) oxazolidin-2-one (Compound (IK)) Example 5 Intermediate Compound (2.6 g, 5.57 mmol) in dichloromethane (40 ml) is cooled, under an atmosphere of hydrogen, in a water bath cooled with ice then 1-chloroethyl chloroformate (0.80 g, 5.59 g) is added dropwise. mmoles) by means of a syringe. The resulting solution is stirred at the freezing temperature for 1 hour before the isolation of the intermediate product (carbamate) by flash chromatography (silica Merck 9385, eluent EtOAc / isohexane (1: 1)). The resulting gum was taken up in MeOH (40 ml) and refluxed for 1 hour. Evaporation of the solvent after this time gave the title product (1.46 g, 64%) as a crystalline solid. 1 H-NMR (300 MHz, DMS0-D6): d = 2.54 (m, 2H), 3.27 (m, 2H), 3.72 (m, 2H), 3.92 (dd, 1H), 4.20 (t, ÍH), 4.38 -4.52 (m, 2H), 5.10 (m, HH), 5.88 (m, HH), 6.38 (d, 1H), 7.37 (m, 2H), 8.68 (d, 1H), 9.39 (s (broad), 2H). MS: ESP + (M + H) + = 378.

(R) -Isoxazol-3-yloxymethyl-3- (4- (1- (3-t-butoxy- (2 (S) -hydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) - 3,5-di luorofenxl) oxazolxdin-2-one (Compound (21)) To a stirred solution of Compound (IK) (6.2 g, 15 mM), N-methyl morpholine (2.27 g, 22.5 mM), hydroxybenzotriazole (2.63 g, 19.5 mM) and 3-t-butoxy-2 (S) -hydroxypropionic acid (Compound (2H); WO 92/00276; 3.16 g, 19.5 mM) in DMF (60 ml) at room temperature is added, in portions, dimethylaminopropyl ethylcarbodiimide (3.73 g, 19.5 mM) The reaction mixture is stirred for 3 hours, the solvent is evaporated and the residue is taken up in ethyl acetate, washed with 2N HCl, water, saturated NaHCO 3. , and brine, dried over anhydrous Na 2 SO 4 and evaporated to a gum.The title compound was isolated by CLRI (Merck silica 9385, gradient of ethyl acetate / isohexane 60-75%) and crystallized during trituration with ether ( 6.4 g, 82%). XH-NMR (300 MHz, DMSQ-D6): d = 1.11 (2s, 9H), 2.34 (2s, 2H), 3.43 (, 2H), 3.70 (m, 2H), 3.93 (d of d, 1H), 4.10 (s, ÍH), 4.20 (t, ÍH), 4.28 (s, ÍH), 4.46 (m, 3H), 5.07 (m, 2H), 5.88 (s, ÍH), 6.40 (s, ÍH), 7.37 (d, 2H), 8.70 (s, ÍH). Mass: ES + (M + H) + = 522.

(R) -isoxazol-3-yloxymethyl-3- (4- (1- (3-t-butoxy- (2 (S) - (di-t-butoxyphosphoryl) -propanoyl) -1,2,5,6 -tetrahydropyrid-4-yl) -3,5-dxfluorophenyl) oxazolidin-2-one (Compound (2J)) To a stirred solution of Compound (21) (3.65 g, 7.0 mM) and tetrazole (2.21 g, 31.5 mM) in THF (50 ml) at room temperature under nitrogen, add (t-BuO) 2PNEt2 (2.61 g, 10.5 mM) for ~ 2 minutes.After stirring for 2 hours more tetrazole (735 mg, 10.5 mM) is added and (BuO) 2PN? T2 (872 mg, 3.5 mM) and stirring is continued for an additional 1 h.The solution is cooled to -40 ° C and m-chloroperbenzoic acid (14 mM, 2.68 g of a 90 concentration) is added. %) in portions The reaction mixture is allowed to warm to 0 ° C and ethyl acetate is added.The solution is washed with aqueous sodium metabisulfite, saturated sodium bicarbonate and brine.The organic phase is dried over anhydrous Na2SO4 and evaporated under reduced pressure.The title compound was isolated by CLR I (silica Merck 9385, gradient of ethyl acetate / isohexane 70-90%) as a well-defined foam (3.63 g, 73%).

XH-NMR (300 MHz, DMSQ-D6): d = 1.10 (2s, 9H), 1.40 (2s, 18H), 2.35 (m, 2H), 3.45-4.5 (complex, 10H), 4.93 (c, ÍH) , 5.10 (m, 1H), 5.88 (s, ÍH), 6.40 (s, ÍH), 7.35 (d, 2H), 8.70 (s, ÍH). Mass: ES + (M + H) = 714.

(R) -Isoxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy-3-phosphoryl-propanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3 , 5-difluorophenyl) oxazolidin-2-one (Compound (2F)) Compound (2J) (4.93 g, 6.9 mM) was dissolved in 4N HCl / dioxane (50 ml) and the solution is stirred at room temperature for 21 hours. It was evaporated to a mobile oil and triturated well with ether to give the title compound as an amorphous, hygroscopic solid, which was removed by filtration under nitrogen and dried under high vacuum (3.75 g, 98%; CLAR = 88%). XH-NMR (300 MHz, DMSO-D6): 2.43 (m, partially obscured), 3.6-4.35 (m, 8H), 4.35-4.60 (m, 3H), 5.09 (m, 1H), 5.85 (s, ÍH), 6.30 (s, ÍH), 7.31 (d, 2H), 8.60 (s, ÍH). Mass: ES + (m + H) = 546.

Example 5: Chemistry of Diol - Reaction Scheme 2A 5 (R) -Isoxazol-3-yloxymethyl-3- (4- (1- (2 (S), 3-cyclophosphoryl-propanoyl) -l, 2,5, 6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one (Compound (2E)) To a stirred partial solution of the starting material, 5 (R) -isoxazol-3-yloxymethyl-3- ( 4- (1- (2 (S), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one (38.13 g, 82 mM) and tetrazole (17.22 g, 246 mM) in THF (500 ml) at room temperature under nitrogen, tert-butyl tetraphosphorodiimidite was added. (30.5 g, 123 mM) for ~ 10 minutes. The reaction mixture was stirred for 30 minutes at room temperature. The solution was cooled to -40 ° C and m-chloroperbenzoic acid (134 itiM, 25.9 g of 90% t concentration) was added in portions. The reaction mixture was allowed to warm to 0 ° C and ethyl acetate was added. The solution was washed with aqueous sodium metabisulfite, saturated sodium bicarbonate and brine. The organic phase is dried over anhydrous MgSO 4 and evaporated under reduced pressure. The title compound was isolated by CLRI (Merck silica 9385, gradient ethyl acetate / isohexane 90-100%) as a gum. The product was used for the next step without characterization or additional delay (22.5 g, 47%).

(R) -Isoxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy-3-phosphoryl-propanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3 , 5-difluorophenxl) oxazolidin-2-one (Compound (2F)) Compound (2E) (22.4 g, 38.4 mM) was dissolved in 4N HCl / dioxane (200 ml) and water (0.69 ml, 38.4 ml) was added . The solution is stirred at room temperature for 18 hours. It was evaporated to a mobile oil and triturated well with ether to give the title compound as an amorphous, hygroscopic solid, which was removed by filtration under nitrogen and dried under high vacuum (18.7 g, 89%, purity by HPLC). = 87%). 'H-NMR (300 MHz, DMSO-D6): 2.43 (m, partially obscured), 3.6 - 4.35 (m, 8H), 4.35 - 4.60 (m, 3H), 5.09 (m, ÍH), 5.85 (s, ÍH), 6.30 (s, ÍH), 7.31 (d, 2H), 8.60 (s, 1H). Mass: ES + (M + H) = 546.

The starting material (Compound (2D)), 5 (R) -isoxazol-3-yloxymethyl-3- (4- (1- (2 (S), 3-dihydroxypropanoyl) -1,2,5,6- tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one, is obtained as follows: - Example 6 of Intermediate: 5 (R) -Isoxazol-3-yloxymethyl-3- (4- (1- (2,2-dimethyl-1,3-dioxolan-4 (S) -aryarbonyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one Compound ( IK), 5 (R) -Isoxazol-3-yloxymethyl-3- (4- (1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) -oxazolidin-2-one; 660 mg, 1.45 mmol), (S) -2,3-0-isopropylideneglyceric acid (240 mg, 1.64 mmol) and pyridine (115 mg, 1.45 mmol) in dichloromethane (15 ml) is stirred and added 1, 3- dicyclohexylcarbodiimide (315 mg, 1.53 mmol) at once at room temperature. The resulting mixture is stirred at room temperature for 18 h then purified by flash chromatography (silica Merck 9385; eluent of EtOAc / isohexane (3: 1)) to give the product (282 mg, 38%) as a colorless crystalline solid. MS: ESP * (M + H) = 506. 1 H-RN (300 MHz, DMSO-D6): d = 1.32 (s, 3H), 1.34 (s, 3H), 2.25-2.50 (m, 2H), 3.63-3.87 (m, 2H), 3.95 (dd, ÍH), 4.02-4.32 (m, 4H), 4.43-4.55 (m, 2H), 4.92 (m, ÍH), 5.12 (m, ÍH), 5.89 (m, 1H), 6.37 (d, ÍH), 7.35 (d, 2H), 8.68 (d, 1H).

Compound (2D): 5 (R) -Isoxazol-3-yloxymethyl-3- (4- (1- (2 (S), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) - 3,5-difluoro enyl) oxazolidin-2-one Example 6 of the Intermediate (282 mg, 0.56 mmol) in a mixture of THF (6 ml) and IN hydrochloric acid (2 ml) is allowed to stand at room temperature for 4 hours. days. The solvent is evaporated and the resulting product purified by flash chromatography (silica Merck 9385; eluent 10% MeOH in dichloromethane) to give the product (183 mg, 70%) as a colorless crystalline solid: m.p. 136-142 ° C. aH-NMR (300 MHz, DMSO-D6): d = 2.20-2.46 (m, 2H), 3.40-3.63 (m, 2H), 3.63-3.85 (m, 2H), 3.92 (dd, ÍH), 4.10 ( m, ÍH), 4.18 (t, 1H), 4.26-4.52 (m, ÍH), 4.68 (m, ÍH), 4.96 (m, ÍH), 5.10 (, ÍH), (, ÍH), 6.37 (d, 1H), 7.34 (m, 2H), 8.68 (d, 2H). MS: ESP (M + H) + = 466. HPLC: Chiralpak AD (250mm x 4.6mm d.i.), eluent 100% MeOH, flow rate 1 ml / min., Retention time = 38.4 min.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A process for the formation of a primary monophosphoryl group (-OPO (OH) 2) in a terminal 1,2-diol-propanoyl functionality ( HO-CH2CH (OH) -C0-), characterized in that it comprises the steps of: (i) formation of a protected primary 1,2-diol species (PgO-CH2CH (OH) -CO-); (ii) formation of a secondary phosphoryl group (optionally protected) and (iii) treatment of this secondary phosphoryl group with an acid to deprotect the protected primary alcohol function and rearrange the secondary phosphoryl group to a primary phosphoryl group (to give a functional (HO) 2OPO-CH2CH (OH) -CO-); where Pg is a protective group.
2. A process according to claim 1, characterized in that the terminal 1,2-diol-propanoyl functionality is present in a compound of the formula (1-2) where X is 0 or S; HET is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, 0 and S, such ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (1-4C) alkyl ), amino, alkylamino (1-4C), alkoxy (1-4C) and halogen, and / or on an available nitrogen atom (provided that the ring is not quaternized by it) by (1-4C) alkyl; or HET is a C-linked 6-membered heteroaryl ring containing 1 or 2 N, such ring is optionally substituted on any available C atom (provided that when the N atom is adjacent to the bond, there is no substitution on any C atom) which is adjacent to this atom N) by 1, 2 or 3 substituents independently selected from (1-4C) alkyl, amino, alkylamino (1-4C), alkoxy (1-4C), alkoxycarbonyl (1-4C) and halogen; R2 and R3 are independently hydrogen or fluoro; Rep is of the formula R13pCO- (wherein R13p is (1-10C) alkyl substituted by two or more hydroxy groups; 2 of which are in an 1,2-diol orientation, ie is a terminal primary alcohol with a secondary secondary alcohol), or pharmaceutically acceptable salts, or esters thereof hydrolyzable in vivo.
3. A process according to claim 1 or 2, characterized in that the terminal 1,2-diol-propanoyl functionality is present in a compound of the formula (I) (D wherein HET is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O, and S, such ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from alkyl ( 1-4C), amino, alkylamino (1-4C), alkoxy (1-4C) and halogen, and / or on an available nitrogen atom (provided that the ring is not quaternized by means of this) by alkyl (1-) 4C); R2 and R3 are independently hydrogen or fluoro; Rep is of the formula R13pCO- (wherein R13p is (1-10C) alkyl substituted by two or more hydroxy groups; 2 of which are in an 1,2-diol orientation, ie there is a terminal primary alcohol with a secondary secondary alcohol), or pharmaceutically acceptable salts, or in vivo hydrolysable esters thereof.
4. A process according to any of claims 1 to 3, characterized in that the terminal 1,2-diol-propanoyl functionality is present in a compound of the formula (1-1)
5. A method according to any of claims 1 to 4, characterized in that it comprises: (i) the reaction of 5 (R) -Isoxazol-3-yloxymethyl-3- (4- (1,2,5,6-tetrahydropyrid) -4-yl) -3,5-difluorophenyl) oxazolidin-2-one with 3-t-butoxy-2 (S) -hydroxypropionic acid to form 5 (R) -Isoxazol-3-yloxymethyl-3- (4- (1- (3-t-butoxy- (2 (S) -hydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one; (ii) phosphorylation of this compound to give 5 (R) -isoxazol-3-yloxymethyl-3- (4- (1- (3-t-butoxy- (2 (S) - (di-t-butoxyphosphoryl) -propanoyl) -1, 2, 5, 6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one and (iii) the treatment of this compound with acid to give 5 (R) -isoxazole -3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy-3-phosphoryl-propanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin -2-one
6. A process according to any of claims 1 to 4, characterized in that in step (i) the protecting group is t-butyl
7. A method according to any of claims 1 to 6, characterized in that the step (ii) is carried out using tert-butyl tetraethylphosphorodiimidite.
8. A process according to any of claims 1 to 7, characterized in that step (iii) is carried out using hydrochloric acid.
9. A process for the preparation of 5- (HET-X-methyl) -3- (4- (1-benzyl-l, 2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin -2-one, characterized in that it comprises the reaction of (3- (2, 3-oxiranopropyl-X-HET with N-benzyloxycarbonyl-3,5-difluoro-4- (1-benzyl-l, 2,5,6- tetrahydropyrid-4-yl) aniline, wherein X and HET are as defined in claim 2.
10. A process according to claim 9 for the preparation of 5-isoxazol-3-yloxymethyl-3- (4- (1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one, characterized in that it comprises the reaction of (3- (2, 3-oxiranpropyloxy) isoxazole with N-benzyloxycarbonyl-3,5-difluoro-4- (1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) aniline
11. A chemical intermediate compound, characterized in that it is selected from: 5 (R) -Isoxazol-3-yloxymethyl-3- (4- (1- (3-t-butoxy- (2 (S) -hydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5- difluorophenyl) oxazolidin-2-one and 5 (R) - Isoxazol-3-yloxymethyl-3- (4- (1- (3-t-butoxy- (2 (S) - (di-t-butoxyphosphoryl) -propanoyl) -1,2,5,6-tetrahydropyrid-4- il) -3,5-difluorophenyl) oxazolidin-2-one.
12. A chemical intermediate, characterized in that it is selected from: 3- (2,3-oxiranpropyloxy) isoxazole and 5-isoxazol-3-yloxymethyl-3- (3,5-difluorophenyl) oxazolidin-2-one.
13. A chemical intermediate compound, characterized in that it is selected from: 5 (R) -Isoxazol-3-yloxymethyl-3- (4- (1- (2 (S), 3-cyclophosphoryl-propanoyl) -1,2,5 , 6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one and 1- [4- (1-Benzyl-l, 2,3,6-tetrahydro-pyridin-4-yl) -3 , 5-difluoro-phenylamino] -3- (isoxazol-3-yloxy) -propan-2-ol.